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Selecting safe psychotropics for post-MI patients
How do you safely treat a psychiatrically ill patient who is taking seven to nine potent cardiovascular medications? Our approach is to organize the effects of psychiatric drugs into a systematic, easy-to-use framework, which we remember by the mnemonic HALT. It reminds us to consider any drug’s effect on hypertension, arrhythmias, lipids and liver enzymes, and risk of thrombosis. Using HALT as a decision tool can help you avoid drug-drug interactions when selecting psychotropics for patients with a history of myocardial infarction (MI).
The multi-medication challenge
In psychiatry, medication guidelines and algorithms encourage us to start with monotherapy before we try more complex regimens.1-3 Cardiologists, however, jump directly to a multimedication, cardio-protective approach for today’s post-MI patient.4-5 The cardiac standard of care includes angiotensin-converting enzyme (ACE) inhibitors, cardioselective beta-blockers, lipid-lowering agents, and platelet and clotting inhibitors.
Adding even one psychotropic to such a complex daily regimen could risk an adverse reaction. But, unfortunately, no guidelines exist for the medical management of psychiatrically ill post-MI patients, and research is very limited:
- only one randomized, controlled trial has examined drug treatment of their depression
- no randomized, controlled trials have addressed bipolar mania or psychosis drug treatment.
Table
THREE TYPES OF ACUTE CORONARY SYNDROMES
| Type | Diagnostic features |
|---|---|
| ST elevation MI | ST elevation in two contiguous ECG leads or new left bundle-branch block |
| Non-ST elevation MI | Positive CPK-MB or positive troponin levels and ST depression on ECG |
| Unstable angina | ST depression or T-wave inversion with no enzyme release |
| MI: myocardial infarction | |
| CPK-MB: creatine phosphokinase of muscle band (an enzyme released by ischemic heart muscle) | |
Pathophysiology of acute coronary syndromes
Acute coronary syndromes present as three broad types: ST elevation MI, non-ST elevation MI, and unstable angina (Table ). ST elevation MI, non-ST elevation MI and—to a lesser extent—unstable angina result from plaque rupture within the coronary intima, with sudden occlusion of one or more coronary arteries or branches and ischemia to the affected myocardium. Multiple pathologic processes—such as hypertension, dyslipidemia, or inflammatory disease—may weaken or injure the vascular lumen, and the development of a thrombus at the plaque rupture site involves many steps and triggers.
Ischemic myocardial injury increases an acute MI survivor’s risk of arrhythmias, heart failure, and sudden death. Tachycardia related to psychological stress can trigger these cardiac events in patients with heart disease. The goal of post-MI medical therapy is to protect the heart from further hypertensive injuries, arrhythmias, dyslipidemias, and thrombus formation.
Typical post-MI medications
ACE inhibitors. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II—a vasoconstrictor—increases blood pressure, restricts blood flow to the kidney, and stimulates aldosterone secretion by the adrenal cortex. ACE inhibition results in lower plasma levels of angiotensin II, with decreased blood pressure, vasopressor activity, and aldosterone secretion; this last effect may increase serum potassium.
Two ACE inhibitors—lisinopril and ramipril—have been shown in clinical trials to protect against recurrent cardiac events.6,7 ACE inhibitors may have variable effects among different ethnic groups. For example, ACE inhibitors have shown a less robust blood pressure-lowering effect in black patients than in non-blacks in some clinical trials.8
Beta blockers. Beta-adrenergic receptor blocking agents compete with beta-adrenergic agonists for available receptor sites in the heart and lungs. Cardioselective or beta-1 adrenergic agents such as metoprolol affect primarily the receptors in the heart and can slow the sinus rate and decrease AV nodal conduction. Metoprolol reduces heart rate, cardiac output, and systolic blood pressure, and inhibits reflex and drug-induced tachycardia. These pharmacologic actions lower oxygen demand, thus reducing the risk of ischemia and arrhythmias.
Beta blockers are a mainstay in regimens prescribed for post-MI outpatient treatment.9 Although earlier studies suggested that these drugs might cause depression, a recent systematic review rebuts that conclusion.10
Lipid-lowering agents. First-line treatments of hyperlipidemia include HMG-CoA reductase inhibitors (or “statins”) and niacin (also known as nicotinic acid). These drugs have been shown to lower lipids (cholesterol and triglycerides), reduce low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and increase high-density lipoproteins (HDL).
HMG-CoA reductase inhibitors have been shown in large international trials to reduce mortality from cardiac events in post-MI patients.11 These agents—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are associated with some side effect risks, including hepatotoxicity and rhabdomyolysis. Most are metabolized by cytochrome P450 3A4; the exception is fluvastatin, which is metabolized by CYP 2C9.
Niacin has been shown to decrease serum levels of apolipoprotein B-100—the major protein component of VLDL and LDL fractions—and of lipoprotein (a), an LDL variant independently associated with coronary risk.12 Niaspan—a long-acting formulation of niacin—is indicated to reduce recurrent nonfatal MI risk in patients with a history of MI and hypercholesterolemia. Niacin’s side effects include flushing, increased serum transaminase levels, slightly reduced platelet count, and (rarely) rhabdomyolysis.
Clotting and platelet inhibitors. Anticoagulants such as warfarin sodium and platelet inhibitors such as clopidogrel are major components of drug therapy to prevent blood clots in post-MI patients.
Warfarin is indicated to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. It acts by inhibiting the synthesis of vitamin Kdependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
Warfarin is metabolized by numerous CYP isoenzymes—principally 2C9, but also 2C19, 2C8, 2C18, 1A2, and 3A4—and interacts with many drugs that are metabolized by the same enzyme systems.12 Although some cardio-protective drugs and NSAIDs may lead to drug interactions due to CYP2C9, most common psychotropics do not inhibit this isoenzyme.
The protein-binding properties of some psychotropics—such as fluoxetine, sertraline, paroxetine, and risperidone—may increase warfarin levels in some patients. Thus, closer monitoring of warfarin levels is warranted when using these agents. Divalproex—because of its protein binding and potential for thrombocytopenia and liver injury—should be used with caution in patients receiving warfarin.
H Can this agent cause or worsen hypertension?
A Can this agent increase the risk of arrhythmia?
L Can this agent adversely affect lipids? Can it affect medication serum levels due to liver enzyme inhibition or liver injury?
T Can this agent increase the risk of thrombosis or bleeding?
Clopidogrel is indicated for reducing the risk of MI, stroke, and vascular death in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease.13 This drug selectively inhibits adenosine diphosphate (ADP) from binding to its platelet receptor and activates the ADP-mediated glycoprotein GPIIb/IIIa complex, which inhibits platelet aggregation. Clopidogrel can inhibit the CYP 2C9 isoenzyme. Thrombotic thrombocytopenic purpura has been reported rarely following use of clopidogrel, sometimes after brief exposure (< 2 weeks). The medical team must watch for GI bleeding, a potential side effect.
HALT: A decision framework
A decision tool based on the mnemonic HALT can help psychiatrists systematically and safely add antidepressants, antipsychotics, and mood-stabilizing agents to the complicated regimens of post-MI patients (Box). As HALT suggests, any selection strategy must address the agent’s impact on:
- Hypertension
- Arrhythmias
- Lipids and Liver enzymes
- Thrombosis risk.
The following section lists examples of medications that fit the HALT framework well and others that do not. The psychiatrist, cardiologist, and primary care physician should all be aware of the different agents the post-MI patient is taking and monitor for adherence and drug interactions.
Selecting an antidepressant
Most newer-generation antidepressants are safe and effective for patients with heart disease. Venlafaxine increases heart rate and blood pressure minimally. Fluoxetine, paroxetine, and bupropion tend to interact to some degree with drugs metabolized by CYP2D6, including beta blockers. Mirtazapine may increase appetite and cause weight gain, which can exacerbate hypertension and alter lipid levels. Even so, minimal drug interactions and end-organ effects should not preclude the use of any of these antidepressants when the drug is best suited for managing a patient’s depressive disorder.
Sertraline. Excellent articles and systematic reviews have addressed the importance of treating depression in patients with heart disease.14-16 However, only one recent randomized, double-blind, controlled trial has addressed antidepressant therapy for major depressive disorder in patients with acute MI or unstable angina.17 The trial included 369 patients (64% male; mean age 57) with MDD who received the selective serotonin reuptake inhibitor (SSRI) sertraline, 50 to 200 mg/d, or placebo for 24 weeks.
Compared with placebo, sertraline did not significantly affect left ventricular ejection fraction, ventricular premature complexes, QTc interval, or other cardiac measures. Depressive symptoms improved more with sertraline than with placebo in patients who had a history of at least one episode of major depressive disorder (MDD) or severe MDD (defined as a Hamilton Depression Scale score 18 and two or more prior episodes of MDD). The authors concluded that sertraline is safe and effective for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Using the HALT framework, sertraline does not exacerbate hypertension or increase heart rate, which can trigger arrhythmias. It does not cause weight gain or affect lipid levels and is a weak inhibitor of liver enzymes. Like other SSRIs, it may make platelets “less sticky” and reduce the risk of thrombogenesis.
Selecting an antipsychotic
Using the HALT framework reminds us that all atypical antipsychotics carry some cardiovascular risks in the post-MI population. Although none are known to directly increase heart rate, ziprasidone can increase the QT interval and pose a significant risk for arrhythmia. It therefore should be avoided in post-MI patients.18
Olanzapine has greater potential for causing weight gain than risperidone or quetiapine and may increase the risk of excessive weight gain and hyperlipidemia in patients who are not on a well-controlled diet. Quetiapine causes some significant orthostatic hypotension, no significant QT prolongation, and some weight gain. Risperidone is metabolized by the CYP2D6 isoenzyme and can cause orthostatic hypotension, some weight gain, and slight QT prolongation; it—like other atypical antipsychotics—is not known to alter thrombocyte function or thrombus formation.
The recently approved antipsychotic aripiprazole causes some orthostatic hypotension, no significant QT prolongation, and slight weight gain. It is metabolized by CYP3A4 and 2D6 and does not inhibit those enzymes. It is highly bound to albumin and does not interfere with warfarin.19
Selecting a mood stabilizer
Bipolar disorder presents numerous dilemmas when treating the post-MI patient. The three agents approved for treating bipolar mania—lithium, divalproex, and olanzapine—all require close therapeutic monitoring.
Lithium, olanzapine, and divalproex are the standard first-choice therapies for patients with acute mania, whereas olanzapine and divalproex are known to be more effective than lithium in patients with mixed states.1 Using the HALT framework, none of these mood stabilizers directly aggravates hypertension. However, lithium can cause significant electrolyte aberrations, and its combination with ACE inhibitors could increase the risk of sudden death from arrhythmia.20
Divalproex is known to elevate liver enzymes, and its combination with lipid-lowering agents carries the risk of significant liver injury.12 Divalproex also is known to result in some thrombocytopenia and could increase patients’ risk for bleeding complications when combined with clopidogrel, aspirin, warfarin, or niacin.
Divalproex has a black-box warning of increased risk of hemorrhagic pancreatitis. Patients who take divalproex with other agents known to affect platelet and clotting function should be watched closely.
Olanzapine, as discussed above, carries a risk of weight gain and requires careful dietary control in post-MI patients. Alternate atypical antipsychotics may need to be considered as mood-stabilizing therapy if the risk/benefit ratio of electrolyte imbalance (lithium), liver enzyme elevation and thrombocytopenia (divalproex), or weight gain (olanzapine) is not favorable.
Related resources
- American College of Cardiology www.acc.org
- Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
Drug brand names
- Aripiprazole • Abilify
- Atorvastatin • Lipitor
- Bupropion • Wellbutrin
- Clopidogrel bisulfate • Plavix
- Divalproex • Depakote
- Fluoxetine • Prozac
- Fluvastatin • Lescol
- Lisinopril • Prinivil
- Lovastatin • Mevacor
- Metoprolol • Toprol-XL
- Mirtazapine • Remeron
- Niacin • Niaspan
- Paroxetine • Paxil
- Pravastatin • Pravachol
- Olanzapine • Zyprexa
- Ramipril • Altace
- Sertraline • Zoloft
- Simvastatin • Zocor
- Venlafaxine • Effexor-XR
- Warfarin • Coumadin
- Ziprasidone • Geodon
Disclosure
Dr. Dewan receives grant/research support from Eli Lilly and Co. and is a speaker for Eli Lilly and Co. and Janssen Pharmaceutica.
Dr. Suresh and Dr. Blomkalns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors wish to acknowledge the assistance of W. Andrew Jenkins, BS, medical student, University of Cincinnati College of Medicine, in preparing this manuscript for publication.
1. Dennehy EB, Suppes T. Medication algorithms in bipolar disorder. J Pract Psychiatry Behav Health 1999;5:142-52.
2. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.
3. Chiles JA, Miller AL, Crismon ML, et al. The Texas Medication Algorithm Project: Development and implementation of the schizophrenic algorithm. Psychiatric Services 1999;50(1):69-74.
4. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. Executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction.) J Am Coll Cardiol 1999;34(3):890-911.
5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
6. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96(12):4239-45.
7. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001;104(5):522-6.
8. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
9. Andersen K, Ehlers D, Wiedemann HC, et al. Beta blockers: evidence versus wishful thinking. Am J Cardiol 1999;83(5B):64D-67D.
10. Ko DT, Hebert PR, Coffey CS, Sedrakayan A, Jeptha CP, Krumholz HM. B-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
11. Newby L, Kristinsson A, Bhapkar M, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287(23):3087-95.
12. Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
13. Yusuf S, Zhoa F, Mehta SR. et al, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
14. Glassman AH, Roose SP, Bigger JT, Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993;269:2673-5.
15. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4-11.
16. Rugulies R. Depression as a predictor for coronary heart disease: a review and metaanalysis. Am J Prev Med 2002;23(1):1-11.
17. Glassman AH, O’Connor C, Califf R, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9.
18. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(suppl 9):9-17.
19. Bristol-Myers Squibb Co. Aripiprazole (Abilify): prescribing information. www.abilify.com.
20. Chandragiri SS, Pasol E, Gallagher RM. Lithium, ACE inhibitors, NSAIDs, and verapamil: a possible fatal combination. Psychosomatics 1998;39(3):281-2.
How do you safely treat a psychiatrically ill patient who is taking seven to nine potent cardiovascular medications? Our approach is to organize the effects of psychiatric drugs into a systematic, easy-to-use framework, which we remember by the mnemonic HALT. It reminds us to consider any drug’s effect on hypertension, arrhythmias, lipids and liver enzymes, and risk of thrombosis. Using HALT as a decision tool can help you avoid drug-drug interactions when selecting psychotropics for patients with a history of myocardial infarction (MI).
The multi-medication challenge
In psychiatry, medication guidelines and algorithms encourage us to start with monotherapy before we try more complex regimens.1-3 Cardiologists, however, jump directly to a multimedication, cardio-protective approach for today’s post-MI patient.4-5 The cardiac standard of care includes angiotensin-converting enzyme (ACE) inhibitors, cardioselective beta-blockers, lipid-lowering agents, and platelet and clotting inhibitors.
Adding even one psychotropic to such a complex daily regimen could risk an adverse reaction. But, unfortunately, no guidelines exist for the medical management of psychiatrically ill post-MI patients, and research is very limited:
- only one randomized, controlled trial has examined drug treatment of their depression
- no randomized, controlled trials have addressed bipolar mania or psychosis drug treatment.
Table
THREE TYPES OF ACUTE CORONARY SYNDROMES
| Type | Diagnostic features |
|---|---|
| ST elevation MI | ST elevation in two contiguous ECG leads or new left bundle-branch block |
| Non-ST elevation MI | Positive CPK-MB or positive troponin levels and ST depression on ECG |
| Unstable angina | ST depression or T-wave inversion with no enzyme release |
| MI: myocardial infarction | |
| CPK-MB: creatine phosphokinase of muscle band (an enzyme released by ischemic heart muscle) | |
Pathophysiology of acute coronary syndromes
Acute coronary syndromes present as three broad types: ST elevation MI, non-ST elevation MI, and unstable angina (Table ). ST elevation MI, non-ST elevation MI and—to a lesser extent—unstable angina result from plaque rupture within the coronary intima, with sudden occlusion of one or more coronary arteries or branches and ischemia to the affected myocardium. Multiple pathologic processes—such as hypertension, dyslipidemia, or inflammatory disease—may weaken or injure the vascular lumen, and the development of a thrombus at the plaque rupture site involves many steps and triggers.
Ischemic myocardial injury increases an acute MI survivor’s risk of arrhythmias, heart failure, and sudden death. Tachycardia related to psychological stress can trigger these cardiac events in patients with heart disease. The goal of post-MI medical therapy is to protect the heart from further hypertensive injuries, arrhythmias, dyslipidemias, and thrombus formation.
Typical post-MI medications
ACE inhibitors. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II—a vasoconstrictor—increases blood pressure, restricts blood flow to the kidney, and stimulates aldosterone secretion by the adrenal cortex. ACE inhibition results in lower plasma levels of angiotensin II, with decreased blood pressure, vasopressor activity, and aldosterone secretion; this last effect may increase serum potassium.
Two ACE inhibitors—lisinopril and ramipril—have been shown in clinical trials to protect against recurrent cardiac events.6,7 ACE inhibitors may have variable effects among different ethnic groups. For example, ACE inhibitors have shown a less robust blood pressure-lowering effect in black patients than in non-blacks in some clinical trials.8
Beta blockers. Beta-adrenergic receptor blocking agents compete with beta-adrenergic agonists for available receptor sites in the heart and lungs. Cardioselective or beta-1 adrenergic agents such as metoprolol affect primarily the receptors in the heart and can slow the sinus rate and decrease AV nodal conduction. Metoprolol reduces heart rate, cardiac output, and systolic blood pressure, and inhibits reflex and drug-induced tachycardia. These pharmacologic actions lower oxygen demand, thus reducing the risk of ischemia and arrhythmias.
Beta blockers are a mainstay in regimens prescribed for post-MI outpatient treatment.9 Although earlier studies suggested that these drugs might cause depression, a recent systematic review rebuts that conclusion.10
Lipid-lowering agents. First-line treatments of hyperlipidemia include HMG-CoA reductase inhibitors (or “statins”) and niacin (also known as nicotinic acid). These drugs have been shown to lower lipids (cholesterol and triglycerides), reduce low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and increase high-density lipoproteins (HDL).
HMG-CoA reductase inhibitors have been shown in large international trials to reduce mortality from cardiac events in post-MI patients.11 These agents—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are associated with some side effect risks, including hepatotoxicity and rhabdomyolysis. Most are metabolized by cytochrome P450 3A4; the exception is fluvastatin, which is metabolized by CYP 2C9.
Niacin has been shown to decrease serum levels of apolipoprotein B-100—the major protein component of VLDL and LDL fractions—and of lipoprotein (a), an LDL variant independently associated with coronary risk.12 Niaspan—a long-acting formulation of niacin—is indicated to reduce recurrent nonfatal MI risk in patients with a history of MI and hypercholesterolemia. Niacin’s side effects include flushing, increased serum transaminase levels, slightly reduced platelet count, and (rarely) rhabdomyolysis.
Clotting and platelet inhibitors. Anticoagulants such as warfarin sodium and platelet inhibitors such as clopidogrel are major components of drug therapy to prevent blood clots in post-MI patients.
Warfarin is indicated to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. It acts by inhibiting the synthesis of vitamin Kdependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
Warfarin is metabolized by numerous CYP isoenzymes—principally 2C9, but also 2C19, 2C8, 2C18, 1A2, and 3A4—and interacts with many drugs that are metabolized by the same enzyme systems.12 Although some cardio-protective drugs and NSAIDs may lead to drug interactions due to CYP2C9, most common psychotropics do not inhibit this isoenzyme.
The protein-binding properties of some psychotropics—such as fluoxetine, sertraline, paroxetine, and risperidone—may increase warfarin levels in some patients. Thus, closer monitoring of warfarin levels is warranted when using these agents. Divalproex—because of its protein binding and potential for thrombocytopenia and liver injury—should be used with caution in patients receiving warfarin.
H Can this agent cause or worsen hypertension?
A Can this agent increase the risk of arrhythmia?
L Can this agent adversely affect lipids? Can it affect medication serum levels due to liver enzyme inhibition or liver injury?
T Can this agent increase the risk of thrombosis or bleeding?
Clopidogrel is indicated for reducing the risk of MI, stroke, and vascular death in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease.13 This drug selectively inhibits adenosine diphosphate (ADP) from binding to its platelet receptor and activates the ADP-mediated glycoprotein GPIIb/IIIa complex, which inhibits platelet aggregation. Clopidogrel can inhibit the CYP 2C9 isoenzyme. Thrombotic thrombocytopenic purpura has been reported rarely following use of clopidogrel, sometimes after brief exposure (< 2 weeks). The medical team must watch for GI bleeding, a potential side effect.
HALT: A decision framework
A decision tool based on the mnemonic HALT can help psychiatrists systematically and safely add antidepressants, antipsychotics, and mood-stabilizing agents to the complicated regimens of post-MI patients (Box). As HALT suggests, any selection strategy must address the agent’s impact on:
- Hypertension
- Arrhythmias
- Lipids and Liver enzymes
- Thrombosis risk.
The following section lists examples of medications that fit the HALT framework well and others that do not. The psychiatrist, cardiologist, and primary care physician should all be aware of the different agents the post-MI patient is taking and monitor for adherence and drug interactions.
Selecting an antidepressant
Most newer-generation antidepressants are safe and effective for patients with heart disease. Venlafaxine increases heart rate and blood pressure minimally. Fluoxetine, paroxetine, and bupropion tend to interact to some degree with drugs metabolized by CYP2D6, including beta blockers. Mirtazapine may increase appetite and cause weight gain, which can exacerbate hypertension and alter lipid levels. Even so, minimal drug interactions and end-organ effects should not preclude the use of any of these antidepressants when the drug is best suited for managing a patient’s depressive disorder.
Sertraline. Excellent articles and systematic reviews have addressed the importance of treating depression in patients with heart disease.14-16 However, only one recent randomized, double-blind, controlled trial has addressed antidepressant therapy for major depressive disorder in patients with acute MI or unstable angina.17 The trial included 369 patients (64% male; mean age 57) with MDD who received the selective serotonin reuptake inhibitor (SSRI) sertraline, 50 to 200 mg/d, or placebo for 24 weeks.
Compared with placebo, sertraline did not significantly affect left ventricular ejection fraction, ventricular premature complexes, QTc interval, or other cardiac measures. Depressive symptoms improved more with sertraline than with placebo in patients who had a history of at least one episode of major depressive disorder (MDD) or severe MDD (defined as a Hamilton Depression Scale score 18 and two or more prior episodes of MDD). The authors concluded that sertraline is safe and effective for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Using the HALT framework, sertraline does not exacerbate hypertension or increase heart rate, which can trigger arrhythmias. It does not cause weight gain or affect lipid levels and is a weak inhibitor of liver enzymes. Like other SSRIs, it may make platelets “less sticky” and reduce the risk of thrombogenesis.
Selecting an antipsychotic
Using the HALT framework reminds us that all atypical antipsychotics carry some cardiovascular risks in the post-MI population. Although none are known to directly increase heart rate, ziprasidone can increase the QT interval and pose a significant risk for arrhythmia. It therefore should be avoided in post-MI patients.18
Olanzapine has greater potential for causing weight gain than risperidone or quetiapine and may increase the risk of excessive weight gain and hyperlipidemia in patients who are not on a well-controlled diet. Quetiapine causes some significant orthostatic hypotension, no significant QT prolongation, and some weight gain. Risperidone is metabolized by the CYP2D6 isoenzyme and can cause orthostatic hypotension, some weight gain, and slight QT prolongation; it—like other atypical antipsychotics—is not known to alter thrombocyte function or thrombus formation.
The recently approved antipsychotic aripiprazole causes some orthostatic hypotension, no significant QT prolongation, and slight weight gain. It is metabolized by CYP3A4 and 2D6 and does not inhibit those enzymes. It is highly bound to albumin and does not interfere with warfarin.19
Selecting a mood stabilizer
Bipolar disorder presents numerous dilemmas when treating the post-MI patient. The three agents approved for treating bipolar mania—lithium, divalproex, and olanzapine—all require close therapeutic monitoring.
Lithium, olanzapine, and divalproex are the standard first-choice therapies for patients with acute mania, whereas olanzapine and divalproex are known to be more effective than lithium in patients with mixed states.1 Using the HALT framework, none of these mood stabilizers directly aggravates hypertension. However, lithium can cause significant electrolyte aberrations, and its combination with ACE inhibitors could increase the risk of sudden death from arrhythmia.20
Divalproex is known to elevate liver enzymes, and its combination with lipid-lowering agents carries the risk of significant liver injury.12 Divalproex also is known to result in some thrombocytopenia and could increase patients’ risk for bleeding complications when combined with clopidogrel, aspirin, warfarin, or niacin.
Divalproex has a black-box warning of increased risk of hemorrhagic pancreatitis. Patients who take divalproex with other agents known to affect platelet and clotting function should be watched closely.
Olanzapine, as discussed above, carries a risk of weight gain and requires careful dietary control in post-MI patients. Alternate atypical antipsychotics may need to be considered as mood-stabilizing therapy if the risk/benefit ratio of electrolyte imbalance (lithium), liver enzyme elevation and thrombocytopenia (divalproex), or weight gain (olanzapine) is not favorable.
Related resources
- American College of Cardiology www.acc.org
- Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
Drug brand names
- Aripiprazole • Abilify
- Atorvastatin • Lipitor
- Bupropion • Wellbutrin
- Clopidogrel bisulfate • Plavix
- Divalproex • Depakote
- Fluoxetine • Prozac
- Fluvastatin • Lescol
- Lisinopril • Prinivil
- Lovastatin • Mevacor
- Metoprolol • Toprol-XL
- Mirtazapine • Remeron
- Niacin • Niaspan
- Paroxetine • Paxil
- Pravastatin • Pravachol
- Olanzapine • Zyprexa
- Ramipril • Altace
- Sertraline • Zoloft
- Simvastatin • Zocor
- Venlafaxine • Effexor-XR
- Warfarin • Coumadin
- Ziprasidone • Geodon
Disclosure
Dr. Dewan receives grant/research support from Eli Lilly and Co. and is a speaker for Eli Lilly and Co. and Janssen Pharmaceutica.
Dr. Suresh and Dr. Blomkalns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors wish to acknowledge the assistance of W. Andrew Jenkins, BS, medical student, University of Cincinnati College of Medicine, in preparing this manuscript for publication.
