Evidence-Based Reviews

Depression can exacerbate cardiovascular disease (CVD), and CVD can exacerbate depression (Figure). Thus, effectively treating depression enhances heart disease treatment, particularly if psychiatrists and medical physicians collaborate in providing patient care.

This article describes a patient with risk factors for heart disease, illustrates the physiologic pathways that link depression and CVD, and offers clinical tips to help you improve outcomes for patients with both disorders.

Case report: Trying to ‘get going’

Mr. D, age 51, presents with vegetative symptoms and a personal and family history of CVD, depression, and substance abuse disorders. He was born in a small town in Kentucky and raised in Louisville’s poorest neighborhood. After his mother died at age 42 of “hardening of the arteries,” his father started drinking more, working less, and “never really got going again.”

Figure Neuroendocrine pathways by which depression may cause or promote CVD

Box

Mr. D worked 20 years as a construction contractor, often running several work crews at once. At age 41, he slid into a depressive episode after his second divorce. He struggled with low energy, disturbed sleep, hopelessness, and increased smoking and drinking for 1 year, but he did not seek help.

Two years later, he suffered an inferior wall transmural myocardial infarction. His CVD risk factors included family history of early heart disease, smoking for 32 years, and elevated low-density lipoprotein (LDL) cholesterol. After subsequent episodes of unstable angina, stents were placed in two coronary arteries. Though his cardiologist cleared him to return to work, he felt able to work only part-time and erratically.

During a visit to their family doctor several years later, Mr. D’s wife suggested that her husband might be depressed. Reluctantly, Mr. D consulted a psychiatrist.

The psychiatrist diagnosed major depressive disorder and prescribed sertraline, 50 mg/d. Within 2 months, Mr. D’s symptoms had dropped by 50% on a symptom severity measure. He did not refill his prescription, however, because of concerns about sexual side effects. Two months later he was hospitalized for another episode of unstable angina. His depression had returned within 1 month of stopping sertraline.

The psychiatrist switched him to citalopram, 20 mg/d, and carefully monitored depressive symptoms, side effects, and medication adherence. Aside from talking with the psychiatrist for a half-hour in his family doctor’s office every few weeks, Mr. D refused to undergo psychotherapy. He eventually achieved depression remission with a combination of citalopram, 20 mg/d, and nefazodone, 200 mg/d.

Depression-CVD connection

As in Mr. D’s case, depression and CVD commonly occur together, often with serious consequences (Box). ^1-7 The association between depression and CVD is not limited to depression’s effect on existing disease, however. Depression often precedes coronary disease by about 30 years—suggesting possible cause and effect. Two systematic reviews^8,9 found that depression increased CVD risk by 64%.

Seven well-controlled studies^5-7,10-13 compared the relative effect of depression on the cardiovascular system with that of established CVD predictors. All seven found depression’s independent effect to be significant and comparable to or greater than that of ejection fraction, previous MI history, or number of vessels with >50% narrowing.

Comorbid depression and CVD usually persists months or years,¹⁴ and most studies indicate a dose-response relationship; the more severe the depression, the greater the risk for CVD to develop or progress.^8,15

The link between depression treatment and CVD risk has not been well-studied. The only randomized, controlled trial found that cognitive therapy for depression did not significantly reduce cardiac events among patients with known CVD.¹⁶

Possible mechanisms

Depression’s effect on CVD. How does depression affect CVD development and progression? Both behavioral and biological pathways may be involved.¹⁷ The behavioral pathway proposes that depression triggers behaviors—such as smoking, overeating, and sedentary lifestyles—that increase the risk of developing or worsening CVD. The biological pathway proposes that neuroendocrine changes during depression accelerate CVD development.

About one-half of persons with major depression exhibit hypothalamic-pituitary-adrenal (HPA) axis dysregulation, with excessive secretion of corticotropin releasing factor (CRF) and chronically elevated cortisol.¹⁸ This HPA dysregulation is related to defective negative feedback at the paraventricular nucleus of the hypothalamus. Chronic HPA axis dysregulation promotes vascular inflammation, and several studies have reported C-reactive protein elevation and cytokine changes in patients with major depression.^19,20

 

Major depression is also associated with excessive sympathetic and diminished parasym-pathetic nervous system activity, potentially contributing to hypertension, increased resting heart rate, decreased heart rate variability, and altered endothelial function.^2,21,22 Each of these factors facilitates arterial plaque formation.

Depression may also exacerbate chronic anxiety and other forms of distress. The combined effects of an overtaxed central nervous system, neuroendocrine dysregulation, and unhealthy behaviors may eventually overwhelm the cardiovascular system.

CVD’s effect on depression. How does CVD contribute to depression? The vascular depression hypothesis²³ proposes that diffuse heart and brain atherosclerosis restricts perfusion of limbic and cortical structures that regulate mood. A first depressive episode after acute MI or CABG probably represents exacerbation of cerebrovascular insufficiency that preceded the coronary event.

Table

Four keys to effectively treat depression in patients with heart disease

Monitor depressive symptom severity Provide adequate trials of SSRIs to maximum tolerable dosages before switching to another agent Combine medications and psychotherapy whenever possible Collaborate closely with the primary care physician

In practical terms, this means that pathways linking depression and heart disease include not only biological factors but also:

• psychological factors such as depression, anxiety, and chronic stress
• behavioral factors such as smoking, physical inactivity, and high-fat diet.

How to improve outcomes

Patients with CVD commonly do not receive effective depression treatment:

• Internists and family physicians give preferential attention to physical illness.
• Patients may have insufficient access to mental health specialists.
• Physicians do not adequately monitor depression treatment.
• Patients are reluctant to accept the stigma of mental illness.

By collaborating with primary care physicians, you can improve the likelihood that depression treatment will achieve remission and prevent relapse (Table).

Risk factors for CVD. Depression contributes to heart disease by exacerbating four major CVD risk factors—smoking, diabetes, obesity, and physical inactivity. By effectively treating depression, you may help patients avoid common depressive symptoms—such as overeating and sedentary behaviors—that are related to low energy or fatigue.

Educate middle-aged patients with depression about CVD’s associated risk. Prochaska’s “stages of change” (see Related resources) can help them stop smoking, lose weight, and exercise.

Access to cardiac care. Depressed patients may be less motivated than nondepressed patients to pursue cardiac care.²⁴ Therefore, you may need to:

• encourage your patients to take advantage of indicated state-of-the-art care, including stents, bypass surgery, and medications
• understand patients’ complex cardiac regimens and help them adhere when depression interferes with their motivation.

Effective depression treatment

Patient history. For depressed patients older than 40, take a careful inventory of CVD risk factors:

• family history of heart disease before age 60 for men and age 70 for women
• personal history of smoking, blood pressure >140/90 mm Hg, LDL cholesterol >100 mg/dL, type 2 diabetes, body mass index >30, or physical inactivity (<30 minutes of walking 3 days a week).

In general, the more risk factors, the greater the risk of CVD.

Antidepressant selection. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective for treating major depression in CVD and congestive heart failure.²⁵ Venlafaxine at doses >300 mg/d may increase blood pressure, so use this drug with caution in depressed patients with hypertension.

No controlled clinical trials have gauged the safety and efficacy of bupropion or mirtazapine in patients with CVD.

Tricyclic antidepressants are contraindicated for 6 months post-MI because they may contribute to arrhythmias. Avoid using them in depressed patients with CVD or conduction defects because of their quinidine-like effects on conduction.

Cardiac medications. Contrary to folk wisdom, beta blockers do not cause depression.²⁶ Whether or not a patient is depressed, our primary care and cardiology colleagues can use beta blockers to help regulate the peripheral autonomic nervous system, reducing high blood pressure and the risk of arrhythmias.

SSRIs may increase blood levels of beta blockers, warfarin, and other cardiac medications via cytochrome P-450 isoenzyme inhibition. Make sure warfarin levels and other cardiac drug effects are well monitored when you adjust psychotropic dosages.

