Current Psychiatry

Knowing each patient’s problems and life situation is critical to conducting an effective follow-up examination. But with limits on your time and patients often changing psychiatrists, keeping track can be challenging.

A multiaxial problem (MAP) list, which we devised based on clinical experience, can help you organize key symptoms and remember which issues to address during repeat visits. It can quickly get you up to speed with a patient who:

• has multiple disorders or symptoms
• is treatment-resistant
• has not been seen in months or years
• is a candidate for a change in treatment
• or was treated by another psychiatrist.

Table

Sample multiaxial problem (MAP) list

Creating the list

The MAP list can be compiled from information obtained by:

• asking the patient to list complaints
• reviewing the patient’s chart
• interviewing family members
• or talking with other care team members.

On a blank sheet of paper, write at the top the patient’s name, age, race/sex (for fast identification), and age at onset of symptoms (to differentiate between chronic, episodic, and recent onset).

Then draw four quadrants and organize the information as follows (Table):

• Axis A—symptoms and issues addressed by the psychiatrist
• Axis B—behavior patterns and attitudes that might affect treatment. Also include intellectual limitations. A behavior attributed to a personality disorder (such as selfmutilation) falls under Axis A because the psychiatrist would treat it directly.
• Axis C—physical symptoms or disorders to be addressed by another physician
• Axis D—psychosocial, physical, and other patient stressors. A physical illness may fall under both Axes C and D if the stress is significant.

Pertinent negatives such as “No suicide attempt” may be recorded on Axis A or C, psychological strengths/coping skills on Axis B, and supportive persons and factors (such as “Mother helps financially”) on Axis D.

Using the list

Keep the MAP list handy while seeing the patient. Start by going through the symptoms/problems listed under Axis A. Review the patterns noted under Axis B and look for ways to promote insight and coping by reflecting those patterns back to the patient. For the hypothetical patient illustrated in the Table, we would prescribe a medication, then tell her, “We’ve discussed your pattern of stopping medications because you’re afraid of becoming dependent on them. We need to discuss this further so that you can keep taking this medication regularly.”

Next, check the physical conditions under Axis C before choosing a medication to avoid possible drug-drug interactions or side effects. We find that Axis C also helps us ensure that the patient seeks appropriate medical care from another physician. Finally, Axis D reminds us to be empathic toward patients who report psychosocial stressors and to intervene where appropriate.

Remember that the MAP list is not a substitute for taking a full history and physical.

MAP maintenance

Revise the MAP list after each visit as the patient responds to treatment or as his or her life changes. For example, a psychosocial stressor that has been resolved should be struck, although some cases call for leaving the item in and noting “resolved” or “in remission” after it. For example, even if a patient was no longer being physically abused by her spouse, we would not delete the problem because we would want to keep monitoring it.

Include only relevant data on the list or it will become unwieldy. Add diagnoses only if they are certain.

Knowing each patient’s problems and life situation is critical to conducting an effective follow-up examination. But with limits on your time and patients often changing psychiatrists, keeping track can be challenging.

A multiaxial problem (MAP) list, which we devised based on clinical experience, can help you organize key symptoms and remember which issues to address during repeat visits. It can quickly get you up to speed with a patient who:

• has multiple disorders or symptoms
• is treatment-resistant
• has not been seen in months or years
• is a candidate for a change in treatment
• or was treated by another psychiatrist.

Table

Sample multiaxial problem (MAP) list

Creating the list

The MAP list can be compiled from information obtained by:

• asking the patient to list complaints
• reviewing the patient’s chart
• interviewing family members
• or talking with other care team members.

On a blank sheet of paper, write at the top the patient’s name, age, race/sex (for fast identification), and age at onset of symptoms (to differentiate between chronic, episodic, and recent onset).

Then draw four quadrants and organize the information as follows (Table):

• Axis A—symptoms and issues addressed by the psychiatrist
• Axis B—behavior patterns and attitudes that might affect treatment. Also include intellectual limitations. A behavior attributed to a personality disorder (such as selfmutilation) falls under Axis A because the psychiatrist would treat it directly.
• Axis C—physical symptoms or disorders to be addressed by another physician
• Axis D—psychosocial, physical, and other patient stressors. A physical illness may fall under both Axes C and D if the stress is significant.

Pertinent negatives such as “No suicide attempt” may be recorded on Axis A or C, psychological strengths/coping skills on Axis B, and supportive persons and factors (such as “Mother helps financially”) on Axis D.

Using the list

Keep the MAP list handy while seeing the patient. Start by going through the symptoms/problems listed under Axis A. Review the patterns noted under Axis B and look for ways to promote insight and coping by reflecting those patterns back to the patient. For the hypothetical patient illustrated in the Table, we would prescribe a medication, then tell her, “We’ve discussed your pattern of stopping medications because you’re afraid of becoming dependent on them. We need to discuss this further so that you can keep taking this medication regularly.”

Next, check the physical conditions under Axis C before choosing a medication to avoid possible drug-drug interactions or side effects. We find that Axis C also helps us ensure that the patient seeks appropriate medical care from another physician. Finally, Axis D reminds us to be empathic toward patients who report psychosocial stressors and to intervene where appropriate.

Remember that the MAP list is not a substitute for taking a full history and physical.

MAP maintenance

Revise the MAP list after each visit as the patient responds to treatment or as his or her life changes. For example, a psychosocial stressor that has been resolved should be struck, although some cases call for leaving the item in and noting “resolved” or “in remission” after it. For example, even if a patient was no longer being physically abused by her spouse, we would not delete the problem because we would want to keep monitoring it.

Include only relevant data on the list or it will become unwieldy. Add diagnoses only if they are certain.

Knowing each patient’s problems and life situation is critical to conducting an effective follow-up examination. But with limits on your time and patients often changing psychiatrists, keeping track can be challenging.

A multiaxial problem (MAP) list, which we devised based on clinical experience, can help you organize key symptoms and remember which issues to address during repeat visits. It can quickly get you up to speed with a patient who:

• has multiple disorders or symptoms
• is treatment-resistant
• has not been seen in months or years
• is a candidate for a change in treatment
• or was treated by another psychiatrist.

Table

Sample multiaxial problem (MAP) list

Creating the list

The MAP list can be compiled from information obtained by:

• asking the patient to list complaints
• reviewing the patient’s chart
• interviewing family members
• or talking with other care team members.

On a blank sheet of paper, write at the top the patient’s name, age, race/sex (for fast identification), and age at onset of symptoms (to differentiate between chronic, episodic, and recent onset).

Then draw four quadrants and organize the information as follows (Table):

• Axis A—symptoms and issues addressed by the psychiatrist
• Axis B—behavior patterns and attitudes that might affect treatment. Also include intellectual limitations. A behavior attributed to a personality disorder (such as selfmutilation) falls under Axis A because the psychiatrist would treat it directly.
• Axis C—physical symptoms or disorders to be addressed by another physician
• Axis D—psychosocial, physical, and other patient stressors. A physical illness may fall under both Axes C and D if the stress is significant.

Pertinent negatives such as “No suicide attempt” may be recorded on Axis A or C, psychological strengths/coping skills on Axis B, and supportive persons and factors (such as “Mother helps financially”) on Axis D.

Using the list

Keep the MAP list handy while seeing the patient. Start by going through the symptoms/problems listed under Axis A. Review the patterns noted under Axis B and look for ways to promote insight and coping by reflecting those patterns back to the patient. For the hypothetical patient illustrated in the Table, we would prescribe a medication, then tell her, “We’ve discussed your pattern of stopping medications because you’re afraid of becoming dependent on them. We need to discuss this further so that you can keep taking this medication regularly.”

Next, check the physical conditions under Axis C before choosing a medication to avoid possible drug-drug interactions or side effects. We find that Axis C also helps us ensure that the patient seeks appropriate medical care from another physician. Finally, Axis D reminds us to be empathic toward patients who report psychosocial stressors and to intervene where appropriate.

Remember that the MAP list is not a substitute for taking a full history and physical.

MAP maintenance

Revise the MAP list after each visit as the patient responds to treatment or as his or her life changes. For example, a psychosocial stressor that has been resolved should be struck, although some cases call for leaving the item in and noting “resolved” or “in remission” after it. For example, even if a patient was no longer being physically abused by her spouse, we would not delete the problem because we would want to keep monitoring it.

Include only relevant data on the list or it will become unwieldy. Add diagnoses only if they are certain.

The SAD PERSONS scale, an acronym based on 10 suicide risk factors,¹ has found widespread acceptance in assessing the likelihood of a suicide attempt. It also has been adapted for use with children.²

However, a major risk factor omitted from the scale is the availability of a lethal means for suicide, such as a firearm, stockpiled medication, or other potentially lethal item. In particular, where firearm ownership levels are higher, a disproportionately higher number of people die from suicide.³

Include ‘Availability of lethal means’

SAD PERSONS can be modified to “SAD PERSONAS” to remedy this omission, with the second ‘A’ representing “Availability of lethal means” (Table). This modification reminds the clinician to ask about lethal means when assessing suicidality. If lethal means are available, the clinician can then take whatever action is reasonably indicated to reduce the likelihood of a suicide.

Eliminate scoring

Because the listed risk factors are not equivalent with regard to suicide potential, a second modification is to eliminate scoring.

In SAD PERSONS, one point is scored for each risk factor. Consider these two patients:

• a man who is depressed and has an organized plan to shoot himself with his handgun
• an elderly widower who has dementia and is physically ill.

Both men would score a 4, but the risk of suicide would be substantially greater in the first case. Suicide risk factors are qualitative—not quantitative—measures and should be considered within the overall context of the clinical presentation.

Table

Modified SAD PERSONAS scale

The SAD PERSONS scale, an acronym based on 10 suicide risk factors,¹ has found widespread acceptance in assessing the likelihood of a suicide attempt. It also has been adapted for use with children.²

However, a major risk factor omitted from the scale is the availability of a lethal means for suicide, such as a firearm, stockpiled medication, or other potentially lethal item. In particular, where firearm ownership levels are higher, a disproportionately higher number of people die from suicide.³

Include ‘Availability of lethal means’

SAD PERSONS can be modified to “SAD PERSONAS” to remedy this omission, with the second ‘A’ representing “Availability of lethal means” (Table). This modification reminds the clinician to ask about lethal means when assessing suicidality. If lethal means are available, the clinician can then take whatever action is reasonably indicated to reduce the likelihood of a suicide.

Eliminate scoring

Because the listed risk factors are not equivalent with regard to suicide potential, a second modification is to eliminate scoring.

In SAD PERSONS, one point is scored for each risk factor. Consider these two patients:

• a man who is depressed and has an organized plan to shoot himself with his handgun
• an elderly widower who has dementia and is physically ill.

Both men would score a 4, but the risk of suicide would be substantially greater in the first case. Suicide risk factors are qualitative—not quantitative—measures and should be considered within the overall context of the clinical presentation.

Table

Modified SAD PERSONAS scale

The SAD PERSONS scale, an acronym based on 10 suicide risk factors,¹ has found widespread acceptance in assessing the likelihood of a suicide attempt. It also has been adapted for use with children.²

However, a major risk factor omitted from the scale is the availability of a lethal means for suicide, such as a firearm, stockpiled medication, or other potentially lethal item. In particular, where firearm ownership levels are higher, a disproportionately higher number of people die from suicide.³

Include ‘Availability of lethal means’

SAD PERSONS can be modified to “SAD PERSONAS” to remedy this omission, with the second ‘A’ representing “Availability of lethal means” (Table). This modification reminds the clinician to ask about lethal means when assessing suicidality. If lethal means are available, the clinician can then take whatever action is reasonably indicated to reduce the likelihood of a suicide.

Eliminate scoring

Because the listed risk factors are not equivalent with regard to suicide potential, a second modification is to eliminate scoring.

In SAD PERSONS, one point is scored for each risk factor. Consider these two patients:

• a man who is depressed and has an organized plan to shoot himself with his handgun
• an elderly widower who has dementia and is physically ill.

Both men would score a 4, but the risk of suicide would be substantially greater in the first case. Suicide risk factors are qualitative—not quantitative—measures and should be considered within the overall context of the clinical presentation.

Table

Modified SAD PERSONAS scale

Many psychotropics can cause erectile dysfunction (ED) and other sexual problems (Tables 1 and 2). This side effect can discourage treatment compliance and jeopardize outcomes.

This article offers evidence-based strategies for preventing and treating psychotropic-induced ED. We also review information psychiatrists need to share with primary care physicians when treating a patient with ED.

Case report: A good relationship

Mr. A, age 52, has experienced diminishing erectile function for 6 months and now cannot achieve an erection. His relationship with his wife is good; he attributes loss of libido to his erection problem.

A pack-a-day smoker since age 18, Mr. A has type 2 diabetes and has been taking metformin, 850 mg bid, for 2 years. For about 2 months he has been taking sertraline, 50 mg, for depression and reports significantly improved mood, sleep, concentration, and appetite. He also has been taking lisinopril, 20 mg/d, for hypertension, and simvastatin, 40 mg nightly, for hyperlipidemia.

Table 1

Antidepressants associated with sexual dysfunction

Mr. A’s hemoglobin A1C is 9.8%, indicating poor diabetes control. His blood pressure is 168/94 mm Hg, well above his goal of <135/80. He has no chest pain or history of myocardial infarction; a recent exercise stress test indicated no coronary disease.

Discussion. Several medical causes—diabetes, hypertension, hyperlipidemia, and 34 years of heavy smoking—could explain Mr. A’s ED. Vascular disease is suspected, although the stress test was negative.

Identifying a specific cause is crucial to treating ED but may be difficult. Up to 80% of cases can be traced to one or more organic causes.¹ Mr. A’s depression could be a factor, although psychogenic ED is not common. Adding the selective serotonin reuptake inhibitor (SSRI) sertraline may also have worsened his ED.

Other possible causes of ED include:

• nonpsychotropic drugs (to view a list of agents, see this article at currentpsychiatry.com)
• decreased libido, delayed orgasm, and anorgasmia. Decreased libido and anorgasmia are often misdiagnosed as primary ED because the presenting symptoms are similar.

ED treatment begins with managing underlying medical problems, although optimal control alone may not alleviate ED. Encourage the patient to stop smoking and offer smoking cessation strategies.

Alert the primary care physician and patient when prescribing a psychotropic associated with sexual side effects, and explain the drug’s potential benefits. Assess baseline sexual function before starting the psychotropic so that changes in sexual function can be detected. Report your findings to the referring physician after each visit.

If ED is believed to be psychotropic-induced:

• maintain the psychotropic regimen for 6 to 8 weeksto see if the patient builds a tolerance to its sexual side effects.
• lower the psychotropic dosage. In one study,² nearly 75% of patients whose SSRI dosages were reduced by one-half reported improved sexual function with sustained antidepressant effectiveness. This SSRIeffect has been replicated and has also been demonstrated with imipramine.^3-5
• schedule 1- to 2-day drug “holidays” (on weekends, for example) for medications with a short halflife (such as sertraline or paroxetine) if the underlying condition permits.⁷

Table 2

Other psychotropics associated with sexual dysfunction

If these measures do not work, individualized treatment of the sexual dysfunction becomes necessary. For some patients, switching psychotropics may be necessary to ensure compliance and preserve response. In cases such as Mr. A’s, however, the physician and patient may not want to stop a psychotropic that is working. For these patients, consider adding a drug to restore sexual function.

If ED persists after treatment, the primary care physician may refer the patient to a urologist.

Case report:Continued

Mr. A was advised to quit smoking and control his blood pressure and diabetes. His primary care doctor restarted lisinopril, 20 mg/d, increased his metformin to 1,000 mg bid, and added sildenafil, 50 mg before anticipated sexual activity. Mr. A says sildenafil has worked well.

Psychotropics and sexual dysfunction

Several physiologic processes contribute to psychotropics’ sexual side effects.

Libido is primarily a function of hormonal and CNS control. By contrast, erectile functions are mediated through local parasympathetic stimulation and ejaculation, which are controlled by norepinephrine. Orgasm is a cerebral cortical event distinct from ejaculation; either process can be disturbed independently. Elevated central serotonin levels inhibit orgasm and, to a lesser extent, ejaculation. Dopamine elevation over time leads to hyperprolactinemia and resultant hypotestosteronemia, decreasing libido.

SSRIs have been associated with ED and ejaculatory disturbances. A high serotonin-to-dopamine reuptake inhibition ratio associated with these agents may contribute to ED. Paroxetine has a higher serotonin-to-dopamine reuptake inhibition ratio—and is associated with a higher incidence of sexual dysfunction—than other SSRIs.⁷

Elevated central serotonin concentrations associated with SSRIs may also inhibit orgasm. SSRIs have been used to prolong orgasm in patients experiencing premature ejaculation.⁸

Venlafaxine, a serotonin/norepinephrine reuptake inhibitor, exhibits similar effects on sexual function as SSRIs, probably via the same serotonin/dopamine reuptake mechanisms. The lowest effective dosage can still cause sexual dysfunction but may reduce the likelihood.

TCAs. Tricyclic antidepressants may have fewer effects on sexual function than SSRIs. The mechanisms by which TCAs decrease libido and cause ED seem to be mediated through their CNS sedative and local anticholinergic effects.

MAOIs. Monoamine oxidase inhibitors have fewer effects on sexual function than SSRIs or TCAs, but these agents are rarely used to treat depression because of their adverse effects and drug-drug interactions.