How do you safely treat a psychiatrically ill patient who is taking seven to nine potent cardiovascular medications? Our approach is to organize the effects of psychiatric drugs into a systematic, easy-to-use framework, which we remember by the mnemonic HALT. It reminds us to consider any drug’s effect on hypertension, arrhythmias, lipids and liver enzymes, and risk of thrombosis. Using HALT as a decision tool can help you avoid drug-drug interactions when selecting psychotropics for patients with a history of myocardial infarction (MI).
The multi-medication challenge
In psychiatry, medication guidelines and algorithms encourage us to start with monotherapy before we try more complex regimens.1-3 Cardiologists, however, jump directly to a multimedication, cardio-protective approach for today’s post-MI patient.4-5 The cardiac standard of care includes angiotensin-converting enzyme (ACE) inhibitors, cardioselective beta-blockers, lipid-lowering agents, and platelet and clotting inhibitors.
Adding even one psychotropic to such a complex daily regimen could risk an adverse reaction. But, unfortunately, no guidelines exist for the medical management of psychiatrically ill post-MI patients, and research is very limited:
- only one randomized, controlled trial has examined drug treatment of their depression
- no randomized, controlled trials have addressed bipolar mania or psychosis drug treatment.
Table
THREE TYPES OF ACUTE CORONARY SYNDROMES
| Type | Diagnostic features |
|---|---|
| ST elevation MI | ST elevation in two contiguous ECG leads or new left bundle-branch block |
| Non-ST elevation MI | Positive CPK-MB or positive troponin levels and ST depression on ECG |
| Unstable angina | ST depression or T-wave inversion with no enzyme release |
| MI: myocardial infarction | |
| CPK-MB: creatine phosphokinase of muscle band (an enzyme released by ischemic heart muscle) | |
Pathophysiology of acute coronary syndromes
Acute coronary syndromes present as three broad types: ST elevation MI, non-ST elevation MI, and unstable angina (Table ). ST elevation MI, non-ST elevation MI and—to a lesser extent—unstable angina result from plaque rupture within the coronary intima, with sudden occlusion of one or more coronary arteries or branches and ischemia to the affected myocardium. Multiple pathologic processes—such as hypertension, dyslipidemia, or inflammatory disease—may weaken or injure the vascular lumen, and the development of a thrombus at the plaque rupture site involves many steps and triggers.
Ischemic myocardial injury increases an acute MI survivor’s risk of arrhythmias, heart failure, and sudden death. Tachycardia related to psychological stress can trigger these cardiac events in patients with heart disease. The goal of post-MI medical therapy is to protect the heart from further hypertensive injuries, arrhythmias, dyslipidemias, and thrombus formation.
Typical post-MI medications
ACE inhibitors. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II—a vasoconstrictor—increases blood pressure, restricts blood flow to the kidney, and stimulates aldosterone secretion by the adrenal cortex. ACE inhibition results in lower plasma levels of angiotensin II, with decreased blood pressure, vasopressor activity, and aldosterone secretion; this last effect may increase serum potassium.
Two ACE inhibitors—lisinopril and ramipril—have been shown in clinical trials to protect against recurrent cardiac events.6,7 ACE inhibitors may have variable effects among different ethnic groups. For example, ACE inhibitors have shown a less robust blood pressure-lowering effect in black patients than in non-blacks in some clinical trials.8
Beta blockers. Beta-adrenergic receptor blocking agents compete with beta-adrenergic agonists for available receptor sites in the heart and lungs. Cardioselective or beta-1 adrenergic agents such as metoprolol affect primarily the receptors in the heart and can slow the sinus rate and decrease AV nodal conduction. Metoprolol reduces heart rate, cardiac output, and systolic blood pressure, and inhibits reflex and drug-induced tachycardia. These pharmacologic actions lower oxygen demand, thus reducing the risk of ischemia and arrhythmias.
Beta blockers are a mainstay in regimens prescribed for post-MI outpatient treatment.9 Although earlier studies suggested that these drugs might cause depression, a recent systematic review rebuts that conclusion.10
Lipid-lowering agents. First-line treatments of hyperlipidemia include HMG-CoA reductase inhibitors (or “statins”) and niacin (also known as nicotinic acid). These drugs have been shown to lower lipids (cholesterol and triglycerides), reduce low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and increase high-density lipoproteins (HDL).
HMG-CoA reductase inhibitors have been shown in large international trials to reduce mortality from cardiac events in post-MI patients.11 These agents—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are associated with some side effect risks, including hepatotoxicity and rhabdomyolysis. Most are metabolized by cytochrome P450 3A4; the exception is fluvastatin, which is metabolized by CYP 2C9.
Niacin has been shown to decrease serum levels of apolipoprotein B-100—the major protein component of VLDL and LDL fractions—and of lipoprotein (a), an LDL variant independently associated with coronary risk.12 Niaspan—a long-acting formulation of niacin—is indicated to reduce recurrent nonfatal MI risk in patients with a history of MI and hypercholesterolemia. Niacin’s side effects include flushing, increased serum transaminase levels, slightly reduced platelet count, and (rarely) rhabdomyolysis.
Clotting and platelet inhibitors. Anticoagulants such as warfarin sodium and platelet inhibitors such as clopidogrel are major components of drug therapy to prevent blood clots in post-MI patients.
Warfarin is indicated to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. It acts by inhibiting the synthesis of vitamin Kdependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
Warfarin is metabolized by numerous CYP isoenzymes—principally 2C9, but also 2C19, 2C8, 2C18, 1A2, and 3A4—and interacts with many drugs that are metabolized by the same enzyme systems.12 Although some cardio-protective drugs and NSAIDs may lead to drug interactions due to CYP2C9, most common psychotropics do not inhibit this isoenzyme.
The protein-binding properties of some psychotropics—such as fluoxetine, sertraline, paroxetine, and risperidone—may increase warfarin levels in some patients. Thus, closer monitoring of warfarin levels is warranted when using these agents. Divalproex—because of its protein binding and potential for thrombocytopenia and liver injury—should be used with caution in patients receiving warfarin.
H Can this agent cause or worsen hypertension?
A Can this agent increase the risk of arrhythmia?
L Can this agent adversely affect lipids? Can it affect medication serum levels due to liver enzyme inhibition or liver injury?
T Can this agent increase the risk of thrombosis or bleeding?
Clopidogrel is indicated for reducing the risk of MI, stroke, and vascular death in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease.13 This drug selectively inhibits adenosine diphosphate (ADP) from binding to its platelet receptor and activates the ADP-mediated glycoprotein GPIIb/IIIa complex, which inhibits platelet aggregation. Clopidogrel can inhibit the CYP 2C9 isoenzyme. Thrombotic thrombocytopenic purpura has been reported rarely following use of clopidogrel, sometimes after brief exposure (< 2 weeks). The medical team must watch for GI bleeding, a potential side effect.
HALT: A decision framework
A decision tool based on the mnemonic HALT can help psychiatrists systematically and safely add antidepressants, antipsychotics, and mood-stabilizing agents to the complicated regimens of post-MI patients (Box). As HALT suggests, any selection strategy must address the agent’s impact on:
- Hypertension
- Arrhythmias
- Lipids and Liver enzymes
- Thrombosis risk.
The following section lists examples of medications that fit the HALT framework well and others that do not. The psychiatrist, cardiologist, and primary care physician should all be aware of the different agents the post-MI patient is taking and monitor for adherence and drug interactions.
Selecting an antidepressant
Most newer-generation antidepressants are safe and effective for patients with heart disease. Venlafaxine increases heart rate and blood pressure minimally. Fluoxetine, paroxetine, and bupropion tend to interact to some degree with drugs metabolized by CYP2D6, including beta blockers. Mirtazapine may increase appetite and cause weight gain, which can exacerbate hypertension and alter lipid levels. Even so, minimal drug interactions and end-organ effects should not preclude the use of any of these antidepressants when the drug is best suited for managing a patient’s depressive disorder.
Sertraline. Excellent articles and systematic reviews have addressed the importance of treating depression in patients with heart disease.14-16 However, only one recent randomized, double-blind, controlled trial has addressed antidepressant therapy for major depressive disorder in patients with acute MI or unstable angina.17 The trial included 369 patients (64% male; mean age 57) with MDD who received the selective serotonin reuptake inhibitor (SSRI) sertraline, 50 to 200 mg/d, or placebo for 24 weeks.
Compared with placebo, sertraline did not significantly affect left ventricular ejection fraction, ventricular premature complexes, QTc interval, or other cardiac measures. Depressive symptoms improved more with sertraline than with placebo in patients who had a history of at least one episode of major depressive disorder (MDD) or severe MDD (defined as a Hamilton Depression Scale score 18 and two or more prior episodes of MDD). The authors concluded that sertraline is safe and effective for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Using the HALT framework, sertraline does not exacerbate hypertension or increase heart rate, which can trigger arrhythmias. It does not cause weight gain or affect lipid levels and is a weak inhibitor of liver enzymes. Like other SSRIs, it may make platelets “less sticky” and reduce the risk of thrombogenesis.
Selecting an antipsychotic
Using the HALT framework reminds us that all atypical antipsychotics carry some cardiovascular risks in the post-MI population. Although none are known to directly increase heart rate, ziprasidone can increase the QT interval and pose a significant risk for arrhythmia. It therefore should be avoided in post-MI patients.18
Olanzapine has greater potential for causing weight gain than risperidone or quetiapine and may increase the risk of excessive weight gain and hyperlipidemia in patients who are not on a well-controlled diet. Quetiapine causes some significant orthostatic hypotension, no significant QT prolongation, and some weight gain. Risperidone is metabolized by the CYP2D6 isoenzyme and can cause orthostatic hypotension, some weight gain, and slight QT prolongation; it—like other atypical antipsychotics—is not known to alter thrombocyte function or thrombus formation.
The recently approved antipsychotic aripiprazole causes some orthostatic hypotension, no significant QT prolongation, and slight weight gain. It is metabolized by CYP3A4 and 2D6 and does not inhibit those enzymes. It is highly bound to albumin and does not interfere with warfarin.19
Selecting a mood stabilizer
Bipolar disorder presents numerous dilemmas when treating the post-MI patient. The three agents approved for treating bipolar mania—lithium, divalproex, and olanzapine—all require close therapeutic monitoring.
Lithium, olanzapine, and divalproex are the standard first-choice therapies for patients with acute mania, whereas olanzapine and divalproex are known to be more effective than lithium in patients with mixed states.1 Using the HALT framework, none of these mood stabilizers directly aggravates hypertension. However, lithium can cause significant electrolyte aberrations, and its combination with ACE inhibitors could increase the risk of sudden death from arrhythmia.20
Divalproex is known to elevate liver enzymes, and its combination with lipid-lowering agents carries the risk of significant liver injury.12 Divalproex also is known to result in some thrombocytopenia and could increase patients’ risk for bleeding complications when combined with clopidogrel, aspirin, warfarin, or niacin.
Divalproex has a black-box warning of increased risk of hemorrhagic pancreatitis. Patients who take divalproex with other agents known to affect platelet and clotting function should be watched closely.
Olanzapine, as discussed above, carries a risk of weight gain and requires careful dietary control in post-MI patients. Alternate atypical antipsychotics may need to be considered as mood-stabilizing therapy if the risk/benefit ratio of electrolyte imbalance (lithium), liver enzyme elevation and thrombocytopenia (divalproex), or weight gain (olanzapine) is not favorable.
Related resources
- American College of Cardiology www.acc.org
- Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
Drug brand names
- Aripiprazole • Abilify
- Atorvastatin • Lipitor
- Bupropion • Wellbutrin
- Clopidogrel bisulfate • Plavix
- Divalproex • Depakote
- Fluoxetine • Prozac
- Fluvastatin • Lescol
- Lisinopril • Prinivil
- Lovastatin • Mevacor
- Metoprolol • Toprol-XL
- Mirtazapine • Remeron
- Niacin • Niaspan
- Paroxetine • Paxil
- Pravastatin • Pravachol
- Olanzapine • Zyprexa
- Ramipril • Altace
- Sertraline • Zoloft
- Simvastatin • Zocor
- Venlafaxine • Effexor-XR
- Warfarin • Coumadin
- Ziprasidone • Geodon
Disclosure
Dr. Dewan receives grant/research support from Eli Lilly and Co. and is a speaker for Eli Lilly and Co. and Janssen Pharmaceutica.
Dr. Suresh and Dr. Blomkalns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors wish to acknowledge the assistance of W. Andrew Jenkins, BS, medical student, University of Cincinnati College of Medicine, in preparing this manuscript for publication.
1. Dennehy EB, Suppes T. Medication algorithms in bipolar disorder. J Pract Psychiatry Behav Health 1999;5:142-52.
2. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.
3. Chiles JA, Miller AL, Crismon ML, et al. The Texas Medication Algorithm Project: Development and implementation of the schizophrenic algorithm. Psychiatric Services 1999;50(1):69-74.
4. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. Executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction.) J Am Coll Cardiol 1999;34(3):890-911.
5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
6. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96(12):4239-45.
7. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001;104(5):522-6.
8. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
9. Andersen K, Ehlers D, Wiedemann HC, et al. Beta blockers: evidence versus wishful thinking. Am J Cardiol 1999;83(5B):64D-67D.
10. Ko DT, Hebert PR, Coffey CS, Sedrakayan A, Jeptha CP, Krumholz HM. B-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
11. Newby L, Kristinsson A, Bhapkar M, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287(23):3087-95.
12. Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
13. Yusuf S, Zhoa F, Mehta SR. et al, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
14. Glassman AH, Roose SP, Bigger JT, Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993;269:2673-5.
15. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4-11.
16. Rugulies R. Depression as a predictor for coronary heart disease: a review and metaanalysis. Am J Prev Med 2002;23(1):1-11.
17. Glassman AH, O’Connor C, Califf R, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9.
18. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(suppl 9):9-17.
19. Bristol-Myers Squibb Co. Aripiprazole (Abilify): prescribing information. www.abilify.com.
20. Chandragiri SS, Pasol E, Gallagher RM. Lithium, ACE inhibitors, NSAIDs, and verapamil: a possible fatal combination. Psychosomatics 1998;39(3):281-2.
1. Dennehy EB, Suppes T. Medication algorithms in bipolar disorder. J Pract Psychiatry Behav Health 1999;5:142-52.
2. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.
3. Chiles JA, Miller AL, Crismon ML, et al. The Texas Medication Algorithm Project: Development and implementation of the schizophrenic algorithm. Psychiatric Services 1999;50(1):69-74.
4. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. Executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction.) J Am Coll Cardiol 1999;34(3):890-911.
5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
6. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96(12):4239-45.
7. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001;104(5):522-6.
8. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
9. Andersen K, Ehlers D, Wiedemann HC, et al. Beta blockers: evidence versus wishful thinking. Am J Cardiol 1999;83(5B):64D-67D.
10. Ko DT, Hebert PR, Coffey CS, Sedrakayan A, Jeptha CP, Krumholz HM. B-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
11. Newby L, Kristinsson A, Bhapkar M, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287(23):3087-95.
12. Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
13. Yusuf S, Zhoa F, Mehta SR. et al, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
14. Glassman AH, Roose SP, Bigger JT, Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993;269:2673-5.
15. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4-11.
16. Rugulies R. Depression as a predictor for coronary heart disease: a review and metaanalysis. Am J Prev Med 2002;23(1):1-11.
17. Glassman AH, O’Connor C, Califf R, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9.
18. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(suppl 9):9-17.
19. Bristol-Myers Squibb Co. Aripiprazole (Abilify): prescribing information. www.abilify.com.
20. Chandragiri SS, Pasol E, Gallagher RM. Lithium, ACE inhibitors, NSAIDs, and verapamil: a possible fatal combination. Psychosomatics 1998;39(3):281-2.
Selecting safe psychotropics for post-MI patients
How do you safely treat a psychiatrically ill patient who is taking seven to nine potent cardiovascular medications? Our approach is to organize the effects of psychiatric drugs into a systematic, easy-to-use framework, which we remember by the mnemonic HALT. It reminds us to consider any drug’s effect on hypertension, arrhythmias, lipids and liver enzymes, and risk of thrombosis. Using HALT as a decision tool can help you avoid drug-drug interactions when selecting psychotropics for patients with a history of myocardial infarction (MI).
The multi-medication challenge
In psychiatry, medication guidelines and algorithms encourage us to start with monotherapy before we try more complex regimens.1-3 Cardiologists, however, jump directly to a multimedication, cardio-protective approach for today’s post-MI patient.4-5 The cardiac standard of care includes angiotensin-converting enzyme (ACE) inhibitors, cardioselective beta-blockers, lipid-lowering agents, and platelet and clotting inhibitors.
Adding even one psychotropic to such a complex daily regimen could risk an adverse reaction. But, unfortunately, no guidelines exist for the medical management of psychiatrically ill post-MI patients, and research is very limited:
- only one randomized, controlled trial has examined drug treatment of their depression
- no randomized, controlled trials have addressed bipolar mania or psychosis drug treatment.
Table
THREE TYPES OF ACUTE CORONARY SYNDROMES
| Type | Diagnostic features |
|---|---|
| ST elevation MI | ST elevation in two contiguous ECG leads or new left bundle-branch block |
| Non-ST elevation MI | Positive CPK-MB or positive troponin levels and ST depression on ECG |
| Unstable angina | ST depression or T-wave inversion with no enzyme release |
| MI: myocardial infarction | |
| CPK-MB: creatine phosphokinase of muscle band (an enzyme released by ischemic heart muscle) | |
Pathophysiology of acute coronary syndromes
Acute coronary syndromes present as three broad types: ST elevation MI, non-ST elevation MI, and unstable angina (Table ). ST elevation MI, non-ST elevation MI and—to a lesser extent—unstable angina result from plaque rupture within the coronary intima, with sudden occlusion of one or more coronary arteries or branches and ischemia to the affected myocardium. Multiple pathologic processes—such as hypertension, dyslipidemia, or inflammatory disease—may weaken or injure the vascular lumen, and the development of a thrombus at the plaque rupture site involves many steps and triggers.
Ischemic myocardial injury increases an acute MI survivor’s risk of arrhythmias, heart failure, and sudden death. Tachycardia related to psychological stress can trigger these cardiac events in patients with heart disease. The goal of post-MI medical therapy is to protect the heart from further hypertensive injuries, arrhythmias, dyslipidemias, and thrombus formation.
Typical post-MI medications
ACE inhibitors. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II—a vasoconstrictor—increases blood pressure, restricts blood flow to the kidney, and stimulates aldosterone secretion by the adrenal cortex. ACE inhibition results in lower plasma levels of angiotensin II, with decreased blood pressure, vasopressor activity, and aldosterone secretion; this last effect may increase serum potassium.
Two ACE inhibitors—lisinopril and ramipril—have been shown in clinical trials to protect against recurrent cardiac events.6,7 ACE inhibitors may have variable effects among different ethnic groups. For example, ACE inhibitors have shown a less robust blood pressure-lowering effect in black patients than in non-blacks in some clinical trials.8
Beta blockers. Beta-adrenergic receptor blocking agents compete with beta-adrenergic agonists for available receptor sites in the heart and lungs. Cardioselective or beta-1 adrenergic agents such as metoprolol affect primarily the receptors in the heart and can slow the sinus rate and decrease AV nodal conduction. Metoprolol reduces heart rate, cardiac output, and systolic blood pressure, and inhibits reflex and drug-induced tachycardia. These pharmacologic actions lower oxygen demand, thus reducing the risk of ischemia and arrhythmias.
Beta blockers are a mainstay in regimens prescribed for post-MI outpatient treatment.9 Although earlier studies suggested that these drugs might cause depression, a recent systematic review rebuts that conclusion.10
Lipid-lowering agents. First-line treatments of hyperlipidemia include HMG-CoA reductase inhibitors (or “statins”) and niacin (also known as nicotinic acid). These drugs have been shown to lower lipids (cholesterol and triglycerides), reduce low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and increase high-density lipoproteins (HDL).
HMG-CoA reductase inhibitors have been shown in large international trials to reduce mortality from cardiac events in post-MI patients.11 These agents—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are associated with some side effect risks, including hepatotoxicity and rhabdomyolysis. Most are metabolized by cytochrome P450 3A4; the exception is fluvastatin, which is metabolized by CYP 2C9.
Niacin has been shown to decrease serum levels of apolipoprotein B-100—the major protein component of VLDL and LDL fractions—and of lipoprotein (a), an LDL variant independently associated with coronary risk.12 Niaspan—a long-acting formulation of niacin—is indicated to reduce recurrent nonfatal MI risk in patients with a history of MI and hypercholesterolemia. Niacin’s side effects include flushing, increased serum transaminase levels, slightly reduced platelet count, and (rarely) rhabdomyolysis.
Clotting and platelet inhibitors. Anticoagulants such as warfarin sodium and platelet inhibitors such as clopidogrel are major components of drug therapy to prevent blood clots in post-MI patients.
Warfarin is indicated to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. It acts by inhibiting the synthesis of vitamin Kdependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
Warfarin is metabolized by numerous CYP isoenzymes—principally 2C9, but also 2C19, 2C8, 2C18, 1A2, and 3A4—and interacts with many drugs that are metabolized by the same enzyme systems.12 Although some cardio-protective drugs and NSAIDs may lead to drug interactions due to CYP2C9, most common psychotropics do not inhibit this isoenzyme.
The protein-binding properties of some psychotropics—such as fluoxetine, sertraline, paroxetine, and risperidone—may increase warfarin levels in some patients. Thus, closer monitoring of warfarin levels is warranted when using these agents. Divalproex—because of its protein binding and potential for thrombocytopenia and liver injury—should be used with caution in patients receiving warfarin.
H Can this agent cause or worsen hypertension?
A Can this agent increase the risk of arrhythmia?
L Can this agent adversely affect lipids? Can it affect medication serum levels due to liver enzyme inhibition or liver injury?
T Can this agent increase the risk of thrombosis or bleeding?
Clopidogrel is indicated for reducing the risk of MI, stroke, and vascular death in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease.13 This drug selectively inhibits adenosine diphosphate (ADP) from binding to its platelet receptor and activates the ADP-mediated glycoprotein GPIIb/IIIa complex, which inhibits platelet aggregation. Clopidogrel can inhibit the CYP 2C9 isoenzyme. Thrombotic thrombocytopenic purpura has been reported rarely following use of clopidogrel, sometimes after brief exposure (< 2 weeks). The medical team must watch for GI bleeding, a potential side effect.
HALT: A decision framework
A decision tool based on the mnemonic HALT can help psychiatrists systematically and safely add antidepressants, antipsychotics, and mood-stabilizing agents to the complicated regimens of post-MI patients (Box). As HALT suggests, any selection strategy must address the agent’s impact on:
- Hypertension
- Arrhythmias
- Lipids and Liver enzymes
- Thrombosis risk.
The following section lists examples of medications that fit the HALT framework well and others that do not. The psychiatrist, cardiologist, and primary care physician should all be aware of the different agents the post-MI patient is taking and monitor for adherence and drug interactions.
Selecting an antidepressant
Most newer-generation antidepressants are safe and effective for patients with heart disease. Venlafaxine increases heart rate and blood pressure minimally. Fluoxetine, paroxetine, and bupropion tend to interact to some degree with drugs metabolized by CYP2D6, including beta blockers. Mirtazapine may increase appetite and cause weight gain, which can exacerbate hypertension and alter lipid levels. Even so, minimal drug interactions and end-organ effects should not preclude the use of any of these antidepressants when the drug is best suited for managing a patient’s depressive disorder.
Sertraline. Excellent articles and systematic reviews have addressed the importance of treating depression in patients with heart disease.14-16 However, only one recent randomized, double-blind, controlled trial has addressed antidepressant therapy for major depressive disorder in patients with acute MI or unstable angina.17 The trial included 369 patients (64% male; mean age 57) with MDD who received the selective serotonin reuptake inhibitor (SSRI) sertraline, 50 to 200 mg/d, or placebo for 24 weeks.
Compared with placebo, sertraline did not significantly affect left ventricular ejection fraction, ventricular premature complexes, QTc interval, or other cardiac measures. Depressive symptoms improved more with sertraline than with placebo in patients who had a history of at least one episode of major depressive disorder (MDD) or severe MDD (defined as a Hamilton Depression Scale score 18 and two or more prior episodes of MDD). The authors concluded that sertraline is safe and effective for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Using the HALT framework, sertraline does not exacerbate hypertension or increase heart rate, which can trigger arrhythmias. It does not cause weight gain or affect lipid levels and is a weak inhibitor of liver enzymes. Like other SSRIs, it may make platelets “less sticky” and reduce the risk of thrombogenesis.
Selecting an antipsychotic
Using the HALT framework reminds us that all atypical antipsychotics carry some cardiovascular risks in the post-MI population. Although none are known to directly increase heart rate, ziprasidone can increase the QT interval and pose a significant risk for arrhythmia. It therefore should be avoided in post-MI patients.18
Olanzapine has greater potential for causing weight gain than risperidone or quetiapine and may increase the risk of excessive weight gain and hyperlipidemia in patients who are not on a well-controlled diet. Quetiapine causes some significant orthostatic hypotension, no significant QT prolongation, and some weight gain. Risperidone is metabolized by the CYP2D6 isoenzyme and can cause orthostatic hypotension, some weight gain, and slight QT prolongation; it—like other atypical antipsychotics—is not known to alter thrombocyte function or thrombus formation.
The recently approved antipsychotic aripiprazole causes some orthostatic hypotension, no significant QT prolongation, and slight weight gain. It is metabolized by CYP3A4 and 2D6 and does not inhibit those enzymes. It is highly bound to albumin and does not interfere with warfarin.19
Selecting a mood stabilizer
Bipolar disorder presents numerous dilemmas when treating the post-MI patient. The three agents approved for treating bipolar mania—lithium, divalproex, and olanzapine—all require close therapeutic monitoring.
Lithium, olanzapine, and divalproex are the standard first-choice therapies for patients with acute mania, whereas olanzapine and divalproex are known to be more effective than lithium in patients with mixed states.1 Using the HALT framework, none of these mood stabilizers directly aggravates hypertension. However, lithium can cause significant electrolyte aberrations, and its combination with ACE inhibitors could increase the risk of sudden death from arrhythmia.20
Divalproex is known to elevate liver enzymes, and its combination with lipid-lowering agents carries the risk of significant liver injury.12 Divalproex also is known to result in some thrombocytopenia and could increase patients’ risk for bleeding complications when combined with clopidogrel, aspirin, warfarin, or niacin.
Divalproex has a black-box warning of increased risk of hemorrhagic pancreatitis. Patients who take divalproex with other agents known to affect platelet and clotting function should be watched closely.