Divalproex and SSRIs also may reduce platelet aggregation. Patients who are receiving concomitant aspirin or warfarin may bruise or bleed easily and require dosage reductions or medication changes.

Psychotherapy. All patients with major or minor depression and CVD are considered high-risk and are candidates for a trial of brief psychotherapy. Therapeutic goals are to achieve full remission of depressive symptoms as rapidly as possible, prevent relapse, and maximize adherence to cardiac and depression drug regimens.

Collaborate closely with the cardiologist or primary care physician during the patient’s depressive episode and occasionally during maintenance treatment. Discuss or share notes on the patient’s depressive and cardiac disorders, medication management, symptom monitoring, and behavior changes needed to reduce cardiac risk.

 

With your added support, patients with depression and CVD are more likely to adhere to antidepressant medications and achieve symptom remission.

Related resources

• National Institute of Mental Health. Depression and heart disease. www.nimh.nih.gov/publicat/depheart.cfm.
• Dewan NA, Suresh DP, Blomkalns A. Selecting safe psychotropics for post-MI patients. Current Psychiatry. 2003;2(3):15-21.
• Prochaska JO, Norcross JC, DiClemente CC. Changing for good. New York: Avon, 1994.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Wulsin is a consultant to Pfizer Inc. and Janssen Pharmaceutica.

Dr. Vieweg is a speaker for Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Depression can exacerbate cardiovascular disease (CVD), and CVD can exacerbate depression (Figure). Thus, effectively treating depression enhances heart disease treatment, particularly if psychiatrists and medical physicians collaborate in providing patient care.

This article describes a patient with risk factors for heart disease, illustrates the physiologic pathways that link depression and CVD, and offers clinical tips to help you improve outcomes for patients with both disorders.

Case report: Trying to ‘get going’

Mr. D, age 51, presents with vegetative symptoms and a personal and family history of CVD, depression, and substance abuse disorders. He was born in a small town in Kentucky and raised in Louisville’s poorest neighborhood. After his mother died at age 42 of “hardening of the arteries,” his father started drinking more, working less, and “never really got going again.”

Figure Neuroendocrine pathways by which depression may cause or promote CVD

Box

Mr. D worked 20 years as a construction contractor, often running several work crews at once. At age 41, he slid into a depressive episode after his second divorce. He struggled with low energy, disturbed sleep, hopelessness, and increased smoking and drinking for 1 year, but he did not seek help.

Two years later, he suffered an inferior wall transmural myocardial infarction. His CVD risk factors included family history of early heart disease, smoking for 32 years, and elevated low-density lipoprotein (LDL) cholesterol. After subsequent episodes of unstable angina, stents were placed in two coronary arteries. Though his cardiologist cleared him to return to work, he felt able to work only part-time and erratically.

During a visit to their family doctor several years later, Mr. D’s wife suggested that her husband might be depressed. Reluctantly, Mr. D consulted a psychiatrist.

The psychiatrist diagnosed major depressive disorder and prescribed sertraline, 50 mg/d. Within 2 months, Mr. D’s symptoms had dropped by 50% on a symptom severity measure. He did not refill his prescription, however, because of concerns about sexual side effects. Two months later he was hospitalized for another episode of unstable angina. His depression had returned within 1 month of stopping sertraline.

The psychiatrist switched him to citalopram, 20 mg/d, and carefully monitored depressive symptoms, side effects, and medication adherence. Aside from talking with the psychiatrist for a half-hour in his family doctor’s office every few weeks, Mr. D refused to undergo psychotherapy. He eventually achieved depression remission with a combination of citalopram, 20 mg/d, and nefazodone, 200 mg/d.

Depression-CVD connection

As in Mr. D’s case, depression and CVD commonly occur together, often with serious consequences (Box). ^1-7 The association between depression and CVD is not limited to depression’s effect on existing disease, however. Depression often precedes coronary disease by about 30 years—suggesting possible cause and effect. Two systematic reviews^8,9 found that depression increased CVD risk by 64%.

Seven well-controlled studies^5-7,10-13 compared the relative effect of depression on the cardiovascular system with that of established CVD predictors. All seven found depression’s independent effect to be significant and comparable to or greater than that of ejection fraction, previous MI history, or number of vessels with >50% narrowing.

Comorbid depression and CVD usually persists months or years,¹⁴ and most studies indicate a dose-response relationship; the more severe the depression, the greater the risk for CVD to develop or progress.^8,15

The link between depression treatment and CVD risk has not been well-studied. The only randomized, controlled trial found that cognitive therapy for depression did not significantly reduce cardiac events among patients with known CVD.¹⁶

Possible mechanisms

Depression’s effect on CVD. How does depression affect CVD development and progression? Both behavioral and biological pathways may be involved.¹⁷ The behavioral pathway proposes that depression triggers behaviors—such as smoking, overeating, and sedentary lifestyles—that increase the risk of developing or worsening CVD. The biological pathway proposes that neuroendocrine changes during depression accelerate CVD development.

About one-half of persons with major depression exhibit hypothalamic-pituitary-adrenal (HPA) axis dysregulation, with excessive secretion of corticotropin releasing factor (CRF) and chronically elevated cortisol.¹⁸ This HPA dysregulation is related to defective negative feedback at the paraventricular nucleus of the hypothalamus. Chronic HPA axis dysregulation promotes vascular inflammation, and several studies have reported C-reactive protein elevation and cytokine changes in patients with major depression.^19,20

 

Major depression is also associated with excessive sympathetic and diminished parasym-pathetic nervous system activity, potentially contributing to hypertension, increased resting heart rate, decreased heart rate variability, and altered endothelial function.^2,21,22 Each of these factors facilitates arterial plaque formation.

Depression may also exacerbate chronic anxiety and other forms of distress. The combined effects of an overtaxed central nervous system, neuroendocrine dysregulation, and unhealthy behaviors may eventually overwhelm the cardiovascular system.

CVD’s effect on depression. How does CVD contribute to depression? The vascular depression hypothesis²³ proposes that diffuse heart and brain atherosclerosis restricts perfusion of limbic and cortical structures that regulate mood. A first depressive episode after acute MI or CABG probably represents exacerbation of cerebrovascular insufficiency that preceded the coronary event.

Table

Four keys to effectively treat depression in patients with heart disease

Monitor depressive symptom severity Provide adequate trials of SSRIs to maximum tolerable dosages before switching to another agent Combine medications and psychotherapy whenever possible Collaborate closely with the primary care physician

In practical terms, this means that pathways linking depression and heart disease include not only biological factors but also:

• psychological factors such as depression, anxiety, and chronic stress
• behavioral factors such as smoking, physical inactivity, and high-fat diet.

How to improve outcomes

Patients with CVD commonly do not receive effective depression treatment:

• Internists and family physicians give preferential attention to physical illness.
• Patients may have insufficient access to mental health specialists.
• Physicians do not adequately monitor depression treatment.
• Patients are reluctant to accept the stigma of mental illness.

By collaborating with primary care physicians, you can improve the likelihood that depression treatment will achieve remission and prevent relapse (Table).

Risk factors for CVD. Depression contributes to heart disease by exacerbating four major CVD risk factors—smoking, diabetes, obesity, and physical inactivity. By effectively treating depression, you may help patients avoid common depressive symptoms—such as overeating and sedentary behaviors—that are related to low energy or fatigue.

Educate middle-aged patients with depression about CVD’s associated risk. Prochaska’s “stages of change” (see Related resources) can help them stop smoking, lose weight, and exercise.

Access to cardiac care. Depressed patients may be less motivated than nondepressed patients to pursue cardiac care.²⁴ Therefore, you may need to:

• encourage your patients to take advantage of indicated state-of-the-art care, including stents, bypass surgery, and medications
• understand patients’ complex cardiac regimens and help them adhere when depression interferes with their motivation.