Other antidepressants. Trazodone and nefazodone exhibit similar mechanisms of antidepressant action as SSRIs, but neither agent causes significant ED or ejaculatory disturbances. Priapism has been described with use of these agents, however.

Avoid using nefazodone in patients with hepatic dysfunction and in those who have taken an MAOI within 14 days.

Mirtazapine, a novel antidepressant with antiserotonergic actions, and bupropion, a dopamine and norepinephrine reuptake inhibitor, are not associated with significant sexual dysfunction compared with placebo. These agents are good alternatives to SSRIs^9-11 and may alleviate sexual dysfunction when used to augment SSRIs.^12,13

Lithium has been shown to decrease libido and cause ED. Lithium-mediated CNS sedation contributes to decreased libido; other mechanisms of lithium’s sexual side effects are not known. It is unclear whether lower dosages reduce the likelihood of sexual dysfunction.

Anticonvulsants. In two small studies, phenytoin increased sex hormone-binding globulin, resulting in lower free testosterone levels, which may lead to sexual dysfunction.^18,19 Barbiturates have been shown to decrease libido, probably because of CNS sedation. Carbamazepine and gabapentin exhibit antiandrogenic effects, leading to various types of sexual dysfunction. These effects have not been observed with oxcarbazepine, however.

Lamotrigine may be an effective alternative in patients exhibiting sexual dysfunction with gabapentin.²⁰

Typical antipsychotics can impair all aspects of sexual function:¹⁴

• CNS sedation and hyperprolactinemia account for decreased libido.
• Local anticholinergic effects may cause ED. Thus, the greater the anticholinergic effects, the presumably higher the incidence of ED.
• Alpha-receptor blockade and inhibition of inner urethral sphincter closure may cause retarded and retrograde ejaculation, respectively.

Of the conventional antipsychotics, thioridazine is associated with the highest incidence of sexual dysfunction.¹⁵

Table 3

Side effects, drug interactions associated with PDE-5 inhibitors

Atypical antipsychotics exhibit fewer adverse effects on sexual function than their typical counterparts, but the mechanisms that mediate these effects are the same.

Of these agents, risperidone causes the greatest prolactin elevation.¹⁶ Aripiprazole may also be associated with minimal sexual dysfunction.¹⁷ Other atypicals decrease prolactin levels or raise them transiently,^16,17 so consider switching to one of these agents if a patient experiences ED.

Anxiolytics. Benzodiazepines, with their CNS sedative effects, are associated with decreased libido. Their potential for abuse may augment this effect. Buspirone, a novel anxiolytic that exhibits serotonergic and dopaminergic effects, is not associated with significant sexual dysfunction and may be a viable alternative.

Others. Amphetamines can increase the local sympathetic-to-parasympathetic activity ratio, resulting in ED. This effect is more pronounced with long-term use, though it is also seen with short-term use.

ED also has been reported in patients taking disulfiram, though it is unclear whether the drug or long-term alcohol use caused the dysfunction.

Drug treatment of ED

Because primary ED is a quality-of-life issue and not a health risk, few comparative trials have tested medications that improve erectile function. Thus, ED drug treatment may require trials of two or more agents.

Adverse effects and drug-drug interactions of selected agents used for ED treatment are listed in Tables 3 and 4.

Phosphodiesterase (PDE-5) inhibitors have become widely used as first-line oral medications for ED secondary to numerous causes. Sildenafil has demonstrated effectiveness in treating SSRI-induced ED compared with placebo. Tadalafil and vardenafil have not been studied in patients taking SSRIs.

Table 4

Side effects, drug interactions associated with other ED agents

In one 6-week study,²¹ 54.4% of patients taking both an SSRI and sildenafil, up to 100 mg, showed significantly improved erectile function, arousal, ejaculation, orgasm, and overall satisfaction. In another study,²² SSRI-treated patients receiving sildenafil, 5 to 200 mg before sexual activity, reported noticeably improved ability to achieve and maintain erection, ejaculate, and achieve orgasm.

Sildenafil should not be taken concomitantly with agents or products containing nitrates. Use sildenafil with caution in patients with a blood pressure >170/110 mm Hg or <90/50 mm Hg, unstable angina, or retinitis pigmentosa. Also use sildenafil cautiously in patients who have suffered myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months.

Bupropion. In double-blind trials,^11,12 the agent’s sustained-release form has shown effectiveness as an alternative or adjunct to SSRIs in treating SSRI-induced ED. Prescribe at 150 mg nightly when used as an adjunct.

Bupropion is contraindicated in patients with bulimia, anorexia nervosa, and seizure disorders, and in patients taking MAOIs. Use bupropion cautiously in patients with cranial trauma, renal or hepatic insufficiency, uncontrolled hypertension, myocardial infarction, unstable cardiovascular disease, psychosis, and bipolar disorder, and in patients abusing alcohol or taking warfarin.

Amantadine, an oral dopamine-receptor agonist with innate cholinergic effects, has shown effectiveness against SSRI-induced ED when given at 200 mg bid in a small trial.²³

Avoid using amantadine in patients with closed-angle glaucoma, and use with caution in patients with heart failure and in persons age 65 and older.

Mirtazapine, 15 mg/d, has shown effectiveness as an SSRI alternative and as SSRI augmentation therapy to alleviate sexual dysfunction.^12,13

Mirtazapine is contraindicated in patients with hypersensitivity or in patients who have used an MAOI within 14 days. Be careful when combining mirtazapine with an SSRI as the combination may increase the risk of serotonin syndrome.

Ropinirole, an oral dopamine 2-receptor agonist used to treat Parkinson’s disease, has shown effectiveness against antidepressant-induced ED when given at 0.25 mg/d and titrated across 4 weeks to 2 to 4 mg/d.²⁴ Use ropinirole carefully in patients with bradycardia, dyskinesias, hallucinations, renal or hepatic insufficiency, and hypotension.

Bethanechol, an oral cholinergic agent used to treat urinary retention, has been described in case reports to alleviate TCA-induced ED when given at 20 mg 1 to 2 hours before sexual activity.^25,26 Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, Parkinson’s disease, urinary bladder neck obstruction, spastic GI disturbances, acute inflammatory GI lesions, peritonitis, and vagotonia.

Related resources

• Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-110.
• Viera AJ, Clenney TL, Shenenberger DW, Green GF. Newer pharmacologic alternatives for erectile dysfunction. Am Fam Physician 1999;60:1159-72.
• British Medical Journal Web site search: erectile dysfunction. http://bmj.bmjjournals.com/cgi/collection/erectile_dysfunction

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bethanechol • Urecholine
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Dihydrocodeine • Synalgos
• Disulfiram • Antabuse
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Linezolid • Zyvox
• Lisinopril • Prinivil, others
• Lithium • Eskalith, others
• Metformin • Glucophage
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Phenytoin • Dilantin
• Risperidone • Risperdal
• Ropinirole • Requip
• Sertraline • Zoloft
• Sildenafil • Viagra
• Simvastatin • Zocor
• Tadalafil • Cialis
• Triamterene • Dyazide, others
• Trazodone • Desyrel, others
• Vardenafil • Levitra
• Warfarin • Coumadin

Disclosure

Dr. Viera and Mr. Conrad report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Choksi is a regional scientific manager for cardiovascular medicine with Novartis Pharmaceuticals Corp. When he co-wrote this article he was clinical coordinator, pharmacy department, Naval Hospital, Jacksonville, FL.

Many psychotropics can cause erectile dysfunction (ED) and other sexual problems (Tables 1 and 2). This side effect can discourage treatment compliance and jeopardize outcomes.

This article offers evidence-based strategies for preventing and treating psychotropic-induced ED. We also review information psychiatrists need to share with primary care physicians when treating a patient with ED.

Case report: A good relationship

Mr. A, age 52, has experienced diminishing erectile function for 6 months and now cannot achieve an erection. His relationship with his wife is good; he attributes loss of libido to his erection problem.

A pack-a-day smoker since age 18, Mr. A has type 2 diabetes and has been taking metformin, 850 mg bid, for 2 years. For about 2 months he has been taking sertraline, 50 mg, for depression and reports significantly improved mood, sleep, concentration, and appetite. He also has been taking lisinopril, 20 mg/d, for hypertension, and simvastatin, 40 mg nightly, for hyperlipidemia.

Table 1

Antidepressants associated with sexual dysfunction

Mr. A’s hemoglobin A1C is 9.8%, indicating poor diabetes control. His blood pressure is 168/94 mm Hg, well above his goal of <135/80. He has no chest pain or history of myocardial infarction; a recent exercise stress test indicated no coronary disease.

Discussion. Several medical causes—diabetes, hypertension, hyperlipidemia, and 34 years of heavy smoking—could explain Mr. A’s ED. Vascular disease is suspected, although the stress test was negative.

Identifying a specific cause is crucial to treating ED but may be difficult. Up to 80% of cases can be traced to one or more organic causes.¹ Mr. A’s depression could be a factor, although psychogenic ED is not common. Adding the selective serotonin reuptake inhibitor (SSRI) sertraline may also have worsened his ED.

Other possible causes of ED include:

• nonpsychotropic drugs (to view a list of agents, see this article at currentpsychiatry.com)
• decreased libido, delayed orgasm, and anorgasmia. Decreased libido and anorgasmia are often misdiagnosed as primary ED because the presenting symptoms are similar.

ED treatment begins with managing underlying medical problems, although optimal control alone may not alleviate ED. Encourage the patient to stop smoking and offer smoking cessation strategies.

Alert the primary care physician and patient when prescribing a psychotropic associated with sexual side effects, and explain the drug’s potential benefits. Assess baseline sexual function before starting the psychotropic so that changes in sexual function can be detected. Report your findings to the referring physician after each visit.

If ED is believed to be psychotropic-induced:

• maintain the psychotropic regimen for 6 to 8 weeksto see if the patient builds a tolerance to its sexual side effects.
• lower the psychotropic dosage. In one study,² nearly 75% of patients whose SSRI dosages were reduced by one-half reported improved sexual function with sustained antidepressant effectiveness. This SSRIeffect has been replicated and has also been demonstrated with imipramine.^3-5
• schedule 1- to 2-day drug “holidays” (on weekends, for example) for medications with a short halflife (such as sertraline or paroxetine) if the underlying condition permits.⁷

Table 2

Other psychotropics associated with sexual dysfunction

If these measures do not work, individualized treatment of the sexual dysfunction becomes necessary. For some patients, switching psychotropics may be necessary to ensure compliance and preserve response. In cases such as Mr. A’s, however, the physician and patient may not want to stop a psychotropic that is working. For these patients, consider adding a drug to restore sexual function.

If ED persists after treatment, the primary care physician may refer the patient to a urologist.

Case report:Continued

Mr. A was advised to quit smoking and control his blood pressure and diabetes. His primary care doctor restarted lisinopril, 20 mg/d, increased his metformin to 1,000 mg bid, and added sildenafil, 50 mg before anticipated sexual activity. Mr. A says sildenafil has worked well.

Psychotropics and sexual dysfunction

Several physiologic processes contribute to psychotropics’ sexual side effects.

Libido is primarily a function of hormonal and CNS control. By contrast, erectile functions are mediated through local parasympathetic stimulation and ejaculation, which are controlled by norepinephrine. Orgasm is a cerebral cortical event distinct from ejaculation; either process can be disturbed independently. Elevated central serotonin levels inhibit orgasm and, to a lesser extent, ejaculation. Dopamine elevation over time leads to hyperprolactinemia and resultant hypotestosteronemia, decreasing libido.

SSRIs have been associated with ED and ejaculatory disturbances. A high serotonin-to-dopamine reuptake inhibition ratio associated with these agents may contribute to ED. Paroxetine has a higher serotonin-to-dopamine reuptake inhibition ratio—and is associated with a higher incidence of sexual dysfunction—than other SSRIs.⁷

Elevated central serotonin concentrations associated with SSRIs may also inhibit orgasm. SSRIs have been used to prolong orgasm in patients experiencing premature ejaculation.⁸

Venlafaxine, a serotonin/norepinephrine reuptake inhibitor, exhibits similar effects on sexual function as SSRIs, probably via the same serotonin/dopamine reuptake mechanisms. The lowest effective dosage can still cause sexual dysfunction but may reduce the likelihood.

TCAs. Tricyclic antidepressants may have fewer effects on sexual function than SSRIs. The mechanisms by which TCAs decrease libido and cause ED seem to be mediated through their CNS sedative and local anticholinergic effects.

MAOIs. Monoamine oxidase inhibitors have fewer effects on sexual function than SSRIs or TCAs, but these agents are rarely used to treat depression because of their adverse effects and drug-drug interactions.

Other antidepressants. Trazodone and nefazodone exhibit similar mechanisms of antidepressant action as SSRIs, but neither agent causes significant ED or ejaculatory disturbances. Priapism has been described with use of these agents, however.

Avoid using nefazodone in patients with hepatic dysfunction and in those who have taken an MAOI within 14 days.

Mirtazapine, a novel antidepressant with antiserotonergic actions, and bupropion, a dopamine and norepinephrine reuptake inhibitor, are not associated with significant sexual dysfunction compared with placebo. These agents are good alternatives to SSRIs^9-11 and may alleviate sexual dysfunction when used to augment SSRIs.^12,13

Lithium has been shown to decrease libido and cause ED. Lithium-mediated CNS sedation contributes to decreased libido; other mechanisms of lithium’s sexual side effects are not known. It is unclear whether lower dosages reduce the likelihood of sexual dysfunction.

Anticonvulsants. In two small studies, phenytoin increased sex hormone-binding globulin, resulting in lower free testosterone levels, which may lead to sexual dysfunction.^18,19 Barbiturates have been shown to decrease libido, probably because of CNS sedation. Carbamazepine and gabapentin exhibit antiandrogenic effects, leading to various types of sexual dysfunction. These effects have not been observed with oxcarbazepine, however.

Lamotrigine may be an effective alternative in patients exhibiting sexual dysfunction with gabapentin.²⁰

Typical antipsychotics can impair all aspects of sexual function:¹⁴

• CNS sedation and hyperprolactinemia account for decreased libido.
• Local anticholinergic effects may cause ED. Thus, the greater the anticholinergic effects, the presumably higher the incidence of ED.
• Alpha-receptor blockade and inhibition of inner urethral sphincter closure may cause retarded and retrograde ejaculation, respectively.

Of the conventional antipsychotics, thioridazine is associated with the highest incidence of sexual dysfunction.¹⁵

Table 3

Side effects, drug interactions associated with PDE-5 inhibitors

Atypical antipsychotics exhibit fewer adverse effects on sexual function than their typical counterparts, but the mechanisms that mediate these effects are the same.

Of these agents, risperidone causes the greatest prolactin elevation.¹⁶ Aripiprazole may also be associated with minimal sexual dysfunction.¹⁷ Other atypicals decrease prolactin levels or raise them transiently,^16,17 so consider switching to one of these agents if a patient experiences ED.

Anxiolytics. Benzodiazepines, with their CNS sedative effects, are associated with decreased libido. Their potential for abuse may augment this effect. Buspirone, a novel anxiolytic that exhibits serotonergic and dopaminergic effects, is not associated with significant sexual dysfunction and may be a viable alternative.

Others. Amphetamines can increase the local sympathetic-to-parasympathetic activity ratio, resulting in ED. This effect is more pronounced with long-term use, though it is also seen with short-term use.

ED also has been reported in patients taking disulfiram, though it is unclear whether the drug or long-term alcohol use caused the dysfunction.

Drug treatment of ED

Because primary ED is a quality-of-life issue and not a health risk, few comparative trials have tested medications that improve erectile function. Thus, ED drug treatment may require trials of two or more agents.

Adverse effects and drug-drug interactions of selected agents used for ED treatment are listed in Tables 3 and 4.

Phosphodiesterase (PDE-5) inhibitors have become widely used as first-line oral medications for ED secondary to numerous causes. Sildenafil has demonstrated effectiveness in treating SSRI-induced ED compared with placebo. Tadalafil and vardenafil have not been studied in patients taking SSRIs.

Table 4

Side effects, drug interactions associated with other ED agents

In one 6-week study,²¹ 54.4% of patients taking both an SSRI and sildenafil, up to 100 mg, showed significantly improved erectile function, arousal, ejaculation, orgasm, and overall satisfaction. In another study,²² SSRI-treated patients receiving sildenafil, 5 to 200 mg before sexual activity, reported noticeably improved ability to achieve and maintain erection, ejaculate, and achieve orgasm.

Sildenafil should not be taken concomitantly with agents or products containing nitrates. Use sildenafil with caution in patients with a blood pressure >170/110 mm Hg or <90/50 mm Hg, unstable angina, or retinitis pigmentosa. Also use sildenafil cautiously in patients who have suffered myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months.

Bupropion. In double-blind trials,^11,12 the agent’s sustained-release form has shown effectiveness as an alternative or adjunct to SSRIs in treating SSRI-induced ED. Prescribe at 150 mg nightly when used as an adjunct.

Bupropion is contraindicated in patients with bulimia, anorexia nervosa, and seizure disorders, and in patients taking MAOIs. Use bupropion cautiously in patients with cranial trauma, renal or hepatic insufficiency, uncontrolled hypertension, myocardial infarction, unstable cardiovascular disease, psychosis, and bipolar disorder, and in patients abusing alcohol or taking warfarin.