Olanzapine, as discussed above, carries a risk of weight gain and requires careful dietary control in post-MI patients. Alternate atypical antipsychotics may need to be considered as mood-stabilizing therapy if the risk/benefit ratio of electrolyte imbalance (lithium), liver enzyme elevation and thrombocytopenia (divalproex), or weight gain (olanzapine) is not favorable.
Related resources
- American College of Cardiology www.acc.org
- Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
Drug brand names
- Aripiprazole • Abilify
- Atorvastatin • Lipitor
- Bupropion • Wellbutrin
- Clopidogrel bisulfate • Plavix
- Divalproex • Depakote
- Fluoxetine • Prozac
- Fluvastatin • Lescol
- Lisinopril • Prinivil
- Lovastatin • Mevacor
- Metoprolol • Toprol-XL
- Mirtazapine • Remeron
- Niacin • Niaspan
- Paroxetine • Paxil
- Pravastatin • Pravachol
- Olanzapine • Zyprexa
- Ramipril • Altace
- Sertraline • Zoloft
- Simvastatin • Zocor
- Venlafaxine • Effexor-XR
- Warfarin • Coumadin
- Ziprasidone • Geodon
Disclosure
Dr. Dewan receives grant/research support from Eli Lilly and Co. and is a speaker for Eli Lilly and Co. and Janssen Pharmaceutica.
Dr. Suresh and Dr. Blomkalns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors wish to acknowledge the assistance of W. Andrew Jenkins, BS, medical student, University of Cincinnati College of Medicine, in preparing this manuscript for publication.
1. Dennehy EB, Suppes T. Medication algorithms in bipolar disorder. J Pract Psychiatry Behav Health 1999;5:142-52.
2. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.
3. Chiles JA, Miller AL, Crismon ML, et al. The Texas Medication Algorithm Project: Development and implementation of the schizophrenic algorithm. Psychiatric Services 1999;50(1):69-74.
4. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. Executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction.) J Am Coll Cardiol 1999;34(3):890-911.
5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
6. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96(12):4239-45.
7. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001;104(5):522-6.
8. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
9. Andersen K, Ehlers D, Wiedemann HC, et al. Beta blockers: evidence versus wishful thinking. Am J Cardiol 1999;83(5B):64D-67D.
10. Ko DT, Hebert PR, Coffey CS, Sedrakayan A, Jeptha CP, Krumholz HM. B-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
11. Newby L, Kristinsson A, Bhapkar M, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287(23):3087-95.
12. Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
13. Yusuf S, Zhoa F, Mehta SR. et al, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
14. Glassman AH, Roose SP, Bigger JT, Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993;269:2673-5.
15. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4-11.
16. Rugulies R. Depression as a predictor for coronary heart disease: a review and metaanalysis. Am J Prev Med 2002;23(1):1-11.
17. Glassman AH, O’Connor C, Califf R, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9.
18. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(suppl 9):9-17.
19. Bristol-Myers Squibb Co. Aripiprazole (Abilify): prescribing information. www.abilify.com.
20. Chandragiri SS, Pasol E, Gallagher RM. Lithium, ACE inhibitors, NSAIDs, and verapamil: a possible fatal combination. Psychosomatics 1998;39(3):281-2.
How do you safely treat a psychiatrically ill patient who is taking seven to nine potent cardiovascular medications? Our approach is to organize the effects of psychiatric drugs into a systematic, easy-to-use framework, which we remember by the mnemonic HALT. It reminds us to consider any drug’s effect on hypertension, arrhythmias, lipids and liver enzymes, and risk of thrombosis. Using HALT as a decision tool can help you avoid drug-drug interactions when selecting psychotropics for patients with a history of myocardial infarction (MI).
The multi-medication challenge
In psychiatry, medication guidelines and algorithms encourage us to start with monotherapy before we try more complex regimens.1-3 Cardiologists, however, jump directly to a multimedication, cardio-protective approach for today’s post-MI patient.4-5 The cardiac standard of care includes angiotensin-converting enzyme (ACE) inhibitors, cardioselective beta-blockers, lipid-lowering agents, and platelet and clotting inhibitors.
Adding even one psychotropic to such a complex daily regimen could risk an adverse reaction. But, unfortunately, no guidelines exist for the medical management of psychiatrically ill post-MI patients, and research is very limited:
- only one randomized, controlled trial has examined drug treatment of their depression
- no randomized, controlled trials have addressed bipolar mania or psychosis drug treatment.
Table
THREE TYPES OF ACUTE CORONARY SYNDROMES
| Type | Diagnostic features |
|---|---|
| ST elevation MI | ST elevation in two contiguous ECG leads or new left bundle-branch block |
| Non-ST elevation MI | Positive CPK-MB or positive troponin levels and ST depression on ECG |
| Unstable angina | ST depression or T-wave inversion with no enzyme release |
| MI: myocardial infarction | |
| CPK-MB: creatine phosphokinase of muscle band (an enzyme released by ischemic heart muscle) | |
Pathophysiology of acute coronary syndromes
Acute coronary syndromes present as three broad types: ST elevation MI, non-ST elevation MI, and unstable angina (Table ). ST elevation MI, non-ST elevation MI and—to a lesser extent—unstable angina result from plaque rupture within the coronary intima, with sudden occlusion of one or more coronary arteries or branches and ischemia to the affected myocardium. Multiple pathologic processes—such as hypertension, dyslipidemia, or inflammatory disease—may weaken or injure the vascular lumen, and the development of a thrombus at the plaque rupture site involves many steps and triggers.
Ischemic myocardial injury increases an acute MI survivor’s risk of arrhythmias, heart failure, and sudden death. Tachycardia related to psychological stress can trigger these cardiac events in patients with heart disease. The goal of post-MI medical therapy is to protect the heart from further hypertensive injuries, arrhythmias, dyslipidemias, and thrombus formation.
Typical post-MI medications
ACE inhibitors. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II—a vasoconstrictor—increases blood pressure, restricts blood flow to the kidney, and stimulates aldosterone secretion by the adrenal cortex. ACE inhibition results in lower plasma levels of angiotensin II, with decreased blood pressure, vasopressor activity, and aldosterone secretion; this last effect may increase serum potassium.
Two ACE inhibitors—lisinopril and ramipril—have been shown in clinical trials to protect against recurrent cardiac events.6,7 ACE inhibitors may have variable effects among different ethnic groups. For example, ACE inhibitors have shown a less robust blood pressure-lowering effect in black patients than in non-blacks in some clinical trials.8
Beta blockers. Beta-adrenergic receptor blocking agents compete with beta-adrenergic agonists for available receptor sites in the heart and lungs. Cardioselective or beta-1 adrenergic agents such as metoprolol affect primarily the receptors in the heart and can slow the sinus rate and decrease AV nodal conduction. Metoprolol reduces heart rate, cardiac output, and systolic blood pressure, and inhibits reflex and drug-induced tachycardia. These pharmacologic actions lower oxygen demand, thus reducing the risk of ischemia and arrhythmias.
Beta blockers are a mainstay in regimens prescribed for post-MI outpatient treatment.9 Although earlier studies suggested that these drugs might cause depression, a recent systematic review rebuts that conclusion.10
Lipid-lowering agents. First-line treatments of hyperlipidemia include HMG-CoA reductase inhibitors (or “statins”) and niacin (also known as nicotinic acid). These drugs have been shown to lower lipids (cholesterol and triglycerides), reduce low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and increase high-density lipoproteins (HDL).
HMG-CoA reductase inhibitors have been shown in large international trials to reduce mortality from cardiac events in post-MI patients.11 These agents—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are associated with some side effect risks, including hepatotoxicity and rhabdomyolysis. Most are metabolized by cytochrome P450 3A4; the exception is fluvastatin, which is metabolized by CYP 2C9.
Niacin has been shown to decrease serum levels of apolipoprotein B-100—the major protein component of VLDL and LDL fractions—and of lipoprotein (a), an LDL variant independently associated with coronary risk.12 Niaspan—a long-acting formulation of niacin—is indicated to reduce recurrent nonfatal MI risk in patients with a history of MI and hypercholesterolemia. Niacin’s side effects include flushing, increased serum transaminase levels, slightly reduced platelet count, and (rarely) rhabdomyolysis.
Clotting and platelet inhibitors. Anticoagulants such as warfarin sodium and platelet inhibitors such as clopidogrel are major components of drug therapy to prevent blood clots in post-MI patients.
Warfarin is indicated to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. It acts by inhibiting the synthesis of vitamin Kdependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
Warfarin is metabolized by numerous CYP isoenzymes—principally 2C9, but also 2C19, 2C8, 2C18, 1A2, and 3A4—and interacts with many drugs that are metabolized by the same enzyme systems.12 Although some cardio-protective drugs and NSAIDs may lead to drug interactions due to CYP2C9, most common psychotropics do not inhibit this isoenzyme.
The protein-binding properties of some psychotropics—such as fluoxetine, sertraline, paroxetine, and risperidone—may increase warfarin levels in some patients. Thus, closer monitoring of warfarin levels is warranted when using these agents. Divalproex—because of its protein binding and potential for thrombocytopenia and liver injury—should be used with caution in patients receiving warfarin.
H Can this agent cause or worsen hypertension?
A Can this agent increase the risk of arrhythmia?
L Can this agent adversely affect lipids? Can it affect medication serum levels due to liver enzyme inhibition or liver injury?
T Can this agent increase the risk of thrombosis or bleeding?
Clopidogrel is indicated for reducing the risk of MI, stroke, and vascular death in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease.13 This drug selectively inhibits adenosine diphosphate (ADP) from binding to its platelet receptor and activates the ADP-mediated glycoprotein GPIIb/IIIa complex, which inhibits platelet aggregation. Clopidogrel can inhibit the CYP 2C9 isoenzyme. Thrombotic thrombocytopenic purpura has been reported rarely following use of clopidogrel, sometimes after brief exposure (< 2 weeks). The medical team must watch for GI bleeding, a potential side effect.
HALT: A decision framework
A decision tool based on the mnemonic HALT can help psychiatrists systematically and safely add antidepressants, antipsychotics, and mood-stabilizing agents to the complicated regimens of post-MI patients (Box). As HALT suggests, any selection strategy must address the agent’s impact on:
- Hypertension
- Arrhythmias
- Lipids and Liver enzymes
- Thrombosis risk.
The following section lists examples of medications that fit the HALT framework well and others that do not. The psychiatrist, cardiologist, and primary care physician should all be aware of the different agents the post-MI patient is taking and monitor for adherence and drug interactions.
Selecting an antidepressant
Most newer-generation antidepressants are safe and effective for patients with heart disease. Venlafaxine increases heart rate and blood pressure minimally. Fluoxetine, paroxetine, and bupropion tend to interact to some degree with drugs metabolized by CYP2D6, including beta blockers. Mirtazapine may increase appetite and cause weight gain, which can exacerbate hypertension and alter lipid levels. Even so, minimal drug interactions and end-organ effects should not preclude the use of any of these antidepressants when the drug is best suited for managing a patient’s depressive disorder.
Sertraline. Excellent articles and systematic reviews have addressed the importance of treating depression in patients with heart disease.14-16 However, only one recent randomized, double-blind, controlled trial has addressed antidepressant therapy for major depressive disorder in patients with acute MI or unstable angina.17 The trial included 369 patients (64% male; mean age 57) with MDD who received the selective serotonin reuptake inhibitor (SSRI) sertraline, 50 to 200 mg/d, or placebo for 24 weeks.
Compared with placebo, sertraline did not significantly affect left ventricular ejection fraction, ventricular premature complexes, QTc interval, or other cardiac measures. Depressive symptoms improved more with sertraline than with placebo in patients who had a history of at least one episode of major depressive disorder (MDD) or severe MDD (defined as a Hamilton Depression Scale score 18 and two or more prior episodes of MDD). The authors concluded that sertraline is safe and effective for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Using the HALT framework, sertraline does not exacerbate hypertension or increase heart rate, which can trigger arrhythmias. It does not cause weight gain or affect lipid levels and is a weak inhibitor of liver enzymes. Like other SSRIs, it may make platelets “less sticky” and reduce the risk of thrombogenesis.
Selecting an antipsychotic
Using the HALT framework reminds us that all atypical antipsychotics carry some cardiovascular risks in the post-MI population. Although none are known to directly increase heart rate, ziprasidone can increase the QT interval and pose a significant risk for arrhythmia. It therefore should be avoided in post-MI patients.18
Olanzapine has greater potential for causing weight gain than risperidone or quetiapine and may increase the risk of excessive weight gain and hyperlipidemia in patients who are not on a well-controlled diet. Quetiapine causes some significant orthostatic hypotension, no significant QT prolongation, and some weight gain. Risperidone is metabolized by the CYP2D6 isoenzyme and can cause orthostatic hypotension, some weight gain, and slight QT prolongation; it—like other atypical antipsychotics—is not known to alter thrombocyte function or thrombus formation.
The recently approved antipsychotic aripiprazole causes some orthostatic hypotension, no significant QT prolongation, and slight weight gain. It is metabolized by CYP3A4 and 2D6 and does not inhibit those enzymes. It is highly bound to albumin and does not interfere with warfarin.19
Selecting a mood stabilizer
Bipolar disorder presents numerous dilemmas when treating the post-MI patient. The three agents approved for treating bipolar mania—lithium, divalproex, and olanzapine—all require close therapeutic monitoring.
Lithium, olanzapine, and divalproex are the standard first-choice therapies for patients with acute mania, whereas olanzapine and divalproex are known to be more effective than lithium in patients with mixed states.1 Using the HALT framework, none of these mood stabilizers directly aggravates hypertension. However, lithium can cause significant electrolyte aberrations, and its combination with ACE inhibitors could increase the risk of sudden death from arrhythmia.20
Divalproex is known to elevate liver enzymes, and its combination with lipid-lowering agents carries the risk of significant liver injury.12 Divalproex also is known to result in some thrombocytopenia and could increase patients’ risk for bleeding complications when combined with clopidogrel, aspirin, warfarin, or niacin.
Divalproex has a black-box warning of increased risk of hemorrhagic pancreatitis. Patients who take divalproex with other agents known to affect platelet and clotting function should be watched closely.
Olanzapine, as discussed above, carries a risk of weight gain and requires careful dietary control in post-MI patients. Alternate atypical antipsychotics may need to be considered as mood-stabilizing therapy if the risk/benefit ratio of electrolyte imbalance (lithium), liver enzyme elevation and thrombocytopenia (divalproex), or weight gain (olanzapine) is not favorable.
Related resources
- American College of Cardiology www.acc.org
- Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
Drug brand names
- Aripiprazole • Abilify
- Atorvastatin • Lipitor
- Bupropion • Wellbutrin
- Clopidogrel bisulfate • Plavix
- Divalproex • Depakote
- Fluoxetine • Prozac
- Fluvastatin • Lescol
- Lisinopril • Prinivil
- Lovastatin • Mevacor
- Metoprolol • Toprol-XL
- Mirtazapine • Remeron
- Niacin • Niaspan
- Paroxetine • Paxil
- Pravastatin • Pravachol
- Olanzapine • Zyprexa
- Ramipril • Altace
- Sertraline • Zoloft
- Simvastatin • Zocor
- Venlafaxine • Effexor-XR
- Warfarin • Coumadin
- Ziprasidone • Geodon
Disclosure
Dr. Dewan receives grant/research support from Eli Lilly and Co. and is a speaker for Eli Lilly and Co. and Janssen Pharmaceutica.
Dr. Suresh and Dr. Blomkalns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors wish to acknowledge the assistance of W. Andrew Jenkins, BS, medical student, University of Cincinnati College of Medicine, in preparing this manuscript for publication.
How do you safely treat a psychiatrically ill patient who is taking seven to nine potent cardiovascular medications? Our approach is to organize the effects of psychiatric drugs into a systematic, easy-to-use framework, which we remember by the mnemonic HALT. It reminds us to consider any drug’s effect on hypertension, arrhythmias, lipids and liver enzymes, and risk of thrombosis. Using HALT as a decision tool can help you avoid drug-drug interactions when selecting psychotropics for patients with a history of myocardial infarction (MI).
The multi-medication challenge
In psychiatry, medication guidelines and algorithms encourage us to start with monotherapy before we try more complex regimens.1-3 Cardiologists, however, jump directly to a multimedication, cardio-protective approach for today’s post-MI patient.4-5 The cardiac standard of care includes angiotensin-converting enzyme (ACE) inhibitors, cardioselective beta-blockers, lipid-lowering agents, and platelet and clotting inhibitors.
Adding even one psychotropic to such a complex daily regimen could risk an adverse reaction. But, unfortunately, no guidelines exist for the medical management of psychiatrically ill post-MI patients, and research is very limited:
- only one randomized, controlled trial has examined drug treatment of their depression
- no randomized, controlled trials have addressed bipolar mania or psychosis drug treatment.
Table
THREE TYPES OF ACUTE CORONARY SYNDROMES
| Type | Diagnostic features |
|---|---|
| ST elevation MI | ST elevation in two contiguous ECG leads or new left bundle-branch block |
| Non-ST elevation MI | Positive CPK-MB or positive troponin levels and ST depression on ECG |
| Unstable angina | ST depression or T-wave inversion with no enzyme release |
| MI: myocardial infarction | |
| CPK-MB: creatine phosphokinase of muscle band (an enzyme released by ischemic heart muscle) | |
Pathophysiology of acute coronary syndromes
Acute coronary syndromes present as three broad types: ST elevation MI, non-ST elevation MI, and unstable angina (Table ). ST elevation MI, non-ST elevation MI and—to a lesser extent—unstable angina result from plaque rupture within the coronary intima, with sudden occlusion of one or more coronary arteries or branches and ischemia to the affected myocardium. Multiple pathologic processes—such as hypertension, dyslipidemia, or inflammatory disease—may weaken or injure the vascular lumen, and the development of a thrombus at the plaque rupture site involves many steps and triggers.
Ischemic myocardial injury increases an acute MI survivor’s risk of arrhythmias, heart failure, and sudden death. Tachycardia related to psychological stress can trigger these cardiac events in patients with heart disease. The goal of post-MI medical therapy is to protect the heart from further hypertensive injuries, arrhythmias, dyslipidemias, and thrombus formation.
Typical post-MI medications
ACE inhibitors. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II—a vasoconstrictor—increases blood pressure, restricts blood flow to the kidney, and stimulates aldosterone secretion by the adrenal cortex. ACE inhibition results in lower plasma levels of angiotensin II, with decreased blood pressure, vasopressor activity, and aldosterone secretion; this last effect may increase serum potassium.
Two ACE inhibitors—lisinopril and ramipril—have been shown in clinical trials to protect against recurrent cardiac events.6,7 ACE inhibitors may have variable effects among different ethnic groups. For example, ACE inhibitors have shown a less robust blood pressure-lowering effect in black patients than in non-blacks in some clinical trials.8
Beta blockers. Beta-adrenergic receptor blocking agents compete with beta-adrenergic agonists for available receptor sites in the heart and lungs. Cardioselective or beta-1 adrenergic agents such as metoprolol affect primarily the receptors in the heart and can slow the sinus rate and decrease AV nodal conduction. Metoprolol reduces heart rate, cardiac output, and systolic blood pressure, and inhibits reflex and drug-induced tachycardia. These pharmacologic actions lower oxygen demand, thus reducing the risk of ischemia and arrhythmias.
Beta blockers are a mainstay in regimens prescribed for post-MI outpatient treatment.9 Although earlier studies suggested that these drugs might cause depression, a recent systematic review rebuts that conclusion.10
Lipid-lowering agents. First-line treatments of hyperlipidemia include HMG-CoA reductase inhibitors (or “statins”) and niacin (also known as nicotinic acid). These drugs have been shown to lower lipids (cholesterol and triglycerides), reduce low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and increase high-density lipoproteins (HDL).
HMG-CoA reductase inhibitors have been shown in large international trials to reduce mortality from cardiac events in post-MI patients.11 These agents—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are associated with some side effect risks, including hepatotoxicity and rhabdomyolysis. Most are metabolized by cytochrome P450 3A4; the exception is fluvastatin, which is metabolized by CYP 2C9.
Niacin has been shown to decrease serum levels of apolipoprotein B-100—the major protein component of VLDL and LDL fractions—and of lipoprotein (a), an LDL variant independently associated with coronary risk.12 Niaspan—a long-acting formulation of niacin—is indicated to reduce recurrent nonfatal MI risk in patients with a history of MI and hypercholesterolemia. Niacin’s side effects include flushing, increased serum transaminase levels, slightly reduced platelet count, and (rarely) rhabdomyolysis.
Clotting and platelet inhibitors. Anticoagulants such as warfarin sodium and platelet inhibitors such as clopidogrel are major components of drug therapy to prevent blood clots in post-MI patients.
Warfarin is indicated to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. It acts by inhibiting the synthesis of vitamin Kdependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
Warfarin is metabolized by numerous CYP isoenzymes—principally 2C9, but also 2C19, 2C8, 2C18, 1A2, and 3A4—and interacts with many drugs that are metabolized by the same enzyme systems.12 Although some cardio-protective drugs and NSAIDs may lead to drug interactions due to CYP2C9, most common psychotropics do not inhibit this isoenzyme.
The protein-binding properties of some psychotropics—such as fluoxetine, sertraline, paroxetine, and risperidone—may increase warfarin levels in some patients. Thus, closer monitoring of warfarin levels is warranted when using these agents. Divalproex—because of its protein binding and potential for thrombocytopenia and liver injury—should be used with caution in patients receiving warfarin.
H Can this agent cause or worsen hypertension?
A Can this agent increase the risk of arrhythmia?
L Can this agent adversely affect lipids? Can it affect medication serum levels due to liver enzyme inhibition or liver injury?
T Can this agent increase the risk of thrombosis or bleeding?
Clopidogrel is indicated for reducing the risk of MI, stroke, and vascular death in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease.13 This drug selectively inhibits adenosine diphosphate (ADP) from binding to its platelet receptor and activates the ADP-mediated glycoprotein GPIIb/IIIa complex, which inhibits platelet aggregation. Clopidogrel can inhibit the CYP 2C9 isoenzyme. Thrombotic thrombocytopenic purpura has been reported rarely following use of clopidogrel, sometimes after brief exposure (< 2 weeks). The medical team must watch for GI bleeding, a potential side effect.
HALT: A decision framework
A decision tool based on the mnemonic HALT can help psychiatrists systematically and safely add antidepressants, antipsychotics, and mood-stabilizing agents to the complicated regimens of post-MI patients (Box). As HALT suggests, any selection strategy must address the agent’s impact on:
- Hypertension
- Arrhythmias
- Lipids and Liver enzymes
- Thrombosis risk.
The following section lists examples of medications that fit the HALT framework well and others that do not. The psychiatrist, cardiologist, and primary care physician should all be aware of the different agents the post-MI patient is taking and monitor for adherence and drug interactions.
Selecting an antidepressant
Most newer-generation antidepressants are safe and effective for patients with heart disease. Venlafaxine increases heart rate and blood pressure minimally. Fluoxetine, paroxetine, and bupropion tend to interact to some degree with drugs metabolized by CYP2D6, including beta blockers. Mirtazapine may increase appetite and cause weight gain, which can exacerbate hypertension and alter lipid levels. Even so, minimal drug interactions and end-organ effects should not preclude the use of any of these antidepressants when the drug is best suited for managing a patient’s depressive disorder.
Sertraline. Excellent articles and systematic reviews have addressed the importance of treating depression in patients with heart disease.14-16 However, only one recent randomized, double-blind, controlled trial has addressed antidepressant therapy for major depressive disorder in patients with acute MI or unstable angina.17 The trial included 369 patients (64% male; mean age 57) with MDD who received the selective serotonin reuptake inhibitor (SSRI) sertraline, 50 to 200 mg/d, or placebo for 24 weeks.
Compared with placebo, sertraline did not significantly affect left ventricular ejection fraction, ventricular premature complexes, QTc interval, or other cardiac measures. Depressive symptoms improved more with sertraline than with placebo in patients who had a history of at least one episode of major depressive disorder (MDD) or severe MDD (defined as a Hamilton Depression Scale score 18 and two or more prior episodes of MDD). The authors concluded that sertraline is safe and effective for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Using the HALT framework, sertraline does not exacerbate hypertension or increase heart rate, which can trigger arrhythmias. It does not cause weight gain or affect lipid levels and is a weak inhibitor of liver enzymes. Like other SSRIs, it may make platelets “less sticky” and reduce the risk of thrombogenesis.
Selecting an antipsychotic
Using the HALT framework reminds us that all atypical antipsychotics carry some cardiovascular risks in the post-MI population. Although none are known to directly increase heart rate, ziprasidone can increase the QT interval and pose a significant risk for arrhythmia. It therefore should be avoided in post-MI patients.18
Olanzapine has greater potential for causing weight gain than risperidone or quetiapine and may increase the risk of excessive weight gain and hyperlipidemia in patients who are not on a well-controlled diet. Quetiapine causes some significant orthostatic hypotension, no significant QT prolongation, and some weight gain. Risperidone is metabolized by the CYP2D6 isoenzyme and can cause orthostatic hypotension, some weight gain, and slight QT prolongation; it—like other atypical antipsychotics—is not known to alter thrombocyte function or thrombus formation.
The recently approved antipsychotic aripiprazole causes some orthostatic hypotension, no significant QT prolongation, and slight weight gain. It is metabolized by CYP3A4 and 2D6 and does not inhibit those enzymes. It is highly bound to albumin and does not interfere with warfarin.19
Selecting a mood stabilizer
Bipolar disorder presents numerous dilemmas when treating the post-MI patient. The three agents approved for treating bipolar mania—lithium, divalproex, and olanzapine—all require close therapeutic monitoring.
Lithium, olanzapine, and divalproex are the standard first-choice therapies for patients with acute mania, whereas olanzapine and divalproex are known to be more effective than lithium in patients with mixed states.1 Using the HALT framework, none of these mood stabilizers directly aggravates hypertension. However, lithium can cause significant electrolyte aberrations, and its combination with ACE inhibitors could increase the risk of sudden death from arrhythmia.20
Divalproex is known to elevate liver enzymes, and its combination with lipid-lowering agents carries the risk of significant liver injury.12 Divalproex also is known to result in some thrombocytopenia and could increase patients’ risk for bleeding complications when combined with clopidogrel, aspirin, warfarin, or niacin.
Divalproex has a black-box warning of increased risk of hemorrhagic pancreatitis. Patients who take divalproex with other agents known to affect platelet and clotting function should be watched closely.
Olanzapine, as discussed above, carries a risk of weight gain and requires careful dietary control in post-MI patients. Alternate atypical antipsychotics may need to be considered as mood-stabilizing therapy if the risk/benefit ratio of electrolyte imbalance (lithium), liver enzyme elevation and thrombocytopenia (divalproex), or weight gain (olanzapine) is not favorable.