Effective depression treatment

Patient history. For depressed patients older than 40, take a careful inventory of CVD risk factors:

• family history of heart disease before age 60 for men and age 70 for women
• personal history of smoking, blood pressure >140/90 mm Hg, LDL cholesterol >100 mg/dL, type 2 diabetes, body mass index >30, or physical inactivity (<30 minutes of walking 3 days a week).

In general, the more risk factors, the greater the risk of CVD.

Antidepressant selection. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective for treating major depression in CVD and congestive heart failure.²⁵ Venlafaxine at doses >300 mg/d may increase blood pressure, so use this drug with caution in depressed patients with hypertension.

No controlled clinical trials have gauged the safety and efficacy of bupropion or mirtazapine in patients with CVD.

Tricyclic antidepressants are contraindicated for 6 months post-MI because they may contribute to arrhythmias. Avoid using them in depressed patients with CVD or conduction defects because of their quinidine-like effects on conduction.

Cardiac medications. Contrary to folk wisdom, beta blockers do not cause depression.²⁶ Whether or not a patient is depressed, our primary care and cardiology colleagues can use beta blockers to help regulate the peripheral autonomic nervous system, reducing high blood pressure and the risk of arrhythmias.

SSRIs may increase blood levels of beta blockers, warfarin, and other cardiac medications via cytochrome P-450 isoenzyme inhibition. Make sure warfarin levels and other cardiac drug effects are well monitored when you adjust psychotropic dosages.

Divalproex and SSRIs also may reduce platelet aggregation. Patients who are receiving concomitant aspirin or warfarin may bruise or bleed easily and require dosage reductions or medication changes.

Psychotherapy. All patients with major or minor depression and CVD are considered high-risk and are candidates for a trial of brief psychotherapy. Therapeutic goals are to achieve full remission of depressive symptoms as rapidly as possible, prevent relapse, and maximize adherence to cardiac and depression drug regimens.

Collaborate closely with the cardiologist or primary care physician during the patient’s depressive episode and occasionally during maintenance treatment. Discuss or share notes on the patient’s depressive and cardiac disorders, medication management, symptom monitoring, and behavior changes needed to reduce cardiac risk.

 

With your added support, patients with depression and CVD are more likely to adhere to antidepressant medications and achieve symptom remission.

Related resources

• National Institute of Mental Health. Depression and heart disease. www.nimh.nih.gov/publicat/depheart.cfm.
• Dewan NA, Suresh DP, Blomkalns A. Selecting safe psychotropics for post-MI patients. Current Psychiatry. 2003;2(3):15-21.
• Prochaska JO, Norcross JC, DiClemente CC. Changing for good. New York: Avon, 1994.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Wulsin is a consultant to Pfizer Inc. and Janssen Pharmaceutica.

Dr. Vieweg is a speaker for Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Depression can exacerbate cardiovascular disease (CVD), and CVD can exacerbate depression (Figure). Thus, effectively treating depression enhances heart disease treatment, particularly if psychiatrists and medical physicians collaborate in providing patient care.

This article describes a patient with risk factors for heart disease, illustrates the physiologic pathways that link depression and CVD, and offers clinical tips to help you improve outcomes for patients with both disorders.

Case report: Trying to ‘get going’

Mr. D, age 51, presents with vegetative symptoms and a personal and family history of CVD, depression, and substance abuse disorders. He was born in a small town in Kentucky and raised in Louisville’s poorest neighborhood. After his mother died at age 42 of “hardening of the arteries,” his father started drinking more, working less, and “never really got going again.”

Figure Neuroendocrine pathways by which depression may cause or promote CVD

Box

Mr. D worked 20 years as a construction contractor, often running several work crews at once. At age 41, he slid into a depressive episode after his second divorce. He struggled with low energy, disturbed sleep, hopelessness, and increased smoking and drinking for 1 year, but he did not seek help.

Two years later, he suffered an inferior wall transmural myocardial infarction. His CVD risk factors included family history of early heart disease, smoking for 32 years, and elevated low-density lipoprotein (LDL) cholesterol. After subsequent episodes of unstable angina, stents were placed in two coronary arteries. Though his cardiologist cleared him to return to work, he felt able to work only part-time and erratically.

During a visit to their family doctor several years later, Mr. D’s wife suggested that her husband might be depressed. Reluctantly, Mr. D consulted a psychiatrist.

The psychiatrist diagnosed major depressive disorder and prescribed sertraline, 50 mg/d. Within 2 months, Mr. D’s symptoms had dropped by 50% on a symptom severity measure. He did not refill his prescription, however, because of concerns about sexual side effects. Two months later he was hospitalized for another episode of unstable angina. His depression had returned within 1 month of stopping sertraline.

The psychiatrist switched him to citalopram, 20 mg/d, and carefully monitored depressive symptoms, side effects, and medication adherence. Aside from talking with the psychiatrist for a half-hour in his family doctor’s office every few weeks, Mr. D refused to undergo psychotherapy. He eventually achieved depression remission with a combination of citalopram, 20 mg/d, and nefazodone, 200 mg/d.

Depression-CVD connection

As in Mr. D’s case, depression and CVD commonly occur together, often with serious consequences (Box). ^1-7 The association between depression and CVD is not limited to depression’s effect on existing disease, however. Depression often precedes coronary disease by about 30 years—suggesting possible cause and effect. Two systematic reviews^8,9 found that depression increased CVD risk by 64%.

Seven well-controlled studies^5-7,10-13 compared the relative effect of depression on the cardiovascular system with that of established CVD predictors. All seven found depression’s independent effect to be significant and comparable to or greater than that of ejection fraction, previous MI history, or number of vessels with >50% narrowing.

Comorbid depression and CVD usually persists months or years,¹⁴ and most studies indicate a dose-response relationship; the more severe the depression, the greater the risk for CVD to develop or progress.^8,15

The link between depression treatment and CVD risk has not been well-studied. The only randomized, controlled trial found that cognitive therapy for depression did not significantly reduce cardiac events among patients with known CVD.¹⁶

Possible mechanisms

Depression’s effect on CVD. How does depression affect CVD development and progression? Both behavioral and biological pathways may be involved.¹⁷ The behavioral pathway proposes that depression triggers behaviors—such as smoking, overeating, and sedentary lifestyles—that increase the risk of developing or worsening CVD. The biological pathway proposes that neuroendocrine changes during depression accelerate CVD development.

About one-half of persons with major depression exhibit hypothalamic-pituitary-adrenal (HPA) axis dysregulation, with excessive secretion of corticotropin releasing factor (CRF) and chronically elevated cortisol.¹⁸ This HPA dysregulation is related to defective negative feedback at the paraventricular nucleus of the hypothalamus. Chronic HPA axis dysregulation promotes vascular inflammation, and several studies have reported C-reactive protein elevation and cytokine changes in patients with major depression.^19,20

 

Major depression is also associated with excessive sympathetic and diminished parasym-pathetic nervous system activity, potentially contributing to hypertension, increased resting heart rate, decreased heart rate variability, and altered endothelial function.^2,21,22 Each of these factors facilitates arterial plaque formation.

Depression may also exacerbate chronic anxiety and other forms of distress. The combined effects of an overtaxed central nervous system, neuroendocrine dysregulation, and unhealthy behaviors may eventually overwhelm the cardiovascular system.

CVD’s effect on depression. How does CVD contribute to depression? The vascular depression hypothesis²³ proposes that diffuse heart and brain atherosclerosis restricts perfusion of limbic and cortical structures that regulate mood. A first depressive episode after acute MI or CABG probably represents exacerbation of cerebrovascular insufficiency that preceded the coronary event.

Table

Four keys to effectively treat depression in patients with heart disease

Monitor depressive symptom severity Provide adequate trials of SSRIs to maximum tolerable dosages before switching to another agent Combine medications and psychotherapy whenever possible Collaborate closely with the primary care physician

In practical terms, this means that pathways linking depression and heart disease include not only biological factors but also:

• psychological factors such as depression, anxiety, and chronic stress
• behavioral factors such as smoking, physical inactivity, and high-fat diet.