Amantadine, an oral dopamine-receptor agonist with innate cholinergic effects, has shown effectiveness against SSRI-induced ED when given at 200 mg bid in a small trial.²³

Avoid using amantadine in patients with closed-angle glaucoma, and use with caution in patients with heart failure and in persons age 65 and older.

Mirtazapine, 15 mg/d, has shown effectiveness as an SSRI alternative and as SSRI augmentation therapy to alleviate sexual dysfunction.^12,13

Mirtazapine is contraindicated in patients with hypersensitivity or in patients who have used an MAOI within 14 days. Be careful when combining mirtazapine with an SSRI as the combination may increase the risk of serotonin syndrome.

Ropinirole, an oral dopamine 2-receptor agonist used to treat Parkinson’s disease, has shown effectiveness against antidepressant-induced ED when given at 0.25 mg/d and titrated across 4 weeks to 2 to 4 mg/d.²⁴ Use ropinirole carefully in patients with bradycardia, dyskinesias, hallucinations, renal or hepatic insufficiency, and hypotension.

Bethanechol, an oral cholinergic agent used to treat urinary retention, has been described in case reports to alleviate TCA-induced ED when given at 20 mg 1 to 2 hours before sexual activity.^25,26 Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, Parkinson’s disease, urinary bladder neck obstruction, spastic GI disturbances, acute inflammatory GI lesions, peritonitis, and vagotonia.

Related resources

• Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-110.
• Viera AJ, Clenney TL, Shenenberger DW, Green GF. Newer pharmacologic alternatives for erectile dysfunction. Am Fam Physician 1999;60:1159-72.
• British Medical Journal Web site search: erectile dysfunction. http://bmj.bmjjournals.com/cgi/collection/erectile_dysfunction

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bethanechol • Urecholine
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Dihydrocodeine • Synalgos
• Disulfiram • Antabuse
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Linezolid • Zyvox
• Lisinopril • Prinivil, others
• Lithium • Eskalith, others
• Metformin • Glucophage
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Phenytoin • Dilantin
• Risperidone • Risperdal
• Ropinirole • Requip
• Sertraline • Zoloft
• Sildenafil • Viagra
• Simvastatin • Zocor
• Tadalafil • Cialis
• Triamterene • Dyazide, others
• Trazodone • Desyrel, others
• Vardenafil • Levitra
• Warfarin • Coumadin

Disclosure

Dr. Viera and Mr. Conrad report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Choksi is a regional scientific manager for cardiovascular medicine with Novartis Pharmaceuticals Corp. When he co-wrote this article he was clinical coordinator, pharmacy department, Naval Hospital, Jacksonville, FL.

Many psychotropics can cause erectile dysfunction (ED) and other sexual problems (Tables 1 and 2). This side effect can discourage treatment compliance and jeopardize outcomes.

This article offers evidence-based strategies for preventing and treating psychotropic-induced ED. We also review information psychiatrists need to share with primary care physicians when treating a patient with ED.

Case report: A good relationship

Mr. A, age 52, has experienced diminishing erectile function for 6 months and now cannot achieve an erection. His relationship with his wife is good; he attributes loss of libido to his erection problem.

A pack-a-day smoker since age 18, Mr. A has type 2 diabetes and has been taking metformin, 850 mg bid, for 2 years. For about 2 months he has been taking sertraline, 50 mg, for depression and reports significantly improved mood, sleep, concentration, and appetite. He also has been taking lisinopril, 20 mg/d, for hypertension, and simvastatin, 40 mg nightly, for hyperlipidemia.

Table 1

Antidepressants associated with sexual dysfunction

Mr. A’s hemoglobin A1C is 9.8%, indicating poor diabetes control. His blood pressure is 168/94 mm Hg, well above his goal of <135/80. He has no chest pain or history of myocardial infarction; a recent exercise stress test indicated no coronary disease.

Discussion. Several medical causes—diabetes, hypertension, hyperlipidemia, and 34 years of heavy smoking—could explain Mr. A’s ED. Vascular disease is suspected, although the stress test was negative.

Identifying a specific cause is crucial to treating ED but may be difficult. Up to 80% of cases can be traced to one or more organic causes.¹ Mr. A’s depression could be a factor, although psychogenic ED is not common. Adding the selective serotonin reuptake inhibitor (SSRI) sertraline may also have worsened his ED.

Other possible causes of ED include:

• nonpsychotropic drugs (to view a list of agents, see this article at currentpsychiatry.com)
• decreased libido, delayed orgasm, and anorgasmia. Decreased libido and anorgasmia are often misdiagnosed as primary ED because the presenting symptoms are similar.

ED treatment begins with managing underlying medical problems, although optimal control alone may not alleviate ED. Encourage the patient to stop smoking and offer smoking cessation strategies.

Alert the primary care physician and patient when prescribing a psychotropic associated with sexual side effects, and explain the drug’s potential benefits. Assess baseline sexual function before starting the psychotropic so that changes in sexual function can be detected. Report your findings to the referring physician after each visit.

If ED is believed to be psychotropic-induced:

• maintain the psychotropic regimen for 6 to 8 weeksto see if the patient builds a tolerance to its sexual side effects.
• lower the psychotropic dosage. In one study,² nearly 75% of patients whose SSRI dosages were reduced by one-half reported improved sexual function with sustained antidepressant effectiveness. This SSRIeffect has been replicated and has also been demonstrated with imipramine.^3-5
• schedule 1- to 2-day drug “holidays” (on weekends, for example) for medications with a short halflife (such as sertraline or paroxetine) if the underlying condition permits.⁷

Table 2

Other psychotropics associated with sexual dysfunction

If these measures do not work, individualized treatment of the sexual dysfunction becomes necessary. For some patients, switching psychotropics may be necessary to ensure compliance and preserve response. In cases such as Mr. A’s, however, the physician and patient may not want to stop a psychotropic that is working. For these patients, consider adding a drug to restore sexual function.

If ED persists after treatment, the primary care physician may refer the patient to a urologist.

Case report:Continued

Mr. A was advised to quit smoking and control his blood pressure and diabetes. His primary care doctor restarted lisinopril, 20 mg/d, increased his metformin to 1,000 mg bid, and added sildenafil, 50 mg before anticipated sexual activity. Mr. A says sildenafil has worked well.

Psychotropics and sexual dysfunction

Several physiologic processes contribute to psychotropics’ sexual side effects.

Libido is primarily a function of hormonal and CNS control. By contrast, erectile functions are mediated through local parasympathetic stimulation and ejaculation, which are controlled by norepinephrine. Orgasm is a cerebral cortical event distinct from ejaculation; either process can be disturbed independently. Elevated central serotonin levels inhibit orgasm and, to a lesser extent, ejaculation. Dopamine elevation over time leads to hyperprolactinemia and resultant hypotestosteronemia, decreasing libido.

SSRIs have been associated with ED and ejaculatory disturbances. A high serotonin-to-dopamine reuptake inhibition ratio associated with these agents may contribute to ED. Paroxetine has a higher serotonin-to-dopamine reuptake inhibition ratio—and is associated with a higher incidence of sexual dysfunction—than other SSRIs.⁷

Elevated central serotonin concentrations associated with SSRIs may also inhibit orgasm. SSRIs have been used to prolong orgasm in patients experiencing premature ejaculation.⁸

Venlafaxine, a serotonin/norepinephrine reuptake inhibitor, exhibits similar effects on sexual function as SSRIs, probably via the same serotonin/dopamine reuptake mechanisms. The lowest effective dosage can still cause sexual dysfunction but may reduce the likelihood.

TCAs. Tricyclic antidepressants may have fewer effects on sexual function than SSRIs. The mechanisms by which TCAs decrease libido and cause ED seem to be mediated through their CNS sedative and local anticholinergic effects.

MAOIs. Monoamine oxidase inhibitors have fewer effects on sexual function than SSRIs or TCAs, but these agents are rarely used to treat depression because of their adverse effects and drug-drug interactions.

Other antidepressants. Trazodone and nefazodone exhibit similar mechanisms of antidepressant action as SSRIs, but neither agent causes significant ED or ejaculatory disturbances. Priapism has been described with use of these agents, however.

Avoid using nefazodone in patients with hepatic dysfunction and in those who have taken an MAOI within 14 days.

Mirtazapine, a novel antidepressant with antiserotonergic actions, and bupropion, a dopamine and norepinephrine reuptake inhibitor, are not associated with significant sexual dysfunction compared with placebo. These agents are good alternatives to SSRIs^9-11 and may alleviate sexual dysfunction when used to augment SSRIs.^12,13

Lithium has been shown to decrease libido and cause ED. Lithium-mediated CNS sedation contributes to decreased libido; other mechanisms of lithium’s sexual side effects are not known. It is unclear whether lower dosages reduce the likelihood of sexual dysfunction.

Anticonvulsants. In two small studies, phenytoin increased sex hormone-binding globulin, resulting in lower free testosterone levels, which may lead to sexual dysfunction.^18,19 Barbiturates have been shown to decrease libido, probably because of CNS sedation. Carbamazepine and gabapentin exhibit antiandrogenic effects, leading to various types of sexual dysfunction. These effects have not been observed with oxcarbazepine, however.

Lamotrigine may be an effective alternative in patients exhibiting sexual dysfunction with gabapentin.²⁰

Typical antipsychotics can impair all aspects of sexual function:¹⁴

• CNS sedation and hyperprolactinemia account for decreased libido.
• Local anticholinergic effects may cause ED. Thus, the greater the anticholinergic effects, the presumably higher the incidence of ED.
• Alpha-receptor blockade and inhibition of inner urethral sphincter closure may cause retarded and retrograde ejaculation, respectively.

Of the conventional antipsychotics, thioridazine is associated with the highest incidence of sexual dysfunction.¹⁵

Table 3

Side effects, drug interactions associated with PDE-5 inhibitors

Atypical antipsychotics exhibit fewer adverse effects on sexual function than their typical counterparts, but the mechanisms that mediate these effects are the same.

Of these agents, risperidone causes the greatest prolactin elevation.¹⁶ Aripiprazole may also be associated with minimal sexual dysfunction.¹⁷ Other atypicals decrease prolactin levels or raise them transiently,^16,17 so consider switching to one of these agents if a patient experiences ED.

Anxiolytics. Benzodiazepines, with their CNS sedative effects, are associated with decreased libido. Their potential for abuse may augment this effect. Buspirone, a novel anxiolytic that exhibits serotonergic and dopaminergic effects, is not associated with significant sexual dysfunction and may be a viable alternative.

Others. Amphetamines can increase the local sympathetic-to-parasympathetic activity ratio, resulting in ED. This effect is more pronounced with long-term use, though it is also seen with short-term use.

ED also has been reported in patients taking disulfiram, though it is unclear whether the drug or long-term alcohol use caused the dysfunction.

Drug treatment of ED

Because primary ED is a quality-of-life issue and not a health risk, few comparative trials have tested medications that improve erectile function. Thus, ED drug treatment may require trials of two or more agents.

Adverse effects and drug-drug interactions of selected agents used for ED treatment are listed in Tables 3 and 4.

Phosphodiesterase (PDE-5) inhibitors have become widely used as first-line oral medications for ED secondary to numerous causes. Sildenafil has demonstrated effectiveness in treating SSRI-induced ED compared with placebo. Tadalafil and vardenafil have not been studied in patients taking SSRIs.

Table 4

Side effects, drug interactions associated with other ED agents

In one 6-week study,²¹ 54.4% of patients taking both an SSRI and sildenafil, up to 100 mg, showed significantly improved erectile function, arousal, ejaculation, orgasm, and overall satisfaction. In another study,²² SSRI-treated patients receiving sildenafil, 5 to 200 mg before sexual activity, reported noticeably improved ability to achieve and maintain erection, ejaculate, and achieve orgasm.

Sildenafil should not be taken concomitantly with agents or products containing nitrates. Use sildenafil with caution in patients with a blood pressure >170/110 mm Hg or <90/50 mm Hg, unstable angina, or retinitis pigmentosa. Also use sildenafil cautiously in patients who have suffered myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months.

Bupropion. In double-blind trials,^11,12 the agent’s sustained-release form has shown effectiveness as an alternative or adjunct to SSRIs in treating SSRI-induced ED. Prescribe at 150 mg nightly when used as an adjunct.

Bupropion is contraindicated in patients with bulimia, anorexia nervosa, and seizure disorders, and in patients taking MAOIs. Use bupropion cautiously in patients with cranial trauma, renal or hepatic insufficiency, uncontrolled hypertension, myocardial infarction, unstable cardiovascular disease, psychosis, and bipolar disorder, and in patients abusing alcohol or taking warfarin.

Amantadine, an oral dopamine-receptor agonist with innate cholinergic effects, has shown effectiveness against SSRI-induced ED when given at 200 mg bid in a small trial.²³

Avoid using amantadine in patients with closed-angle glaucoma, and use with caution in patients with heart failure and in persons age 65 and older.

Mirtazapine, 15 mg/d, has shown effectiveness as an SSRI alternative and as SSRI augmentation therapy to alleviate sexual dysfunction.^12,13

Mirtazapine is contraindicated in patients with hypersensitivity or in patients who have used an MAOI within 14 days. Be careful when combining mirtazapine with an SSRI as the combination may increase the risk of serotonin syndrome.

Ropinirole, an oral dopamine 2-receptor agonist used to treat Parkinson’s disease, has shown effectiveness against antidepressant-induced ED when given at 0.25 mg/d and titrated across 4 weeks to 2 to 4 mg/d.²⁴ Use ropinirole carefully in patients with bradycardia, dyskinesias, hallucinations, renal or hepatic insufficiency, and hypotension.

Bethanechol, an oral cholinergic agent used to treat urinary retention, has been described in case reports to alleviate TCA-induced ED when given at 20 mg 1 to 2 hours before sexual activity.^25,26 Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, Parkinson’s disease, urinary bladder neck obstruction, spastic GI disturbances, acute inflammatory GI lesions, peritonitis, and vagotonia.

Related resources

• Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-110.
• Viera AJ, Clenney TL, Shenenberger DW, Green GF. Newer pharmacologic alternatives for erectile dysfunction. Am Fam Physician 1999;60:1159-72.
• British Medical Journal Web site search: erectile dysfunction. http://bmj.bmjjournals.com/cgi/collection/erectile_dysfunction

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bethanechol • Urecholine
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Dihydrocodeine • Synalgos
• Disulfiram • Antabuse
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Linezolid • Zyvox
• Lisinopril • Prinivil, others
• Lithium • Eskalith, others
• Metformin • Glucophage
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Phenytoin • Dilantin
• Risperidone • Risperdal
• Ropinirole • Requip
• Sertraline • Zoloft
• Sildenafil • Viagra
• Simvastatin • Zocor
• Tadalafil • Cialis
• Triamterene • Dyazide, others
• Trazodone • Desyrel, others
• Vardenafil • Levitra
• Warfarin • Coumadin

Disclosure

Dr. Viera and Mr. Conrad report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Choksi is a regional scientific manager for cardiovascular medicine with Novartis Pharmaceuticals Corp. When he co-wrote this article he was clinical coordinator, pharmacy department, Naval Hospital, Jacksonville, FL.

Emergency presentation: A rough commute

Mr. R, age 25, presented to the emergency room confused and severely agitated. That morning, his parents found him in his Philadelphia apartment covering his mouth and nose with a T-shirt to guard against imminent chemical warfare.

The day before, Mr. R had developed auditory and visual hallucinations and paranoid and persecutory delusions. That day, on his way to work, he said he had seen “terrorists releasing toxic chemicals into the air” and heard “whispers of terrorists plotting an attack on the East Coast.”

Mr. R showed no suicidal or homicidal ideations. He denied significant medical or surgical history but reported that he had recently been diagnosed with depression after a “bad Ecstasy experience.” For 6 months he had been taking paroxetine, 20 mg once daily, and bupropion, 150 mg once daily, for his depression.

At age 18, Mr. R was diagnosed with attention-deficit/hyperactivity disorder (ADHD) after years of struggling through school with impaired concentration. At that time, he began taking methylphenidate, 10 mg each morning, and completed 3 years of college in North Carolina. He then dropped out of college and attempted suicide twice.

After the second suicide attempt, a psychiatrist diagnosed Mr. R as having major depression. The psychiatrist discontinued methylphenidate and started bupropion, dosage unknown. After 1 year, he stopped taking the antidepressant, thinking he no longer needed it.

Last year, Mr. R moved back to Philadelphia to be closer to his parents. Shortly afterward, he began obtaining methylphenidate illegally and later starting using cocaine, marijuana, amphetamines, and 3,4-methylenedioxymethamphetamine (“Ecstasy”).

At presentation, Mr. R’s mood was dysphoric with bizarre affect. Eye contact was poor with easy distractibility. Speech was pressured, with full range. His thought process was grossly disorganized with tangential thinking and flight of ideas. His short- and long-term memory were intact; insight and judgment were limited. A Mini-Mental State Examination could not be completed because of his disorganization and distractibility.

Does Mr. R. have schizophrenia or schizoaffective disorder? Or are his symptoms related to ADHD or substance abuse?

The authors’ observations

Mr. R’s paranoid delusions and hallucinations may suggest schizophrenia. With his history of suicide attempts, a depressive or schizoaffective disorder may also be considered.

However, Mr. R is close with his family and has several friends. His parents say he has not been withdrawn or paranoid, and there is no known family history of mood disorder, substance abuse, or other psychiatric illness. Mr. R also has been working steadily and had worked the night before presenting to us, so schizophrenia and schizoaffective disorder are ruled out. ADHD and abuse of multiple substances could explain his behavior because overdose of stimulants and illicit drugs may produce a psychotic event.