Related resources
- American College of Cardiology www.acc.org
- Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
Drug brand names
- Aripiprazole • Abilify
- Atorvastatin • Lipitor
- Bupropion • Wellbutrin
- Clopidogrel bisulfate • Plavix
- Divalproex • Depakote
- Fluoxetine • Prozac
- Fluvastatin • Lescol
- Lisinopril • Prinivil
- Lovastatin • Mevacor
- Metoprolol • Toprol-XL
- Mirtazapine • Remeron
- Niacin • Niaspan
- Paroxetine • Paxil
- Pravastatin • Pravachol
- Olanzapine • Zyprexa
- Ramipril • Altace
- Sertraline • Zoloft
- Simvastatin • Zocor
- Venlafaxine • Effexor-XR
- Warfarin • Coumadin
- Ziprasidone • Geodon
Disclosure
Dr. Dewan receives grant/research support from Eli Lilly and Co. and is a speaker for Eli Lilly and Co. and Janssen Pharmaceutica.
Dr. Suresh and Dr. Blomkalns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors wish to acknowledge the assistance of W. Andrew Jenkins, BS, medical student, University of Cincinnati College of Medicine, in preparing this manuscript for publication.
1. Dennehy EB, Suppes T. Medication algorithms in bipolar disorder. J Pract Psychiatry Behav Health 1999;5:142-52.
2. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.
3. Chiles JA, Miller AL, Crismon ML, et al. The Texas Medication Algorithm Project: Development and implementation of the schizophrenic algorithm. Psychiatric Services 1999;50(1):69-74.
4. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. Executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction.) J Am Coll Cardiol 1999;34(3):890-911.
5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
6. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96(12):4239-45.
7. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001;104(5):522-6.
8. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
9. Andersen K, Ehlers D, Wiedemann HC, et al. Beta blockers: evidence versus wishful thinking. Am J Cardiol 1999;83(5B):64D-67D.
10. Ko DT, Hebert PR, Coffey CS, Sedrakayan A, Jeptha CP, Krumholz HM. B-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
11. Newby L, Kristinsson A, Bhapkar M, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287(23):3087-95.
12. Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
13. Yusuf S, Zhoa F, Mehta SR. et al, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
14. Glassman AH, Roose SP, Bigger JT, Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993;269:2673-5.
15. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4-11.
16. Rugulies R. Depression as a predictor for coronary heart disease: a review and metaanalysis. Am J Prev Med 2002;23(1):1-11.
17. Glassman AH, O’Connor C, Califf R, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9.
18. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(suppl 9):9-17.
19. Bristol-Myers Squibb Co. Aripiprazole (Abilify): prescribing information. www.abilify.com.
20. Chandragiri SS, Pasol E, Gallagher RM. Lithium, ACE inhibitors, NSAIDs, and verapamil: a possible fatal combination. Psychosomatics 1998;39(3):281-2.
1. Dennehy EB, Suppes T. Medication algorithms in bipolar disorder. J Pract Psychiatry Behav Health 1999;5:142-52.
2. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.
3. Chiles JA, Miller AL, Crismon ML, et al. The Texas Medication Algorithm Project: Development and implementation of the schizophrenic algorithm. Psychiatric Services 1999;50(1):69-74.
4. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. Executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction.) J Am Coll Cardiol 1999;34(3):890-911.
5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
6. Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96(12):4239-45.
7. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001;104(5):522-6.
8. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
9. Andersen K, Ehlers D, Wiedemann HC, et al. Beta blockers: evidence versus wishful thinking. Am J Cardiol 1999;83(5B):64D-67D.
10. Ko DT, Hebert PR, Coffey CS, Sedrakayan A, Jeptha CP, Krumholz HM. B-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
11. Newby L, Kristinsson A, Bhapkar M, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287(23):3087-95.
12. Physicians’ Desk Reference (56th ed). Montvale, NJ: Medical Economics, 2002.
13. Yusuf S, Zhoa F, Mehta SR. et al, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
14. Glassman AH, Roose SP, Bigger JT, Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993;269:2673-5.
15. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4-11.
16. Rugulies R. Depression as a predictor for coronary heart disease: a review and metaanalysis. Am J Prev Med 2002;23(1):1-11.
17. Glassman AH, O’Connor C, Califf R, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9.
18. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(suppl 9):9-17.
19. Bristol-Myers Squibb Co. Aripiprazole (Abilify): prescribing information. www.abilify.com.
20. Chandragiri SS, Pasol E, Gallagher RM. Lithium, ACE inhibitors, NSAIDs, and verapamil: a possible fatal combination. Psychosomatics 1998;39(3):281-2.
UPDATE ON ATYPICALS: Practical tips to manage common side effects
Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.
We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.
Weight gain
Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.
Table 1
POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS
| Metabolic changes | Weight gain | Increased prolactin | QT interval | EPS | Sedation | Orthostasis | |
|---|---|---|---|---|---|---|---|
| Risperidone | + | + | +++ | + | ++ | + | ++ |
| Ziprasidone | + | + | − | ++ | + | + | + |
| Clozapine | +++ | +++ | − | ++ | +/− | +++ | +++ |
| Olanzapine | +++ | +++ | − | + | + | ++ | + |
| Quetiapine | ++ | ++ | − | ++ | + | ++ | ++ |
| Aripiprazole | + | + | − | + | + | +/− | +/− |
Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6
Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:
- A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
- Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8
These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9
Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12
Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14
Diabetes
The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19
Atypical antipsychotics probably increase diabetes risk in a number of ways:
- An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
- Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
- Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
- The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.
Hyperlipidemia
Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23
Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we:
- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
|
Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48
Priapism has been reported with all atypicals except ziprasidone.49 The vascular tone of the penis is in part sympathetically mediated, and alpha-1 blockade can inhibit detumescence via its indirect tendency to increase nitric oxide levels.50 Although priapism does not appear to be common, it is a urologic emergency with potential long-term consequences, including permanent erectile dysfunction. Patients developing abnormally prolonged and painful erections must be counseled to seek immediate medical attention.
Aripiprazole: Preliminary impressions
The recently approved antipsychotic aripiprazole differs from the now-familiar dopaminergic theme by being a partial agonist at the D2 receptor. Aripiprazole has the greatest affinity for the D2 receptor of any available drug, activates the postsynaptic complex at about 30% of the full endogenous DA affect, and appears to lack the metabolic consequences of the other atypicals.
In our research laboratory, aripiprazole has shown a profound prolactin lowering effect, superior subjective tolerability, and a more salutary impact on sexual function, compared with other antipsychotics. Although not devoid of EPS, aripiprazole appears to alter a patient’s subjective distress in a way that alters the risk/benefit ratio. Although aripiprazole’s clinical niche has yet to be established, it would be reasonable to use it for overweight patients intolerant of the dysphorogenic effects of other antipsychotics.
Related resources
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities J Clin Psychiatry 1999;60(6)358-63.
- Wirshing DA, Spellberg B, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44(8):778-83.
- Wirshing DA, Pierre JM, Marder SR, Saunders CS, Wirshing WC. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56(1-2):25-30.
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Donna Wirshing receives grant/research support from Pfizer Inc., Eli Lilly and Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co., Janssen Pharmaceutica, and Pfizer Inc., and is a speaker for Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Itai Danovitch reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Pierre receives grant/research support from Cephalon Inc.; is a consultant to Eli Lilly and Co., Bristol-Myers Squibb Co., AstraZeneca, and Pfizer Inc.; and is a speaker for Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. William Wirshing receives grant/research support from Janssen Pharmaceutica, Eli Lilly and Co., Otsuka America Pharmaceutical, Abbot Laboratories, Pfizer Inc., Sanofi-Synthelabo, Organon, Bristol-Myers Squibb Co., and Knoll Pharmaceuticals, and is a consultant to Janssen Pharmaceutica, Hoechst Marion Roussel, and Eli Lilly and Co.
1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
2. Henderson D, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain and lipid abnormalities: a five year naturalistic study. Am J Psychiatry 2000;157(6):975-81.
3. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001;62:92-100.
4. Ganguli R. Weight gain associated with antipsychotic drugs J Clin Psychiatry 1999;60:20-4.
5. McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-281.
6. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatry Scand 2000;101:416-32.
7. Haapasalo-Pesu KM, Saarijarvi S. Olanzapine induces remarkable weight gain in adolescent patients. Eur Child Adolesc Psychiatry 2001;10:205-8.
8. Martin A, Landau J, Leebens P, et al. Risperidone-associated weight gain in children and adolescents: a retrospective chart review. J Child Adolesc Psychopharmacol 2000;10:259-68.
9. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44:778-83.
10. Bray G. Drug treatment of obesity. Rev Endocr Metab Disord 2001;2(4):403-18.
11. Kaur G, Kulkarni SK. Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277-85.
12. Wirshing D, Wirshing W, Kysar L, et al. Novel antipsychotics: Comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
13. Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771-6.
14. Baptista T, Lacruz A, De Mendoza D, et al. Body weight gain after administration of antipsychotic drugs. Pharmacopsychiatry 2002;35:36.-
15. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
16. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
17. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77-89.
18. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatry Scand 2002;105:235-7.
19. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278-82.
20. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994-94:1714-21.
21. Wozniak K, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci 1991;49:101-9.
22. Ardizzone TD, Bradley RJ, Freeman AM, 3rd, et al. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90.
23. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994;7:7S-12S.
24. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-74.
25. Niaura R, Banks SM, Ward KD, et al. Hostility and the metabolic syndrome in older males: the normative aging study. Psychosom Med 2000;62:7-16.
26. Diebold K, Michel G, Schweizer J, et al. Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders? Pharmacopsychiatry 1998;31:60-7.
27. Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001;21:1444-7.
28. Garson A, Jr. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B-16B.
29. Tan HL, Hou CJ, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-14.
30. Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-6.
31. Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations Diabetes Care 2000;23:S4.-
32. Joerg C K-WS, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;2:35-40.
33. Association of Clozaril with cardiovascular toxicity. [Dear healthcare professional letter]. Novartis Pharmaceuticals Canada Inc, 2002.
34. Killian JG, Kerr K, Lawrence C. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.
35. Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
36. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.
37. Breier AF, Malhotra AK, Su T, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156:294-8.
38. Caracci G. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacology 1999;19:194-6.
39. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
40. Segal S, Yaffe H, Laufer N, et al. Male hyperprolactinemia: effects on fertility. Fertil Steril 1979;32:556-61.
41. Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab 1992;75:698-703.
42. Gazzola LR, Opler LA. Return of menstruation after switching from risperidone to olanzapine. J Clin Psychopharmacol 1998;18:486-7.
43. Boyd A. Bromocriptine and psychosis: a literature review. Psychiatr Q 1995;66:87-95.
44. Aizenberg D, Modai I, Landa A, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001;62:541-4.
45. Meston CM. Sympathetic nervous system activity and female sexual arousal. Am J Cardiol 2000;86:30F-34F.
46. Wirshing DA, Pierre JM, Marder SR, et al. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56:25-30.
47. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995;56:137-41.
48. Hummer M, Kemmler G, Kurz M, et al. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999;156:631-3.
49. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology 2001;58:462.-
50. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362-6.
Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.
We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.
Weight gain
Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.
Table 1
POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS
| Metabolic changes | Weight gain | Increased prolactin | QT interval | EPS | Sedation | Orthostasis | |
|---|---|---|---|---|---|---|---|
| Risperidone | + | + | +++ | + | ++ | + | ++ |
| Ziprasidone | + | + | − | ++ | + | + | + |
| Clozapine | +++ | +++ | − | ++ | +/− | +++ | +++ |
| Olanzapine | +++ | +++ | − | + | + | ++ | + |
| Quetiapine | ++ | ++ | − | ++ | + | ++ | ++ |
| Aripiprazole | + | + | − | + | + | +/− | +/− |
Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6
Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:
- A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
- Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8
These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9
Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12
Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14
Diabetes
The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19
Atypical antipsychotics probably increase diabetes risk in a number of ways:
- An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
- Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
- Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
- The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.
Hyperlipidemia
Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23
Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we:
- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
|
Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48
Priapism has been reported with all atypicals except ziprasidone.49 The vascular tone of the penis is in part sympathetically mediated, and alpha-1 blockade can inhibit detumescence via its indirect tendency to increase nitric oxide levels.50 Although priapism does not appear to be common, it is a urologic emergency with potential long-term consequences, including permanent erectile dysfunction. Patients developing abnormally prolonged and painful erections must be counseled to seek immediate medical attention.
Aripiprazole: Preliminary impressions
The recently approved antipsychotic aripiprazole differs from the now-familiar dopaminergic theme by being a partial agonist at the D2 receptor. Aripiprazole has the greatest affinity for the D2 receptor of any available drug, activates the postsynaptic complex at about 30% of the full endogenous DA affect, and appears to lack the metabolic consequences of the other atypicals.
In our research laboratory, aripiprazole has shown a profound prolactin lowering effect, superior subjective tolerability, and a more salutary impact on sexual function, compared with other antipsychotics. Although not devoid of EPS, aripiprazole appears to alter a patient’s subjective distress in a way that alters the risk/benefit ratio. Although aripiprazole’s clinical niche has yet to be established, it would be reasonable to use it for overweight patients intolerant of the dysphorogenic effects of other antipsychotics.
Related resources
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities J Clin Psychiatry 1999;60(6)358-63.
- Wirshing DA, Spellberg B, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44(8):778-83.
- Wirshing DA, Pierre JM, Marder SR, Saunders CS, Wirshing WC. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56(1-2):25-30.
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Donna Wirshing receives grant/research support from Pfizer Inc., Eli Lilly and Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co., Janssen Pharmaceutica, and Pfizer Inc., and is a speaker for Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Itai Danovitch reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Pierre receives grant/research support from Cephalon Inc.; is a consultant to Eli Lilly and Co., Bristol-Myers Squibb Co., AstraZeneca, and Pfizer Inc.; and is a speaker for Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. William Wirshing receives grant/research support from Janssen Pharmaceutica, Eli Lilly and Co., Otsuka America Pharmaceutical, Abbot Laboratories, Pfizer Inc., Sanofi-Synthelabo, Organon, Bristol-Myers Squibb Co., and Knoll Pharmaceuticals, and is a consultant to Janssen Pharmaceutica, Hoechst Marion Roussel, and Eli Lilly and Co.
Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.
We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.
Weight gain
Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.
Table 1
POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS
| Metabolic changes | Weight gain | Increased prolactin | QT interval | EPS | Sedation | Orthostasis | |
|---|---|---|---|---|---|---|---|
| Risperidone | + | + | +++ | + | ++ | + | ++ |
| Ziprasidone | + | + | − | ++ | + | + | + |
| Clozapine | +++ | +++ | − | ++ | +/− | +++ | +++ |
| Olanzapine | +++ | +++ | − | + | + | ++ | + |
| Quetiapine | ++ | ++ | − | ++ | + | ++ | ++ |
| Aripiprazole | + | + | − | + | + | +/− | +/− |
Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6
Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:
- A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
- Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8
These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9
Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12
Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14
Diabetes
The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19
Atypical antipsychotics probably increase diabetes risk in a number of ways:
- An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
- Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
- Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
- The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.
Hyperlipidemia
Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23
Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we:
- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
|
Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48
Priapism has been reported with all atypicals except ziprasidone.49 The vascular tone of the penis is in part sympathetically mediated, and alpha-1 blockade can inhibit detumescence via its indirect tendency to increase nitric oxide levels.50 Although priapism does not appear to be common, it is a urologic emergency with potential long-term consequences, including permanent erectile dysfunction. Patients developing abnormally prolonged and painful erections must be counseled to seek immediate medical attention.
Aripiprazole: Preliminary impressions
The recently approved antipsychotic aripiprazole differs from the now-familiar dopaminergic theme by being a partial agonist at the D2 receptor. Aripiprazole has the greatest affinity for the D2 receptor of any available drug, activates the postsynaptic complex at about 30% of the full endogenous DA affect, and appears to lack the metabolic consequences of the other atypicals.
In our research laboratory, aripiprazole has shown a profound prolactin lowering effect, superior subjective tolerability, and a more salutary impact on sexual function, compared with other antipsychotics. Although not devoid of EPS, aripiprazole appears to alter a patient’s subjective distress in a way that alters the risk/benefit ratio. Although aripiprazole’s clinical niche has yet to be established, it would be reasonable to use it for overweight patients intolerant of the dysphorogenic effects of other antipsychotics.
Related resources
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities J Clin Psychiatry 1999;60(6)358-63.
- Wirshing DA, Spellberg B, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44(8):778-83.
- Wirshing DA, Pierre JM, Marder SR, Saunders CS, Wirshing WC. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56(1-2):25-30.
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Donna Wirshing receives grant/research support from Pfizer Inc., Eli Lilly and Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co., Janssen Pharmaceutica, and Pfizer Inc., and is a speaker for Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Itai Danovitch reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Pierre receives grant/research support from Cephalon Inc.; is a consultant to Eli Lilly and Co., Bristol-Myers Squibb Co., AstraZeneca, and Pfizer Inc.; and is a speaker for Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. William Wirshing receives grant/research support from Janssen Pharmaceutica, Eli Lilly and Co., Otsuka America Pharmaceutical, Abbot Laboratories, Pfizer Inc., Sanofi-Synthelabo, Organon, Bristol-Myers Squibb Co., and Knoll Pharmaceuticals, and is a consultant to Janssen Pharmaceutica, Hoechst Marion Roussel, and Eli Lilly and Co.
1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
2. Henderson D, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain and lipid abnormalities: a five year naturalistic study. Am J Psychiatry 2000;157(6):975-81.
3. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001;62:92-100.
4. Ganguli R. Weight gain associated with antipsychotic drugs J Clin Psychiatry 1999;60:20-4.
5. McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-281.
6. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatry Scand 2000;101:416-32.
7. Haapasalo-Pesu KM, Saarijarvi S. Olanzapine induces remarkable weight gain in adolescent patients. Eur Child Adolesc Psychiatry 2001;10:205-8.
8. Martin A, Landau J, Leebens P, et al. Risperidone-associated weight gain in children and adolescents: a retrospective chart review. J Child Adolesc Psychopharmacol 2000;10:259-68.
9. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44:778-83.
10. Bray G. Drug treatment of obesity. Rev Endocr Metab Disord 2001;2(4):403-18.
11. Kaur G, Kulkarni SK. Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277-85.
12. Wirshing D, Wirshing W, Kysar L, et al. Novel antipsychotics: Comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
13. Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771-6.
14. Baptista T, Lacruz A, De Mendoza D, et al. Body weight gain after administration of antipsychotic drugs. Pharmacopsychiatry 2002;35:36.-
15. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
16. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
17. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77-89.
18. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatry Scand 2002;105:235-7.
19. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278-82.
20. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994-94:1714-21.
21. Wozniak K, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci 1991;49:101-9.
22. Ardizzone TD, Bradley RJ, Freeman AM, 3rd, et al. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90.
23. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994;7:7S-12S.
24. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-74.
25. Niaura R, Banks SM, Ward KD, et al. Hostility and the metabolic syndrome in older males: the normative aging study. Psychosom Med 2000;62:7-16.
26. Diebold K, Michel G, Schweizer J, et al. Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders? Pharmacopsychiatry 1998;31:60-7.
27. Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001;21:1444-7.
28. Garson A, Jr. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B-16B.
29. Tan HL, Hou CJ, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-14.
30. Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-6.
31. Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations Diabetes Care 2000;23:S4.-
32. Joerg C K-WS, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;2:35-40.
33. Association of Clozaril with cardiovascular toxicity. [Dear healthcare professional letter]. Novartis Pharmaceuticals Canada Inc, 2002.
34. Killian JG, Kerr K, Lawrence C. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.
35. Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
36. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.
37. Breier AF, Malhotra AK, Su T, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156:294-8.
38. Caracci G. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacology 1999;19:194-6.
39. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
40. Segal S, Yaffe H, Laufer N, et al. Male hyperprolactinemia: effects on fertility. Fertil Steril 1979;32:556-61.
41. Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab 1992;75:698-703.
42. Gazzola LR, Opler LA. Return of menstruation after switching from risperidone to olanzapine. J Clin Psychopharmacol 1998;18:486-7.
43. Boyd A. Bromocriptine and psychosis: a literature review. Psychiatr Q 1995;66:87-95.
44. Aizenberg D, Modai I, Landa A, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001;62:541-4.
45. Meston CM. Sympathetic nervous system activity and female sexual arousal. Am J Cardiol 2000;86:30F-34F.
46. Wirshing DA, Pierre JM, Marder SR, et al. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56:25-30.
47. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995;56:137-41.
48. Hummer M, Kemmler G, Kurz M, et al. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999;156:631-3.
49. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology 2001;58:462.-
50. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362-6.
1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
2. Henderson D, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain and lipid abnormalities: a five year naturalistic study. Am J Psychiatry 2000;157(6):975-81.
3. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001;62:92-100.
4. Ganguli R. Weight gain associated with antipsychotic drugs J Clin Psychiatry 1999;60:20-4.
5. McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-281.
6. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatry Scand 2000;101:416-32.
7. Haapasalo-Pesu KM, Saarijarvi S. Olanzapine induces remarkable weight gain in adolescent patients. Eur Child Adolesc Psychiatry 2001;10:205-8.
8. Martin A, Landau J, Leebens P, et al. Risperidone-associated weight gain in children and adolescents: a retrospective chart review. J Child Adolesc Psychopharmacol 2000;10:259-68.
9. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44:778-83.
10. Bray G. Drug treatment of obesity. Rev Endocr Metab Disord 2001;2(4):403-18.
11. Kaur G, Kulkarni SK. Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277-85.
12. Wirshing D, Wirshing W, Kysar L, et al. Novel antipsychotics: Comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
13. Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771-6.
14. Baptista T, Lacruz A, De Mendoza D, et al. Body weight gain after administration of antipsychotic drugs. Pharmacopsychiatry 2002;35:36.-
15. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
16. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
17. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77-89.
18. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatry Scand 2002;105:235-7.
19. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278-82.
20. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994-94:1714-21.
21. Wozniak K, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci 1991;49:101-9.
22. Ardizzone TD, Bradley RJ, Freeman AM, 3rd, et al. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90.
23. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994;7:7S-12S.
24. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-74.
25. Niaura R, Banks SM, Ward KD, et al. Hostility and the metabolic syndrome in older males: the normative aging study. Psychosom Med 2000;62:7-16.
26. Diebold K, Michel G, Schweizer J, et al. Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders? Pharmacopsychiatry 1998;31:60-7.
27. Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001;21:1444-7.
28. Garson A, Jr. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B-16B.
29. Tan HL, Hou CJ, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-14.
30. Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-6.
31. Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations Diabetes Care 2000;23:S4.-
32. Joerg C K-WS, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;2:35-40.
33. Association of Clozaril with cardiovascular toxicity. [Dear healthcare professional letter]. Novartis Pharmaceuticals Canada Inc, 2002.
34. Killian JG, Kerr K, Lawrence C. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.
35. Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
36. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.
37. Breier AF, Malhotra AK, Su T, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156:294-8.
38. Caracci G. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacology 1999;19:194-6.
39. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
40. Segal S, Yaffe H, Laufer N, et al. Male hyperprolactinemia: effects on fertility. Fertil Steril 1979;32:556-61.
41. Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab 1992;75:698-703.
42. Gazzola LR, Opler LA. Return of menstruation after switching from risperidone to olanzapine. J Clin Psychopharmacol 1998;18:486-7.
43. Boyd A. Bromocriptine and psychosis: a literature review. Psychiatr Q 1995;66:87-95.
44. Aizenberg D, Modai I, Landa A, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001;62:541-4.
45. Meston CM. Sympathetic nervous system activity and female sexual arousal. Am J Cardiol 2000;86:30F-34F.
46. Wirshing DA, Pierre JM, Marder SR, et al. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56:25-30.
47. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995;56:137-41.
48. Hummer M, Kemmler G, Kurz M, et al. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999;156:631-3.
49. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology 2001;58:462.-
50. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362-6.
UPDATE ON ATYPICALS: Practical tips to manage common side effects
Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.
We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.
Weight gain
Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.
Table 1
POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS
| Metabolic changes | Weight gain | Increased prolactin | QT interval | EPS | Sedation | Orthostasis | |
|---|---|---|---|---|---|---|---|
| Risperidone | + | + | +++ | + | ++ | + | ++ |
| Ziprasidone | + | + | − | ++ | + | + | + |
| Clozapine | +++ | +++ | − | ++ | +/− | +++ | +++ |
| Olanzapine | +++ | +++ | − | + | + | ++ | + |
| Quetiapine | ++ | ++ | − | ++ | + | ++ | ++ |
| Aripiprazole | + | + | − | + | + | +/− | +/− |
Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6
Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:
- A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
- Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8
These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9
Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12
Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14
Diabetes
The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19
Atypical antipsychotics probably increase diabetes risk in a number of ways:
- An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
- Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
- Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
- The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.
Hyperlipidemia
Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23
Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we:
- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
|
Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48
Priapism has been reported with all atypicals except ziprasidone.49 The vascular tone of the penis is in part sympathetically mediated, and alpha-1 blockade can inhibit detumescence via its indirect tendency to increase nitric oxide levels.50 Although priapism does not appear to be common, it is a urologic emergency with potential long-term consequences, including permanent erectile dysfunction. Patients developing abnormally prolonged and painful erections must be counseled to seek immediate medical attention.
Aripiprazole: Preliminary impressions
The recently approved antipsychotic aripiprazole differs from the now-familiar dopaminergic theme by being a partial agonist at the D2 receptor. Aripiprazole has the greatest affinity for the D2 receptor of any available drug, activates the postsynaptic complex at about 30% of the full endogenous DA affect, and appears to lack the metabolic consequences of the other atypicals.
In our research laboratory, aripiprazole has shown a profound prolactin lowering effect, superior subjective tolerability, and a more salutary impact on sexual function, compared with other antipsychotics. Although not devoid of EPS, aripiprazole appears to alter a patient’s subjective distress in a way that alters the risk/benefit ratio. Although aripiprazole’s clinical niche has yet to be established, it would be reasonable to use it for overweight patients intolerant of the dysphorogenic effects of other antipsychotics.
Related resources
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities J Clin Psychiatry 1999;60(6)358-63.
- Wirshing DA, Spellberg B, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44(8):778-83.
- Wirshing DA, Pierre JM, Marder SR, Saunders CS, Wirshing WC. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56(1-2):25-30.