How to improve outcomes

Patients with CVD commonly do not receive effective depression treatment:

• Internists and family physicians give preferential attention to physical illness.
• Patients may have insufficient access to mental health specialists.
• Physicians do not adequately monitor depression treatment.
• Patients are reluctant to accept the stigma of mental illness.

By collaborating with primary care physicians, you can improve the likelihood that depression treatment will achieve remission and prevent relapse (Table).

Risk factors for CVD. Depression contributes to heart disease by exacerbating four major CVD risk factors—smoking, diabetes, obesity, and physical inactivity. By effectively treating depression, you may help patients avoid common depressive symptoms—such as overeating and sedentary behaviors—that are related to low energy or fatigue.

Educate middle-aged patients with depression about CVD’s associated risk. Prochaska’s “stages of change” (see Related resources) can help them stop smoking, lose weight, and exercise.

Access to cardiac care. Depressed patients may be less motivated than nondepressed patients to pursue cardiac care.²⁴ Therefore, you may need to:

• encourage your patients to take advantage of indicated state-of-the-art care, including stents, bypass surgery, and medications
• understand patients’ complex cardiac regimens and help them adhere when depression interferes with their motivation.

Effective depression treatment

Patient history. For depressed patients older than 40, take a careful inventory of CVD risk factors:

• family history of heart disease before age 60 for men and age 70 for women
• personal history of smoking, blood pressure >140/90 mm Hg, LDL cholesterol >100 mg/dL, type 2 diabetes, body mass index >30, or physical inactivity (<30 minutes of walking 3 days a week).

In general, the more risk factors, the greater the risk of CVD.

Antidepressant selection. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective for treating major depression in CVD and congestive heart failure.²⁵ Venlafaxine at doses >300 mg/d may increase blood pressure, so use this drug with caution in depressed patients with hypertension.

No controlled clinical trials have gauged the safety and efficacy of bupropion or mirtazapine in patients with CVD.

Tricyclic antidepressants are contraindicated for 6 months post-MI because they may contribute to arrhythmias. Avoid using them in depressed patients with CVD or conduction defects because of their quinidine-like effects on conduction.

Cardiac medications. Contrary to folk wisdom, beta blockers do not cause depression.²⁶ Whether or not a patient is depressed, our primary care and cardiology colleagues can use beta blockers to help regulate the peripheral autonomic nervous system, reducing high blood pressure and the risk of arrhythmias.

SSRIs may increase blood levels of beta blockers, warfarin, and other cardiac medications via cytochrome P-450 isoenzyme inhibition. Make sure warfarin levels and other cardiac drug effects are well monitored when you adjust psychotropic dosages.

Divalproex and SSRIs also may reduce platelet aggregation. Patients who are receiving concomitant aspirin or warfarin may bruise or bleed easily and require dosage reductions or medication changes.

Psychotherapy. All patients with major or minor depression and CVD are considered high-risk and are candidates for a trial of brief psychotherapy. Therapeutic goals are to achieve full remission of depressive symptoms as rapidly as possible, prevent relapse, and maximize adherence to cardiac and depression drug regimens.

Collaborate closely with the cardiologist or primary care physician during the patient’s depressive episode and occasionally during maintenance treatment. Discuss or share notes on the patient’s depressive and cardiac disorders, medication management, symptom monitoring, and behavior changes needed to reduce cardiac risk.

 

With your added support, patients with depression and CVD are more likely to adhere to antidepressant medications and achieve symptom remission.

Related resources

• National Institute of Mental Health. Depression and heart disease. www.nimh.nih.gov/publicat/depheart.cfm.
• Dewan NA, Suresh DP, Blomkalns A. Selecting safe psychotropics for post-MI patients. Current Psychiatry. 2003;2(3):15-21.
• Prochaska JO, Norcross JC, DiClemente CC. Changing for good. New York: Avon, 1994.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Wulsin is a consultant to Pfizer Inc. and Janssen Pharmaceutica.

Dr. Vieweg is a speaker for Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Caitlin McIntosh, 12, hanged herself with shoelaces weeks after starting treatment for depression with a selective serotonin reuptake inhibitor (SSRI). Matt Miller, 13, hanged himself in his bedroom closet after taking his seventh SSRI dose. Michael Shivak, 11, slashed his wrists in class—but survived—while taking an SSRI.

These adolescents’ parents testified at an FDA hearing Feb. 2 about possible increased risk of suicidality with SSRIs in depressed children and adolescents.

Other families related positive experiences. Sherri Walton said her daughter, Jordan, 14, has achieved “enormous benefit” from taking SSRIs for obsessive-compulsive disorder. Suzanne Vogel-Scibilia told the FDA panel she is convinced that her two children with psychiatric disorders lead full lives because of SSRIs.

Sensitive to the anguish of grieving families but not wanting to deprive seriously depressed children of effective treatment, the FDA is proceeding methodically with its inquiry—probably at least until summer.

In the meantime, this article offers resources to help you answer questions from parents concerned about their children starting or continuing SSRIs. We include pediatric antidepressant dosing recommendations and data on benefits and risks of SSRIs and other reuptake inhibitors in young patients.

Why the FDA inquiry?

SSRI-associated behavioral activation and suicidal ideation in children and adolescents were reported anecdotally, as case reports, in the early 1990s,¹ and more recently.² No convincing evidence has shown, however, that SSRIs increase the risk of suicide. In fact, widespread use of SSRIs has been associated with reduced suicide rates.³

In May 2003, unpublished data submitted to the FDA from placebo-controlled trials suggested an increased risk of “possibly suicide-related” events and “suicide attempts” in pediatric patients taking paroxetine for major depression. No suicides were reported.

The Medicines and Healthcare Products Regulatory Agency (MHRA)—the United Kingdom’s equivalent of the Food and Drug Administration—responded by warning British physicians against prescribing paroxetine for depressed patients younger than 18. It also ordered a labeling change for paroxetine, contraindicating its use in pediatric major depression.

The FDA advised U.S. doctors against using paroxetine for children under age 18 with major depressive disorder and began investigating data on pediatric use of antidepressants, including all approved SSRIs. Since then:

• In the United States, venlafaxine’s manufacturer changed the drug’s labeling to include increased reports of hostility and suicidality in pediatric trial data. A “Dear Health Care Professional” letter in August 2003 indicated that venlafaxine is not recommended in depressed pediatric patients.
• Britain’s MHRA added pediatric con-traindications to labeling of venlafaxine, sertraline, citalopram, and escitalopram in December 2003. The agency opined that fluoxetine is the only SSRI with a favorable risk-benefit profile for pediatric major depression.
• At press time, the FDA had not changed any SSRI labeling.

At the Feb. 2 public hearing, the FDA’s Psycho-pharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee heard public comments from patients, families, and physicians and reviewed the inquiry’s progress. To locate the Web site containing the FDA’s memorandum on this hearing, see Related resources.

For the next several months, an expert group at Columbia University is under contract with the FDA to develop a system to classify events that might represent suicidality. The group will then analyze data from 24 studies involving more than 4,000 depressed pediatric patients and nine antidepressants (paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram, bupropion, venlafaxine, nefazodone, and mirtazapine).

Independent findings. In January, an American College of Neuropsychopharmacology (ACNP) report concluded that SSRIs do not increase suicidal thoughts or suicide attempts in youth (Table 1). An ACNP task force examined the use of SSRIs in more than 2,000 children and adolescents, including all published clinical trial data, unpublished data from several pharmaceutical companies, and data reported to Britain’s MHRA. An executive summary is available on the ACNP’s Web site (see Related resources).