Further history: The power of addiction

After more questioning, Mr. R said that he had recently started using gamma butyrolactone (GBL) in a failed attempt to build muscle. For 4 months he had been taking 3.5 oz of GBL daily—0.25 oz every 2 to 3 hours and 0.75 oz at night to help him sleep.

Within 6 hours of his most recent GBL dose (reportedly 1 oz), Mr. R developed intractable nausea, vomiting, and flatus, followed quickly by anxiety, palpitations, and generalized hand/body tremors that disturbed his sleep. Hallucinations and delusions started the next day.

At presentation, Mr. R’s blood pressure was 188/92 mm Hg, his heart rate was 110 bpm, and his respiratory rate was 22 breaths per minute. Pupils were 5 mm and reactive with intact extraocular movement. A urine drug screen indicated amphetamine use.

Mr. R was tentatively diagnosed as having GBL withdrawal syndrome and was admitted for observation and treatment. The psychiatry service followed him for change in mental status and drug dependence.

Can a withdrawal syndrome reasonably account for Mr. R’s symptoms?

The authors’ observations

GBL is a precursor of gamma-hydroxybutyrate (GHB), a highly addictive agent that is used illicitly, typically at parties and nightclubs (Box). GBL is among the clinical analogues of GHB that have become popular street drugs.

GHB withdrawal syndrome has only recently been described in the literature and is virtually indistinguishable from withdrawal after cessation of GBL and other precursors. To date, 71 deaths have been attributed to GHB withdrawal.²

A constellation of symptoms exhibited by Mr. R point to GHB withdrawal, which should be included in the differential diagnosis of any sedative/hypnotic withdrawal (Table 1).

How GHB works. GHB easily crosses the blood-brain barrier. Like other sedative/hypnotics, its depressant effects on the brain in low doses (2 to 4 grams) produce a euphoric feeling as inhibitions are depressed. Profound coma or death result from higher doses (>4 grams).³ Heart rate may also be slowed and CNS effects may result in myoclonus, producing seizure-like movements. Combining GHB with other drugs can increase the other agents’ depressant effects, leading to confusion, amnesia, vomiting, irregular breathing, or death.²

Box

A tiny increase in GHB dose can dramatically increase the symptoms and risk of overdose.⁴ GHB’s effects are also variable: A 1-teaspoon dose can produce the desired “high” one time and an overdose the next.

GHB and ethanol share a common mechanism of action.⁵ At pharmacologic doses, GHB appears to act in part through effects on the structurally related GABA neurotransmitter or its receptors.

Not surprisingly, a withdrawal syndrome characterized by delirium and autonomic instability ensues after GHB use is abruptly stopped. By functioning as indirect GABA agonists and ultimately evoking inhibitory neurotransmission, benzodiazepines and most barbiturates may alleviate GHB withdrawal symptoms.⁴ Thiamine is added to prevent Wernicke-Korsakoff syndrome, as is seen in alcohol withdrawal.⁵

GHB withdrawal. Symptoms are divided into three phases:

• Phase 1 (acute, first 24 hours). Presenting symptoms include anxiety, restlessness, insomnia, tremor, diaphoresis, tachycardia, and hypertension. Nausea and vomiting are variable but can be unrelenting.

While symptoms vary in severity, most prominent are agitation, restlessness, and insomnia. Some patients do not sleep for days after their last dose, and diffuse body tremors prevent them from sitting or lying still. Tachycardia and hypertension are hard to evaluate at this phase because patients present at different stages of withdrawal. Initial blood pressure readings as high as 240/130 mm Hg and heart rates of 120 bpm have been reported, however.

• Phase 2 (days 2 through 6). Worsening autonomic symptoms, progressive GI symptoms, and overall worsening of the withdrawal mark this tumultuous period. Patients usually present at this point—in acute distress and no longer able to self-treat.

Confusion, delirium, and florid psychosis characterize this phase. Mr. R’s paranoid delusions and hallucinations are the most common form of psychosis seen in GHB withdrawal.⁵ In some cases, the psychosis impairs social, occupational, and other functioning.

Table 1

Comparison of sedative-hypnotic withdrawal syndromes

Underlying or concurrent causes of delirium must be ruled out. Patients at this stage often require physical restraint or immediate sedation to prevent injury and dangerous complications, including hyperthermia and rhabdomyolysis. Benzodiazepines are often used in high doses¹ for sedation. IV hydration and antiemetics are also treatment mainstays. Atypical antipsychotics are added ASAP to control the paranoia.

• Phase 3 (days 7 through 13). Symptoms usually resolve at this stage. The delirium most often clears first, followed by restored autonomic stability and GI rest. While decreased sleep and periods of psychosis persist, agitation is less severe. The patient is discharged on average after 11 days.

Intense outpatient follow-up should include individual psychotherapy, substance abuse counseling, and drug therapy. Highly addictive medications should be avoided because of the patient’s substance abuse history.

Did Mr. R accurately report the amount of GBL he had taken? How should GBL and GHB blood levels be measured, given the agents’ rapid absorption rates?

The authors’ observations

As with most drugs of abuse, high doses over time contribute to severe GHB withdrawal syndrome. GHB doses taken before withdrawal are up to 10 times greater than those taken in typical recreational use.⁵

However, quantifying GHB levels with standard urine drug screens is nearly impossible because:

• the agent is absorbed within 20 to 60 minutes
• only 2% to 5% of the agent is eliminated in the urine.

GHB—which comes in powder, tablet, and liquid form and is usually dissolved in water before use—often is mixed with other drugs or alcohol. Varying preparations and use with multiple substances can produce inconsistent GHB levels and decrease sensitivity and specificity in routine drug screening. GHB abusers also report the amount ingested in “capfuls,” ounces, and teaspoons, making accurate quantification harder still.²

Though infrequently used because of feasibility and cost, gas chromatography and infrared spectroscopy of a urine specimen are the only known methods for determining GHB levels. Chronic GHB use, negative polypharmacy history, and negative urine and blood analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances usually confirm GHB withdrawal diagnosis.¹

Treatment: ‘Bad’ medicine

In the ER, Mr. R was given two 1-mg doses of lorazepam IV 1 hour apart. After 1 hour, his vital signs improved slightly (heart rate: 100/min; blood pressure: 165/99 mm Hg). Thiamine and folate were also started. Mr. R’s severe agitation and paranoia persisted, so three more 2-mg doses of lorazepam IV were given at 4-hour intervals.

Within 2 days, Mr. R was transferred to the voluntary inpatient psychiatric unit. His nausea, vomiting, and autonomic instability resolved, but his delirium and psychosis persisted. Quetiapine, 100 mg bid, was started to address his psychosis, and bupropion, 150 mg once daily, was restarted to manage his previously diagnosed depression. Three days after starting bupropion, Mr. R’s mood improved based on patient reports and Clinical Global Impression scores (6 at baseline, 2 at discharge), but his persecutory delusions persisted, causing mild anxiety.

The next day, Mr. R’s auditory and visual hallucinations had ceased, his preoccupation with terrorists began to subside, and his concentration, sleep, and appetite were improving. By day 6 of hospitalization, he still complained of mild tremors and anxiety, but his persecutory delusions resolved.

After 9 days, Mr. R was discharged. Autonomic stability was achieved and his delirium had mostly resolved. Outpatient drug rehabilitation and psychiatric services were arranged.

As of this writing, Mr. R had not sought outpatient treatment. His current medical status is unknown.

Related resources

• Miglani J, Kim K, Chahil R. Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry. 2000;22:213-6.
• Columbo G, Agabio R, Lobina C, et al. Cross tolerance to ethanol and gamma-hydroxybutyric acid. Eur J Pharmacol. 1995;273:235-8.
• Project GHB. www.projectghb.org

Drug brand names

• Bupropion • Wellbutrin
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta
• Paroxetine • Paxil
• Quetiapine • Seroquel

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Emergency presentation: A rough commute

Mr. R, age 25, presented to the emergency room confused and severely agitated. That morning, his parents found him in his Philadelphia apartment covering his mouth and nose with a T-shirt to guard against imminent chemical warfare.

The day before, Mr. R had developed auditory and visual hallucinations and paranoid and persecutory delusions. That day, on his way to work, he said he had seen “terrorists releasing toxic chemicals into the air” and heard “whispers of terrorists plotting an attack on the East Coast.”

Mr. R showed no suicidal or homicidal ideations. He denied significant medical or surgical history but reported that he had recently been diagnosed with depression after a “bad Ecstasy experience.” For 6 months he had been taking paroxetine, 20 mg once daily, and bupropion, 150 mg once daily, for his depression.

At age 18, Mr. R was diagnosed with attention-deficit/hyperactivity disorder (ADHD) after years of struggling through school with impaired concentration. At that time, he began taking methylphenidate, 10 mg each morning, and completed 3 years of college in North Carolina. He then dropped out of college and attempted suicide twice.

After the second suicide attempt, a psychiatrist diagnosed Mr. R as having major depression. The psychiatrist discontinued methylphenidate and started bupropion, dosage unknown. After 1 year, he stopped taking the antidepressant, thinking he no longer needed it.

Last year, Mr. R moved back to Philadelphia to be closer to his parents. Shortly afterward, he began obtaining methylphenidate illegally and later starting using cocaine, marijuana, amphetamines, and 3,4-methylenedioxymethamphetamine (“Ecstasy”).

At presentation, Mr. R’s mood was dysphoric with bizarre affect. Eye contact was poor with easy distractibility. Speech was pressured, with full range. His thought process was grossly disorganized with tangential thinking and flight of ideas. His short- and long-term memory were intact; insight and judgment were limited. A Mini-Mental State Examination could not be completed because of his disorganization and distractibility.

Does Mr. R. have schizophrenia or schizoaffective disorder? Or are his symptoms related to ADHD or substance abuse?

The authors’ observations

Mr. R’s paranoid delusions and hallucinations may suggest schizophrenia. With his history of suicide attempts, a depressive or schizoaffective disorder may also be considered.

However, Mr. R is close with his family and has several friends. His parents say he has not been withdrawn or paranoid, and there is no known family history of mood disorder, substance abuse, or other psychiatric illness. Mr. R also has been working steadily and had worked the night before presenting to us, so schizophrenia and schizoaffective disorder are ruled out. ADHD and abuse of multiple substances could explain his behavior because overdose of stimulants and illicit drugs may produce a psychotic event.

Further history: The power of addiction

After more questioning, Mr. R said that he had recently started using gamma butyrolactone (GBL) in a failed attempt to build muscle. For 4 months he had been taking 3.5 oz of GBL daily—0.25 oz every 2 to 3 hours and 0.75 oz at night to help him sleep.

Within 6 hours of his most recent GBL dose (reportedly 1 oz), Mr. R developed intractable nausea, vomiting, and flatus, followed quickly by anxiety, palpitations, and generalized hand/body tremors that disturbed his sleep. Hallucinations and delusions started the next day.

At presentation, Mr. R’s blood pressure was 188/92 mm Hg, his heart rate was 110 bpm, and his respiratory rate was 22 breaths per minute. Pupils were 5 mm and reactive with intact extraocular movement. A urine drug screen indicated amphetamine use.

Mr. R was tentatively diagnosed as having GBL withdrawal syndrome and was admitted for observation and treatment. The psychiatry service followed him for change in mental status and drug dependence.

Can a withdrawal syndrome reasonably account for Mr. R’s symptoms?

The authors’ observations

GBL is a precursor of gamma-hydroxybutyrate (GHB), a highly addictive agent that is used illicitly, typically at parties and nightclubs (Box). GBL is among the clinical analogues of GHB that have become popular street drugs.

GHB withdrawal syndrome has only recently been described in the literature and is virtually indistinguishable from withdrawal after cessation of GBL and other precursors. To date, 71 deaths have been attributed to GHB withdrawal.²

A constellation of symptoms exhibited by Mr. R point to GHB withdrawal, which should be included in the differential diagnosis of any sedative/hypnotic withdrawal (Table 1).

How GHB works. GHB easily crosses the blood-brain barrier. Like other sedative/hypnotics, its depressant effects on the brain in low doses (2 to 4 grams) produce a euphoric feeling as inhibitions are depressed. Profound coma or death result from higher doses (>4 grams).³ Heart rate may also be slowed and CNS effects may result in myoclonus, producing seizure-like movements. Combining GHB with other drugs can increase the other agents’ depressant effects, leading to confusion, amnesia, vomiting, irregular breathing, or death.²

Box

A tiny increase in GHB dose can dramatically increase the symptoms and risk of overdose.⁴ GHB’s effects are also variable: A 1-teaspoon dose can produce the desired “high” one time and an overdose the next.

GHB and ethanol share a common mechanism of action.⁵ At pharmacologic doses, GHB appears to act in part through effects on the structurally related GABA neurotransmitter or its receptors.

Not surprisingly, a withdrawal syndrome characterized by delirium and autonomic instability ensues after GHB use is abruptly stopped. By functioning as indirect GABA agonists and ultimately evoking inhibitory neurotransmission, benzodiazepines and most barbiturates may alleviate GHB withdrawal symptoms.⁴ Thiamine is added to prevent Wernicke-Korsakoff syndrome, as is seen in alcohol withdrawal.⁵

GHB withdrawal. Symptoms are divided into three phases:

• Phase 1 (acute, first 24 hours). Presenting symptoms include anxiety, restlessness, insomnia, tremor, diaphoresis, tachycardia, and hypertension. Nausea and vomiting are variable but can be unrelenting.

While symptoms vary in severity, most prominent are agitation, restlessness, and insomnia. Some patients do not sleep for days after their last dose, and diffuse body tremors prevent them from sitting or lying still. Tachycardia and hypertension are hard to evaluate at this phase because patients present at different stages of withdrawal. Initial blood pressure readings as high as 240/130 mm Hg and heart rates of 120 bpm have been reported, however.

• Phase 2 (days 2 through 6). Worsening autonomic symptoms, progressive GI symptoms, and overall worsening of the withdrawal mark this tumultuous period. Patients usually present at this point—in acute distress and no longer able to self-treat.

Confusion, delirium, and florid psychosis characterize this phase. Mr. R’s paranoid delusions and hallucinations are the most common form of psychosis seen in GHB withdrawal.⁵ In some cases, the psychosis impairs social, occupational, and other functioning.

Table 1

Comparison of sedative-hypnotic withdrawal syndromes

Underlying or concurrent causes of delirium must be ruled out. Patients at this stage often require physical restraint or immediate sedation to prevent injury and dangerous complications, including hyperthermia and rhabdomyolysis. Benzodiazepines are often used in high doses¹ for sedation. IV hydration and antiemetics are also treatment mainstays. Atypical antipsychotics are added ASAP to control the paranoia.

• Phase 3 (days 7 through 13). Symptoms usually resolve at this stage. The delirium most often clears first, followed by restored autonomic stability and GI rest. While decreased sleep and periods of psychosis persist, agitation is less severe. The patient is discharged on average after 11 days.

Intense outpatient follow-up should include individual psychotherapy, substance abuse counseling, and drug therapy. Highly addictive medications should be avoided because of the patient’s substance abuse history.

Did Mr. R accurately report the amount of GBL he had taken? How should GBL and GHB blood levels be measured, given the agents’ rapid absorption rates?

The authors’ observations

As with most drugs of abuse, high doses over time contribute to severe GHB withdrawal syndrome. GHB doses taken before withdrawal are up to 10 times greater than those taken in typical recreational use.⁵

However, quantifying GHB levels with standard urine drug screens is nearly impossible because:

• the agent is absorbed within 20 to 60 minutes
• only 2% to 5% of the agent is eliminated in the urine.

GHB—which comes in powder, tablet, and liquid form and is usually dissolved in water before use—often is mixed with other drugs or alcohol. Varying preparations and use with multiple substances can produce inconsistent GHB levels and decrease sensitivity and specificity in routine drug screening. GHB abusers also report the amount ingested in “capfuls,” ounces, and teaspoons, making accurate quantification harder still.²

Though infrequently used because of feasibility and cost, gas chromatography and infrared spectroscopy of a urine specimen are the only known methods for determining GHB levels. Chronic GHB use, negative polypharmacy history, and negative urine and blood analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances usually confirm GHB withdrawal diagnosis.¹

Treatment: ‘Bad’ medicine

In the ER, Mr. R was given two 1-mg doses of lorazepam IV 1 hour apart. After 1 hour, his vital signs improved slightly (heart rate: 100/min; blood pressure: 165/99 mm Hg). Thiamine and folate were also started. Mr. R’s severe agitation and paranoia persisted, so three more 2-mg doses of lorazepam IV were given at 4-hour intervals.

Within 2 days, Mr. R was transferred to the voluntary inpatient psychiatric unit. His nausea, vomiting, and autonomic instability resolved, but his delirium and psychosis persisted. Quetiapine, 100 mg bid, was started to address his psychosis, and bupropion, 150 mg once daily, was restarted to manage his previously diagnosed depression. Three days after starting bupropion, Mr. R’s mood improved based on patient reports and Clinical Global Impression scores (6 at baseline, 2 at discharge), but his persecutory delusions persisted, causing mild anxiety.