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Donna Wirshing receives grant/research support from Pfizer Inc., Eli Lilly and Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co., Janssen Pharmaceutica, and Pfizer Inc., and is a speaker for Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Itai Danovitch reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Pierre receives grant/research support from Cephalon Inc.; is a consultant to Eli Lilly and Co., Bristol-Myers Squibb Co., AstraZeneca, and Pfizer Inc.; and is a speaker for Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. William Wirshing receives grant/research support from Janssen Pharmaceutica, Eli Lilly and Co., Otsuka America Pharmaceutical, Abbot Laboratories, Pfizer Inc., Sanofi-Synthelabo, Organon, Bristol-Myers Squibb Co., and Knoll Pharmaceuticals, and is a consultant to Janssen Pharmaceutica, Hoechst Marion Roussel, and Eli Lilly and Co.
1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
2. Henderson D, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain and lipid abnormalities: a five year naturalistic study. Am J Psychiatry 2000;157(6):975-81.
3. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001;62:92-100.
4. Ganguli R. Weight gain associated with antipsychotic drugs J Clin Psychiatry 1999;60:20-4.
5. McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-281.
6. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatry Scand 2000;101:416-32.
7. Haapasalo-Pesu KM, Saarijarvi S. Olanzapine induces remarkable weight gain in adolescent patients. Eur Child Adolesc Psychiatry 2001;10:205-8.
8. Martin A, Landau J, Leebens P, et al. Risperidone-associated weight gain in children and adolescents: a retrospective chart review. J Child Adolesc Psychopharmacol 2000;10:259-68.
9. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44:778-83.
10. Bray G. Drug treatment of obesity. Rev Endocr Metab Disord 2001;2(4):403-18.
11. Kaur G, Kulkarni SK. Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277-85.
12. Wirshing D, Wirshing W, Kysar L, et al. Novel antipsychotics: Comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
13. Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771-6.
14. Baptista T, Lacruz A, De Mendoza D, et al. Body weight gain after administration of antipsychotic drugs. Pharmacopsychiatry 2002;35:36.-
15. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
16. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
17. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77-89.
18. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatry Scand 2002;105:235-7.
19. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278-82.
20. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994-94:1714-21.
21. Wozniak K, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci 1991;49:101-9.
22. Ardizzone TD, Bradley RJ, Freeman AM, 3rd, et al. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90.
23. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994;7:7S-12S.
24. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-74.
25. Niaura R, Banks SM, Ward KD, et al. Hostility and the metabolic syndrome in older males: the normative aging study. Psychosom Med 2000;62:7-16.
26. Diebold K, Michel G, Schweizer J, et al. Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders? Pharmacopsychiatry 1998;31:60-7.
27. Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001;21:1444-7.
28. Garson A, Jr. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B-16B.
29. Tan HL, Hou CJ, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-14.
30. Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-6.
31. Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations Diabetes Care 2000;23:S4.-
32. Joerg C K-WS, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;2:35-40.
33. Association of Clozaril with cardiovascular toxicity. [Dear healthcare professional letter]. Novartis Pharmaceuticals Canada Inc, 2002.
34. Killian JG, Kerr K, Lawrence C. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.
35. Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
36. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.
37. Breier AF, Malhotra AK, Su T, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156:294-8.
38. Caracci G. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacology 1999;19:194-6.
39. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
40. Segal S, Yaffe H, Laufer N, et al. Male hyperprolactinemia: effects on fertility. Fertil Steril 1979;32:556-61.
41. Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab 1992;75:698-703.
42. Gazzola LR, Opler LA. Return of menstruation after switching from risperidone to olanzapine. J Clin Psychopharmacol 1998;18:486-7.
43. Boyd A. Bromocriptine and psychosis: a literature review. Psychiatr Q 1995;66:87-95.
44. Aizenberg D, Modai I, Landa A, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001;62:541-4.
45. Meston CM. Sympathetic nervous system activity and female sexual arousal. Am J Cardiol 2000;86:30F-34F.
46. Wirshing DA, Pierre JM, Marder SR, et al. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56:25-30.
47. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995;56:137-41.
48. Hummer M, Kemmler G, Kurz M, et al. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999;156:631-3.
49. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology 2001;58:462.-
50. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362-6.
Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.
We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.
Weight gain
Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.
Table 1
POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS
| Metabolic changes | Weight gain | Increased prolactin | QT interval | EPS | Sedation | Orthostasis | |
|---|---|---|---|---|---|---|---|
| Risperidone | + | + | +++ | + | ++ | + | ++ |
| Ziprasidone | + | + | − | ++ | + | + | + |
| Clozapine | +++ | +++ | − | ++ | +/− | +++ | +++ |
| Olanzapine | +++ | +++ | − | + | + | ++ | + |
| Quetiapine | ++ | ++ | − | ++ | + | ++ | ++ |
| Aripiprazole | + | + | − | + | + | +/− | +/− |
Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6
Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:
- A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
- Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8
These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9
Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12
Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14
Diabetes
The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19
Atypical antipsychotics probably increase diabetes risk in a number of ways:
- An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
- Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
- Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
- The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.
Hyperlipidemia
Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23
Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we:
- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
|
Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48
Priapism has been reported with all atypicals except ziprasidone.49 The vascular tone of the penis is in part sympathetically mediated, and alpha-1 blockade can inhibit detumescence via its indirect tendency to increase nitric oxide levels.50 Although priapism does not appear to be common, it is a urologic emergency with potential long-term consequences, including permanent erectile dysfunction. Patients developing abnormally prolonged and painful erections must be counseled to seek immediate medical attention.
Aripiprazole: Preliminary impressions
The recently approved antipsychotic aripiprazole differs from the now-familiar dopaminergic theme by being a partial agonist at the D2 receptor. Aripiprazole has the greatest affinity for the D2 receptor of any available drug, activates the postsynaptic complex at about 30% of the full endogenous DA affect, and appears to lack the metabolic consequences of the other atypicals.
In our research laboratory, aripiprazole has shown a profound prolactin lowering effect, superior subjective tolerability, and a more salutary impact on sexual function, compared with other antipsychotics. Although not devoid of EPS, aripiprazole appears to alter a patient’s subjective distress in a way that alters the risk/benefit ratio. Although aripiprazole’s clinical niche has yet to be established, it would be reasonable to use it for overweight patients intolerant of the dysphorogenic effects of other antipsychotics.
Related resources
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities J Clin Psychiatry 1999;60(6)358-63.
- Wirshing DA, Spellberg B, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44(8):778-83.
- Wirshing DA, Pierre JM, Marder SR, Saunders CS, Wirshing WC. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56(1-2):25-30.
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Donna Wirshing receives grant/research support from Pfizer Inc., Eli Lilly and Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co., Janssen Pharmaceutica, and Pfizer Inc., and is a speaker for Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Itai Danovitch reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Pierre receives grant/research support from Cephalon Inc.; is a consultant to Eli Lilly and Co., Bristol-Myers Squibb Co., AstraZeneca, and Pfizer Inc.; and is a speaker for Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. William Wirshing receives grant/research support from Janssen Pharmaceutica, Eli Lilly and Co., Otsuka America Pharmaceutical, Abbot Laboratories, Pfizer Inc., Sanofi-Synthelabo, Organon, Bristol-Myers Squibb Co., and Knoll Pharmaceuticals, and is a consultant to Janssen Pharmaceutica, Hoechst Marion Roussel, and Eli Lilly and Co.
Atypical antipsychotics are powerful medications for acute and chronic psychotic disorders, with a similarly powerful potential for adverse systemic effects. To use these agents to their greatest advantage, we must balance the benefits against the risks.
We often see patients with weight gain, diabetes, dyslipidemia, cardiac toxicity, hyperprolactinemia, and sexual dysfunction—all possible effects of atypical antipsychotics. Based on the latest evidence and our experience, we offer tips for using clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and preliminary impressions about the newly approved agent, aripiprazole.
Weight gain
Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most older antipsychotics.1 Overweight and obesity are associated with increased risks of hypertension, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and some forms of cancer. Moreover, obesity’s socially stigmatizing effect can discourage patients with schizophrenia—particularly adolescents—from taking their medication.
Table 1
POTENTIAL FOR ADVERSE EFFECTS WITH ATYPICAL ANTIPSYCHOTICS
| Metabolic changes | Weight gain | Increased prolactin | QT interval | EPS | Sedation | Orthostasis | |
|---|---|---|---|---|---|---|---|
| Risperidone | + | + | +++ | + | ++ | + | ++ |
| Ziprasidone | + | + | − | ++ | + | + | + |
| Clozapine | +++ | +++ | − | ++ | +/− | +++ | +++ |
| Olanzapine | +++ | +++ | − | + | + | ++ | + |
| Quetiapine | ++ | ++ | − | ++ | + | ++ | ++ |
| Aripiprazole | + | + | − | + | + | +/− | +/− |
Comparative effects. Olanzapine and clozapine are associated with greater weight gain (Table 1)1-3 than risperidone and ziprasidone.4 Data regarding quetiapine are inconsistent—some studies show weight gain similar to that caused by olanzapine, and others find much less.5 Weight gain associated with quetiapine, ziprasidone, and risperidone tends to plateau within the first few months, whereas patients taking olanzapine and clozapine may continue to gain weight for 9 months or more.6
Adolescents and young adults may be particularly susceptible to antipsychotic-induced weight gain.7 No studies have directly compared weight gain in adults versus adolescents, but adolescents are exceedingly susceptible to the atypicals’ metabolic dysregulation. For example:
- A higher prevalence of extreme weight gain (>7% of baseline body mass) with olanzapine and risperidone has been reported in adolescent inpatients than among adults.7
- Extreme weight gain was seen in 78% of a group of risperidone-treated children; for 6 months, their weight gain averaged 1.2 kg/month without leveling off.8
These findings suggest that risperidone’s apparent metabolic advantage in adults disappears in children and adolescents. Risperidone’s effect on prolactin may account for a higher risk of weight gain in younger patients. These populations have exquisite end-organ sensitivity to changes in prolactin levels and may be more susceptible to the weight gain—and perhaps diabetes—believed related to hyperprolactinemia.9
Mechanisms. The mechanism(s) of weight gain may be related to the receptor systems upon which the atypicals act. These agents block noradrenergic, dopamine, serotonin, and histamine receptors, all of which are thought to affect metabolism or appetite control. Stimulation of alpha and D2 receptors by sympathomimetic amines causes weight loss, as does stimulation of certain 5HT receptors by weight-loss drugs such as fenfluramine.10 With respect to appetite, it has been suggested that peripheral antagonism of H1 receptors interferes with normal satiety signals.11 This may explain why affinity to histamine H1 receptors is among the best of correlates with potential for weight gain.12
Increases in serum levels of leptin—a peptide hormone produced in direct proportion to adiposity and thought to be anorexigenic, possibly through effects on satiety13 —parallel weight gain during treatment with atypicals. However, there is no indication that leptin imbalance causes weight gain; it may instead be the result. Altered sensitivity to leptin may be a contributing factor, perhaps at the hypothalamus.14
Diabetes
The risk of type 2 diabetes increases with weight gain,15 so it is no surprise that diabetes is more prevalent among patients taking atypicals. In a study of 38,000 schizophrenic patients, those taking atypicals were 9% more likely to have diabetes than those receiving typical antipsychotics,16 and all atypicals were associated with a significant increase in diabetes risk in patients younger than 40. The pervasiveness of diabetes17 and reports of new-onset diabetes in non-overweight patients18 suggest that—in addition to their effect on weight—atypicals may alter insulin and glucose metabolism.19
Atypical antipsychotics probably increase diabetes risk in a number of ways:
- An increase in adipose tissue can lead to insulin resistance, glucose intolerance, and ultimately diabetes.20
- Serotonin receptor antagonism may lead to hyperglycemia by decreasing pancreatic beta cell response to signals that advance insulin production.21
- Atypicals may contribute to hyperglycemia by impeding cellular uptake of glucose.22
- The increase in free fatty acids associated with atypicals can alter glucose metabolism. This may explain why clozapine and olanzapine—the atypicals with the greatest potential for severe hyperlipidemia—have the strongest association with new-onset diabetes.
Hyperlipidemia
Case reports and controlled studies have linked atypical antipsychotics with hyperlipidemia. Whether the hyperlipidemia is a consequence of weight gain or some other metabolic disturbance is unknown. Even without conclusive data, however, the link is of concern because elevated triglyceride levels represent an independent risk factor for heart disease.23
Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we:
- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
|
Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48
Priapism has been reported with all atypicals except ziprasidone.49 The vascular tone of the penis is in part sympathetically mediated, and alpha-1 blockade can inhibit detumescence via its indirect tendency to increase nitric oxide levels.50 Although priapism does not appear to be common, it is a urologic emergency with potential long-term consequences, including permanent erectile dysfunction. Patients developing abnormally prolonged and painful erections must be counseled to seek immediate medical attention.
Aripiprazole: Preliminary impressions
The recently approved antipsychotic aripiprazole differs from the now-familiar dopaminergic theme by being a partial agonist at the D2 receptor. Aripiprazole has the greatest affinity for the D2 receptor of any available drug, activates the postsynaptic complex at about 30% of the full endogenous DA affect, and appears to lack the metabolic consequences of the other atypicals.
In our research laboratory, aripiprazole has shown a profound prolactin lowering effect, superior subjective tolerability, and a more salutary impact on sexual function, compared with other antipsychotics. Although not devoid of EPS, aripiprazole appears to alter a patient’s subjective distress in a way that alters the risk/benefit ratio. Although aripiprazole’s clinical niche has yet to be established, it would be reasonable to use it for overweight patients intolerant of the dysphorogenic effects of other antipsychotics.
Related resources
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities J Clin Psychiatry 1999;60(6)358-63.
- Wirshing DA, Spellberg B, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44(8):778-83.
- Wirshing DA, Pierre JM, Marder SR, Saunders CS, Wirshing WC. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56(1-2):25-30.
Drug brand names
- Aripiprazole • Abilify
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Donna Wirshing receives grant/research support from Pfizer Inc., Eli Lilly and Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co., Janssen Pharmaceutica, and Pfizer Inc., and is a speaker for Eli Lilly and Co., Pfizer Inc., and Janssen Pharmaceutica.
Itai Danovitch reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Pierre receives grant/research support from Cephalon Inc.; is a consultant to Eli Lilly and Co., Bristol-Myers Squibb Co., AstraZeneca, and Pfizer Inc.; and is a speaker for Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.
Dr. William Wirshing receives grant/research support from Janssen Pharmaceutica, Eli Lilly and Co., Otsuka America Pharmaceutical, Abbot Laboratories, Pfizer Inc., Sanofi-Synthelabo, Organon, Bristol-Myers Squibb Co., and Knoll Pharmaceuticals, and is a consultant to Janssen Pharmaceutica, Hoechst Marion Roussel, and Eli Lilly and Co.
1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
2. Henderson D, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain and lipid abnormalities: a five year naturalistic study. Am J Psychiatry 2000;157(6):975-81.
3. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001;62:92-100.
4. Ganguli R. Weight gain associated with antipsychotic drugs J Clin Psychiatry 1999;60:20-4.
5. McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-281.
6. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatry Scand 2000;101:416-32.
7. Haapasalo-Pesu KM, Saarijarvi S. Olanzapine induces remarkable weight gain in adolescent patients. Eur Child Adolesc Psychiatry 2001;10:205-8.
8. Martin A, Landau J, Leebens P, et al. Risperidone-associated weight gain in children and adolescents: a retrospective chart review. J Child Adolesc Psychopharmacol 2000;10:259-68.
9. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44:778-83.
10. Bray G. Drug treatment of obesity. Rev Endocr Metab Disord 2001;2(4):403-18.
11. Kaur G, Kulkarni SK. Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277-85.
12. Wirshing D, Wirshing W, Kysar L, et al. Novel antipsychotics: Comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
13. Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771-6.
14. Baptista T, Lacruz A, De Mendoza D, et al. Body weight gain after administration of antipsychotic drugs. Pharmacopsychiatry 2002;35:36.-
15. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
16. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
17. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77-89.
18. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatry Scand 2002;105:235-7.
19. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278-82.
20. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994-94:1714-21.
21. Wozniak K, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci 1991;49:101-9.
22. Ardizzone TD, Bradley RJ, Freeman AM, 3rd, et al. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90.
23. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994;7:7S-12S.
24. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-74.
25. Niaura R, Banks SM, Ward KD, et al. Hostility and the metabolic syndrome in older males: the normative aging study. Psychosom Med 2000;62:7-16.
26. Diebold K, Michel G, Schweizer J, et al. Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders? Pharmacopsychiatry 1998;31:60-7.
27. Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001;21:1444-7.
28. Garson A, Jr. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B-16B.
29. Tan HL, Hou CJ, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-14.
30. Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-6.
31. Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations Diabetes Care 2000;23:S4.-
32. Joerg C K-WS, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;2:35-40.
33. Association of Clozaril with cardiovascular toxicity. [Dear healthcare professional letter]. Novartis Pharmaceuticals Canada Inc, 2002.
34. Killian JG, Kerr K, Lawrence C. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.
35. Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
36. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.
37. Breier AF, Malhotra AK, Su T, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156:294-8.
38. Caracci G. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacology 1999;19:194-6.
39. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
40. Segal S, Yaffe H, Laufer N, et al. Male hyperprolactinemia: effects on fertility. Fertil Steril 1979;32:556-61.
41. Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab 1992;75:698-703.
42. Gazzola LR, Opler LA. Return of menstruation after switching from risperidone to olanzapine. J Clin Psychopharmacol 1998;18:486-7.
43. Boyd A. Bromocriptine and psychosis: a literature review. Psychiatr Q 1995;66:87-95.
44. Aizenberg D, Modai I, Landa A, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001;62:541-4.
45. Meston CM. Sympathetic nervous system activity and female sexual arousal. Am J Cardiol 2000;86:30F-34F.
46. Wirshing DA, Pierre JM, Marder SR, et al. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56:25-30.
47. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995;56:137-41.
48. Hummer M, Kemmler G, Kurz M, et al. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999;156:631-3.
49. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology 2001;58:462.-
50. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362-6.
1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
2. Henderson D, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain and lipid abnormalities: a five year naturalistic study. Am J Psychiatry 2000;157(6):975-81.
3. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001;62:92-100.
4. Ganguli R. Weight gain associated with antipsychotic drugs J Clin Psychiatry 1999;60:20-4.
5. McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-281.
6. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatry Scand 2000;101:416-32.
7. Haapasalo-Pesu KM, Saarijarvi S. Olanzapine induces remarkable weight gain in adolescent patients. Eur Child Adolesc Psychiatry 2001;10:205-8.
8. Martin A, Landau J, Leebens P, et al. Risperidone-associated weight gain in children and adolescents: a retrospective chart review. J Child Adolesc Psychopharmacol 2000;10:259-68.
9. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new-onset diabetes. Biol Psychiatry 1998;44:778-83.
10. Bray G. Drug treatment of obesity. Rev Endocr Metab Disord 2001;2(4):403-18.
11. Kaur G, Kulkarni SK. Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277-85.
12. Wirshing D, Wirshing W, Kysar L, et al. Novel antipsychotics: Comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
13. Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771-6.
14. Baptista T, Lacruz A, De Mendoza D, et al. Body weight gain after administration of antipsychotic drugs. Pharmacopsychiatry 2002;35:36.-
15. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
16. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-6.
17. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77-89.
18. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain. Acta Psychiatry Scand 2002;105:235-7.
19. Muench J, Carey M. Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278-82.
20. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994-94:1714-21.
21. Wozniak K, Linnoila M. Hyperglycemic properties of serotonin receptor antagonists. Life Sci 1991;49:101-9.
22. Ardizzone TD, Bradley RJ, Freeman AM, 3rd, et al. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90.
23. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994;7:7S-12S.
24. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-74.
25. Niaura R, Banks SM, Ward KD, et al. Hostility and the metabolic syndrome in older males: the normative aging study. Psychosom Med 2000;62:7-16.
26. Diebold K, Michel G, Schweizer J, et al. Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders? Pharmacopsychiatry 1998;31:60-7.
27. Bechara CI, Goldman-Levine JD. Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. Pharmacotherapy 2001;21:1444-7.
28. Garson A, Jr. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B-16B.
29. Tan HL, Hou CJ, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-14.
30. Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-6.
31. Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Practice Recommendations Diabetes Care 2000;23:S4.-
32. Joerg C K-WS, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;2:35-40.
33. Association of Clozaril with cardiovascular toxicity. [Dear healthcare professional letter]. Novartis Pharmaceuticals Canada Inc, 2002.
34. Killian JG, Kerr K, Lawrence C. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.
35. Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
36. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.
37. Breier AF, Malhotra AK, Su T, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156:294-8.
38. Caracci G. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacology 1999;19:194-6.
39. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
40. Segal S, Yaffe H, Laufer N, et al. Male hyperprolactinemia: effects on fertility. Fertil Steril 1979;32:556-61.
41. Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab 1992;75:698-703.
42. Gazzola LR, Opler LA. Return of menstruation after switching from risperidone to olanzapine. J Clin Psychopharmacol 1998;18:486-7.
43. Boyd A. Bromocriptine and psychosis: a literature review. Psychiatr Q 1995;66:87-95.
44. Aizenberg D, Modai I, Landa A, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001;62:541-4.
45. Meston CM. Sympathetic nervous system activity and female sexual arousal. Am J Cardiol 2000;86:30F-34F.
46. Wirshing DA, Pierre JM, Marder SR, et al. Sexual side effects of novel antipsychotic medications. Schizophr Res 2002;56:25-30.
47. Aizenberg D, Zemishlany Z, Dorfman-Etrog P, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995;56:137-41.
48. Hummer M, Kemmler G, Kurz M, et al. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999;156:631-3.
49. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology 2001;58:462.-
50. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362-6.
Text-entry solutions: which ‘type’ is right for you?
If you cannot type—or don’t like to—read on.
Text-entry advances offer alternatives to traditional keystroking. From voice recognition to online dictation, these options promise increased efficiency and relief from typing-related repetitive stress injuries.
The truth about typing
Few people know that the original typewriter keyboard layout—known as QWERTY, for the row of keys on the upper left-hand side—was designed to decrease typing speed so that the mechanical typewriter’s keys would not jam.1 More recently designed keyboard layouts, such as DVORAK and IDEAL, are reportedly more efficient but are not widely used. It would take months to retrain a typist to work with either keyboard.
Dictation is a well-established alternative to typing, but if the transcriber is not 100% accurate, much time is wasted correcting mistakes, returning the document, and proofreading the corrections.
Voice recognition
Voice recognition technology has been touted as the successor to dictation. With increasing computer power and more sophisticated algorithms to improve recognition, many programs2 can record continuous speech onto a document with approximately 95% accuracy.
Using voice recognition software and hardware to dictate text can save worlds of time compared with typing or writing by hand. But beware: accents and background noise often confound voice-based systems.
What’s more, a voice-recognition package that is suited to medical practice may be considerably more expensive than an entry-level model. Entry-level programs such as ScanSoft Dragon Naturally Speaking and IBM ViaVoice start at less than $100 each, but the medical version of ScanSoft is $1,000. The Trigram Psychiatry Specialty Module, at $300, may be an option. ViaVoice users can get a medical vocabulary module for an additional $142.
Other text-entry solutions
Internet-based dictation is a possible alternative to voice recognition or traditional dictation. Dictaphone’s Physician Workstation, which will reach the market in March, will allow the user to dictate with a specialized microphone linked to the computer or offsite by calling a toll-free telephone number. The computer then sends the voice data securely via the Internet to off-site transcriptionists. The physician logs into the transcript and makes corrections online via a Web browser. The user electronically signs the note to finalize it, and it is automatically delivered to the desired locations.
For a nominal investment in hardware, Physician Workstation can significantly simplify and speed up the transcription process. Dictaphone also provides 24-7 support and maintenance for these services, which cost $86 a month for 500 minutes. The setup has its drawbacks: Dictaphone provides the secure infrastructure and support, but transcription is a separate contracted service at 15.5 cents per line. However, you can select another transcription service to receive your voice files, or you can use Dictaphone’s new voice recognition software (also available in March).
Similarly, other online transcription services, such as HealthScribes and Kinetxhc, allow mobile users to dictate via a telephone, dedicated device, or personal digital assistant (PDA). HealthScribes charges 12.5 cents per line for PDA dictation, plus $45 a month for the software contract. In contrast, Dictaphone offers more services to handle the volume and connectivity of electronic medical records.
Many PDAs are equipped to work like tape recorders: The user talks into a receiver, creates a digital voice file, and sends the file electronically to the transcription/voice recognition service. For example, HealthcareOne provides a solution for the Palm OS based-Handera PDA, and ProVox utilizes Pocket PC OS-based handhelds to deliver dictation to TalkNotes.
In addition to PDA-based entry, TalkNotes can enter information into customized forms. Voice command shortcuts, or macros, can be created to dictate commonly used phrases or norms. TalkNotes goes one step further by automatically pulling patient demographic data into your customized macro. The basic package for an individual user costs $3,900, which includes the desktop and handheld software and creation of specialized dictionaries and voice files.
Although these solutions are costly, they minimize hardware and software investments as well as dependency on a local transcription service. Not to be overlooked is the decreased risk of repetitive stress injury from typing.
Computer-generated documents. The ICANotes system creates medical notes with just a few clicks to reduce text entry. By selecting key words in headings (e.g., “chief complaint”), the program generates approximate “template text” that comprises 80% of the text necessary. Information from previous notes is also brought forward to reduce typing. While generating the note, the program will also determine the appropriate E & M (evaluation and management) and psychotherapy codes based on the entries made.
A basic ICANotes system that creates initial history and assessment reports, progress notes, discharge summaries, and psychotherapy notes can be purchased for $550. Additional modules to produce prescriptions and other notes cost extra. ICANotes will cut out a lot of typing, although the generated text will have a simplistic and repetitive sentence structure.
Handwriting programs. Although handwriting is obviously much slower than other modes of text entry, it is both silent and within your control, making it perfect for taking notes during medical meetings or sessions with patients.
Seiko’s Smartpad2 System for $150 captures notes and drawings directly into your personal or notebook computer or PDA. This information exists only digitally as a picture, however.
The newly available io personal digital pen from Logitech, at $200, offers another cost-effective handwriting alternative. Instead of a pad underneath to capture pen strokes, a tiny camera in the system captures your pen movements, which are transferred to the computer via a cradle. The drawback is that handwriting recognition is limited.
By using Advanced Recognition Technology’s smARTwriter, printed handwriting can be converted into electronic text, which can be then inserted into any document. The program is affordable ($70) but carries significant drawbacks: Printing may be slow, and handwriting recognition is not 100 % accurate.
The Tablet PC presents a possible all-in-one handwriting solution. New to the market, Tablet PC offers built-in handwriting recognition and conversion, voice recognition, and other rich features. Microsoft adapted the Windows XP operating system for the device, which is manufactured by such vendors as Toshiba, Acer, and Hewlett-Packard. It comes in either a slate or clamshell design; the latter style features an integrated keyboard.