Table 1

Suicide deaths, behavior, or ideation in clinical trials of youth with major depressive disorder

Medication	Total youth* in trials	No. of suicide deaths	% of youth with suicidal behavior or ideation**		P value	Statistical significance
			Antidepressant	Placebo
Citalopram	418	0	8.9%(19)	7.3% (15)	0.5	No
Fluoxetine	458	0	3.6%(9)	3.8% (8)	0.9	No
Paroxetine	669	0	3.7%(14)	2.5% (7)	0.4	No
Sertraline	376	0	2.7%(5)	1.1% (2)	0.3	No
Venlafaxine	334	0	2%(NA)	0%	0.25	No
* Total number of youth given antidepressants and placebo
** Number inside parenthesis is actual number of youth
NA = Not available
Source: Data from published clinical trials, unpublished clinical trials provided by drug sponsor, and clinical data compiled by the Medicines and Healthcare Products Regulatory Agency of the United Kingdom.
Reprinted with permission of the American College of Neuropsychopharmacology from Preliminary report of the Task Force on SSRIs and Suicidal Behavior in Youth (executive summary), January 2004:18.

Depression’s impact on children

The prevalence of depression in youth age 18 and younger is 8.3%,⁴ and the rate increases with patient age. Before puberty, common signs of depression include somatic symptoms such as abdominal pain, headaches, and irritability, whereas adolescents are more likely to express feelings of depression and exhibit suicidal behavior. Girls and boys are equally at risk for depression until puberty, when girls begin to outnumber boys and the presentation begins to resemble adult depression.

 

Untreated pediatric depression is associated with substantial morbidity, including reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life,^4,5 It also increases the risk of suicide.

Early-onset depression is considered a more malignant illness than adult-onset depression because of its effect on development, potential for recurrence,⁶ and chronicity into adulthood.⁷ The quest to develop appropriate treatment for depressed children and adolescents has been spurred by:

• the substantial risks of morbidity and mortality from childhood depression
• advances in drug treatments for adult-onset depression
• recognition that early-onset depression is treatable.

Physiologically, children are not “mini-adults.” Thus, practicing evidence-based medicine requires separate empirical research for pediatric conditions.

Despite some efforts by the National Institute of Mental Health (NIMH) and the pharmaceutical industry, research in pediatric psychopharmacology and ancillary treatments lags decades behind evidence-based treatment in adults.

Table 2

Efficacy of SSRIs and other newer antidepressants in short-term, placebo-controlled pediatric studies in major depressive disorder

Drug	Age range	Outcome* (drug vs. placebo)
Paroxetine
Study 1  Study 2  Study 3	12 to 18 13 to 18 7 to 17	Negative† Negative Negative
Fluoxetine
Study 1  Study 2	8 to 17 8 to 17	Positive Positive
Sertraline
Study 1  Study 2	6 to 17 6 to 17	Trend Negative§
Venlafaxine
Study 1  Study 2	7 to 17 7 to 17	Negative Negative
Citalopram
Study 1  Study 2	7 to 17 13 to 18	Positive Negative
Nefazodone
Study 1  Study 2	12 to 18 7 to 17	Trend Negative
Mirtazapine
Study 1  Study 2	7 to 17 7 to 17	Negative Negative
* Positive (P 0.05); Negative (P >0.10; Trend (0.05
† Positive on most secondary endpoints
§ Positive on pooling of 2 studies
Source: Adapted and reprinted from Laughren TP. Memorandum: Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee. Appendix I. Center for Drug Evaluation and Research. Food and Drug Administration, Public Health Service, Department of Health and Human Services.

From tricyclics to SSRIS

Tricyclic antidepressants (TCAs) were the mainstay in treating childhood depression two decades ago, based on clinical and anecdotal evidence. However, double blind, placebo-controlled studies failed to show that TCAs were effective in treating depressed children and adolescents. The few controlled studies included small samples of children and adolescents, and the methodologies were often flawed.

In the late 1980s, TCA use in children dropped precipitously because of:

• episodes of sudden death in pediatric patients taking desipramine
• introduction of SSRIs as safer alternatives.

The causal link between sudden death and desipramine was tenuous; Biederman’s article comparing children exposed versus not exposed to TCAs did not demonstrate a statistically significant difference in sudden death.⁸ Even so, fear of cardiotoxicity in children curtailed TCAs’ use.

SSRIs are now are now usually considered firstline antidepressants for children and adolescents because they are presumed to be safer than TCAs. SSRIs are associated with minimal cardiotoxicity and anticholinergic effects, a wider margin of safety in overdose than TCAs, and demonstrated efficacy.

A 12-week, double-blind study compared paroxetine, 20 to 40 mg/d, imipramine, up to 300 mg/d, and placebo in 275 adolescents with major depression.⁹ Patients receiving paroxetine improved significantly more than patients receiving placebo, as measured by reductions in the Hamilton Rating Scale for Depression (HAM-D) total scores and other scales. Response to imipramine was not significantly different from placebo.

Discontinuation rates because of side effects were 9.7% for paroxetine and 31.5% (nearly one-third because of cardiovascular side effects) for imipramine. The average imipramine dosage of 200 mg/d was higher than usual, however.

Table 3

Recommended antidepressant dosages for children and adolescents

Selective serotonin reuptake inhibitors
Drug	Dosage	Comments
Citalopram	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Antianxiety component Limited pediatric data Less effect on P-450 isoenzyme systems than other SSRIs, with fewer drug-drug interactions claimed
Escitalopram	Once-daily Children: 5 to 10 mg Adolescents: 10 mg	L-isomer of citalopram, purported to have lesser side effects than parent compound No data in children
Fluoxetine	Once-daily Children: 5 to 20 mg Adolescents: 10 to 60 mg	Antianxiety properties More effective than placebo in trials of adolescent depression11-12 Long half-life; watch for drug-drug interactions
Fluvoxamine	Divided Children: 50 to 100 mg/d Adolescents: 50 to 200 mg/d	Useful in depression with comorbid obsessive-compulsive symptoms No data for pediatric depression
Paroxetine	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Similar profile as fluoxetine but shorter half-life Not recommended in pediatric patients (FDA advisory)
Sertraline	Divided Children: 25 to100 mg/d Adolescents: 50 to 200 mg/d	Less activating and shorter half-life than fluoxetine
Other reuptake inhibitors
Drug	Dosage	Comment
Bupropion	Divided Children: 75 to 250 mg/d Adolescents: 75 to 400 mg/d	Useful in depression with comorbid attention- deficit/hyperactivity disorder No controlled data in children
Nefazodone	Divided Children: 100 to 300 mg/d Adolescents: 200 to 600 mg/d	5HT2-receptor and serotonin-reuptake blocker
Venlafaxine	Divided or once-daily Children: 18.75 to 75 mg/d Adolescents: 37.5 to 150 mg/d	Noradrenergic and serotonergic effects Limited pediatric data; not recommended in depressed pediatric patients (manufacturer advisory)
Source: Adapted and reprinted with permission from Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000:244.

 

Head-to-head studies of children with obsessive-compulsive disorder have shown fewer side effects with paroxetine compared with clomipramine. Paroxetine’s side effects included anxiety and headaches; clomipra-ALmine’s included headache, tremor, nausea, insomnia, dry mouth and anxiety.¹⁰

Efficacy data. Two double-blind, placebo-controlled studies have shown fluoxetine to be more effective than placebo in treating children and adolescents with depression.^11-13 In general, however, not all SSRIs have shown consistent efficacy in placebo-controlled trials of pediatric major depression. Among 15 such trials submitted to the FDA, three (20%) showed positive results (Table 2). The success rate of drug therapy trials for adult major depression is about 50%.

The FDA’s Feb. 2 hearing memorandum notes several reasons why the agency does not view these findings as proof that SSRIs lack benefit for pediatric patients. For one, the FDA’s program allowing drug companies to apply for pediatric marketing exclusivity—for which the 15 studies were submitted—did not require positive efficacy results.