The next day, Mr. R’s auditory and visual hallucinations had ceased, his preoccupation with terrorists began to subside, and his concentration, sleep, and appetite were improving. By day 6 of hospitalization, he still complained of mild tremors and anxiety, but his persecutory delusions resolved.

After 9 days, Mr. R was discharged. Autonomic stability was achieved and his delirium had mostly resolved. Outpatient drug rehabilitation and psychiatric services were arranged.

As of this writing, Mr. R had not sought outpatient treatment. His current medical status is unknown.

Related resources

• Miglani J, Kim K, Chahil R. Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry. 2000;22:213-6.
• Columbo G, Agabio R, Lobina C, et al. Cross tolerance to ethanol and gamma-hydroxybutyric acid. Eur J Pharmacol. 1995;273:235-8.
• Project GHB. www.projectghb.org

Drug brand names

• Bupropion • Wellbutrin
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta
• Paroxetine • Paxil
• Quetiapine • Seroquel

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Emergency presentation: A rough commute

Mr. R, age 25, presented to the emergency room confused and severely agitated. That morning, his parents found him in his Philadelphia apartment covering his mouth and nose with a T-shirt to guard against imminent chemical warfare.

The day before, Mr. R had developed auditory and visual hallucinations and paranoid and persecutory delusions. That day, on his way to work, he said he had seen “terrorists releasing toxic chemicals into the air” and heard “whispers of terrorists plotting an attack on the East Coast.”

Mr. R showed no suicidal or homicidal ideations. He denied significant medical or surgical history but reported that he had recently been diagnosed with depression after a “bad Ecstasy experience.” For 6 months he had been taking paroxetine, 20 mg once daily, and bupropion, 150 mg once daily, for his depression.

At age 18, Mr. R was diagnosed with attention-deficit/hyperactivity disorder (ADHD) after years of struggling through school with impaired concentration. At that time, he began taking methylphenidate, 10 mg each morning, and completed 3 years of college in North Carolina. He then dropped out of college and attempted suicide twice.

After the second suicide attempt, a psychiatrist diagnosed Mr. R as having major depression. The psychiatrist discontinued methylphenidate and started bupropion, dosage unknown. After 1 year, he stopped taking the antidepressant, thinking he no longer needed it.

Last year, Mr. R moved back to Philadelphia to be closer to his parents. Shortly afterward, he began obtaining methylphenidate illegally and later starting using cocaine, marijuana, amphetamines, and 3,4-methylenedioxymethamphetamine (“Ecstasy”).

At presentation, Mr. R’s mood was dysphoric with bizarre affect. Eye contact was poor with easy distractibility. Speech was pressured, with full range. His thought process was grossly disorganized with tangential thinking and flight of ideas. His short- and long-term memory were intact; insight and judgment were limited. A Mini-Mental State Examination could not be completed because of his disorganization and distractibility.

Does Mr. R. have schizophrenia or schizoaffective disorder? Or are his symptoms related to ADHD or substance abuse?

The authors’ observations

Mr. R’s paranoid delusions and hallucinations may suggest schizophrenia. With his history of suicide attempts, a depressive or schizoaffective disorder may also be considered.

However, Mr. R is close with his family and has several friends. His parents say he has not been withdrawn or paranoid, and there is no known family history of mood disorder, substance abuse, or other psychiatric illness. Mr. R also has been working steadily and had worked the night before presenting to us, so schizophrenia and schizoaffective disorder are ruled out. ADHD and abuse of multiple substances could explain his behavior because overdose of stimulants and illicit drugs may produce a psychotic event.

Further history: The power of addiction

After more questioning, Mr. R said that he had recently started using gamma butyrolactone (GBL) in a failed attempt to build muscle. For 4 months he had been taking 3.5 oz of GBL daily—0.25 oz every 2 to 3 hours and 0.75 oz at night to help him sleep.

Within 6 hours of his most recent GBL dose (reportedly 1 oz), Mr. R developed intractable nausea, vomiting, and flatus, followed quickly by anxiety, palpitations, and generalized hand/body tremors that disturbed his sleep. Hallucinations and delusions started the next day.

At presentation, Mr. R’s blood pressure was 188/92 mm Hg, his heart rate was 110 bpm, and his respiratory rate was 22 breaths per minute. Pupils were 5 mm and reactive with intact extraocular movement. A urine drug screen indicated amphetamine use.

Mr. R was tentatively diagnosed as having GBL withdrawal syndrome and was admitted for observation and treatment. The psychiatry service followed him for change in mental status and drug dependence.

Can a withdrawal syndrome reasonably account for Mr. R’s symptoms?

The authors’ observations

GBL is a precursor of gamma-hydroxybutyrate (GHB), a highly addictive agent that is used illicitly, typically at parties and nightclubs (Box). GBL is among the clinical analogues of GHB that have become popular street drugs.

GHB withdrawal syndrome has only recently been described in the literature and is virtually indistinguishable from withdrawal after cessation of GBL and other precursors. To date, 71 deaths have been attributed to GHB withdrawal.²

A constellation of symptoms exhibited by Mr. R point to GHB withdrawal, which should be included in the differential diagnosis of any sedative/hypnotic withdrawal (Table 1).

How GHB works. GHB easily crosses the blood-brain barrier. Like other sedative/hypnotics, its depressant effects on the brain in low doses (2 to 4 grams) produce a euphoric feeling as inhibitions are depressed. Profound coma or death result from higher doses (>4 grams).³ Heart rate may also be slowed and CNS effects may result in myoclonus, producing seizure-like movements. Combining GHB with other drugs can increase the other agents’ depressant effects, leading to confusion, amnesia, vomiting, irregular breathing, or death.²

Box

A tiny increase in GHB dose can dramatically increase the symptoms and risk of overdose.⁴ GHB’s effects are also variable: A 1-teaspoon dose can produce the desired “high” one time and an overdose the next.

GHB and ethanol share a common mechanism of action.⁵ At pharmacologic doses, GHB appears to act in part through effects on the structurally related GABA neurotransmitter or its receptors.

Not surprisingly, a withdrawal syndrome characterized by delirium and autonomic instability ensues after GHB use is abruptly stopped. By functioning as indirect GABA agonists and ultimately evoking inhibitory neurotransmission, benzodiazepines and most barbiturates may alleviate GHB withdrawal symptoms.⁴ Thiamine is added to prevent Wernicke-Korsakoff syndrome, as is seen in alcohol withdrawal.⁵

GHB withdrawal. Symptoms are divided into three phases:

• Phase 1 (acute, first 24 hours). Presenting symptoms include anxiety, restlessness, insomnia, tremor, diaphoresis, tachycardia, and hypertension. Nausea and vomiting are variable but can be unrelenting.

While symptoms vary in severity, most prominent are agitation, restlessness, and insomnia. Some patients do not sleep for days after their last dose, and diffuse body tremors prevent them from sitting or lying still. Tachycardia and hypertension are hard to evaluate at this phase because patients present at different stages of withdrawal. Initial blood pressure readings as high as 240/130 mm Hg and heart rates of 120 bpm have been reported, however.

• Phase 2 (days 2 through 6). Worsening autonomic symptoms, progressive GI symptoms, and overall worsening of the withdrawal mark this tumultuous period. Patients usually present at this point—in acute distress and no longer able to self-treat.

Confusion, delirium, and florid psychosis characterize this phase. Mr. R’s paranoid delusions and hallucinations are the most common form of psychosis seen in GHB withdrawal.⁵ In some cases, the psychosis impairs social, occupational, and other functioning.

Table 1

Comparison of sedative-hypnotic withdrawal syndromes

Underlying or concurrent causes of delirium must be ruled out. Patients at this stage often require physical restraint or immediate sedation to prevent injury and dangerous complications, including hyperthermia and rhabdomyolysis. Benzodiazepines are often used in high doses¹ for sedation. IV hydration and antiemetics are also treatment mainstays. Atypical antipsychotics are added ASAP to control the paranoia.

• Phase 3 (days 7 through 13). Symptoms usually resolve at this stage. The delirium most often clears first, followed by restored autonomic stability and GI rest. While decreased sleep and periods of psychosis persist, agitation is less severe. The patient is discharged on average after 11 days.

Intense outpatient follow-up should include individual psychotherapy, substance abuse counseling, and drug therapy. Highly addictive medications should be avoided because of the patient’s substance abuse history.

Did Mr. R accurately report the amount of GBL he had taken? How should GBL and GHB blood levels be measured, given the agents’ rapid absorption rates?

The authors’ observations

As with most drugs of abuse, high doses over time contribute to severe GHB withdrawal syndrome. GHB doses taken before withdrawal are up to 10 times greater than those taken in typical recreational use.⁵

However, quantifying GHB levels with standard urine drug screens is nearly impossible because:

• the agent is absorbed within 20 to 60 minutes
• only 2% to 5% of the agent is eliminated in the urine.

GHB—which comes in powder, tablet, and liquid form and is usually dissolved in water before use—often is mixed with other drugs or alcohol. Varying preparations and use with multiple substances can produce inconsistent GHB levels and decrease sensitivity and specificity in routine drug screening. GHB abusers also report the amount ingested in “capfuls,” ounces, and teaspoons, making accurate quantification harder still.²

Though infrequently used because of feasibility and cost, gas chromatography and infrared spectroscopy of a urine specimen are the only known methods for determining GHB levels. Chronic GHB use, negative polypharmacy history, and negative urine and blood analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances usually confirm GHB withdrawal diagnosis.¹

Treatment: ‘Bad’ medicine

In the ER, Mr. R was given two 1-mg doses of lorazepam IV 1 hour apart. After 1 hour, his vital signs improved slightly (heart rate: 100/min; blood pressure: 165/99 mm Hg). Thiamine and folate were also started. Mr. R’s severe agitation and paranoia persisted, so three more 2-mg doses of lorazepam IV were given at 4-hour intervals.

Within 2 days, Mr. R was transferred to the voluntary inpatient psychiatric unit. His nausea, vomiting, and autonomic instability resolved, but his delirium and psychosis persisted. Quetiapine, 100 mg bid, was started to address his psychosis, and bupropion, 150 mg once daily, was restarted to manage his previously diagnosed depression. Three days after starting bupropion, Mr. R’s mood improved based on patient reports and Clinical Global Impression scores (6 at baseline, 2 at discharge), but his persecutory delusions persisted, causing mild anxiety.

The next day, Mr. R’s auditory and visual hallucinations had ceased, his preoccupation with terrorists began to subside, and his concentration, sleep, and appetite were improving. By day 6 of hospitalization, he still complained of mild tremors and anxiety, but his persecutory delusions resolved.

After 9 days, Mr. R was discharged. Autonomic stability was achieved and his delirium had mostly resolved. Outpatient drug rehabilitation and psychiatric services were arranged.

As of this writing, Mr. R had not sought outpatient treatment. His current medical status is unknown.

Related resources

• Miglani J, Kim K, Chahil R. Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry. 2000;22:213-6.
• Columbo G, Agabio R, Lobina C, et al. Cross tolerance to ethanol and gamma-hydroxybutyric acid. Eur J Pharmacol. 1995;273:235-8.
• Project GHB. www.projectghb.org

Drug brand names

• Bupropion • Wellbutrin
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta
• Paroxetine • Paxil
• Quetiapine • Seroquel

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

f

Before I see them, most of my depressed patients have failed an SSRI trial prescribed by their primary care physicians. Some have already tried two or more antidepressants. I bet your practice is the same.

Unfortunately, few medications have been tested on patients with treatment-resistant depression. To gain FDA approval, an investigational drug needs to show a treatment effect greater than placebo, and testing a drug on a treatment-resistant population is risky for pharmaceutical companies. Compared with monotherapy, even fewer large-scale studies have combined two or more medications for major depressive disorder.

In this issue, A. John Rush, MD, of the University of Texas Southwestern Medical Center, provides the best synthesis I have seen of the literature on treatment-resistant depression. I am already incorporating his insights into my clinical practice.

Not to minimize the suffering of patients with treatment-resistant depression, but I believe this disorder saved psychiatry. Ten years ago, doomsayers predicted psychiatry’s demise, assuming anyone could do psychotherapy and any physician could prescribe 20 mg of Prozac. Those predictions have proven wrong, and demand for psychiatrists has grown.

We do not compete with primary care physicians. The more depressed patients our medical colleagues treat, the more treatment-resistant cases they refer for psychiatric care. We may not be seeing as many patients with nontreatment depression, but fewer with major depressive disorder are suffering without receiving effective treatment.

f

Before I see them, most of my depressed patients have failed an SSRI trial prescribed by their primary care physicians. Some have already tried two or more antidepressants. I bet your practice is the same.

Unfortunately, few medications have been tested on patients with treatment-resistant depression. To gain FDA approval, an investigational drug needs to show a treatment effect greater than placebo, and testing a drug on a treatment-resistant population is risky for pharmaceutical companies. Compared with monotherapy, even fewer large-scale studies have combined two or more medications for major depressive disorder.

In this issue, A. John Rush, MD, of the University of Texas Southwestern Medical Center, provides the best synthesis I have seen of the literature on treatment-resistant depression. I am already incorporating his insights into my clinical practice.

Not to minimize the suffering of patients with treatment-resistant depression, but I believe this disorder saved psychiatry. Ten years ago, doomsayers predicted psychiatry’s demise, assuming anyone could do psychotherapy and any physician could prescribe 20 mg of Prozac. Those predictions have proven wrong, and demand for psychiatrists has grown.

We do not compete with primary care physicians. The more depressed patients our medical colleagues treat, the more treatment-resistant cases they refer for psychiatric care. We may not be seeing as many patients with nontreatment depression, but fewer with major depressive disorder are suffering without receiving effective treatment.

f

Before I see them, most of my depressed patients have failed an SSRI trial prescribed by their primary care physicians. Some have already tried two or more antidepressants. I bet your practice is the same.

Unfortunately, few medications have been tested on patients with treatment-resistant depression. To gain FDA approval, an investigational drug needs to show a treatment effect greater than placebo, and testing a drug on a treatment-resistant population is risky for pharmaceutical companies. Compared with monotherapy, even fewer large-scale studies have combined two or more medications for major depressive disorder.

In this issue, A. John Rush, MD, of the University of Texas Southwestern Medical Center, provides the best synthesis I have seen of the literature on treatment-resistant depression. I am already incorporating his insights into my clinical practice.

Not to minimize the suffering of patients with treatment-resistant depression, but I believe this disorder saved psychiatry. Ten years ago, doomsayers predicted psychiatry’s demise, assuming anyone could do psychotherapy and any physician could prescribe 20 mg of Prozac. Those predictions have proven wrong, and demand for psychiatrists has grown.

We do not compete with primary care physicians. The more depressed patients our medical colleagues treat, the more treatment-resistant cases they refer for psychiatric care. We may not be seeing as many patients with nontreatment depression, but fewer with major depressive disorder are suffering without receiving effective treatment.

Many well-controlled trials in the past 4 years have evaluated new medications for treating bipolar disorder. It’s time to build a consensus on how this data may apply to clinical practice.

This year, our group will re-examine the Texas Medication Algorithm Project (TMAP) treatment algorithms for bipolar I disorder.

What makes TMAP unique? It is the first project to evaluate treatment algorithm use in community mental health settings for patients with a history of mania (see Box).^1-5 Severely, persistently ill outpatients such as these are seldom included in research but are frequently seen in clinical practice.

To preview for psychiatrists the changes expected in 2004, this article describes the goals of TMAP and the controlled study on which the medication algorithms are based. We review the medication algorithms of 2000 as a starting point and present the evidence that is changing clinical practice.

Guiding principles of TMAP

A treatment algorithm is no substitute for clinical judgment; rather, medication guidelines and algorithms are guideposts to help the clinician and patient collaboratively develop the most effective medication strategy with the fewest side effects.

Box

TMAP’s treatment manual (see Related resources) describes clinicians’ preferred tactics and decision points, which we summarize here. The guidelines are an ongoing effort to apply evidence-based medicine to everyday practice and are meant to be adapted to patient needs.

Treatment goals that guided TMAP algorithm development are:

• symptomatic remission
• full return of psychosocial functioning
• prevention of relapse and recurrence.

Suggestions came from controlled clinical trials, open trials, retrospective data analyses, expert clinical consensus, and input from consumers.

Treatment selection. Initial algorithm stages recommend simple treatments (in terms of safety, tolerability, and side effects), whereas later stages recommend more-complicated regimens. A patient’s symptoms, comorbid conditions, and treatment history guide treatment selection. Patients may enter an algorithm at any stage, depending on their clinical presentation and medication history.

The clinician may consider patient preference when deciding among equivalent medications. The algorithm strongly encourages patients and families to participate, such as by keeping daily mood charts and completing symptom and side-effect checklists. When clinicians face a choice among medication brands, generics, or forms (such as immediate- versus slow-release), agents with greater tolerability are preferred.

Patient management. When patients enter the algorithm, clinic visits are frequent (such as every 2 weeks). Follow-up appointments address medication adherence, dosage adjustments, and side effects or adverse reactions.

If a patient’s symptoms show no change after two treatment stages, re-evaluate the diagnosis and consider mitigating factors such as substance abuse. Patients who complete acute treatment should receive continuation treatment.

Documentation. Clinicians are advised to document decision points and the rationale for treatment choices made outside the algorithm package.

Treating mania or hypomania

After clinical evaluation confirms the diagnosis of bipolar illness,⁴ the TMAP mania/hypomania algorithm (Algorithm 1) splits into three treatment pathways:

• euphoric mania/hypomania
• mixed or dysphoric mania/hypomania
• psychotic mania.