Tablet PCs range in cost from $1,500 to $2,500, and are touted to be as easy to use as Microsoft Windows XP with additional practical features. This is a new product, however, and future versions will offer improved accuracy, hardiness, and longevity.
If you have any questions about these methods or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to [email protected].
Disclosure:
Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.
If you cannot type—or don’t like to—read on.
Text-entry advances offer alternatives to traditional keystroking. From voice recognition to online dictation, these options promise increased efficiency and relief from typing-related repetitive stress injuries.
The truth about typing
Few people know that the original typewriter keyboard layout—known as QWERTY, for the row of keys on the upper left-hand side—was designed to decrease typing speed so that the mechanical typewriter’s keys would not jam.1 More recently designed keyboard layouts, such as DVORAK and IDEAL, are reportedly more efficient but are not widely used. It would take months to retrain a typist to work with either keyboard.
Dictation is a well-established alternative to typing, but if the transcriber is not 100% accurate, much time is wasted correcting mistakes, returning the document, and proofreading the corrections.
Voice recognition
Voice recognition technology has been touted as the successor to dictation. With increasing computer power and more sophisticated algorithms to improve recognition, many programs2 can record continuous speech onto a document with approximately 95% accuracy.
Using voice recognition software and hardware to dictate text can save worlds of time compared with typing or writing by hand. But beware: accents and background noise often confound voice-based systems.
What’s more, a voice-recognition package that is suited to medical practice may be considerably more expensive than an entry-level model. Entry-level programs such as ScanSoft Dragon Naturally Speaking and IBM ViaVoice start at less than $100 each, but the medical version of ScanSoft is $1,000. The Trigram Psychiatry Specialty Module, at $300, may be an option. ViaVoice users can get a medical vocabulary module for an additional $142.
Other text-entry solutions
Internet-based dictation is a possible alternative to voice recognition or traditional dictation. Dictaphone’s Physician Workstation, which will reach the market in March, will allow the user to dictate with a specialized microphone linked to the computer or offsite by calling a toll-free telephone number. The computer then sends the voice data securely via the Internet to off-site transcriptionists. The physician logs into the transcript and makes corrections online via a Web browser. The user electronically signs the note to finalize it, and it is automatically delivered to the desired locations.
For a nominal investment in hardware, Physician Workstation can significantly simplify and speed up the transcription process. Dictaphone also provides 24-7 support and maintenance for these services, which cost $86 a month for 500 minutes. The setup has its drawbacks: Dictaphone provides the secure infrastructure and support, but transcription is a separate contracted service at 15.5 cents per line. However, you can select another transcription service to receive your voice files, or you can use Dictaphone’s new voice recognition software (also available in March).
Similarly, other online transcription services, such as HealthScribes and Kinetxhc, allow mobile users to dictate via a telephone, dedicated device, or personal digital assistant (PDA). HealthScribes charges 12.5 cents per line for PDA dictation, plus $45 a month for the software contract. In contrast, Dictaphone offers more services to handle the volume and connectivity of electronic medical records.
Many PDAs are equipped to work like tape recorders: The user talks into a receiver, creates a digital voice file, and sends the file electronically to the transcription/voice recognition service. For example, HealthcareOne provides a solution for the Palm OS based-Handera PDA, and ProVox utilizes Pocket PC OS-based handhelds to deliver dictation to TalkNotes.
In addition to PDA-based entry, TalkNotes can enter information into customized forms. Voice command shortcuts, or macros, can be created to dictate commonly used phrases or norms. TalkNotes goes one step further by automatically pulling patient demographic data into your customized macro. The basic package for an individual user costs $3,900, which includes the desktop and handheld software and creation of specialized dictionaries and voice files.
Although these solutions are costly, they minimize hardware and software investments as well as dependency on a local transcription service. Not to be overlooked is the decreased risk of repetitive stress injury from typing.
Computer-generated documents. The ICANotes system creates medical notes with just a few clicks to reduce text entry. By selecting key words in headings (e.g., “chief complaint”), the program generates approximate “template text” that comprises 80% of the text necessary. Information from previous notes is also brought forward to reduce typing. While generating the note, the program will also determine the appropriate E & M (evaluation and management) and psychotherapy codes based on the entries made.
A basic ICANotes system that creates initial history and assessment reports, progress notes, discharge summaries, and psychotherapy notes can be purchased for $550. Additional modules to produce prescriptions and other notes cost extra. ICANotes will cut out a lot of typing, although the generated text will have a simplistic and repetitive sentence structure.
Handwriting programs. Although handwriting is obviously much slower than other modes of text entry, it is both silent and within your control, making it perfect for taking notes during medical meetings or sessions with patients.
Seiko’s Smartpad2 System for $150 captures notes and drawings directly into your personal or notebook computer or PDA. This information exists only digitally as a picture, however.
The newly available io personal digital pen from Logitech, at $200, offers another cost-effective handwriting alternative. Instead of a pad underneath to capture pen strokes, a tiny camera in the system captures your pen movements, which are transferred to the computer via a cradle. The drawback is that handwriting recognition is limited.
By using Advanced Recognition Technology’s smARTwriter, printed handwriting can be converted into electronic text, which can be then inserted into any document. The program is affordable ($70) but carries significant drawbacks: Printing may be slow, and handwriting recognition is not 100 % accurate.
The Tablet PC presents a possible all-in-one handwriting solution. New to the market, Tablet PC offers built-in handwriting recognition and conversion, voice recognition, and other rich features. Microsoft adapted the Windows XP operating system for the device, which is manufactured by such vendors as Toshiba, Acer, and Hewlett-Packard. It comes in either a slate or clamshell design; the latter style features an integrated keyboard.
Tablet PCs range in cost from $1,500 to $2,500, and are touted to be as easy to use as Microsoft Windows XP with additional practical features. This is a new product, however, and future versions will offer improved accuracy, hardiness, and longevity.
If you have any questions about these methods or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to [email protected].
Disclosure:
Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.
If you cannot type—or don’t like to—read on.
Text-entry advances offer alternatives to traditional keystroking. From voice recognition to online dictation, these options promise increased efficiency and relief from typing-related repetitive stress injuries.
The truth about typing
Few people know that the original typewriter keyboard layout—known as QWERTY, for the row of keys on the upper left-hand side—was designed to decrease typing speed so that the mechanical typewriter’s keys would not jam.1 More recently designed keyboard layouts, such as DVORAK and IDEAL, are reportedly more efficient but are not widely used. It would take months to retrain a typist to work with either keyboard.
Dictation is a well-established alternative to typing, but if the transcriber is not 100% accurate, much time is wasted correcting mistakes, returning the document, and proofreading the corrections.
Voice recognition
Voice recognition technology has been touted as the successor to dictation. With increasing computer power and more sophisticated algorithms to improve recognition, many programs2 can record continuous speech onto a document with approximately 95% accuracy.
Using voice recognition software and hardware to dictate text can save worlds of time compared with typing or writing by hand. But beware: accents and background noise often confound voice-based systems.
What’s more, a voice-recognition package that is suited to medical practice may be considerably more expensive than an entry-level model. Entry-level programs such as ScanSoft Dragon Naturally Speaking and IBM ViaVoice start at less than $100 each, but the medical version of ScanSoft is $1,000. The Trigram Psychiatry Specialty Module, at $300, may be an option. ViaVoice users can get a medical vocabulary module for an additional $142.
Other text-entry solutions
Internet-based dictation is a possible alternative to voice recognition or traditional dictation. Dictaphone’s Physician Workstation, which will reach the market in March, will allow the user to dictate with a specialized microphone linked to the computer or offsite by calling a toll-free telephone number. The computer then sends the voice data securely via the Internet to off-site transcriptionists. The physician logs into the transcript and makes corrections online via a Web browser. The user electronically signs the note to finalize it, and it is automatically delivered to the desired locations.
For a nominal investment in hardware, Physician Workstation can significantly simplify and speed up the transcription process. Dictaphone also provides 24-7 support and maintenance for these services, which cost $86 a month for 500 minutes. The setup has its drawbacks: Dictaphone provides the secure infrastructure and support, but transcription is a separate contracted service at 15.5 cents per line. However, you can select another transcription service to receive your voice files, or you can use Dictaphone’s new voice recognition software (also available in March).
Similarly, other online transcription services, such as HealthScribes and Kinetxhc, allow mobile users to dictate via a telephone, dedicated device, or personal digital assistant (PDA). HealthScribes charges 12.5 cents per line for PDA dictation, plus $45 a month for the software contract. In contrast, Dictaphone offers more services to handle the volume and connectivity of electronic medical records.
Many PDAs are equipped to work like tape recorders: The user talks into a receiver, creates a digital voice file, and sends the file electronically to the transcription/voice recognition service. For example, HealthcareOne provides a solution for the Palm OS based-Handera PDA, and ProVox utilizes Pocket PC OS-based handhelds to deliver dictation to TalkNotes.
In addition to PDA-based entry, TalkNotes can enter information into customized forms. Voice command shortcuts, or macros, can be created to dictate commonly used phrases or norms. TalkNotes goes one step further by automatically pulling patient demographic data into your customized macro. The basic package for an individual user costs $3,900, which includes the desktop and handheld software and creation of specialized dictionaries and voice files.
Although these solutions are costly, they minimize hardware and software investments as well as dependency on a local transcription service. Not to be overlooked is the decreased risk of repetitive stress injury from typing.
Computer-generated documents. The ICANotes system creates medical notes with just a few clicks to reduce text entry. By selecting key words in headings (e.g., “chief complaint”), the program generates approximate “template text” that comprises 80% of the text necessary. Information from previous notes is also brought forward to reduce typing. While generating the note, the program will also determine the appropriate E & M (evaluation and management) and psychotherapy codes based on the entries made.
A basic ICANotes system that creates initial history and assessment reports, progress notes, discharge summaries, and psychotherapy notes can be purchased for $550. Additional modules to produce prescriptions and other notes cost extra. ICANotes will cut out a lot of typing, although the generated text will have a simplistic and repetitive sentence structure.
Handwriting programs. Although handwriting is obviously much slower than other modes of text entry, it is both silent and within your control, making it perfect for taking notes during medical meetings or sessions with patients.
Seiko’s Smartpad2 System for $150 captures notes and drawings directly into your personal or notebook computer or PDA. This information exists only digitally as a picture, however.
The newly available io personal digital pen from Logitech, at $200, offers another cost-effective handwriting alternative. Instead of a pad underneath to capture pen strokes, a tiny camera in the system captures your pen movements, which are transferred to the computer via a cradle. The drawback is that handwriting recognition is limited.
By using Advanced Recognition Technology’s smARTwriter, printed handwriting can be converted into electronic text, which can be then inserted into any document. The program is affordable ($70) but carries significant drawbacks: Printing may be slow, and handwriting recognition is not 100 % accurate.
The Tablet PC presents a possible all-in-one handwriting solution. New to the market, Tablet PC offers built-in handwriting recognition and conversion, voice recognition, and other rich features. Microsoft adapted the Windows XP operating system for the device, which is manufactured by such vendors as Toshiba, Acer, and Hewlett-Packard. It comes in either a slate or clamshell design; the latter style features an integrated keyboard.
Tablet PCs range in cost from $1,500 to $2,500, and are touted to be as easy to use as Microsoft Windows XP with additional practical features. This is a new product, however, and future versions will offer improved accuracy, hardiness, and longevity.
If you have any questions about these methods or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to [email protected].
Disclosure:
Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.
Text-entry solutions: which ‘type’ is right for you?
If you cannot type—or don’t like to—read on.
Text-entry advances offer alternatives to traditional keystroking. From voice recognition to online dictation, these options promise increased efficiency and relief from typing-related repetitive stress injuries.
The truth about typing
Few people know that the original typewriter keyboard layout—known as QWERTY, for the row of keys on the upper left-hand side—was designed to decrease typing speed so that the mechanical typewriter’s keys would not jam.1 More recently designed keyboard layouts, such as DVORAK and IDEAL, are reportedly more efficient but are not widely used. It would take months to retrain a typist to work with either keyboard.
Dictation is a well-established alternative to typing, but if the transcriber is not 100% accurate, much time is wasted correcting mistakes, returning the document, and proofreading the corrections.
Voice recognition
Voice recognition technology has been touted as the successor to dictation. With increasing computer power and more sophisticated algorithms to improve recognition, many programs2 can record continuous speech onto a document with approximately 95% accuracy.
Using voice recognition software and hardware to dictate text can save worlds of time compared with typing or writing by hand. But beware: accents and background noise often confound voice-based systems.
What’s more, a voice-recognition package that is suited to medical practice may be considerably more expensive than an entry-level model. Entry-level programs such as ScanSoft Dragon Naturally Speaking and IBM ViaVoice start at less than $100 each, but the medical version of ScanSoft is $1,000. The Trigram Psychiatry Specialty Module, at $300, may be an option. ViaVoice users can get a medical vocabulary module for an additional $142.
Other text-entry solutions
Internet-based dictation is a possible alternative to voice recognition or traditional dictation. Dictaphone’s Physician Workstation, which will reach the market in March, will allow the user to dictate with a specialized microphone linked to the computer or offsite by calling a toll-free telephone number. The computer then sends the voice data securely via the Internet to off-site transcriptionists. The physician logs into the transcript and makes corrections online via a Web browser. The user electronically signs the note to finalize it, and it is automatically delivered to the desired locations.
For a nominal investment in hardware, Physician Workstation can significantly simplify and speed up the transcription process. Dictaphone also provides 24-7 support and maintenance for these services, which cost $86 a month for 500 minutes. The setup has its drawbacks: Dictaphone provides the secure infrastructure and support, but transcription is a separate contracted service at 15.5 cents per line. However, you can select another transcription service to receive your voice files, or you can use Dictaphone’s new voice recognition software (also available in March).
Similarly, other online transcription services, such as HealthScribes and Kinetxhc, allow mobile users to dictate via a telephone, dedicated device, or personal digital assistant (PDA). HealthScribes charges 12.5 cents per line for PDA dictation, plus $45 a month for the software contract. In contrast, Dictaphone offers more services to handle the volume and connectivity of electronic medical records.
Many PDAs are equipped to work like tape recorders: The user talks into a receiver, creates a digital voice file, and sends the file electronically to the transcription/voice recognition service. For example, HealthcareOne provides a solution for the Palm OS based-Handera PDA, and ProVox utilizes Pocket PC OS-based handhelds to deliver dictation to TalkNotes.
In addition to PDA-based entry, TalkNotes can enter information into customized forms. Voice command shortcuts, or macros, can be created to dictate commonly used phrases or norms. TalkNotes goes one step further by automatically pulling patient demographic data into your customized macro. The basic package for an individual user costs $3,900, which includes the desktop and handheld software and creation of specialized dictionaries and voice files.
Although these solutions are costly, they minimize hardware and software investments as well as dependency on a local transcription service. Not to be overlooked is the decreased risk of repetitive stress injury from typing.
Computer-generated documents. The ICANotes system creates medical notes with just a few clicks to reduce text entry. By selecting key words in headings (e.g., “chief complaint”), the program generates approximate “template text” that comprises 80% of the text necessary. Information from previous notes is also brought forward to reduce typing. While generating the note, the program will also determine the appropriate E & M (evaluation and management) and psychotherapy codes based on the entries made.
A basic ICANotes system that creates initial history and assessment reports, progress notes, discharge summaries, and psychotherapy notes can be purchased for $550. Additional modules to produce prescriptions and other notes cost extra. ICANotes will cut out a lot of typing, although the generated text will have a simplistic and repetitive sentence structure.
Handwriting programs. Although handwriting is obviously much slower than other modes of text entry, it is both silent and within your control, making it perfect for taking notes during medical meetings or sessions with patients.
Seiko’s Smartpad2 System for $150 captures notes and drawings directly into your personal or notebook computer or PDA. This information exists only digitally as a picture, however.
The newly available io personal digital pen from Logitech, at $200, offers another cost-effective handwriting alternative. Instead of a pad underneath to capture pen strokes, a tiny camera in the system captures your pen movements, which are transferred to the computer via a cradle. The drawback is that handwriting recognition is limited.
By using Advanced Recognition Technology’s smARTwriter, printed handwriting can be converted into electronic text, which can be then inserted into any document. The program is affordable ($70) but carries significant drawbacks: Printing may be slow, and handwriting recognition is not 100 % accurate.
The Tablet PC presents a possible all-in-one handwriting solution. New to the market, Tablet PC offers built-in handwriting recognition and conversion, voice recognition, and other rich features. Microsoft adapted the Windows XP operating system for the device, which is manufactured by such vendors as Toshiba, Acer, and Hewlett-Packard. It comes in either a slate or clamshell design; the latter style features an integrated keyboard.
Tablet PCs range in cost from $1,500 to $2,500, and are touted to be as easy to use as Microsoft Windows XP with additional practical features. This is a new product, however, and future versions will offer improved accuracy, hardiness, and longevity.
If you have any questions about these methods or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to [email protected].
Disclosure:
Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.
If you cannot type—or don’t like to—read on.
Text-entry advances offer alternatives to traditional keystroking. From voice recognition to online dictation, these options promise increased efficiency and relief from typing-related repetitive stress injuries.
The truth about typing
Few people know that the original typewriter keyboard layout—known as QWERTY, for the row of keys on the upper left-hand side—was designed to decrease typing speed so that the mechanical typewriter’s keys would not jam.1 More recently designed keyboard layouts, such as DVORAK and IDEAL, are reportedly more efficient but are not widely used. It would take months to retrain a typist to work with either keyboard.
Dictation is a well-established alternative to typing, but if the transcriber is not 100% accurate, much time is wasted correcting mistakes, returning the document, and proofreading the corrections.
Voice recognition
Voice recognition technology has been touted as the successor to dictation. With increasing computer power and more sophisticated algorithms to improve recognition, many programs2 can record continuous speech onto a document with approximately 95% accuracy.
Using voice recognition software and hardware to dictate text can save worlds of time compared with typing or writing by hand. But beware: accents and background noise often confound voice-based systems.
What’s more, a voice-recognition package that is suited to medical practice may be considerably more expensive than an entry-level model. Entry-level programs such as ScanSoft Dragon Naturally Speaking and IBM ViaVoice start at less than $100 each, but the medical version of ScanSoft is $1,000. The Trigram Psychiatry Specialty Module, at $300, may be an option. ViaVoice users can get a medical vocabulary module for an additional $142.
Other text-entry solutions
Internet-based dictation is a possible alternative to voice recognition or traditional dictation. Dictaphone’s Physician Workstation, which will reach the market in March, will allow the user to dictate with a specialized microphone linked to the computer or offsite by calling a toll-free telephone number. The computer then sends the voice data securely via the Internet to off-site transcriptionists. The physician logs into the transcript and makes corrections online via a Web browser. The user electronically signs the note to finalize it, and it is automatically delivered to the desired locations.
For a nominal investment in hardware, Physician Workstation can significantly simplify and speed up the transcription process. Dictaphone also provides 24-7 support and maintenance for these services, which cost $86 a month for 500 minutes. The setup has its drawbacks: Dictaphone provides the secure infrastructure and support, but transcription is a separate contracted service at 15.5 cents per line. However, you can select another transcription service to receive your voice files, or you can use Dictaphone’s new voice recognition software (also available in March).
Similarly, other online transcription services, such as HealthScribes and Kinetxhc, allow mobile users to dictate via a telephone, dedicated device, or personal digital assistant (PDA). HealthScribes charges 12.5 cents per line for PDA dictation, plus $45 a month for the software contract. In contrast, Dictaphone offers more services to handle the volume and connectivity of electronic medical records.
Many PDAs are equipped to work like tape recorders: The user talks into a receiver, creates a digital voice file, and sends the file electronically to the transcription/voice recognition service. For example, HealthcareOne provides a solution for the Palm OS based-Handera PDA, and ProVox utilizes Pocket PC OS-based handhelds to deliver dictation to TalkNotes.
In addition to PDA-based entry, TalkNotes can enter information into customized forms. Voice command shortcuts, or macros, can be created to dictate commonly used phrases or norms. TalkNotes goes one step further by automatically pulling patient demographic data into your customized macro. The basic package for an individual user costs $3,900, which includes the desktop and handheld software and creation of specialized dictionaries and voice files.
Although these solutions are costly, they minimize hardware and software investments as well as dependency on a local transcription service. Not to be overlooked is the decreased risk of repetitive stress injury from typing.
Computer-generated documents. The ICANotes system creates medical notes with just a few clicks to reduce text entry. By selecting key words in headings (e.g., “chief complaint”), the program generates approximate “template text” that comprises 80% of the text necessary. Information from previous notes is also brought forward to reduce typing. While generating the note, the program will also determine the appropriate E & M (evaluation and management) and psychotherapy codes based on the entries made.
A basic ICANotes system that creates initial history and assessment reports, progress notes, discharge summaries, and psychotherapy notes can be purchased for $550. Additional modules to produce prescriptions and other notes cost extra. ICANotes will cut out a lot of typing, although the generated text will have a simplistic and repetitive sentence structure.
Handwriting programs. Although handwriting is obviously much slower than other modes of text entry, it is both silent and within your control, making it perfect for taking notes during medical meetings or sessions with patients.
Seiko’s Smartpad2 System for $150 captures notes and drawings directly into your personal or notebook computer or PDA. This information exists only digitally as a picture, however.
The newly available io personal digital pen from Logitech, at $200, offers another cost-effective handwriting alternative. Instead of a pad underneath to capture pen strokes, a tiny camera in the system captures your pen movements, which are transferred to the computer via a cradle. The drawback is that handwriting recognition is limited.
By using Advanced Recognition Technology’s smARTwriter, printed handwriting can be converted into electronic text, which can be then inserted into any document. The program is affordable ($70) but carries significant drawbacks: Printing may be slow, and handwriting recognition is not 100 % accurate.
The Tablet PC presents a possible all-in-one handwriting solution. New to the market, Tablet PC offers built-in handwriting recognition and conversion, voice recognition, and other rich features. Microsoft adapted the Windows XP operating system for the device, which is manufactured by such vendors as Toshiba, Acer, and Hewlett-Packard. It comes in either a slate or clamshell design; the latter style features an integrated keyboard.
Tablet PCs range in cost from $1,500 to $2,500, and are touted to be as easy to use as Microsoft Windows XP with additional practical features. This is a new product, however, and future versions will offer improved accuracy, hardiness, and longevity.
If you have any questions about these methods or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to [email protected].
Disclosure:
Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.
If you cannot type—or don’t like to—read on.
Text-entry advances offer alternatives to traditional keystroking. From voice recognition to online dictation, these options promise increased efficiency and relief from typing-related repetitive stress injuries.
The truth about typing
Few people know that the original typewriter keyboard layout—known as QWERTY, for the row of keys on the upper left-hand side—was designed to decrease typing speed so that the mechanical typewriter’s keys would not jam.1 More recently designed keyboard layouts, such as DVORAK and IDEAL, are reportedly more efficient but are not widely used. It would take months to retrain a typist to work with either keyboard.
Dictation is a well-established alternative to typing, but if the transcriber is not 100% accurate, much time is wasted correcting mistakes, returning the document, and proofreading the corrections.
Voice recognition
Voice recognition technology has been touted as the successor to dictation. With increasing computer power and more sophisticated algorithms to improve recognition, many programs2 can record continuous speech onto a document with approximately 95% accuracy.
Using voice recognition software and hardware to dictate text can save worlds of time compared with typing or writing by hand. But beware: accents and background noise often confound voice-based systems.
What’s more, a voice-recognition package that is suited to medical practice may be considerably more expensive than an entry-level model. Entry-level programs such as ScanSoft Dragon Naturally Speaking and IBM ViaVoice start at less than $100 each, but the medical version of ScanSoft is $1,000. The Trigram Psychiatry Specialty Module, at $300, may be an option. ViaVoice users can get a medical vocabulary module for an additional $142.
Other text-entry solutions
Internet-based dictation is a possible alternative to voice recognition or traditional dictation. Dictaphone’s Physician Workstation, which will reach the market in March, will allow the user to dictate with a specialized microphone linked to the computer or offsite by calling a toll-free telephone number. The computer then sends the voice data securely via the Internet to off-site transcriptionists. The physician logs into the transcript and makes corrections online via a Web browser. The user electronically signs the note to finalize it, and it is automatically delivered to the desired locations.
For a nominal investment in hardware, Physician Workstation can significantly simplify and speed up the transcription process. Dictaphone also provides 24-7 support and maintenance for these services, which cost $86 a month for 500 minutes. The setup has its drawbacks: Dictaphone provides the secure infrastructure and support, but transcription is a separate contracted service at 15.5 cents per line. However, you can select another transcription service to receive your voice files, or you can use Dictaphone’s new voice recognition software (also available in March).
Similarly, other online transcription services, such as HealthScribes and Kinetxhc, allow mobile users to dictate via a telephone, dedicated device, or personal digital assistant (PDA). HealthScribes charges 12.5 cents per line for PDA dictation, plus $45 a month for the software contract. In contrast, Dictaphone offers more services to handle the volume and connectivity of electronic medical records.
Many PDAs are equipped to work like tape recorders: The user talks into a receiver, creates a digital voice file, and sends the file electronically to the transcription/voice recognition service. For example, HealthcareOne provides a solution for the Palm OS based-Handera PDA, and ProVox utilizes Pocket PC OS-based handhelds to deliver dictation to TalkNotes.
In addition to PDA-based entry, TalkNotes can enter information into customized forms. Voice command shortcuts, or macros, can be created to dictate commonly used phrases or norms. TalkNotes goes one step further by automatically pulling patient demographic data into your customized macro. The basic package for an individual user costs $3,900, which includes the desktop and handheld software and creation of specialized dictionaries and voice files.
Although these solutions are costly, they minimize hardware and software investments as well as dependency on a local transcription service. Not to be overlooked is the decreased risk of repetitive stress injury from typing.
Computer-generated documents. The ICANotes system creates medical notes with just a few clicks to reduce text entry. By selecting key words in headings (e.g., “chief complaint”), the program generates approximate “template text” that comprises 80% of the text necessary. Information from previous notes is also brought forward to reduce typing. While generating the note, the program will also determine the appropriate E & M (evaluation and management) and psychotherapy codes based on the entries made.
A basic ICANotes system that creates initial history and assessment reports, progress notes, discharge summaries, and psychotherapy notes can be purchased for $550. Additional modules to produce prescriptions and other notes cost extra. ICANotes will cut out a lot of typing, although the generated text will have a simplistic and repetitive sentence structure.