Clearly, more research is needed to demonstrate the benefits and risks of SSRIs in children and adolescents with major depression and other disorders.

Using SSRIs safely in youth

During its inquiry, the FDA recommended that prescribers observe standard antidepressant labeling language:

• Be cautious when using SSRIs or related antidepressants in major depressive disorder in children and adolescents.
• Supervise high-risk patients, especially during initial drug therapy.

Monitor suicidality. When treating depressed youth with SSRIs and other antidepressants, ask about suicide attempts, suicidal thinking, and plans for suicide. As part of informed consent, discuss with parents the potential for suicidal behavior in youth with untreated depression.

Discuss antidepressant side effects, which may include disinhibition and impulsivity. Individualize treatment plans; for example, aggressive and impulsive children require especially careful monitoring for risky or suicidal behavior.

Rule out bipolar depression and mixed episodes that are often characterized by marked irritability before prescribing antidepressants to depressed children and adolescents. Early-onset depression is a marker for bipolar disorder in pediatric populations, and bipolar illness may be a possible explanation for behavioral activation and dysphoria when antidepressants are prescribed.

Minimize side effects. Children can tolerate moderately high SSRI dosages but are usually started on lower dosages than are used in adolescents and adults (Table 3). SSRIs do not show a clear dose-response relationship, but their side effects are considered dose-dependent.¹⁴

Most-frequent SSRI side effects are nausea, diarrhea, decreased or increased appetite, headaches, restlessness, tremor, and insomnia or hypersomnia. Rare side effects include ecchymoses.¹⁵ Reduced growth, possibly related to growth hormone suppression, has been reported in four boys treated with SSRIs.¹⁶

Prevent drug interactions. SSRIs are rarely used as monotherapy in pediatric patients because of the high rates of comorbidity and severity of mental illness that presents in childhood. Using two or more medications is the rule, not the exception.¹⁷

SSRIs are highly protein-bound and are metabolized by the cytochrome P-450 isoenzyme system, which increases the likelihood of drug-drug interactions. Thus, be aware of the potential impact of combining SSRIs with other agents.

Some researchers suggest that paroxetine, sertraline, and citalopram’s relatively short half-lives (14 to 16 hours) in children may be a rationale for giving the medications twice daily.¹⁸

Avoid withdrawal. The withdrawal syndrome following abrupt cessation of paroxetine, venlafaxine, or fluvoxamine is well known, and its irritability and depression-like symptoms can be quite distressing for patients. Thus, make decisions thoughtfully when discontinuing SSRIs, and plan to taper for 1 to 2 weeks.

Related resources

• Food and Drug Administration. Report prepared for public hearing Feb. 2, 2004. www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm (click on “Background Memorandum”)
• Preliminary report of the task force on SSRIs and suicidal behavior in youth, Jan. 21, 2004. American College of Neuropsychopharmacology. www.acnp.org/exec_summary.pdf
• Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Sood is a speaker for AstraZeneca, Shire Pharmaceutical Group, and Eli Lilly and Co.

Dr. Elizabeth Weller has received research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis, AstraZeneca, and Otsuka Pharmaceutical.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.

Caitlin McIntosh, 12, hanged herself with shoelaces weeks after starting treatment for depression with a selective serotonin reuptake inhibitor (SSRI). Matt Miller, 13, hanged himself in his bedroom closet after taking his seventh SSRI dose. Michael Shivak, 11, slashed his wrists in class—but survived—while taking an SSRI.

These adolescents’ parents testified at an FDA hearing Feb. 2 about possible increased risk of suicidality with SSRIs in depressed children and adolescents.

Other families related positive experiences. Sherri Walton said her daughter, Jordan, 14, has achieved “enormous benefit” from taking SSRIs for obsessive-compulsive disorder. Suzanne Vogel-Scibilia told the FDA panel she is convinced that her two children with psychiatric disorders lead full lives because of SSRIs.

Sensitive to the anguish of grieving families but not wanting to deprive seriously depressed children of effective treatment, the FDA is proceeding methodically with its inquiry—probably at least until summer.

In the meantime, this article offers resources to help you answer questions from parents concerned about their children starting or continuing SSRIs. We include pediatric antidepressant dosing recommendations and data on benefits and risks of SSRIs and other reuptake inhibitors in young patients.

Why the FDA inquiry?

SSRI-associated behavioral activation and suicidal ideation in children and adolescents were reported anecdotally, as case reports, in the early 1990s,¹ and more recently.² No convincing evidence has shown, however, that SSRIs increase the risk of suicide. In fact, widespread use of SSRIs has been associated with reduced suicide rates.³

In May 2003, unpublished data submitted to the FDA from placebo-controlled trials suggested an increased risk of “possibly suicide-related” events and “suicide attempts” in pediatric patients taking paroxetine for major depression. No suicides were reported.

The Medicines and Healthcare Products Regulatory Agency (MHRA)—the United Kingdom’s equivalent of the Food and Drug Administration—responded by warning British physicians against prescribing paroxetine for depressed patients younger than 18. It also ordered a labeling change for paroxetine, contraindicating its use in pediatric major depression.

The FDA advised U.S. doctors against using paroxetine for children under age 18 with major depressive disorder and began investigating data on pediatric use of antidepressants, including all approved SSRIs. Since then:

• In the United States, venlafaxine’s manufacturer changed the drug’s labeling to include increased reports of hostility and suicidality in pediatric trial data. A “Dear Health Care Professional” letter in August 2003 indicated that venlafaxine is not recommended in depressed pediatric patients.
• Britain’s MHRA added pediatric con-traindications to labeling of venlafaxine, sertraline, citalopram, and escitalopram in December 2003. The agency opined that fluoxetine is the only SSRI with a favorable risk-benefit profile for pediatric major depression.
• At press time, the FDA had not changed any SSRI labeling.

At the Feb. 2 public hearing, the FDA’s Psycho-pharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee heard public comments from patients, families, and physicians and reviewed the inquiry’s progress. To locate the Web site containing the FDA’s memorandum on this hearing, see Related resources.

For the next several months, an expert group at Columbia University is under contract with the FDA to develop a system to classify events that might represent suicidality. The group will then analyze data from 24 studies involving more than 4,000 depressed pediatric patients and nine antidepressants (paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram, bupropion, venlafaxine, nefazodone, and mirtazapine).

Independent findings. In January, an American College of Neuropsychopharmacology (ACNP) report concluded that SSRIs do not increase suicidal thoughts or suicide attempts in youth (Table 1). An ACNP task force examined the use of SSRIs in more than 2,000 children and adolescents, including all published clinical trial data, unpublished data from several pharmaceutical companies, and data reported to Britain’s MHRA. An executive summary is available on the ACNP’s Web site (see Related resources).

Table 1

Suicide deaths, behavior, or ideation in clinical trials of youth with major depressive disorder

Medication	Total youth* in trials	No. of suicide deaths	% of youth with suicidal behavior or ideation**		P value	Statistical significance
			Antidepressant	Placebo
Citalopram	418	0	8.9%(19)	7.3% (15)	0.5	No
Fluoxetine	458	0	3.6%(9)	3.8% (8)	0.9	No
Paroxetine	669	0	3.7%(14)	2.5% (7)	0.4	No
Sertraline	376	0	2.7%(5)	1.1% (2)	0.3	No
Venlafaxine	334	0	2%(NA)	0%	0.25	No
* Total number of youth given antidepressants and placebo
** Number inside parenthesis is actual number of youth
NA = Not available
Source: Data from published clinical trials, unpublished clinical trials provided by drug sponsor, and clinical data compiled by the Medicines and Healthcare Products Regulatory Agency of the United Kingdom.
Reprinted with permission of the American College of Neuropsychopharmacology from Preliminary report of the Task Force on SSRIs and Suicidal Behavior in Youth (executive summary), January 2004:18.