These pathways recognize the need for differing approaches to initial monotherapy and later two-drug combinations. If a patient develops persistent or severe depressive symptoms, the bipolar algorithm for a major depressive episode (Algorithm 2) is used during depressive periods with the primary mania algorithm.

Treatment recommendations. The key to using mood stabilizers is to achieve the optimum response—assuming good tolerability—before switching to another agent. Adjust medication dosages one at a time to allow adequate response and assessment.

When switching medications, use an overlap-and-taper strategy, assuming there is no medical necessity to stop a drug abruptly. Add the new medication, then gradually taper the one that is being discontinued. Monitor serum levels.

Discontinue antidepressants when appropriate in patients with hypomania/mania or rapid cycling, and continually evaluate suicide and homicide potential of patients in mixed or depressive states.

Stage 1: Monotherapy. First medication choices are lithium, divalproex, or olanzapine. For mixed or dysphoric mania, the algorithm recommends divalproex (preferred over valproic acid because of tolerability and side effects) or olanzapine.⁶ Data suggest dysphoric manic patients are less likely to respond to lithium.⁷ A Consensus Panel minority expressed concern about using olanzapine as first-line monotherapy for acute mania because of limited data on the drug’s long-term safety. Patients with partial response or residual symptoms may move to stage 2 or switch to other medication options within stage 1.

Patients with psychotic mania move directly to stage 4 for a broader range of combination therapy.

Stage 2: Combination therapy. Combination therapy has become the standard of care in treating most patients with bipolar disorder. The algorithm recommends using two agents:

• lithium or an anticonvulsant plus another anticonvulsant ([Li or AC]+AC)
• or lithium or an anticonvulsant plus an atypical antipsychotic ([Li or AC]+AAP).⁸

Recommended agents include lithium, divalproex, oxcarbazepine, olanzapine, or risperidone. The experts recommended oxcarbazepine as first choice because it is better tolerated and interacts with fewer drugs than carbamazepine and does not require serum level monitoring.⁹

A Consensus Panel minority expressed concern that few studies had examined using oxcarbazepine in bipolar disorder. Carbamazepine was also considered an option.

Stages 3 and 4: Other two-drug combinations. Other two-drug combinations are tried at these stages, drawing from the same pool of medication classes described in stage 2.

Stage 4 broadens the choice of atypical antipsychotic by adding quetiapine¹⁰ and ziprasidone¹¹ to the recommended stage-2 agents olanzapine and risperidone. When the 2000 algorithm was developed, limited data were available on using some newer atypicals in patients with bipolar mania. Based on recent, high-quality studies of mono- and combination therapy—including quetiapine,¹⁰ ziprasidone,¹¹ risperidone,^12,13 and aripiprazole¹⁴ —the 2004 algorithm update panel will likely recommend using atypicals earlier, including at stage 1.

Algorithm 1 Treating mania/hypomania in patients with bipolar I disorder

Stage 6: ECT or clozapine. For patients with inadequate response to triple-drug combinations, the algorithm recommends adding electroconvulsive therapy (ECT) or clozapine.

ECT¹⁵ is recommended three times a week until the patient achieves remission of manic symptoms or fails to achieve a sustained response over three to six treatment cycles. Treatment resistance is declared if no response is seen after 6 to 10 treatment cycles.

Clozapine’s¹⁶ recommendation at this stage is consistent with its use in patients who fail to respond to other atypical antipsychotics. Blood monitoring for agranulocytosis is required; other adverse effects include an increased risk of seizures, myocarditis, and orthostatic hypotension.

Stage 7: Other. Treatment options such as topiramate^17,18 and lamotrigine¹⁹ are recommended at this stage. These recommendations also will be reviewed and likely revised.

Treating bipolar depression

The TMAP algorithm for treating depression in bipolar disorder (Algorithm 2) assumes that anti-depressants will be used only with optimum mood-stabilizer levels because of the risk of inducing manic symptoms. The bipolar depression algorithm is always used with the primary algorithm for mania/hypomania.

The patient’s clinical presentation guides medication selection. For the “pure” bipolar I patient with a major depressive episode but little mood lability or hypomania, starting an antide-pressant is a clear decision. On the other hand, patients with predominant depressive symptoms plus dysphoric hypomania, mood lability, and irritability need a balance of mood-stabilizing drugs and antidepressants.

Stage 1: Mood stabilizer. Initiate a mood stabilizer and optimize the dosage. Choices are the same mood stabilizers listed in the hypomania/mania treatment algorithm.

Stage 2: Antidepressant. Adding an antidepressant implies that depressive symptoms are severe enough to change treatment. Antidepressant options include a selective serotonin reuptake inhibitor (SSRI), sustained-release bupropion, or lamotrigine.²⁰

Using SSRIs is supported by widespread clinical experience and offers the convenience of once-daily dosing. Recommended SSRIs include fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram. The SSRI escitalopram was introduced after the 2000 algorithms were published; evidence for using it and other newer medications will be reviewed for the 2004 update.

The recommendation for sustained-release bupropion is consistent with the algorithm principle to use medications in the most well-tolerated form when accessible and available.

With lamotrigine, review with patients the risk of serious rash. To minimize rash risk, start lamotrigine slowly and follow the recommended titration schedule.

Stage 3: Multiple choices. At this stage, no definitive studies, safety data, or tolerability issues are available to rank the medication choices. The algorithm suggests:

• adding lithium²¹ or a second antidepressant
• or switching to an alternate antidepressant such as venlafaxine or nefazodone.

If a patient moves to stage 3 because of side effects with one antidepressant class, a different class—preferably with a contrasting side-effect profile—is recommended.

Algorithm 2 Treating depression in bipolar I disorder*

Stage 5. Antipsychotic or MAOI. At this stage, the algorithm recommends adding an atypical antipsychotic²² or switching to a monoamine oxidase inhibitor (MAOI).

Early evidence supported the efficacy of MAOIs in bipolar depression. However, the panel ranked MAOIs lower in the algorithm because they are associated with more bothersome side effects than SSRIs and other antidepressants. When using MAOIs, provide patients with dietary restriction guidelines.

Stage 6. Other therapies. Therapies such as ECT or “other” interventions are recommended at this stage. ECT has proven efficacy in bipolar depression and is appropriate for patients with limited medication response. The panel gave ECT a low ranking because of limited availability, lack of patient acceptance, and newer options.

Medication options include experimental treatments with limited evidence, such as inositol, dopamine agonists, stimulants, thyroid supplementation, conventional antipsychotics, and tri-cyclic antidepressants.

Acute to maintenance treatment

Adjunctive treatments for agitation, insomnia, GI upset, sedation, headache, and tremor are recommended in the physician manual supporting the TMAP guidelines (see Related resources). The manual also suggests ways to manage medication side effects and modify the algorithms for inpatients.

Patient and family psychoeducation plays an important role in helping the patient:

• identify prodromal bipolar symptoms
• understand the need to take medications as prescribed.

Continuation treatment. After mania or hypomania remits, continue medication(s) at the effective acute-phase dosages for at least 3 months. Use follow-up visits to enhance patient adherence, detect early symptoms of relapse, and monitor for side effects.

During the late continuation phase, after a period of sustained stability, clinicians can try to simplify the medications. When discontinuing a medication, taper the dosage by no more than 25% per week. If symptoms recur, promptly return to acute-phase treatment. Consider restarting medications and titrating up to the dosage(s) that resulted in remission.

In a depressive episode, continue the antidepressant(s) for 1 to 3 months at the effective acutephase dosage(s). Follow up frequently, and educate patients to watch for symptom recurrence and to communicate with you to assess when medication changes are needed.

Maintenance treatment. Relatively few well-controlled studies on long-term management of bipolar patients were available for the 2000 algorithm update.²³ In general, all patients need mood stabilizer(s) to prevent relapse, using the lowest dosage that maintains therapeutic efficacy. Based on new evidence for lamotrigine and atypical antipsychotics—including FDAapproval of olanzapine for bipolar maintenace therapy—we anticipate recommendations will be expanded and more delineated in the 2004 update.

Discontinuing antidepressants after 3 to 6 months of initial treatment is now recommended. However, a recent retrospective case series suggests that continuing antidepressants at least 1 year after initial successful therapy may protect against depressive relapse. During this study, continuing antidepressants more than 3 to 6 months did not appear to increase the risk of switching to mania.²⁴

Should antidepressants be continued or discontinued after successful acute treatment of a bipolar I depressive episode? This is an active area of research and debate as to the most appropriate strategy. The 2004 algorithm update panel will consider recent evidence that supports continuing antidepressants after symptom remission.²⁴

Related resources

• Texas Medication Algorithm Project algorithms and physician manual. Texas Department of Mental Health and Mental Retardation. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/TIMA.html
• American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 2002; 159(4):suppl 2.
• Depression and Bipolar Support Alliance. www.dbsalliance.org

Drug brand names

• Bupropion • Wellbutrin SR
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Inositol • Various
• Lamotrigine • Lamictal
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Topiramate • Topamax
• Tranylcypromine • Parnate
• Valproic acid • Depakene
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

Dr. Shivakumar reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Suppes receives research support from or is a consultant to Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, National Institutes of Mental Health, Novartis Pharmaceuticals Corp., Pfizer Inc., Pharmaceutical Research Institute, Ortho-McNeil Pharmaceutical, Robert Wood Johnson Pharmaceutical Research Institute, The Stanley Medical Research Institute, and UCB Pharma.

Many well-controlled trials in the past 4 years have evaluated new medications for treating bipolar disorder. It’s time to build a consensus on how this data may apply to clinical practice.

This year, our group will re-examine the Texas Medication Algorithm Project (TMAP) treatment algorithms for bipolar I disorder.

What makes TMAP unique? It is the first project to evaluate treatment algorithm use in community mental health settings for patients with a history of mania (see Box).^1-5 Severely, persistently ill outpatients such as these are seldom included in research but are frequently seen in clinical practice.

To preview for psychiatrists the changes expected in 2004, this article describes the goals of TMAP and the controlled study on which the medication algorithms are based. We review the medication algorithms of 2000 as a starting point and present the evidence that is changing clinical practice.

Guiding principles of TMAP

A treatment algorithm is no substitute for clinical judgment; rather, medication guidelines and algorithms are guideposts to help the clinician and patient collaboratively develop the most effective medication strategy with the fewest side effects.

Box

TMAP’s treatment manual (see Related resources) describes clinicians’ preferred tactics and decision points, which we summarize here. The guidelines are an ongoing effort to apply evidence-based medicine to everyday practice and are meant to be adapted to patient needs.

Treatment goals that guided TMAP algorithm development are:

• symptomatic remission
• full return of psychosocial functioning
• prevention of relapse and recurrence.

Suggestions came from controlled clinical trials, open trials, retrospective data analyses, expert clinical consensus, and input from consumers.

Treatment selection. Initial algorithm stages recommend simple treatments (in terms of safety, tolerability, and side effects), whereas later stages recommend more-complicated regimens. A patient’s symptoms, comorbid conditions, and treatment history guide treatment selection. Patients may enter an algorithm at any stage, depending on their clinical presentation and medication history.

The clinician may consider patient preference when deciding among equivalent medications. The algorithm strongly encourages patients and families to participate, such as by keeping daily mood charts and completing symptom and side-effect checklists. When clinicians face a choice among medication brands, generics, or forms (such as immediate- versus slow-release), agents with greater tolerability are preferred.

Patient management. When patients enter the algorithm, clinic visits are frequent (such as every 2 weeks). Follow-up appointments address medication adherence, dosage adjustments, and side effects or adverse reactions.

If a patient’s symptoms show no change after two treatment stages, re-evaluate the diagnosis and consider mitigating factors such as substance abuse. Patients who complete acute treatment should receive continuation treatment.

Documentation. Clinicians are advised to document decision points and the rationale for treatment choices made outside the algorithm package.

Treating mania or hypomania

After clinical evaluation confirms the diagnosis of bipolar illness,⁴ the TMAP mania/hypomania algorithm (Algorithm 1) splits into three treatment pathways:

• euphoric mania/hypomania
• mixed or dysphoric mania/hypomania
• psychotic mania.

These pathways recognize the need for differing approaches to initial monotherapy and later two-drug combinations. If a patient develops persistent or severe depressive symptoms, the bipolar algorithm for a major depressive episode (Algorithm 2) is used during depressive periods with the primary mania algorithm.

Treatment recommendations. The key to using mood stabilizers is to achieve the optimum response—assuming good tolerability—before switching to another agent. Adjust medication dosages one at a time to allow adequate response and assessment.

When switching medications, use an overlap-and-taper strategy, assuming there is no medical necessity to stop a drug abruptly. Add the new medication, then gradually taper the one that is being discontinued. Monitor serum levels.

Discontinue antidepressants when appropriate in patients with hypomania/mania or rapid cycling, and continually evaluate suicide and homicide potential of patients in mixed or depressive states.

Stage 1: Monotherapy. First medication choices are lithium, divalproex, or olanzapine. For mixed or dysphoric mania, the algorithm recommends divalproex (preferred over valproic acid because of tolerability and side effects) or olanzapine.⁶ Data suggest dysphoric manic patients are less likely to respond to lithium.⁷ A Consensus Panel minority expressed concern about using olanzapine as first-line monotherapy for acute mania because of limited data on the drug’s long-term safety. Patients with partial response or residual symptoms may move to stage 2 or switch to other medication options within stage 1.

Patients with psychotic mania move directly to stage 4 for a broader range of combination therapy.

Stage 2: Combination therapy. Combination therapy has become the standard of care in treating most patients with bipolar disorder. The algorithm recommends using two agents:

• lithium or an anticonvulsant plus another anticonvulsant ([Li or AC]+AC)
• or lithium or an anticonvulsant plus an atypical antipsychotic ([Li or AC]+AAP).⁸

Recommended agents include lithium, divalproex, oxcarbazepine, olanzapine, or risperidone. The experts recommended oxcarbazepine as first choice because it is better tolerated and interacts with fewer drugs than carbamazepine and does not require serum level monitoring.⁹

A Consensus Panel minority expressed concern that few studies had examined using oxcarbazepine in bipolar disorder. Carbamazepine was also considered an option.

Stages 3 and 4: Other two-drug combinations. Other two-drug combinations are tried at these stages, drawing from the same pool of medication classes described in stage 2.

Stage 4 broadens the choice of atypical antipsychotic by adding quetiapine¹⁰ and ziprasidone¹¹ to the recommended stage-2 agents olanzapine and risperidone. When the 2000 algorithm was developed, limited data were available on using some newer atypicals in patients with bipolar mania. Based on recent, high-quality studies of mono- and combination therapy—including quetiapine,¹⁰ ziprasidone,¹¹ risperidone,^12,13 and aripiprazole¹⁴ —the 2004 algorithm update panel will likely recommend using atypicals earlier, including at stage 1.

Algorithm 1 Treating mania/hypomania in patients with bipolar I disorder

Stage 6: ECT or clozapine. For patients with inadequate response to triple-drug combinations, the algorithm recommends adding electroconvulsive therapy (ECT) or clozapine.

ECT¹⁵ is recommended three times a week until the patient achieves remission of manic symptoms or fails to achieve a sustained response over three to six treatment cycles. Treatment resistance is declared if no response is seen after 6 to 10 treatment cycles.

Clozapine’s¹⁶ recommendation at this stage is consistent with its use in patients who fail to respond to other atypical antipsychotics. Blood monitoring for agranulocytosis is required; other adverse effects include an increased risk of seizures, myocarditis, and orthostatic hypotension.

Stage 7: Other. Treatment options such as topiramate^17,18 and lamotrigine¹⁹ are recommended at this stage. These recommendations also will be reviewed and likely revised.

Treating bipolar depression

The TMAP algorithm for treating depression in bipolar disorder (Algorithm 2) assumes that anti-depressants will be used only with optimum mood-stabilizer levels because of the risk of inducing manic symptoms. The bipolar depression algorithm is always used with the primary algorithm for mania/hypomania.

The patient’s clinical presentation guides medication selection. For the “pure” bipolar I patient with a major depressive episode but little mood lability or hypomania, starting an antide-pressant is a clear decision. On the other hand, patients with predominant depressive symptoms plus dysphoric hypomania, mood lability, and irritability need a balance of mood-stabilizing drugs and antidepressants.

Stage 1: Mood stabilizer. Initiate a mood stabilizer and optimize the dosage. Choices are the same mood stabilizers listed in the hypomania/mania treatment algorithm.

Stage 2: Antidepressant. Adding an antidepressant implies that depressive symptoms are severe enough to change treatment. Antidepressant options include a selective serotonin reuptake inhibitor (SSRI), sustained-release bupropion, or lamotrigine.²⁰

Using SSRIs is supported by widespread clinical experience and offers the convenience of once-daily dosing. Recommended SSRIs include fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram. The SSRI escitalopram was introduced after the 2000 algorithms were published; evidence for using it and other newer medications will be reviewed for the 2004 update.

The recommendation for sustained-release bupropion is consistent with the algorithm principle to use medications in the most well-tolerated form when accessible and available.

With lamotrigine, review with patients the risk of serious rash. To minimize rash risk, start lamotrigine slowly and follow the recommended titration schedule.

Stage 3: Multiple choices. At this stage, no definitive studies, safety data, or tolerability issues are available to rank the medication choices. The algorithm suggests:

• adding lithium²¹ or a second antidepressant
• or switching to an alternate antidepressant such as venlafaxine or nefazodone.