Handwriting programs. Although handwriting is obviously much slower than other modes of text entry, it is both silent and within your control, making it perfect for taking notes during medical meetings or sessions with patients.
Seiko’s Smartpad2 System for $150 captures notes and drawings directly into your personal or notebook computer or PDA. This information exists only digitally as a picture, however.
The newly available io personal digital pen from Logitech, at $200, offers another cost-effective handwriting alternative. Instead of a pad underneath to capture pen strokes, a tiny camera in the system captures your pen movements, which are transferred to the computer via a cradle. The drawback is that handwriting recognition is limited.
By using Advanced Recognition Technology’s smARTwriter, printed handwriting can be converted into electronic text, which can be then inserted into any document. The program is affordable ($70) but carries significant drawbacks: Printing may be slow, and handwriting recognition is not 100 % accurate.
The Tablet PC presents a possible all-in-one handwriting solution. New to the market, Tablet PC offers built-in handwriting recognition and conversion, voice recognition, and other rich features. Microsoft adapted the Windows XP operating system for the device, which is manufactured by such vendors as Toshiba, Acer, and Hewlett-Packard. It comes in either a slate or clamshell design; the latter style features an integrated keyboard.
Tablet PCs range in cost from $1,500 to $2,500, and are touted to be as easy to use as Microsoft Windows XP with additional practical features. This is a new product, however, and future versions will offer improved accuracy, hardiness, and longevity.
If you have any questions about these methods or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to [email protected].
Disclosure:
Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.
How to prevent hyperprolactinemia in patients taking antipsychotics
Antipsychotics have long been linked with hyperprolactinemia.1 This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.
We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.
Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME
Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.
Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
Prolactin physiology
Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.4
Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.5 Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.
Serum prolactin concentrations change during various life stages (Figure 1).6 Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.
Prolactin secretion
Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.5 A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.
Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.
Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.
Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:
- a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
- to a lesser extent, estrogen decreases the number of D2 receptors.
Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.5
Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.
For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.
Prolactin’s actions
Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.
The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.7
Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.
Table 1
COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA
| Organ or syndrome | Clinical effects |
|---|---|
| Behavior | Direct effects Secondary effects due to hypogonadism Possible cognitive impairment |
| Bones | Decreased bone mineral density due to testosterone or estrogen deficits |
| Breast | Engorgement Lactation unrelated to breast feeding |
| Cardiovascular system | Possible adverse effects due to low levels of testosterone or estrogen |
| Menstrual function | Absence of ovulation Amenorrhea |
| Sexual function | Reduced libido Reduced arousal Orgasmic dysfunction |
| Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neurolepticinduced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. | |
Diagnosis of hyperprolactinemia
Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.
Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).8 Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.
Thirty to 80% of women with hyperprolactinemia develop galactorrhea,9 although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.
Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).9 In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass
Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.
Table 2
CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA
| Hypothalamic disease | Tumor, infiltrative disease, pseudotumor cerebri, cranial radiation |
| Pituitary disease | Prolactinoma, acromegaly, Cushing’s disease, glycoprotein-producing tumor, other tumors, pituitary stalk section, empty sella, infiltrative disease |
| Medications | Antipsychotics, dopamine receptor blockers, antidepressants, antihypertensives, estrogens, opiates, cimetidine |
| Others | Primary hypothyroidism, chronic renal failure, cirrhosis, neurogenic and idiopathic causes |
| Source: Adapted and reprinted from Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders, 1995:394-405. Copyright 1995, with permission from Elsevier Science. | |
Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.2 Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.
Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.10
Antipsychotic drugs and hyperprolactinemia
Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.
Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.11 This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.12
Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.8
Atypical antipsychotics
A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.13 The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.
Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.
The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.14
Risperidone. A study sponsored by Janssen Pharmaceutica15 reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.
Table 3
HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE
| Gender and complaint | Taking risperidone (%) | Taking olanzapine (%) | Difference (P-value) |
|---|---|---|---|
| Women | |||
| Galactorrhea | 11 of 47 (23.4%) | 11 of 49 (22.4%) | 1.00 |
| Amenorrhea | 11 of 46 (23.9%) | 9 of 45 (20.0%) | 0.80 |
| Men | |||
| Gynecomastia | 9 of 115 (7.8%) | 4 of 115 (3.5%) | 0.25 |
| Sexual dysfunction | 36 of 115 (31.3%) | 34 of 114 (29.8%) | 0.89 |
| Source: Adapted and reprinted with permission from Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry2001;158:765-74. | |||
Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:
- adverse events did not correlate with plasma prolactin concentrations
- the incidence of adverse events was dose-related
- the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.
Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).16
Olanzapine. A study sponsored by Eli Lilly and Co.17 assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.
Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.
Conclusion
The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.
Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.
Related resources
- Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
- Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.
Drug brand names
- Clozapine • Clozaril
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.
Dr. Fernandez reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
1. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release. Psychopharmacol. 1974;40:123-7.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35(suppl):S67-S73.
3. West ES, Todd WR. The hormones. In: West ES, Todd WR (eds). Textbook of biochemistry. New York: The Macmillan Co., 1961;1315-54.
4. Belchetz PE, Ridley RM, Baker HF. Studies on the accessibility of prolactin and growth hormone to brain: effect of opiate agonists on hormone levels in serial, simultaneous plasma and cerebrospinal fluid samples in the rhesus monkey. Brain Res 1982;239:310-4.
5. Cooke NE. Prolactin: basic physiology. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Company, 1995;368-93.
6. Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
7. Thorner MO, Vance ML, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams textbook of endocrinology. Philadelphia: W.B. Saunders Co., 1998;249-340.
8. Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86.
9. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Co., 1995;394-405.
10. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Kilibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-7.
11. Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99:463-72.
12. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 1982;170:463-7.
13. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002;159:133-5.
14. Alexiadis M, Whitehorn D, Woodley H, Kopala L. Prolactin elevation with quetiapine (letter). Am J Psychiatry 2002;159(Sept):1608-9.
15. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
17. Kim K, Pae C, Chae J, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63:408-13.
Antipsychotics have long been linked with hyperprolactinemia.1 This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.
We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.
Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME
Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.
Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
Prolactin physiology
Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.4
Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.5 Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.
Serum prolactin concentrations change during various life stages (Figure 1).6 Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.
Prolactin secretion
Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.5 A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.
Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.
Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.
Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:
- a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
- to a lesser extent, estrogen decreases the number of D2 receptors.
Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.5
Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.
For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.
Prolactin’s actions
Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.
The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.7
Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.
Table 1
COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA
| Organ or syndrome | Clinical effects |
|---|---|
| Behavior | Direct effects Secondary effects due to hypogonadism Possible cognitive impairment |
| Bones | Decreased bone mineral density due to testosterone or estrogen deficits |
| Breast | Engorgement Lactation unrelated to breast feeding |
| Cardiovascular system | Possible adverse effects due to low levels of testosterone or estrogen |
| Menstrual function | Absence of ovulation Amenorrhea |
| Sexual function | Reduced libido Reduced arousal Orgasmic dysfunction |
| Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neurolepticinduced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. | |
Diagnosis of hyperprolactinemia
Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.
Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).8 Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.
Thirty to 80% of women with hyperprolactinemia develop galactorrhea,9 although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.
Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).9 In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass
Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.
Table 2
CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA
| Hypothalamic disease | Tumor, infiltrative disease, pseudotumor cerebri, cranial radiation |
| Pituitary disease | Prolactinoma, acromegaly, Cushing’s disease, glycoprotein-producing tumor, other tumors, pituitary stalk section, empty sella, infiltrative disease |
| Medications | Antipsychotics, dopamine receptor blockers, antidepressants, antihypertensives, estrogens, opiates, cimetidine |
| Others | Primary hypothyroidism, chronic renal failure, cirrhosis, neurogenic and idiopathic causes |
| Source: Adapted and reprinted from Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders, 1995:394-405. Copyright 1995, with permission from Elsevier Science. | |
Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.2 Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.
Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.10
Antipsychotic drugs and hyperprolactinemia
Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.
Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.11 This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.12
Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.8
Atypical antipsychotics
A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.13 The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.
Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.
The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.14
Risperidone. A study sponsored by Janssen Pharmaceutica15 reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.
Table 3
HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE
| Gender and complaint | Taking risperidone (%) | Taking olanzapine (%) | Difference (P-value) |
|---|---|---|---|
| Women | |||
| Galactorrhea | 11 of 47 (23.4%) | 11 of 49 (22.4%) | 1.00 |
| Amenorrhea | 11 of 46 (23.9%) | 9 of 45 (20.0%) | 0.80 |
| Men | |||
| Gynecomastia | 9 of 115 (7.8%) | 4 of 115 (3.5%) | 0.25 |
| Sexual dysfunction | 36 of 115 (31.3%) | 34 of 114 (29.8%) | 0.89 |
| Source: Adapted and reprinted with permission from Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry2001;158:765-74. | |||
Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:
- adverse events did not correlate with plasma prolactin concentrations
- the incidence of adverse events was dose-related
- the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.
Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).16
Olanzapine. A study sponsored by Eli Lilly and Co.17 assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.
Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.
Conclusion
The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.
Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.
Related resources
- Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
- Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.
Drug brand names
- Clozapine • Clozaril
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.
Dr. Fernandez reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Antipsychotics have long been linked with hyperprolactinemia.1 This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.
We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.
Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME
Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.
Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
Prolactin physiology
Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.4
Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.5 Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.
Serum prolactin concentrations change during various life stages (Figure 1).6 Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.
Prolactin secretion
Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.5 A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.
Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.
Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.
Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:
- a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
- to a lesser extent, estrogen decreases the number of D2 receptors.
Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.5
Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.
For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.
Prolactin’s actions
Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.
The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.7
Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.
Table 1
COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA
| Organ or syndrome | Clinical effects |
|---|---|
| Behavior | Direct effects Secondary effects due to hypogonadism Possible cognitive impairment |
| Bones | Decreased bone mineral density due to testosterone or estrogen deficits |
| Breast | Engorgement Lactation unrelated to breast feeding |
| Cardiovascular system | Possible adverse effects due to low levels of testosterone or estrogen |
| Menstrual function | Absence of ovulation Amenorrhea |
| Sexual function | Reduced libido Reduced arousal Orgasmic dysfunction |
| Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neurolepticinduced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. | |
Diagnosis of hyperprolactinemia
Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.
Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).8 Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.
Thirty to 80% of women with hyperprolactinemia develop galactorrhea,9 although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.
Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).9 In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass
Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.
Table 2
CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA
| Hypothalamic disease | Tumor, infiltrative disease, pseudotumor cerebri, cranial radiation |
| Pituitary disease | Prolactinoma, acromegaly, Cushing’s disease, glycoprotein-producing tumor, other tumors, pituitary stalk section, empty sella, infiltrative disease |
| Medications | Antipsychotics, dopamine receptor blockers, antidepressants, antihypertensives, estrogens, opiates, cimetidine |
| Others | Primary hypothyroidism, chronic renal failure, cirrhosis, neurogenic and idiopathic causes |
| Source: Adapted and reprinted from Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders, 1995:394-405. Copyright 1995, with permission from Elsevier Science. | |
Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.2 Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.
Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.10
Antipsychotic drugs and hyperprolactinemia
Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.
Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.11 This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.12
Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.8
Atypical antipsychotics
A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.13 The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.
Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.
The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.14
Risperidone. A study sponsored by Janssen Pharmaceutica15 reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.
Table 3
HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE
| Gender and complaint | Taking risperidone (%) | Taking olanzapine (%) | Difference (P-value) |
|---|---|---|---|
| Women | |||
| Galactorrhea | 11 of 47 (23.4%) | 11 of 49 (22.4%) | 1.00 |
| Amenorrhea | 11 of 46 (23.9%) | 9 of 45 (20.0%) | 0.80 |
| Men | |||
| Gynecomastia | 9 of 115 (7.8%) | 4 of 115 (3.5%) | 0.25 |
| Sexual dysfunction | 36 of 115 (31.3%) | 34 of 114 (29.8%) | 0.89 |
| Source: Adapted and reprinted with permission from Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry2001;158:765-74. | |||
Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:
- adverse events did not correlate with plasma prolactin concentrations
- the incidence of adverse events was dose-related
- the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.
Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).16
Olanzapine. A study sponsored by Eli Lilly and Co.17 assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.
Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.
Conclusion
The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.
Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.
Related resources
- Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
- Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.
Drug brand names
- Clozapine • Clozaril
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.
Dr. Fernandez reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
1. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release. Psychopharmacol. 1974;40:123-7.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35(suppl):S67-S73.
3. West ES, Todd WR. The hormones. In: West ES, Todd WR (eds). Textbook of biochemistry. New York: The Macmillan Co., 1961;1315-54.
4. Belchetz PE, Ridley RM, Baker HF. Studies on the accessibility of prolactin and growth hormone to brain: effect of opiate agonists on hormone levels in serial, simultaneous plasma and cerebrospinal fluid samples in the rhesus monkey. Brain Res 1982;239:310-4.
5. Cooke NE. Prolactin: basic physiology. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Company, 1995;368-93.
6. Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
7. Thorner MO, Vance ML, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams textbook of endocrinology. Philadelphia: W.B. Saunders Co., 1998;249-340.
8. Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86.
9. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Co., 1995;394-405.
10. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Kilibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-7.
11. Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99:463-72.
12. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 1982;170:463-7.
13. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002;159:133-5.
14. Alexiadis M, Whitehorn D, Woodley H, Kopala L. Prolactin elevation with quetiapine (letter). Am J Psychiatry 2002;159(Sept):1608-9.
15. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
17. Kim K, Pae C, Chae J, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63:408-13.
1. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release. Psychopharmacol. 1974;40:123-7.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35(suppl):S67-S73.
3. West ES, Todd WR. The hormones. In: West ES, Todd WR (eds). Textbook of biochemistry. New York: The Macmillan Co., 1961;1315-54.
4. Belchetz PE, Ridley RM, Baker HF. Studies on the accessibility of prolactin and growth hormone to brain: effect of opiate agonists on hormone levels in serial, simultaneous plasma and cerebrospinal fluid samples in the rhesus monkey. Brain Res 1982;239:310-4.
5. Cooke NE. Prolactin: basic physiology. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Company, 1995;368-93.
6. Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
7. Thorner MO, Vance ML, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams textbook of endocrinology. Philadelphia: W.B. Saunders Co., 1998;249-340.
8. Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86.
9. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Co., 1995;394-405.
10. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Kilibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-7.
11. Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99:463-72.
12. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 1982;170:463-7.
13. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002;159:133-5.
14. Alexiadis M, Whitehorn D, Woodley H, Kopala L. Prolactin elevation with quetiapine (letter). Am J Psychiatry 2002;159(Sept):1608-9.
15. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
17. Kim K, Pae C, Chae J, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63:408-13.
How to prevent hyperprolactinemia in patients taking antipsychotics
Antipsychotics have long been linked with hyperprolactinemia.1 This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.
We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.
Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME
Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.
Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
Prolactin physiology
Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.4
Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.5 Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.
Serum prolactin concentrations change during various life stages (Figure 1).6 Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.
Prolactin secretion
Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.5 A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.
Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.
Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.
Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:
- a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
- to a lesser extent, estrogen decreases the number of D2 receptors.
Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.5
Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.
For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.
Prolactin’s actions
Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.
The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.7
Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.
Table 1
COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA
| Organ or syndrome | Clinical effects |
|---|---|
| Behavior | Direct effects Secondary effects due to hypogonadism Possible cognitive impairment |
| Bones | Decreased bone mineral density due to testosterone or estrogen deficits |
| Breast | Engorgement Lactation unrelated to breast feeding |
| Cardiovascular system | Possible adverse effects due to low levels of testosterone or estrogen |
| Menstrual function | Absence of ovulation Amenorrhea |
| Sexual function | Reduced libido Reduced arousal Orgasmic dysfunction |
| Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neurolepticinduced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. | |
Diagnosis of hyperprolactinemia
Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.
Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).8 Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.
Thirty to 80% of women with hyperprolactinemia develop galactorrhea,9 although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.
Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).9 In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass
Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.
Table 2
CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA
| Hypothalamic disease | Tumor, infiltrative disease, pseudotumor cerebri, cranial radiation |
| Pituitary disease | Prolactinoma, acromegaly, Cushing’s disease, glycoprotein-producing tumor, other tumors, pituitary stalk section, empty sella, infiltrative disease |
| Medications | Antipsychotics, dopamine receptor blockers, antidepressants, antihypertensives, estrogens, opiates, cimetidine |
| Others | Primary hypothyroidism, chronic renal failure, cirrhosis, neurogenic and idiopathic causes |
| Source: Adapted and reprinted from Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders, 1995:394-405. Copyright 1995, with permission from Elsevier Science. | |
Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.2 Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.
Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.10
Antipsychotic drugs and hyperprolactinemia
Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.
Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.11 This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.12
Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.8
Atypical antipsychotics
A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.13 The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.
Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.
The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.14
Risperidone. A study sponsored by Janssen Pharmaceutica15 reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.
Table 3
HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE
| Gender and complaint | Taking risperidone (%) | Taking olanzapine (%) | Difference (P-value) |
|---|---|---|---|
| Women | |||
| Galactorrhea | 11 of 47 (23.4%) | 11 of 49 (22.4%) | 1.00 |
| Amenorrhea | 11 of 46 (23.9%) | 9 of 45 (20.0%) | 0.80 |
| Men | |||
| Gynecomastia | 9 of 115 (7.8%) | 4 of 115 (3.5%) | 0.25 |
| Sexual dysfunction | 36 of 115 (31.3%) | 34 of 114 (29.8%) | 0.89 |
| Source: Adapted and reprinted with permission from Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry2001;158:765-74. | |||
Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:
- adverse events did not correlate with plasma prolactin concentrations
- the incidence of adverse events was dose-related
- the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.
Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).16
Olanzapine. A study sponsored by Eli Lilly and Co.17 assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.
Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.
Conclusion
The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.
Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.
Related resources
- Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
- Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.
Drug brand names
- Clozapine • Clozaril
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.
Dr. Fernandez reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
1. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release. Psychopharmacol. 1974;40:123-7.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35(suppl):S67-S73.
3. West ES, Todd WR. The hormones. In: West ES, Todd WR (eds). Textbook of biochemistry. New York: The Macmillan Co., 1961;1315-54.
4. Belchetz PE, Ridley RM, Baker HF. Studies on the accessibility of prolactin and growth hormone to brain: effect of opiate agonists on hormone levels in serial, simultaneous plasma and cerebrospinal fluid samples in the rhesus monkey. Brain Res 1982;239:310-4.
5. Cooke NE. Prolactin: basic physiology. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Company, 1995;368-93.
6. Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
7. Thorner MO, Vance ML, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams textbook of endocrinology. Philadelphia: W.B. Saunders Co., 1998;249-340.
8. Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86.
9. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Co., 1995;394-405.
10. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Kilibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-7.
11. Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99:463-72.
12. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 1982;170:463-7.
13. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002;159:133-5.
14. Alexiadis M, Whitehorn D, Woodley H, Kopala L. Prolactin elevation with quetiapine (letter). Am J Psychiatry 2002;159(Sept):1608-9.
15. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
17. Kim K, Pae C, Chae J, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63:408-13.
Antipsychotics have long been linked with hyperprolactinemia.1 This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.
We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.
Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME
Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.
Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
Prolactin physiology
Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.4
Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.5 Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.
Serum prolactin concentrations change during various life stages (Figure 1).6 Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.
Prolactin secretion
Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.5 A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.
Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.
Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.
Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:
- a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
- to a lesser extent, estrogen decreases the number of D2 receptors.
Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.5
Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.
For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.
Prolactin’s actions
Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.
The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.7
Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.
Table 1
COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA
| Organ or syndrome | Clinical effects |
|---|---|
| Behavior | Direct effects Secondary effects due to hypogonadism Possible cognitive impairment |
| Bones | Decreased bone mineral density due to testosterone or estrogen deficits |
| Breast | Engorgement Lactation unrelated to breast feeding |
| Cardiovascular system | Possible adverse effects due to low levels of testosterone or estrogen |
| Menstrual function | Absence of ovulation Amenorrhea |
| Sexual function | Reduced libido Reduced arousal Orgasmic dysfunction |
| Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neurolepticinduced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. | |
Diagnosis of hyperprolactinemia
Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.
Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).8 Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.
Thirty to 80% of women with hyperprolactinemia develop galactorrhea,9 although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.
Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).9 In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass
Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.
Table 2
CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA
| Hypothalamic disease | Tumor, infiltrative disease, pseudotumor cerebri, cranial radiation |
| Pituitary disease | Prolactinoma, acromegaly, Cushing’s disease, glycoprotein-producing tumor, other tumors, pituitary stalk section, empty sella, infiltrative disease |
| Medications | Antipsychotics, dopamine receptor blockers, antidepressants, antihypertensives, estrogens, opiates, cimetidine |
| Others | Primary hypothyroidism, chronic renal failure, cirrhosis, neurogenic and idiopathic causes |
| Source: Adapted and reprinted from Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders, 1995:394-405. Copyright 1995, with permission from Elsevier Science. | |
Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.2 Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.
Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.10
Antipsychotic drugs and hyperprolactinemia
Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.
Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.11 This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.12
Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.8
Atypical antipsychotics
A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.13 The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.
Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.
The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.14
Risperidone. A study sponsored by Janssen Pharmaceutica15 reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.
Table 3
HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE
| Gender and complaint | Taking risperidone (%) | Taking olanzapine (%) | Difference (P-value) |
|---|---|---|---|
| Women | |||
| Galactorrhea | 11 of 47 (23.4%) | 11 of 49 (22.4%) | 1.00 |
| Amenorrhea | 11 of 46 (23.9%) | 9 of 45 (20.0%) | 0.80 |
| Men | |||
| Gynecomastia | 9 of 115 (7.8%) | 4 of 115 (3.5%) | 0.25 |
| Sexual dysfunction | 36 of 115 (31.3%) | 34 of 114 (29.8%) | 0.89 |
| Source: Adapted and reprinted with permission from Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry2001;158:765-74. | |||
Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:
- adverse events did not correlate with plasma prolactin concentrations
- the incidence of adverse events was dose-related
- the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.
Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).16
Olanzapine. A study sponsored by Eli Lilly and Co.17 assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.
Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.
Conclusion
The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.
Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.
Related resources
- Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
- Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.
Drug brand names
- Clozapine • Clozaril
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.
Dr. Fernandez reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Antipsychotics have long been linked with hyperprolactinemia.1 This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.
We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.
Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME
Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.
Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
Prolactin physiology
Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.4
Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.5 Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.
Serum prolactin concentrations change during various life stages (Figure 1).6 Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.
Prolactin secretion
Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.5 A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.
Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.
Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.
Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:
- a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
- to a lesser extent, estrogen decreases the number of D2 receptors.
Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.5
Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.
For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.
Prolactin’s actions
Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.
The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.7
Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.
Table 1
COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA
| Organ or syndrome | Clinical effects |
|---|---|
| Behavior | Direct effects Secondary effects due to hypogonadism Possible cognitive impairment |
| Bones | Decreased bone mineral density due to testosterone or estrogen deficits |
| Breast | Engorgement Lactation unrelated to breast feeding |
| Cardiovascular system | Possible adverse effects due to low levels of testosterone or estrogen |
| Menstrual function | Absence of ovulation Amenorrhea |
| Sexual function | Reduced libido Reduced arousal Orgasmic dysfunction |
| Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neurolepticinduced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. | |
Diagnosis of hyperprolactinemia
Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.
Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).8 Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.
Thirty to 80% of women with hyperprolactinemia develop galactorrhea,9 although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.
Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).9 In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass
Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.
Table 2
CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA
| Hypothalamic disease | Tumor, infiltrative disease, pseudotumor cerebri, cranial radiation |
| Pituitary disease | Prolactinoma, acromegaly, Cushing’s disease, glycoprotein-producing tumor, other tumors, pituitary stalk section, empty sella, infiltrative disease |
| Medications | Antipsychotics, dopamine receptor blockers, antidepressants, antihypertensives, estrogens, opiates, cimetidine |
| Others | Primary hypothyroidism, chronic renal failure, cirrhosis, neurogenic and idiopathic causes |
| Source: Adapted and reprinted from Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders, 1995:394-405. Copyright 1995, with permission from Elsevier Science. | |
Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.2 Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.
Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.10
Antipsychotic drugs and hyperprolactinemia
Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.
Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.11 This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.12
Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.8
Atypical antipsychotics
A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.13 The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.
Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.
The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.14
Risperidone. A study sponsored by Janssen Pharmaceutica15 reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.
Table 3
HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE
| Gender and complaint | Taking risperidone (%) | Taking olanzapine (%) | Difference (P-value) |
|---|---|---|---|
| Women | |||
| Galactorrhea | 11 of 47 (23.4%) | 11 of 49 (22.4%) | 1.00 |
| Amenorrhea | 11 of 46 (23.9%) | 9 of 45 (20.0%) | 0.80 |
| Men | |||
| Gynecomastia | 9 of 115 (7.8%) | 4 of 115 (3.5%) | 0.25 |
| Sexual dysfunction | 36 of 115 (31.3%) | 34 of 114 (29.8%) | 0.89 |
| Source: Adapted and reprinted with permission from Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry2001;158:765-74. | |||
Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:
- adverse events did not correlate with plasma prolactin concentrations
- the incidence of adverse events was dose-related
- the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.
Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).16
Olanzapine. A study sponsored by Eli Lilly and Co.17 assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.
Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.
Conclusion
The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.
Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.
Related resources
- Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
- Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.
Drug brand names
- Clozapine • Clozaril
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosure
Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.
Dr. Fernandez reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
1. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release. Psychopharmacol. 1974;40:123-7.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35(suppl):S67-S73.
3. West ES, Todd WR. The hormones. In: West ES, Todd WR (eds). Textbook of biochemistry. New York: The Macmillan Co., 1961;1315-54.
4. Belchetz PE, Ridley RM, Baker HF. Studies on the accessibility of prolactin and growth hormone to brain: effect of opiate agonists on hormone levels in serial, simultaneous plasma and cerebrospinal fluid samples in the rhesus monkey. Brain Res 1982;239:310-4.
5. Cooke NE. Prolactin: basic physiology. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Company, 1995;368-93.
6. Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
7. Thorner MO, Vance ML, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams textbook of endocrinology. Philadelphia: W.B. Saunders Co., 1998;249-340.
8. Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86.
9. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Co., 1995;394-405.
10. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Kilibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-7.
11. Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99:463-72.
12. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 1982;170:463-7.
13. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002;159:133-5.
14. Alexiadis M, Whitehorn D, Woodley H, Kopala L. Prolactin elevation with quetiapine (letter). Am J Psychiatry 2002;159(Sept):1608-9.
15. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
17. Kim K, Pae C, Chae J, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63:408-13.
1. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release. Psychopharmacol. 1974;40:123-7.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35(suppl):S67-S73.
3. West ES, Todd WR. The hormones. In: West ES, Todd WR (eds). Textbook of biochemistry. New York: The Macmillan Co., 1961;1315-54.