Depression’s impact on children

The prevalence of depression in youth age 18 and younger is 8.3%,⁴ and the rate increases with patient age. Before puberty, common signs of depression include somatic symptoms such as abdominal pain, headaches, and irritability, whereas adolescents are more likely to express feelings of depression and exhibit suicidal behavior. Girls and boys are equally at risk for depression until puberty, when girls begin to outnumber boys and the presentation begins to resemble adult depression.

 

Untreated pediatric depression is associated with substantial morbidity, including reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life,^4,5 It also increases the risk of suicide.

Early-onset depression is considered a more malignant illness than adult-onset depression because of its effect on development, potential for recurrence,⁶ and chronicity into adulthood.⁷ The quest to develop appropriate treatment for depressed children and adolescents has been spurred by:

• the substantial risks of morbidity and mortality from childhood depression
• advances in drug treatments for adult-onset depression
• recognition that early-onset depression is treatable.

Physiologically, children are not “mini-adults.” Thus, practicing evidence-based medicine requires separate empirical research for pediatric conditions.

Despite some efforts by the National Institute of Mental Health (NIMH) and the pharmaceutical industry, research in pediatric psychopharmacology and ancillary treatments lags decades behind evidence-based treatment in adults.

Table 2

Efficacy of SSRIs and other newer antidepressants in short-term, placebo-controlled pediatric studies in major depressive disorder

Drug	Age range	Outcome* (drug vs. placebo)
Paroxetine
Study 1  Study 2  Study 3	12 to 18 13 to 18 7 to 17	Negative† Negative Negative
Fluoxetine
Study 1  Study 2	8 to 17 8 to 17	Positive Positive
Sertraline
Study 1  Study 2	6 to 17 6 to 17	Trend Negative§
Venlafaxine
Study 1  Study 2	7 to 17 7 to 17	Negative Negative
Citalopram
Study 1  Study 2	7 to 17 13 to 18	Positive Negative
Nefazodone
Study 1  Study 2	12 to 18 7 to 17	Trend Negative
Mirtazapine
Study 1  Study 2	7 to 17 7 to 17	Negative Negative
* Positive (P 0.05); Negative (P >0.10; Trend (0.05
† Positive on most secondary endpoints
§ Positive on pooling of 2 studies
Source: Adapted and reprinted from Laughren TP. Memorandum: Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee. Appendix I. Center for Drug Evaluation and Research. Food and Drug Administration, Public Health Service, Department of Health and Human Services.

From tricyclics to SSRIS

Tricyclic antidepressants (TCAs) were the mainstay in treating childhood depression two decades ago, based on clinical and anecdotal evidence. However, double blind, placebo-controlled studies failed to show that TCAs were effective in treating depressed children and adolescents. The few controlled studies included small samples of children and adolescents, and the methodologies were often flawed.

In the late 1980s, TCA use in children dropped precipitously because of:

• episodes of sudden death in pediatric patients taking desipramine
• introduction of SSRIs as safer alternatives.

The causal link between sudden death and desipramine was tenuous; Biederman’s article comparing children exposed versus not exposed to TCAs did not demonstrate a statistically significant difference in sudden death.⁸ Even so, fear of cardiotoxicity in children curtailed TCAs’ use.

SSRIs are now are now usually considered firstline antidepressants for children and adolescents because they are presumed to be safer than TCAs. SSRIs are associated with minimal cardiotoxicity and anticholinergic effects, a wider margin of safety in overdose than TCAs, and demonstrated efficacy.

A 12-week, double-blind study compared paroxetine, 20 to 40 mg/d, imipramine, up to 300 mg/d, and placebo in 275 adolescents with major depression.⁹ Patients receiving paroxetine improved significantly more than patients receiving placebo, as measured by reductions in the Hamilton Rating Scale for Depression (HAM-D) total scores and other scales. Response to imipramine was not significantly different from placebo.

Discontinuation rates because of side effects were 9.7% for paroxetine and 31.5% (nearly one-third because of cardiovascular side effects) for imipramine. The average imipramine dosage of 200 mg/d was higher than usual, however.

Table 3

Recommended antidepressant dosages for children and adolescents

Selective serotonin reuptake inhibitors
Drug	Dosage	Comments
Citalopram	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Antianxiety component Limited pediatric data Less effect on P-450 isoenzyme systems than other SSRIs, with fewer drug-drug interactions claimed
Escitalopram	Once-daily Children: 5 to 10 mg Adolescents: 10 mg	L-isomer of citalopram, purported to have lesser side effects than parent compound No data in children
Fluoxetine	Once-daily Children: 5 to 20 mg Adolescents: 10 to 60 mg	Antianxiety properties More effective than placebo in trials of adolescent depression11-12 Long half-life; watch for drug-drug interactions
Fluvoxamine	Divided Children: 50 to 100 mg/d Adolescents: 50 to 200 mg/d	Useful in depression with comorbid obsessive-compulsive symptoms No data for pediatric depression
Paroxetine	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Similar profile as fluoxetine but shorter half-life Not recommended in pediatric patients (FDA advisory)
Sertraline	Divided Children: 25 to100 mg/d Adolescents: 50 to 200 mg/d	Less activating and shorter half-life than fluoxetine
Other reuptake inhibitors
Drug	Dosage	Comment
Bupropion	Divided Children: 75 to 250 mg/d Adolescents: 75 to 400 mg/d	Useful in depression with comorbid attention- deficit/hyperactivity disorder No controlled data in children
Nefazodone	Divided Children: 100 to 300 mg/d Adolescents: 200 to 600 mg/d	5HT2-receptor and serotonin-reuptake blocker
Venlafaxine	Divided or once-daily Children: 18.75 to 75 mg/d Adolescents: 37.5 to 150 mg/d	Noradrenergic and serotonergic effects Limited pediatric data; not recommended in depressed pediatric patients (manufacturer advisory)
Source: Adapted and reprinted with permission from Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000:244.

 

Head-to-head studies of children with obsessive-compulsive disorder have shown fewer side effects with paroxetine compared with clomipramine. Paroxetine’s side effects included anxiety and headaches; clomipra-ALmine’s included headache, tremor, nausea, insomnia, dry mouth and anxiety.¹⁰

Efficacy data. Two double-blind, placebo-controlled studies have shown fluoxetine to be more effective than placebo in treating children and adolescents with depression.^11-13 In general, however, not all SSRIs have shown consistent efficacy in placebo-controlled trials of pediatric major depression. Among 15 such trials submitted to the FDA, three (20%) showed positive results (Table 2). The success rate of drug therapy trials for adult major depression is about 50%.

The FDA’s Feb. 2 hearing memorandum notes several reasons why the agency does not view these findings as proof that SSRIs lack benefit for pediatric patients. For one, the FDA’s program allowing drug companies to apply for pediatric marketing exclusivity—for which the 15 studies were submitted—did not require positive efficacy results.

Clearly, more research is needed to demonstrate the benefits and risks of SSRIs in children and adolescents with major depression and other disorders.

Using SSRIs safely in youth

During its inquiry, the FDA recommended that prescribers observe standard antidepressant labeling language:

• Be cautious when using SSRIs or related antidepressants in major depressive disorder in children and adolescents.
• Supervise high-risk patients, especially during initial drug therapy.

Monitor suicidality. When treating depressed youth with SSRIs and other antidepressants, ask about suicide attempts, suicidal thinking, and plans for suicide. As part of informed consent, discuss with parents the potential for suicidal behavior in youth with untreated depression.

Discuss antidepressant side effects, which may include disinhibition and impulsivity. Individualize treatment plans; for example, aggressive and impulsive children require especially careful monitoring for risky or suicidal behavior.

Rule out bipolar depression and mixed episodes that are often characterized by marked irritability before prescribing antidepressants to depressed children and adolescents. Early-onset depression is a marker for bipolar disorder in pediatric populations, and bipolar illness may be a possible explanation for behavioral activation and dysphoria when antidepressants are prescribed.