If a patient moves to stage 3 because of side effects with one antidepressant class, a different class—preferably with a contrasting side-effect profile—is recommended.

Algorithm 2 Treating depression in bipolar I disorder*

Stage 5. Antipsychotic or MAOI. At this stage, the algorithm recommends adding an atypical antipsychotic²² or switching to a monoamine oxidase inhibitor (MAOI).

Early evidence supported the efficacy of MAOIs in bipolar depression. However, the panel ranked MAOIs lower in the algorithm because they are associated with more bothersome side effects than SSRIs and other antidepressants. When using MAOIs, provide patients with dietary restriction guidelines.

Stage 6. Other therapies. Therapies such as ECT or “other” interventions are recommended at this stage. ECT has proven efficacy in bipolar depression and is appropriate for patients with limited medication response. The panel gave ECT a low ranking because of limited availability, lack of patient acceptance, and newer options.

Medication options include experimental treatments with limited evidence, such as inositol, dopamine agonists, stimulants, thyroid supplementation, conventional antipsychotics, and tri-cyclic antidepressants.

Acute to maintenance treatment

Adjunctive treatments for agitation, insomnia, GI upset, sedation, headache, and tremor are recommended in the physician manual supporting the TMAP guidelines (see Related resources). The manual also suggests ways to manage medication side effects and modify the algorithms for inpatients.

Patient and family psychoeducation plays an important role in helping the patient:

• identify prodromal bipolar symptoms
• understand the need to take medications as prescribed.

Continuation treatment. After mania or hypomania remits, continue medication(s) at the effective acute-phase dosages for at least 3 months. Use follow-up visits to enhance patient adherence, detect early symptoms of relapse, and monitor for side effects.

During the late continuation phase, after a period of sustained stability, clinicians can try to simplify the medications. When discontinuing a medication, taper the dosage by no more than 25% per week. If symptoms recur, promptly return to acute-phase treatment. Consider restarting medications and titrating up to the dosage(s) that resulted in remission.

In a depressive episode, continue the antidepressant(s) for 1 to 3 months at the effective acutephase dosage(s). Follow up frequently, and educate patients to watch for symptom recurrence and to communicate with you to assess when medication changes are needed.

Maintenance treatment. Relatively few well-controlled studies on long-term management of bipolar patients were available for the 2000 algorithm update.²³ In general, all patients need mood stabilizer(s) to prevent relapse, using the lowest dosage that maintains therapeutic efficacy. Based on new evidence for lamotrigine and atypical antipsychotics—including FDAapproval of olanzapine for bipolar maintenace therapy—we anticipate recommendations will be expanded and more delineated in the 2004 update.

Discontinuing antidepressants after 3 to 6 months of initial treatment is now recommended. However, a recent retrospective case series suggests that continuing antidepressants at least 1 year after initial successful therapy may protect against depressive relapse. During this study, continuing antidepressants more than 3 to 6 months did not appear to increase the risk of switching to mania.²⁴

Should antidepressants be continued or discontinued after successful acute treatment of a bipolar I depressive episode? This is an active area of research and debate as to the most appropriate strategy. The 2004 algorithm update panel will consider recent evidence that supports continuing antidepressants after symptom remission.²⁴

Related resources

• Texas Medication Algorithm Project algorithms and physician manual. Texas Department of Mental Health and Mental Retardation. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/TIMA.html
• American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 2002; 159(4):suppl 2.
• Depression and Bipolar Support Alliance. www.dbsalliance.org

Drug brand names

• Bupropion • Wellbutrin SR
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Inositol • Various
• Lamotrigine • Lamictal
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Topiramate • Topamax
• Tranylcypromine • Parnate
• Valproic acid • Depakene
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

Dr. Shivakumar reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Suppes receives research support from or is a consultant to Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, National Institutes of Mental Health, Novartis Pharmaceuticals Corp., Pfizer Inc., Pharmaceutical Research Institute, Ortho-McNeil Pharmaceutical, Robert Wood Johnson Pharmaceutical Research Institute, The Stanley Medical Research Institute, and UCB Pharma.

Many well-controlled trials in the past 4 years have evaluated new medications for treating bipolar disorder. It’s time to build a consensus on how this data may apply to clinical practice.

This year, our group will re-examine the Texas Medication Algorithm Project (TMAP) treatment algorithms for bipolar I disorder.

What makes TMAP unique? It is the first project to evaluate treatment algorithm use in community mental health settings for patients with a history of mania (see Box).^1-5 Severely, persistently ill outpatients such as these are seldom included in research but are frequently seen in clinical practice.

To preview for psychiatrists the changes expected in 2004, this article describes the goals of TMAP and the controlled study on which the medication algorithms are based. We review the medication algorithms of 2000 as a starting point and present the evidence that is changing clinical practice.

Guiding principles of TMAP

A treatment algorithm is no substitute for clinical judgment; rather, medication guidelines and algorithms are guideposts to help the clinician and patient collaboratively develop the most effective medication strategy with the fewest side effects.

Box

TMAP’s treatment manual (see Related resources) describes clinicians’ preferred tactics and decision points, which we summarize here. The guidelines are an ongoing effort to apply evidence-based medicine to everyday practice and are meant to be adapted to patient needs.

Treatment goals that guided TMAP algorithm development are:

• symptomatic remission
• full return of psychosocial functioning
• prevention of relapse and recurrence.

Suggestions came from controlled clinical trials, open trials, retrospective data analyses, expert clinical consensus, and input from consumers.

Treatment selection. Initial algorithm stages recommend simple treatments (in terms of safety, tolerability, and side effects), whereas later stages recommend more-complicated regimens. A patient’s symptoms, comorbid conditions, and treatment history guide treatment selection. Patients may enter an algorithm at any stage, depending on their clinical presentation and medication history.

The clinician may consider patient preference when deciding among equivalent medications. The algorithm strongly encourages patients and families to participate, such as by keeping daily mood charts and completing symptom and side-effect checklists. When clinicians face a choice among medication brands, generics, or forms (such as immediate- versus slow-release), agents with greater tolerability are preferred.

Patient management. When patients enter the algorithm, clinic visits are frequent (such as every 2 weeks). Follow-up appointments address medication adherence, dosage adjustments, and side effects or adverse reactions.

If a patient’s symptoms show no change after two treatment stages, re-evaluate the diagnosis and consider mitigating factors such as substance abuse. Patients who complete acute treatment should receive continuation treatment.

Documentation. Clinicians are advised to document decision points and the rationale for treatment choices made outside the algorithm package.

Treating mania or hypomania

After clinical evaluation confirms the diagnosis of bipolar illness,⁴ the TMAP mania/hypomania algorithm (Algorithm 1) splits into three treatment pathways:

• euphoric mania/hypomania
• mixed or dysphoric mania/hypomania
• psychotic mania.

These pathways recognize the need for differing approaches to initial monotherapy and later two-drug combinations. If a patient develops persistent or severe depressive symptoms, the bipolar algorithm for a major depressive episode (Algorithm 2) is used during depressive periods with the primary mania algorithm.

Treatment recommendations. The key to using mood stabilizers is to achieve the optimum response—assuming good tolerability—before switching to another agent. Adjust medication dosages one at a time to allow adequate response and assessment.

When switching medications, use an overlap-and-taper strategy, assuming there is no medical necessity to stop a drug abruptly. Add the new medication, then gradually taper the one that is being discontinued. Monitor serum levels.

Discontinue antidepressants when appropriate in patients with hypomania/mania or rapid cycling, and continually evaluate suicide and homicide potential of patients in mixed or depressive states.

Stage 1: Monotherapy. First medication choices are lithium, divalproex, or olanzapine. For mixed or dysphoric mania, the algorithm recommends divalproex (preferred over valproic acid because of tolerability and side effects) or olanzapine.⁶ Data suggest dysphoric manic patients are less likely to respond to lithium.⁷ A Consensus Panel minority expressed concern about using olanzapine as first-line monotherapy for acute mania because of limited data on the drug’s long-term safety. Patients with partial response or residual symptoms may move to stage 2 or switch to other medication options within stage 1.

Patients with psychotic mania move directly to stage 4 for a broader range of combination therapy.

Stage 2: Combination therapy. Combination therapy has become the standard of care in treating most patients with bipolar disorder. The algorithm recommends using two agents:

• lithium or an anticonvulsant plus another anticonvulsant ([Li or AC]+AC)
• or lithium or an anticonvulsant plus an atypical antipsychotic ([Li or AC]+AAP).⁸

Recommended agents include lithium, divalproex, oxcarbazepine, olanzapine, or risperidone. The experts recommended oxcarbazepine as first choice because it is better tolerated and interacts with fewer drugs than carbamazepine and does not require serum level monitoring.⁹

A Consensus Panel minority expressed concern that few studies had examined using oxcarbazepine in bipolar disorder. Carbamazepine was also considered an option.

Stages 3 and 4: Other two-drug combinations. Other two-drug combinations are tried at these stages, drawing from the same pool of medication classes described in stage 2.

Stage 4 broadens the choice of atypical antipsychotic by adding quetiapine¹⁰ and ziprasidone¹¹ to the recommended stage-2 agents olanzapine and risperidone. When the 2000 algorithm was developed, limited data were available on using some newer atypicals in patients with bipolar mania. Based on recent, high-quality studies of mono- and combination therapy—including quetiapine,¹⁰ ziprasidone,¹¹ risperidone,^12,13 and aripiprazole¹⁴ —the 2004 algorithm update panel will likely recommend using atypicals earlier, including at stage 1.

Algorithm 1 Treating mania/hypomania in patients with bipolar I disorder

Stage 6: ECT or clozapine. For patients with inadequate response to triple-drug combinations, the algorithm recommends adding electroconvulsive therapy (ECT) or clozapine.

ECT¹⁵ is recommended three times a week until the patient achieves remission of manic symptoms or fails to achieve a sustained response over three to six treatment cycles. Treatment resistance is declared if no response is seen after 6 to 10 treatment cycles.

Clozapine’s¹⁶ recommendation at this stage is consistent with its use in patients who fail to respond to other atypical antipsychotics. Blood monitoring for agranulocytosis is required; other adverse effects include an increased risk of seizures, myocarditis, and orthostatic hypotension.

Stage 7: Other. Treatment options such as topiramate^17,18 and lamotrigine¹⁹ are recommended at this stage. These recommendations also will be reviewed and likely revised.

Treating bipolar depression

The TMAP algorithm for treating depression in bipolar disorder (Algorithm 2) assumes that anti-depressants will be used only with optimum mood-stabilizer levels because of the risk of inducing manic symptoms. The bipolar depression algorithm is always used with the primary algorithm for mania/hypomania.

The patient’s clinical presentation guides medication selection. For the “pure” bipolar I patient with a major depressive episode but little mood lability or hypomania, starting an antide-pressant is a clear decision. On the other hand, patients with predominant depressive symptoms plus dysphoric hypomania, mood lability, and irritability need a balance of mood-stabilizing drugs and antidepressants.

Stage 1: Mood stabilizer. Initiate a mood stabilizer and optimize the dosage. Choices are the same mood stabilizers listed in the hypomania/mania treatment algorithm.

Stage 2: Antidepressant. Adding an antidepressant implies that depressive symptoms are severe enough to change treatment. Antidepressant options include a selective serotonin reuptake inhibitor (SSRI), sustained-release bupropion, or lamotrigine.²⁰

Using SSRIs is supported by widespread clinical experience and offers the convenience of once-daily dosing. Recommended SSRIs include fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram. The SSRI escitalopram was introduced after the 2000 algorithms were published; evidence for using it and other newer medications will be reviewed for the 2004 update.

The recommendation for sustained-release bupropion is consistent with the algorithm principle to use medications in the most well-tolerated form when accessible and available.

With lamotrigine, review with patients the risk of serious rash. To minimize rash risk, start lamotrigine slowly and follow the recommended titration schedule.

Stage 3: Multiple choices. At this stage, no definitive studies, safety data, or tolerability issues are available to rank the medication choices. The algorithm suggests:

• adding lithium²¹ or a second antidepressant
• or switching to an alternate antidepressant such as venlafaxine or nefazodone.

If a patient moves to stage 3 because of side effects with one antidepressant class, a different class—preferably with a contrasting side-effect profile—is recommended.

Algorithm 2 Treating depression in bipolar I disorder*

Stage 5. Antipsychotic or MAOI. At this stage, the algorithm recommends adding an atypical antipsychotic²² or switching to a monoamine oxidase inhibitor (MAOI).

Early evidence supported the efficacy of MAOIs in bipolar depression. However, the panel ranked MAOIs lower in the algorithm because they are associated with more bothersome side effects than SSRIs and other antidepressants. When using MAOIs, provide patients with dietary restriction guidelines.

Stage 6. Other therapies. Therapies such as ECT or “other” interventions are recommended at this stage. ECT has proven efficacy in bipolar depression and is appropriate for patients with limited medication response. The panel gave ECT a low ranking because of limited availability, lack of patient acceptance, and newer options.

Medication options include experimental treatments with limited evidence, such as inositol, dopamine agonists, stimulants, thyroid supplementation, conventional antipsychotics, and tri-cyclic antidepressants.

Acute to maintenance treatment

Adjunctive treatments for agitation, insomnia, GI upset, sedation, headache, and tremor are recommended in the physician manual supporting the TMAP guidelines (see Related resources). The manual also suggests ways to manage medication side effects and modify the algorithms for inpatients.

Patient and family psychoeducation plays an important role in helping the patient:

• identify prodromal bipolar symptoms
• understand the need to take medications as prescribed.

Continuation treatment. After mania or hypomania remits, continue medication(s) at the effective acute-phase dosages for at least 3 months. Use follow-up visits to enhance patient adherence, detect early symptoms of relapse, and monitor for side effects.

During the late continuation phase, after a period of sustained stability, clinicians can try to simplify the medications. When discontinuing a medication, taper the dosage by no more than 25% per week. If symptoms recur, promptly return to acute-phase treatment. Consider restarting medications and titrating up to the dosage(s) that resulted in remission.

In a depressive episode, continue the antidepressant(s) for 1 to 3 months at the effective acutephase dosage(s). Follow up frequently, and educate patients to watch for symptom recurrence and to communicate with you to assess when medication changes are needed.

Maintenance treatment. Relatively few well-controlled studies on long-term management of bipolar patients were available for the 2000 algorithm update.²³ In general, all patients need mood stabilizer(s) to prevent relapse, using the lowest dosage that maintains therapeutic efficacy. Based on new evidence for lamotrigine and atypical antipsychotics—including FDAapproval of olanzapine for bipolar maintenace therapy—we anticipate recommendations will be expanded and more delineated in the 2004 update.

Discontinuing antidepressants after 3 to 6 months of initial treatment is now recommended. However, a recent retrospective case series suggests that continuing antidepressants at least 1 year after initial successful therapy may protect against depressive relapse. During this study, continuing antidepressants more than 3 to 6 months did not appear to increase the risk of switching to mania.²⁴

Should antidepressants be continued or discontinued after successful acute treatment of a bipolar I depressive episode? This is an active area of research and debate as to the most appropriate strategy. The 2004 algorithm update panel will consider recent evidence that supports continuing antidepressants after symptom remission.²⁴

Related resources

• Texas Medication Algorithm Project algorithms and physician manual. Texas Department of Mental Health and Mental Retardation. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/TIMA.html
• American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 2002; 159(4):suppl 2.
• Depression and Bipolar Support Alliance. www.dbsalliance.org

Drug brand names

• Bupropion • Wellbutrin SR
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Inositol • Various
• Lamotrigine • Lamictal
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Topiramate • Topamax
• Tranylcypromine • Parnate
• Valproic acid • Depakene
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

Dr. Shivakumar reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Suppes receives research support from or is a consultant to Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, National Institutes of Mental Health, Novartis Pharmaceuticals Corp., Pfizer Inc., Pharmaceutical Research Institute, Ortho-McNeil Pharmaceutical, Robert Wood Johnson Pharmaceutical Research Institute, The Stanley Medical Research Institute, and UCB Pharma.

Sildenafil has revolutionized management of erectile dysfunction (ED) over the past 5 years. The FDA recently approved two additional medications, vardenafil and tadalafil, for treating ED.

How vardenafil and tadalafil work

Like sildenafil, vardenafil and tadalafil are selective inhibitors of the phosphodiesterase (PDE) isoenzyme PDE-5, which is predominantly responsible for degrading cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

During sexual stimulation, nitric oxide is released from cavernous nerves and endothelial cells and activates the enzyme guanylate cyclase, resulting in increased cGMP synthesis. The cGMP triggers relaxation of smooth muscles, allowing increased blood flow into the penis and expansion of sinusoidal spaces; this prevents venous blood outflow and results in erection. The PDE-5 inhibitors can potentiate erections by enhancing and prolonging the smooth musclerelaxant effects of the nitric oxide-cGMP cascade in the corpus cavernosum.¹ PDE-5 inhibitors have no effect without sexual stimulation.

Table 1

Pharmacokinetics of the PDE-5 inhibitors

Although the three PDE-5 inhibitors have similar mechanisms of action, their selectivity differs for PDE-5 compared with the PDE-6 and PDE-11 isoenzymes. Sildenafil and vardenafil have lower selectivity than tadalafil for PDE-5 over PDE-6, which plays a role in phototransduction, the process by which light impulses are converted into nerve impulses in the retina. Thus, tadalafil is less likely than the other agents to cause visual disturbances such as abnormal color vision, increased brightness of light, or mild haziness.