4. Belchetz PE, Ridley RM, Baker HF. Studies on the accessibility of prolactin and growth hormone to brain: effect of opiate agonists on hormone levels in serial, simultaneous plasma and cerebrospinal fluid samples in the rhesus monkey. Brain Res 1982;239:310-4.
5. Cooke NE. Prolactin: basic physiology. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Company, 1995;368-93.
6. Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.
7. Thorner MO, Vance ML, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams textbook of endocrinology. Philadelphia: W.B. Saunders Co., 1998;249-340.
8. Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86.
9. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, Besser M, Burger HG, et al (eds). Endocrinology. Philadelphia: W.B. Saunders Co., 1995;394-405.
10. Biller BM, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Kilibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992;75:692-7.
11. Baron JC, Martinot JL, Cambon H, et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacol 1989;99:463-72.
12. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 1982;170:463-7.
13. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002;159:133-5.
14. Alexiadis M, Whitehorn D, Woodley H, Kopala L. Prolactin elevation with quetiapine (letter). Am J Psychiatry 2002;159(Sept):1608-9.
15. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765-74.
17. Kim K, Pae C, Chae J, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63:408-13.
Managing polypharmacy: Walking the fine line between help and harm
“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.
Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:
effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31
Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:
- institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
- provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
- having medical insurance.
Steps to avoiding polypharmacy
By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL33 and TIDE—may help you avoid polypharmacy’s negative consequences.
SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.
Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.
Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.
List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.33 Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy34 and drug-drug interactions.35
TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.
Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.
Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.
Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.
Related resources
- Applied Clinical Psychopharmacology. www.Preskorn.com
- Hansten and Horn’s drug interactions. http://hanstenandhorn.com
- FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
- Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org
Disclosure
Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
2. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.
3. Berube MS, Neely DJ, DeVinne PB. American Heritage Dictionary. (2nd College ed). Boston: Houghton Mifflin Co, 1982.
4. Friend DG. Polypharmacy: multiple-ingredient and shotgun prescriptions. N Engl J Med 1959;260(20):1015-8.
5. Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S. Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 1969;(12):765-74.
6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53(1):7-11.
7. Werder SF. Polypharmacy: definitions and risk factors (grand rounds). University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences. Via Christi Regional Medical Center, St. Joseph Campus: Dec 12, 2000.
8. Bjerrum L, Sogaard J, Hallas J, Kragstrup J. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol 1998;54(3):197-202.
9. Bjerrum L. Pharmacoepidemiological Studies of Polypharmacy: Methodological issues, population estimates, and influence of practice patterns (PhD thesis). Odense University Faculty of Health Sciences, Department of clinical pharmacology and research unit of general practice. Denmark; 1998. Available at http://www.sdu.dk/health/IPH/genpract/staff/lbjerrum/PHD/PHD.HTM. Accessed Jan. 9, 2003.
10. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1 suppl):64S-68S.
11. Preskorn SH. The rational basis for the development and use of newer antidepressants. In: Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Publications, Inc; 1999;57-103.
12. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988;145(11):1478.-
13. Meeker JE, Reynolds PC. Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14(5):330-1.
14. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10(1):27-34.
15. Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63(1):28-31.
16. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35(5):1005-15.
17. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000;49(2):158-67.
18. Ebbesen J, Buajordet I, Erikssen J, Svaar H, Brors O, Hilberg T. Drugs as a cause of death. A prospective quality assurance project in a department of medicine (Norwegian). Tidsskr Nor Laegeforen 1995;115(19):2369-72.
19. Alarcon T, Barcena A, Gonzalez-Montalvo JI, Penalosa C, Salgado A. Factors predictive of outcome on admission to an acute geriatric ward. Age Ageing 1999;28(5):429-32.
20. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing 1996;25(2):150-4.
21. Pulska T, Pahkala K, Laippala P, Kivela SL. Six-year survival of depressed elderly Finns: a community study. Int J Geriatr Psychiatry 1997;12(9):942-50.
22. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998;173:325-9.
23. Burns R, Nichols LO, Graney MJ, Cloar FT. Impact of continued geriatric outpatient management on health outcomes of older veterans. Arch Intern Med 1995;155(12):1313-8.
24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;16;287(3):337-44.
25. Flaherty JH, Perry HM, 3rd, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol A Biol Sci Med Sci 2000;55(10):M554-9.
26. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ, 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316(7):363-9.
27. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150(4):841-5.
28. Bero LA, Lipton HL, Bird JA. Characterization of geriatric drug-related hospital readmissions. Med Care 1991;29(10):989-1003.
29. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992;136(7):873-83.
30. Prescription drugs and the elderly. Publication AO/HEHS-95-152. Washington, DC: U.S. General Accounting Office, July 1995.
31. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
32. Fink A, Siu AL, Brook RH, Park RE, Solomon DH. Assuring the quality of health care for older persons. An expert panel’s priorities. JAMA 1987;258(14):1905-8.
33. Lee DR. Polypharmacy: a case report and new protocol for management. J Am Board Fam Pract 1998;11(2):140-4.
34. Hamdy RC, Moore SW, Whalen K, et al. Reducing polypharmacy in extended care. South Med J 1995;88(5):534-8.
35. Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and reporting drug interactions. Am J Hosp Pharm 1987;44(2):345-8.
“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.
Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:
effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31
Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:
- institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
- provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
- having medical insurance.
Steps to avoiding polypharmacy
By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL33 and TIDE—may help you avoid polypharmacy’s negative consequences.
SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.
Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.
Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.
List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.33 Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy34 and drug-drug interactions.35
TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.
Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.
Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.
Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.
Related resources
- Applied Clinical Psychopharmacology. www.Preskorn.com
- Hansten and Horn’s drug interactions. http://hanstenandhorn.com
- FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
- Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org
Disclosure
Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.
“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.
Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:
effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31
Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:
- institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
- provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
- having medical insurance.
Steps to avoiding polypharmacy
By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL33 and TIDE—may help you avoid polypharmacy’s negative consequences.
SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.
Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.
Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.
List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.33 Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy34 and drug-drug interactions.35
TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.
Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.
Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.
Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.
Related resources
- Applied Clinical Psychopharmacology. www.Preskorn.com
- Hansten and Horn’s drug interactions. http://hanstenandhorn.com
- FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
- Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org
Disclosure
Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
2. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.
3. Berube MS, Neely DJ, DeVinne PB. American Heritage Dictionary. (2nd College ed). Boston: Houghton Mifflin Co, 1982.
4. Friend DG. Polypharmacy: multiple-ingredient and shotgun prescriptions. N Engl J Med 1959;260(20):1015-8.
5. Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S. Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 1969;(12):765-74.
6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53(1):7-11.
7. Werder SF. Polypharmacy: definitions and risk factors (grand rounds). University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences. Via Christi Regional Medical Center, St. Joseph Campus: Dec 12, 2000.
8. Bjerrum L, Sogaard J, Hallas J, Kragstrup J. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol 1998;54(3):197-202.
9. Bjerrum L. Pharmacoepidemiological Studies of Polypharmacy: Methodological issues, population estimates, and influence of practice patterns (PhD thesis). Odense University Faculty of Health Sciences, Department of clinical pharmacology and research unit of general practice. Denmark; 1998. Available at http://www.sdu.dk/health/IPH/genpract/staff/lbjerrum/PHD/PHD.HTM. Accessed Jan. 9, 2003.
10. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1 suppl):64S-68S.
11. Preskorn SH. The rational basis for the development and use of newer antidepressants. In: Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Publications, Inc; 1999;57-103.
12. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988;145(11):1478.-
13. Meeker JE, Reynolds PC. Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14(5):330-1.
14. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10(1):27-34.
15. Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63(1):28-31.
16. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35(5):1005-15.
17. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000;49(2):158-67.
18. Ebbesen J, Buajordet I, Erikssen J, Svaar H, Brors O, Hilberg T. Drugs as a cause of death. A prospective quality assurance project in a department of medicine (Norwegian). Tidsskr Nor Laegeforen 1995;115(19):2369-72.
19. Alarcon T, Barcena A, Gonzalez-Montalvo JI, Penalosa C, Salgado A. Factors predictive of outcome on admission to an acute geriatric ward. Age Ageing 1999;28(5):429-32.
20. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing 1996;25(2):150-4.
21. Pulska T, Pahkala K, Laippala P, Kivela SL. Six-year survival of depressed elderly Finns: a community study. Int J Geriatr Psychiatry 1997;12(9):942-50.
22. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998;173:325-9.
23. Burns R, Nichols LO, Graney MJ, Cloar FT. Impact of continued geriatric outpatient management on health outcomes of older veterans. Arch Intern Med 1995;155(12):1313-8.
24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;16;287(3):337-44.
25. Flaherty JH, Perry HM, 3rd, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol A Biol Sci Med Sci 2000;55(10):M554-9.
26. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ, 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316(7):363-9.
27. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150(4):841-5.
28. Bero LA, Lipton HL, Bird JA. Characterization of geriatric drug-related hospital readmissions. Med Care 1991;29(10):989-1003.
29. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992;136(7):873-83.
30. Prescription drugs and the elderly. Publication AO/HEHS-95-152. Washington, DC: U.S. General Accounting Office, July 1995.
31. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
32. Fink A, Siu AL, Brook RH, Park RE, Solomon DH. Assuring the quality of health care for older persons. An expert panel’s priorities. JAMA 1987;258(14):1905-8.
33. Lee DR. Polypharmacy: a case report and new protocol for management. J Am Board Fam Pract 1998;11(2):140-4.
34. Hamdy RC, Moore SW, Whalen K, et al. Reducing polypharmacy in extended care. South Med J 1995;88(5):534-8.
35. Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and reporting drug interactions. Am J Hosp Pharm 1987;44(2):345-8.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
2. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.
3. Berube MS, Neely DJ, DeVinne PB. American Heritage Dictionary. (2nd College ed). Boston: Houghton Mifflin Co, 1982.
4. Friend DG. Polypharmacy: multiple-ingredient and shotgun prescriptions. N Engl J Med 1959;260(20):1015-8.
5. Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S. Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 1969;(12):765-74.
6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53(1):7-11.
7. Werder SF. Polypharmacy: definitions and risk factors (grand rounds). University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences. Via Christi Regional Medical Center, St. Joseph Campus: Dec 12, 2000.
8. Bjerrum L, Sogaard J, Hallas J, Kragstrup J. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol 1998;54(3):197-202.
9. Bjerrum L. Pharmacoepidemiological Studies of Polypharmacy: Methodological issues, population estimates, and influence of practice patterns (PhD thesis). Odense University Faculty of Health Sciences, Department of clinical pharmacology and research unit of general practice. Denmark; 1998. Available at http://www.sdu.dk/health/IPH/genpract/staff/lbjerrum/PHD/PHD.HTM. Accessed Jan. 9, 2003.
10. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1 suppl):64S-68S.
11. Preskorn SH. The rational basis for the development and use of newer antidepressants. In: Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Publications, Inc; 1999;57-103.
12. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988;145(11):1478.-
13. Meeker JE, Reynolds PC. Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14(5):330-1.
14. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10(1):27-34.
15. Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63(1):28-31.
16. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35(5):1005-15.
17. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000;49(2):158-67.
18. Ebbesen J, Buajordet I, Erikssen J, Svaar H, Brors O, Hilberg T. Drugs as a cause of death. A prospective quality assurance project in a department of medicine (Norwegian). Tidsskr Nor Laegeforen 1995;115(19):2369-72.
19. Alarcon T, Barcena A, Gonzalez-Montalvo JI, Penalosa C, Salgado A. Factors predictive of outcome on admission to an acute geriatric ward. Age Ageing 1999;28(5):429-32.
20. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing 1996;25(2):150-4.
21. Pulska T, Pahkala K, Laippala P, Kivela SL. Six-year survival of depressed elderly Finns: a community study. Int J Geriatr Psychiatry 1997;12(9):942-50.
22. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998;173:325-9.
23. Burns R, Nichols LO, Graney MJ, Cloar FT. Impact of continued geriatric outpatient management on health outcomes of older veterans. Arch Intern Med 1995;155(12):1313-8.
24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;16;287(3):337-44.
25. Flaherty JH, Perry HM, 3rd, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol A Biol Sci Med Sci 2000;55(10):M554-9.
26. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ, 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316(7):363-9.
27. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150(4):841-5.
28. Bero LA, Lipton HL, Bird JA. Characterization of geriatric drug-related hospital readmissions. Med Care 1991;29(10):989-1003.
29. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992;136(7):873-83.
30. Prescription drugs and the elderly. Publication AO/HEHS-95-152. Washington, DC: U.S. General Accounting Office, July 1995.
31. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
32. Fink A, Siu AL, Brook RH, Park RE, Solomon DH. Assuring the quality of health care for older persons. An expert panel’s priorities. JAMA 1987;258(14):1905-8.
33. Lee DR. Polypharmacy: a case report and new protocol for management. J Am Board Fam Pract 1998;11(2):140-4.
34. Hamdy RC, Moore SW, Whalen K, et al. Reducing polypharmacy in extended care. South Med J 1995;88(5):534-8.
35. Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and reporting drug interactions. Am J Hosp Pharm 1987;44(2):345-8.
Managing polypharmacy: Walking the fine line between help and harm
“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.
Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:
effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31
Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:
- institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
- provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
- having medical insurance.
Steps to avoiding polypharmacy
By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL33 and TIDE—may help you avoid polypharmacy’s negative consequences.
SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.
Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.
Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.
List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.33 Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy34 and drug-drug interactions.35
TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.
Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.
Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.
Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.
Related resources
- Applied Clinical Psychopharmacology. www.Preskorn.com
- Hansten and Horn’s drug interactions. http://hanstenandhorn.com
- FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
- Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org
Disclosure
Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
2. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.
3. Berube MS, Neely DJ, DeVinne PB. American Heritage Dictionary. (2nd College ed). Boston: Houghton Mifflin Co, 1982.
4. Friend DG. Polypharmacy: multiple-ingredient and shotgun prescriptions. N Engl J Med 1959;260(20):1015-8.
5. Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S. Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 1969;(12):765-74.
6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53(1):7-11.
7. Werder SF. Polypharmacy: definitions and risk factors (grand rounds). University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences. Via Christi Regional Medical Center, St. Joseph Campus: Dec 12, 2000.
8. Bjerrum L, Sogaard J, Hallas J, Kragstrup J. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol 1998;54(3):197-202.
9. Bjerrum L. Pharmacoepidemiological Studies of Polypharmacy: Methodological issues, population estimates, and influence of practice patterns (PhD thesis). Odense University Faculty of Health Sciences, Department of clinical pharmacology and research unit of general practice. Denmark; 1998. Available at http://www.sdu.dk/health/IPH/genpract/staff/lbjerrum/PHD/PHD.HTM. Accessed Jan. 9, 2003.
10. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1 suppl):64S-68S.
11. Preskorn SH. The rational basis for the development and use of newer antidepressants. In: Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Publications, Inc; 1999;57-103.
12. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988;145(11):1478.-
13. Meeker JE, Reynolds PC. Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14(5):330-1.
14. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10(1):27-34.
15. Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63(1):28-31.
16. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35(5):1005-15.
17. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000;49(2):158-67.
18. Ebbesen J, Buajordet I, Erikssen J, Svaar H, Brors O, Hilberg T. Drugs as a cause of death. A prospective quality assurance project in a department of medicine (Norwegian). Tidsskr Nor Laegeforen 1995;115(19):2369-72.
19. Alarcon T, Barcena A, Gonzalez-Montalvo JI, Penalosa C, Salgado A. Factors predictive of outcome on admission to an acute geriatric ward. Age Ageing 1999;28(5):429-32.
20. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing 1996;25(2):150-4.
21. Pulska T, Pahkala K, Laippala P, Kivela SL. Six-year survival of depressed elderly Finns: a community study. Int J Geriatr Psychiatry 1997;12(9):942-50.
22. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998;173:325-9.
23. Burns R, Nichols LO, Graney MJ, Cloar FT. Impact of continued geriatric outpatient management on health outcomes of older veterans. Arch Intern Med 1995;155(12):1313-8.
24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;16;287(3):337-44.
25. Flaherty JH, Perry HM, 3rd, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol A Biol Sci Med Sci 2000;55(10):M554-9.
26. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ, 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316(7):363-9.
27. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150(4):841-5.
28. Bero LA, Lipton HL, Bird JA. Characterization of geriatric drug-related hospital readmissions. Med Care 1991;29(10):989-1003.
29. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992;136(7):873-83.
30. Prescription drugs and the elderly. Publication AO/HEHS-95-152. Washington, DC: U.S. General Accounting Office, July 1995.
31. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
32. Fink A, Siu AL, Brook RH, Park RE, Solomon DH. Assuring the quality of health care for older persons. An expert panel’s priorities. JAMA 1987;258(14):1905-8.
33. Lee DR. Polypharmacy: a case report and new protocol for management. J Am Board Fam Pract 1998;11(2):140-4.
34. Hamdy RC, Moore SW, Whalen K, et al. Reducing polypharmacy in extended care. South Med J 1995;88(5):534-8.
35. Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and reporting drug interactions. Am J Hosp Pharm 1987;44(2):345-8.
“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.
Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:
effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31
Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:
- institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
- provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
- having medical insurance.
Steps to avoiding polypharmacy
By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL33 and TIDE—may help you avoid polypharmacy’s negative consequences.
SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.
Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.
Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.
List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.33 Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy34 and drug-drug interactions.35
TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.
Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.
Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.
Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.
Related resources
- Applied Clinical Psychopharmacology. www.Preskorn.com
- Hansten and Horn’s drug interactions. http://hanstenandhorn.com
- FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
- Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org
Disclosure
Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.
“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.1 In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.2
In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:
- Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
- Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
- Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.
The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.
Poly, from the Greek word polus (many, much) and pharmacy, from the Greek word pharmakon (drug, poison) literally means many drugs or, alternatively, much poison.3 The word polypharmacy first appeared in the medical literature in 1959 in the New England Journal of Medicine4 and in the psychiatric literature in 1969 in an article citing its incidence at a state mental hospital.5
Many definitions have been used to describe and define polypharmacy, both qualitatively and quantitatively. Monotherapy is drug treatment with one drug. Sometimes treatment with two drugs is referred to as co-pharmacy, while treatment with three or more drugs is referred to as polypharmacy.Minor polypharmacy refers to treatment with two to four drugs, while major polypharmacyrefers to treatment with five or more drugs.6
What is polypharmacy?
Many definitions have been used to describe polypharmacy (Box 1).3-6 The most common definition is the use of five or more drugs at the same time in the same patient.7 Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.
Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:
- using multiple drugs can help achieve an intended therapeutic goal
- adding one drug can prevent a known side effect of another drug.
Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.
Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)
Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.
Settings for polypharmacy
Polypharmacy occurs in five principal prescribing situations:
- treatment of symptoms
- treatment of multiple illnesses
- treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
- preventing or treating adverse effects of other drugs
- attempting to accelerate the onset of action or augment the effects of a preceding drug.
As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.
Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:
effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31
Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:
- institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
- provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
- having medical insurance.
Steps to avoiding polypharmacy
By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL33 and TIDE—may help you avoid polypharmacy’s negative consequences.
SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.
Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.
Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.
List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.33 Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy34 and drug-drug interactions.35
TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.
Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.
Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.
Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.
Related resources
- Applied Clinical Psychopharmacology. www.Preskorn.com
- Hansten and Horn’s drug interactions. http://hanstenandhorn.com
- FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
- Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org
Disclosure
Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
2. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.
3. Berube MS, Neely DJ, DeVinne PB. American Heritage Dictionary. (2nd College ed). Boston: Houghton Mifflin Co, 1982.
4. Friend DG. Polypharmacy: multiple-ingredient and shotgun prescriptions. N Engl J Med 1959;260(20):1015-8.
5. Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S. Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 1969;(12):765-74.
6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53(1):7-11.
7. Werder SF. Polypharmacy: definitions and risk factors (grand rounds). University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences. Via Christi Regional Medical Center, St. Joseph Campus: Dec 12, 2000.
8. Bjerrum L, Sogaard J, Hallas J, Kragstrup J. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol 1998;54(3):197-202.
9. Bjerrum L. Pharmacoepidemiological Studies of Polypharmacy: Methodological issues, population estimates, and influence of practice patterns (PhD thesis). Odense University Faculty of Health Sciences, Department of clinical pharmacology and research unit of general practice. Denmark; 1998. Available at http://www.sdu.dk/health/IPH/genpract/staff/lbjerrum/PHD/PHD.HTM. Accessed Jan. 9, 2003.
10. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1 suppl):64S-68S.
11. Preskorn SH. The rational basis for the development and use of newer antidepressants. In: Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Publications, Inc; 1999;57-103.
12. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988;145(11):1478.-
13. Meeker JE, Reynolds PC. Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14(5):330-1.
14. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10(1):27-34.
15. Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63(1):28-31.
16. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35(5):1005-15.
17. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000;49(2):158-67.
18. Ebbesen J, Buajordet I, Erikssen J, Svaar H, Brors O, Hilberg T. Drugs as a cause of death. A prospective quality assurance project in a department of medicine (Norwegian). Tidsskr Nor Laegeforen 1995;115(19):2369-72.
19. Alarcon T, Barcena A, Gonzalez-Montalvo JI, Penalosa C, Salgado A. Factors predictive of outcome on admission to an acute geriatric ward. Age Ageing 1999;28(5):429-32.
20. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing 1996;25(2):150-4.
21. Pulska T, Pahkala K, Laippala P, Kivela SL. Six-year survival of depressed elderly Finns: a community study. Int J Geriatr Psychiatry 1997;12(9):942-50.
22. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998;173:325-9.
23. Burns R, Nichols LO, Graney MJ, Cloar FT. Impact of continued geriatric outpatient management on health outcomes of older veterans. Arch Intern Med 1995;155(12):1313-8.
24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;16;287(3):337-44.
25. Flaherty JH, Perry HM, 3rd, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol A Biol Sci Med Sci 2000;55(10):M554-9.
26. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ, 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316(7):363-9.
27. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150(4):841-5.
28. Bero LA, Lipton HL, Bird JA. Characterization of geriatric drug-related hospital readmissions. Med Care 1991;29(10):989-1003.
29. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992;136(7):873-83.
30. Prescription drugs and the elderly. Publication AO/HEHS-95-152. Washington, DC: U.S. General Accounting Office, July 1995.
31. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
32. Fink A, Siu AL, Brook RH, Park RE, Solomon DH. Assuring the quality of health care for older persons. An expert panel’s priorities. JAMA 1987;258(14):1905-8.
33. Lee DR. Polypharmacy: a case report and new protocol for management. J Am Board Fam Pract 1998;11(2):140-4.
34. Hamdy RC, Moore SW, Whalen K, et al. Reducing polypharmacy in extended care. South Med J 1995;88(5):534-8.
35. Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and reporting drug interactions. Am J Hosp Pharm 1987;44(2):345-8.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
2. Incalzi RA, Gemma A, Capparella O, et al. Predicting mortality and length of stay of geriatric patients in an acute care general hospital. J Gerontol 1992;47(2):M35-9.
3. Berube MS, Neely DJ, DeVinne PB. American Heritage Dictionary. (2nd College ed). Boston: Houghton Mifflin Co, 1982.
4. Friend DG. Polypharmacy: multiple-ingredient and shotgun prescriptions. N Engl J Med 1959;260(20):1015-8.
5. Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S. Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 1969;(12):765-74.
6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53(1):7-11.
7. Werder SF. Polypharmacy: definitions and risk factors (grand rounds). University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences. Via Christi Regional Medical Center, St. Joseph Campus: Dec 12, 2000.
8. Bjerrum L, Sogaard J, Hallas J, Kragstrup J. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol 1998;54(3):197-202.
9. Bjerrum L. Pharmacoepidemiological Studies of Polypharmacy: Methodological issues, population estimates, and influence of practice patterns (PhD thesis). Odense University Faculty of Health Sciences, Department of clinical pharmacology and research unit of general practice. Denmark; 1998. Available at http://www.sdu.dk/health/IPH/genpract/staff/lbjerrum/PHD/PHD.HTM. Accessed Jan. 9, 2003.
10. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1 suppl):64S-68S.
11. Preskorn SH. The rational basis for the development and use of newer antidepressants. In: Outpatient management of depression: a guide for the practitioner (2nd ed). Caddo, OK: Professional Publications, Inc; 1999;57-103.
12. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988;145(11):1478.-
13. Meeker JE, Reynolds PC. Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14(5):330-1.
14. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10(1):27-34.
15. Ellis RJ, Mayo MS, Bodensteiner DM. Ciprofloxacin-warfarin coagulopathy: a case series. Am J Hematol 2000;63(1):28-31.
16. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35(5):1005-15.
17. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000;49(2):158-67.
18. Ebbesen J, Buajordet I, Erikssen J, Svaar H, Brors O, Hilberg T. Drugs as a cause of death. A prospective quality assurance project in a department of medicine (Norwegian). Tidsskr Nor Laegeforen 1995;115(19):2369-72.
19. Alarcon T, Barcena A, Gonzalez-Montalvo JI, Penalosa C, Salgado A. Factors predictive of outcome on admission to an acute geriatric ward. Age Ageing 1999;28(5):429-32.
20. Smith NK, Albazzaz MK. A prospective study of urinary retention and risk of death after proximal femoral fracture. Age Ageing 1996;25(2):150-4.
21. Pulska T, Pahkala K, Laippala P, Kivela SL. Six-year survival of depressed elderly Finns: a community study. Int J Geriatr Psychiatry 1997;12(9):942-50.
22. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998;173:325-9.
23. Burns R, Nichols LO, Graney MJ, Cloar FT. Impact of continued geriatric outpatient management on health outcomes of older veterans. Arch Intern Med 1995;155(12):1313-8.
24. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;16;287(3):337-44.
25. Flaherty JH, Perry HM, 3rd, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol A Biol Sci Med Sci 2000;55(10):M554-9.
26. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ, 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987;316(7):363-9.
27. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150(4):841-5.
28. Bero LA, Lipton HL, Bird JA. Characterization of geriatric drug-related hospital readmissions. Med Care 1991;29(10):989-1003.
29. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992;136(7):873-83.
30. Prescription drugs and the elderly. Publication AO/HEHS-95-152. Washington, DC: U.S. General Accounting Office, July 1995.
31. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949-56.
32. Fink A, Siu AL, Brook RH, Park RE, Solomon DH. Assuring the quality of health care for older persons. An expert panel’s priorities. JAMA 1987;258(14):1905-8.
33. Lee DR. Polypharmacy: a case report and new protocol for management. J Am Board Fam Pract 1998;11(2):140-4.
34. Hamdy RC, Moore SW, Whalen K, et al. Reducing polypharmacy in extended care. South Med J 1995;88(5):534-8.
35. Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and reporting drug interactions. Am J Hosp Pharm 1987;44(2):345-8.