Tadalafil shows lower selectivity than sildenafil or vardenafil for PDE-5 over PDE-11, meaning that tadalafil inhibits PDE-11 at clinical doses. PDE-11 is found in various tissues, but its physiologic significance and consequences of its inhibition are unknown.²

Pharmacokinetics

Vardenafil, tadalafil, and sildenafil have different pharmacokinetic characteristics (Table 1). A lower starting dosage is required with vardenafil than with sildenafil because of the former agent’s greater in vitro and in vivo potency, but whether this results in greater clinical efficacy or tolerability is unknown.³

Vardenafil and sildenafil reach maximum plasma concentration within 30 minutes to 2 hours (median 1 hour for sildenafil and 0.7 hour for vardenafil). By contrast, tadalafil reaches maximum concentration within 30 minutes to 6 hours (median 2 hours). However, studies of time to onset of erection indicate that about one-third of patients using the maximum recommended doses of any of these agents will experience onset within 14 to 16 minutes.^4-6

Absorption rates for sildenafil and vardenafil are reduced when they are taken with a high-fat meal. High-fat foods do not affect tadalafil’s absorption rate.

Table 2

Vardenafil: Fast facts

Because of its 17.5-hour half-life, tadalafil has a longer period of activity than the other PDE-5 inhibitors. Most patients can complete sexual intercourse up to 36 hours after taking tadalafil, which potentially allows spontaneous sexual activity. Sildenafil and vardenafil each are effective for about 4 hours.

All three PDE-5 inhibitors are eliminated by hepatic metabolism, mainly by the CYP 3A4 hepatic enzyme. Therefore, concomitant use with CYP 3A4 inhibitors—such as ketoconazole, ritonavir, grapefruit juice, or erythromycin —results in increased plasma levels of these agents, and the use of CYP 3A4 inducers such as rifampin reduces plasma levels of the concomitant agent.

Table 3

Tadalafil: Fast facts

Efficacy

Vardenafil (Table 2). In a placebo-controlled, 12-week trial,⁷ 601 men with mildly to severely impaired erectile function received placebo or 5, 10, or 20 mg of vardenafil. Subjects receiving vardenafil at any dose saw significantly greater improvement in erectile function than did the placebo group. Percentage of successful intercourse ranged between 71% and 74% for the three vardenafil doses. For the 20-mg dose, 80% of patients experienced improved erections compared with 30% of those taking placebo.⁷

In another trial of 805 men with mild to severe ED,⁸ vardenafil in 5-mg, 10-mg, and 20-mg doses demonstrated efficacy versus placebo. Eighty-five percent of men using vardenafil, 20 mg, reported improved erections at 26 weeks compared with 28% in the placebo group.

Vardenafil, 10 mg and 20 mg, was also an effective ED treatment in men with type 1 or type 2 diabetes mellitus⁹ and in men who underwent radical prostatectomy.¹⁰

Tadalafil (Table 3). An integrated analysis¹¹ of five randomized, placebo-controlled trials of tadalafil at 2.5, 5, 10, or 20 mg for at least 12 weeks found that the agent at all doses significantly enhanced erectile function in mild to severe ED compared with placebo. Successful intercourse was reported in 61% and 75% of sexual encounters among men treated with tadalafil, 10 and 20 mg respectively, compared with 32% in controls. Eighty-one percent of men taking tadalafil, 20 mg, reported improved erections compared with 35% of those taking placebo.

Tadalafil, 10 and 20 mg, also improved erectile function in men with type 1 or type 2 diabetes.¹²

Tolerability

All three PDE-5 inhibitors have been shown in clinical trials to be generally safe and well-tolerated. Apart from visual disturbances, all three agents have similar side effects.

• Patients taking vardenafil most commonly reported headaches, flushing, rhinitis, and dyspepsia. These effects were generally mild to moderate, dose-related, and transient.¹
• Headache, back pain, myalgia, and dyspepsia were most commonly reported with tadalafil.¹³ Similarly, adverse events were mild or moderate, dose-related, and generally abated with treatment.

Treatment-related visual disturbances have been reported in 3% of patients taking sildenafil, >0.1% to <1% of men taking vardenafil, and <0.1% of those taking tadalafil.¹ Laboratory parameters have been unaffected by treatment with the PDE-5 inhibitors, and treatment discontinuation due to adverse events has been consistently low.¹

All three PDE-5 inhibitors cause vasodilatory effects and are contraindicated in patients using organic nitrates. Consensus guidelines have been developed for using PDE-5 inhibitors in patients with cardiovascular conditions.¹⁴

Related resources

• Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92(suppl):9M-18M.
• The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999;11:59-74.
• American Foundation for Urologic Disease. www.afud.org

Drug brand names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Ritonavir • Kaletra, Norvir
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra

Disclosure

The author receives research/grant support and is a consultant to and speaker for Eli Lilly and Co. and Pfizer Inc.

Sildenafil has revolutionized management of erectile dysfunction (ED) over the past 5 years. The FDA recently approved two additional medications, vardenafil and tadalafil, for treating ED.

How vardenafil and tadalafil work

Like sildenafil, vardenafil and tadalafil are selective inhibitors of the phosphodiesterase (PDE) isoenzyme PDE-5, which is predominantly responsible for degrading cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

During sexual stimulation, nitric oxide is released from cavernous nerves and endothelial cells and activates the enzyme guanylate cyclase, resulting in increased cGMP synthesis. The cGMP triggers relaxation of smooth muscles, allowing increased blood flow into the penis and expansion of sinusoidal spaces; this prevents venous blood outflow and results in erection. The PDE-5 inhibitors can potentiate erections by enhancing and prolonging the smooth musclerelaxant effects of the nitric oxide-cGMP cascade in the corpus cavernosum.¹ PDE-5 inhibitors have no effect without sexual stimulation.

Table 1

Pharmacokinetics of the PDE-5 inhibitors

Although the three PDE-5 inhibitors have similar mechanisms of action, their selectivity differs for PDE-5 compared with the PDE-6 and PDE-11 isoenzymes. Sildenafil and vardenafil have lower selectivity than tadalafil for PDE-5 over PDE-6, which plays a role in phototransduction, the process by which light impulses are converted into nerve impulses in the retina. Thus, tadalafil is less likely than the other agents to cause visual disturbances such as abnormal color vision, increased brightness of light, or mild haziness.

Tadalafil shows lower selectivity than sildenafil or vardenafil for PDE-5 over PDE-11, meaning that tadalafil inhibits PDE-11 at clinical doses. PDE-11 is found in various tissues, but its physiologic significance and consequences of its inhibition are unknown.²

Pharmacokinetics

Vardenafil, tadalafil, and sildenafil have different pharmacokinetic characteristics (Table 1). A lower starting dosage is required with vardenafil than with sildenafil because of the former agent’s greater in vitro and in vivo potency, but whether this results in greater clinical efficacy or tolerability is unknown.³

Vardenafil and sildenafil reach maximum plasma concentration within 30 minutes to 2 hours (median 1 hour for sildenafil and 0.7 hour for vardenafil). By contrast, tadalafil reaches maximum concentration within 30 minutes to 6 hours (median 2 hours). However, studies of time to onset of erection indicate that about one-third of patients using the maximum recommended doses of any of these agents will experience onset within 14 to 16 minutes.^4-6

Absorption rates for sildenafil and vardenafil are reduced when they are taken with a high-fat meal. High-fat foods do not affect tadalafil’s absorption rate.

Table 2

Vardenafil: Fast facts

Because of its 17.5-hour half-life, tadalafil has a longer period of activity than the other PDE-5 inhibitors. Most patients can complete sexual intercourse up to 36 hours after taking tadalafil, which potentially allows spontaneous sexual activity. Sildenafil and vardenafil each are effective for about 4 hours.

All three PDE-5 inhibitors are eliminated by hepatic metabolism, mainly by the CYP 3A4 hepatic enzyme. Therefore, concomitant use with CYP 3A4 inhibitors—such as ketoconazole, ritonavir, grapefruit juice, or erythromycin —results in increased plasma levels of these agents, and the use of CYP 3A4 inducers such as rifampin reduces plasma levels of the concomitant agent.

Table 3

Tadalafil: Fast facts

Efficacy

Vardenafil (Table 2). In a placebo-controlled, 12-week trial,⁷ 601 men with mildly to severely impaired erectile function received placebo or 5, 10, or 20 mg of vardenafil. Subjects receiving vardenafil at any dose saw significantly greater improvement in erectile function than did the placebo group. Percentage of successful intercourse ranged between 71% and 74% for the three vardenafil doses. For the 20-mg dose, 80% of patients experienced improved erections compared with 30% of those taking placebo.⁷

In another trial of 805 men with mild to severe ED,⁸ vardenafil in 5-mg, 10-mg, and 20-mg doses demonstrated efficacy versus placebo. Eighty-five percent of men using vardenafil, 20 mg, reported improved erections at 26 weeks compared with 28% in the placebo group.

Vardenafil, 10 mg and 20 mg, was also an effective ED treatment in men with type 1 or type 2 diabetes mellitus⁹ and in men who underwent radical prostatectomy.¹⁰

Tadalafil (Table 3). An integrated analysis¹¹ of five randomized, placebo-controlled trials of tadalafil at 2.5, 5, 10, or 20 mg for at least 12 weeks found that the agent at all doses significantly enhanced erectile function in mild to severe ED compared with placebo. Successful intercourse was reported in 61% and 75% of sexual encounters among men treated with tadalafil, 10 and 20 mg respectively, compared with 32% in controls. Eighty-one percent of men taking tadalafil, 20 mg, reported improved erections compared with 35% of those taking placebo.

Tadalafil, 10 and 20 mg, also improved erectile function in men with type 1 or type 2 diabetes.¹²

Tolerability

All three PDE-5 inhibitors have been shown in clinical trials to be generally safe and well-tolerated. Apart from visual disturbances, all three agents have similar side effects.

• Patients taking vardenafil most commonly reported headaches, flushing, rhinitis, and dyspepsia. These effects were generally mild to moderate, dose-related, and transient.¹
• Headache, back pain, myalgia, and dyspepsia were most commonly reported with tadalafil.¹³ Similarly, adverse events were mild or moderate, dose-related, and generally abated with treatment.

Treatment-related visual disturbances have been reported in 3% of patients taking sildenafil, >0.1% to <1% of men taking vardenafil, and <0.1% of those taking tadalafil.¹ Laboratory parameters have been unaffected by treatment with the PDE-5 inhibitors, and treatment discontinuation due to adverse events has been consistently low.¹

All three PDE-5 inhibitors cause vasodilatory effects and are contraindicated in patients using organic nitrates. Consensus guidelines have been developed for using PDE-5 inhibitors in patients with cardiovascular conditions.¹⁴

Related resources

• Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92(suppl):9M-18M.
• The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999;11:59-74.
• American Foundation for Urologic Disease. www.afud.org

Drug brand names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Ritonavir • Kaletra, Norvir
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra

Disclosure

The author receives research/grant support and is a consultant to and speaker for Eli Lilly and Co. and Pfizer Inc.

Sildenafil has revolutionized management of erectile dysfunction (ED) over the past 5 years. The FDA recently approved two additional medications, vardenafil and tadalafil, for treating ED.

How vardenafil and tadalafil work

Like sildenafil, vardenafil and tadalafil are selective inhibitors of the phosphodiesterase (PDE) isoenzyme PDE-5, which is predominantly responsible for degrading cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

During sexual stimulation, nitric oxide is released from cavernous nerves and endothelial cells and activates the enzyme guanylate cyclase, resulting in increased cGMP synthesis. The cGMP triggers relaxation of smooth muscles, allowing increased blood flow into the penis and expansion of sinusoidal spaces; this prevents venous blood outflow and results in erection. The PDE-5 inhibitors can potentiate erections by enhancing and prolonging the smooth musclerelaxant effects of the nitric oxide-cGMP cascade in the corpus cavernosum.¹ PDE-5 inhibitors have no effect without sexual stimulation.

Table 1

Pharmacokinetics of the PDE-5 inhibitors

Although the three PDE-5 inhibitors have similar mechanisms of action, their selectivity differs for PDE-5 compared with the PDE-6 and PDE-11 isoenzymes. Sildenafil and vardenafil have lower selectivity than tadalafil for PDE-5 over PDE-6, which plays a role in phototransduction, the process by which light impulses are converted into nerve impulses in the retina. Thus, tadalafil is less likely than the other agents to cause visual disturbances such as abnormal color vision, increased brightness of light, or mild haziness.

Tadalafil shows lower selectivity than sildenafil or vardenafil for PDE-5 over PDE-11, meaning that tadalafil inhibits PDE-11 at clinical doses. PDE-11 is found in various tissues, but its physiologic significance and consequences of its inhibition are unknown.²

Pharmacokinetics

Vardenafil, tadalafil, and sildenafil have different pharmacokinetic characteristics (Table 1). A lower starting dosage is required with vardenafil than with sildenafil because of the former agent’s greater in vitro and in vivo potency, but whether this results in greater clinical efficacy or tolerability is unknown.³

Vardenafil and sildenafil reach maximum plasma concentration within 30 minutes to 2 hours (median 1 hour for sildenafil and 0.7 hour for vardenafil). By contrast, tadalafil reaches maximum concentration within 30 minutes to 6 hours (median 2 hours). However, studies of time to onset of erection indicate that about one-third of patients using the maximum recommended doses of any of these agents will experience onset within 14 to 16 minutes.^4-6

Absorption rates for sildenafil and vardenafil are reduced when they are taken with a high-fat meal. High-fat foods do not affect tadalafil’s absorption rate.

Table 2

Vardenafil: Fast facts

Because of its 17.5-hour half-life, tadalafil has a longer period of activity than the other PDE-5 inhibitors. Most patients can complete sexual intercourse up to 36 hours after taking tadalafil, which potentially allows spontaneous sexual activity. Sildenafil and vardenafil each are effective for about 4 hours.

All three PDE-5 inhibitors are eliminated by hepatic metabolism, mainly by the CYP 3A4 hepatic enzyme. Therefore, concomitant use with CYP 3A4 inhibitors—such as ketoconazole, ritonavir, grapefruit juice, or erythromycin —results in increased plasma levels of these agents, and the use of CYP 3A4 inducers such as rifampin reduces plasma levels of the concomitant agent.

Table 3

Tadalafil: Fast facts

Efficacy

Vardenafil (Table 2). In a placebo-controlled, 12-week trial,⁷ 601 men with mildly to severely impaired erectile function received placebo or 5, 10, or 20 mg of vardenafil. Subjects receiving vardenafil at any dose saw significantly greater improvement in erectile function than did the placebo group. Percentage of successful intercourse ranged between 71% and 74% for the three vardenafil doses. For the 20-mg dose, 80% of patients experienced improved erections compared with 30% of those taking placebo.⁷

In another trial of 805 men with mild to severe ED,⁸ vardenafil in 5-mg, 10-mg, and 20-mg doses demonstrated efficacy versus placebo. Eighty-five percent of men using vardenafil, 20 mg, reported improved erections at 26 weeks compared with 28% in the placebo group.

Vardenafil, 10 mg and 20 mg, was also an effective ED treatment in men with type 1 or type 2 diabetes mellitus⁹ and in men who underwent radical prostatectomy.¹⁰

Tadalafil (Table 3). An integrated analysis¹¹ of five randomized, placebo-controlled trials of tadalafil at 2.5, 5, 10, or 20 mg for at least 12 weeks found that the agent at all doses significantly enhanced erectile function in mild to severe ED compared with placebo. Successful intercourse was reported in 61% and 75% of sexual encounters among men treated with tadalafil, 10 and 20 mg respectively, compared with 32% in controls. Eighty-one percent of men taking tadalafil, 20 mg, reported improved erections compared with 35% of those taking placebo.

Tadalafil, 10 and 20 mg, also improved erectile function in men with type 1 or type 2 diabetes.¹²

Tolerability

All three PDE-5 inhibitors have been shown in clinical trials to be generally safe and well-tolerated. Apart from visual disturbances, all three agents have similar side effects.

• Patients taking vardenafil most commonly reported headaches, flushing, rhinitis, and dyspepsia. These effects were generally mild to moderate, dose-related, and transient.¹
• Headache, back pain, myalgia, and dyspepsia were most commonly reported with tadalafil.¹³ Similarly, adverse events were mild or moderate, dose-related, and generally abated with treatment.

Treatment-related visual disturbances have been reported in 3% of patients taking sildenafil, >0.1% to <1% of men taking vardenafil, and <0.1% of those taking tadalafil.¹ Laboratory parameters have been unaffected by treatment with the PDE-5 inhibitors, and treatment discontinuation due to adverse events has been consistently low.¹

All three PDE-5 inhibitors cause vasodilatory effects and are contraindicated in patients using organic nitrates. Consensus guidelines have been developed for using PDE-5 inhibitors in patients with cardiovascular conditions.¹⁴

Related resources

• Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92(suppl):9M-18M.
• The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999;11:59-74.
• American Foundation for Urologic Disease. www.afud.org

Drug brand names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Ritonavir • Kaletra, Norvir
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra

Disclosure

The author receives research/grant support and is a consultant to and speaker for Eli Lilly and Co. and Pfizer Inc.