Minimize side effects. Children can tolerate moderately high SSRI dosages but are usually started on lower dosages than are used in adolescents and adults (Table 3). SSRIs do not show a clear dose-response relationship, but their side effects are considered dose-dependent.¹⁴

Most-frequent SSRI side effects are nausea, diarrhea, decreased or increased appetite, headaches, restlessness, tremor, and insomnia or hypersomnia. Rare side effects include ecchymoses.¹⁵ Reduced growth, possibly related to growth hormone suppression, has been reported in four boys treated with SSRIs.¹⁶

Prevent drug interactions. SSRIs are rarely used as monotherapy in pediatric patients because of the high rates of comorbidity and severity of mental illness that presents in childhood. Using two or more medications is the rule, not the exception.¹⁷

SSRIs are highly protein-bound and are metabolized by the cytochrome P-450 isoenzyme system, which increases the likelihood of drug-drug interactions. Thus, be aware of the potential impact of combining SSRIs with other agents.

Some researchers suggest that paroxetine, sertraline, and citalopram’s relatively short half-lives (14 to 16 hours) in children may be a rationale for giving the medications twice daily.¹⁸

Avoid withdrawal. The withdrawal syndrome following abrupt cessation of paroxetine, venlafaxine, or fluvoxamine is well known, and its irritability and depression-like symptoms can be quite distressing for patients. Thus, make decisions thoughtfully when discontinuing SSRIs, and plan to taper for 1 to 2 weeks.

Related resources

• Food and Drug Administration. Report prepared for public hearing Feb. 2, 2004. www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm (click on “Background Memorandum”)
• Preliminary report of the task force on SSRIs and suicidal behavior in youth, Jan. 21, 2004. American College of Neuropsychopharmacology. www.acnp.org/exec_summary.pdf
• Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Sood is a speaker for AstraZeneca, Shire Pharmaceutical Group, and Eli Lilly and Co.

Dr. Elizabeth Weller has received research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis, AstraZeneca, and Otsuka Pharmaceutical.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.

Caitlin McIntosh, 12, hanged herself with shoelaces weeks after starting treatment for depression with a selective serotonin reuptake inhibitor (SSRI). Matt Miller, 13, hanged himself in his bedroom closet after taking his seventh SSRI dose. Michael Shivak, 11, slashed his wrists in class—but survived—while taking an SSRI.

These adolescents’ parents testified at an FDA hearing Feb. 2 about possible increased risk of suicidality with SSRIs in depressed children and adolescents.

Other families related positive experiences. Sherri Walton said her daughter, Jordan, 14, has achieved “enormous benefit” from taking SSRIs for obsessive-compulsive disorder. Suzanne Vogel-Scibilia told the FDA panel she is convinced that her two children with psychiatric disorders lead full lives because of SSRIs.

Sensitive to the anguish of grieving families but not wanting to deprive seriously depressed children of effective treatment, the FDA is proceeding methodically with its inquiry—probably at least until summer.

In the meantime, this article offers resources to help you answer questions from parents concerned about their children starting or continuing SSRIs. We include pediatric antidepressant dosing recommendations and data on benefits and risks of SSRIs and other reuptake inhibitors in young patients.

Why the FDA inquiry?

SSRI-associated behavioral activation and suicidal ideation in children and adolescents were reported anecdotally, as case reports, in the early 1990s,¹ and more recently.² No convincing evidence has shown, however, that SSRIs increase the risk of suicide. In fact, widespread use of SSRIs has been associated with reduced suicide rates.³

In May 2003, unpublished data submitted to the FDA from placebo-controlled trials suggested an increased risk of “possibly suicide-related” events and “suicide attempts” in pediatric patients taking paroxetine for major depression. No suicides were reported.

The Medicines and Healthcare Products Regulatory Agency (MHRA)—the United Kingdom’s equivalent of the Food and Drug Administration—responded by warning British physicians against prescribing paroxetine for depressed patients younger than 18. It also ordered a labeling change for paroxetine, contraindicating its use in pediatric major depression.

The FDA advised U.S. doctors against using paroxetine for children under age 18 with major depressive disorder and began investigating data on pediatric use of antidepressants, including all approved SSRIs. Since then:

• In the United States, venlafaxine’s manufacturer changed the drug’s labeling to include increased reports of hostility and suicidality in pediatric trial data. A “Dear Health Care Professional” letter in August 2003 indicated that venlafaxine is not recommended in depressed pediatric patients.
• Britain’s MHRA added pediatric con-traindications to labeling of venlafaxine, sertraline, citalopram, and escitalopram in December 2003. The agency opined that fluoxetine is the only SSRI with a favorable risk-benefit profile for pediatric major depression.
• At press time, the FDA had not changed any SSRI labeling.

At the Feb. 2 public hearing, the FDA’s Psycho-pharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee heard public comments from patients, families, and physicians and reviewed the inquiry’s progress. To locate the Web site containing the FDA’s memorandum on this hearing, see Related resources.

For the next several months, an expert group at Columbia University is under contract with the FDA to develop a system to classify events that might represent suicidality. The group will then analyze data from 24 studies involving more than 4,000 depressed pediatric patients and nine antidepressants (paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram, bupropion, venlafaxine, nefazodone, and mirtazapine).

Independent findings. In January, an American College of Neuropsychopharmacology (ACNP) report concluded that SSRIs do not increase suicidal thoughts or suicide attempts in youth (Table 1). An ACNP task force examined the use of SSRIs in more than 2,000 children and adolescents, including all published clinical trial data, unpublished data from several pharmaceutical companies, and data reported to Britain’s MHRA. An executive summary is available on the ACNP’s Web site (see Related resources).

Table 1

Suicide deaths, behavior, or ideation in clinical trials of youth with major depressive disorder

Medication	Total youth* in trials	No. of suicide deaths	% of youth with suicidal behavior or ideation**		P value	Statistical significance
			Antidepressant	Placebo
Citalopram	418	0	8.9%(19)	7.3% (15)	0.5	No
Fluoxetine	458	0	3.6%(9)	3.8% (8)	0.9	No
Paroxetine	669	0	3.7%(14)	2.5% (7)	0.4	No
Sertraline	376	0	2.7%(5)	1.1% (2)	0.3	No
Venlafaxine	334	0	2%(NA)	0%	0.25	No
* Total number of youth given antidepressants and placebo
** Number inside parenthesis is actual number of youth
NA = Not available
Source: Data from published clinical trials, unpublished clinical trials provided by drug sponsor, and clinical data compiled by the Medicines and Healthcare Products Regulatory Agency of the United Kingdom.
Reprinted with permission of the American College of Neuropsychopharmacology from Preliminary report of the Task Force on SSRIs and Suicidal Behavior in Youth (executive summary), January 2004:18.

Depression’s impact on children

The prevalence of depression in youth age 18 and younger is 8.3%,⁴ and the rate increases with patient age. Before puberty, common signs of depression include somatic symptoms such as abdominal pain, headaches, and irritability, whereas adolescents are more likely to express feelings of depression and exhibit suicidal behavior. Girls and boys are equally at risk for depression until puberty, when girls begin to outnumber boys and the presentation begins to resemble adult depression.

 

Untreated pediatric depression is associated with substantial morbidity, including reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life,^4,5 It also increases the risk of suicide.

Early-onset depression is considered a more malignant illness than adult-onset depression because of its effect on development, potential for recurrence,⁶ and chronicity into adulthood.⁷ The quest to develop appropriate treatment for depressed children and adolescents has been spurred by:

• the substantial risks of morbidity and mortality from childhood depression
• advances in drug treatments for adult-onset depression
• recognition that early-onset depression is treatable.

Physiologically, children are not “mini-adults.” Thus, practicing evidence-based medicine requires separate empirical research for pediatric conditions.

Despite some efforts by the National Institute of Mental Health (NIMH) and the pharmaceutical industry, research in pediatric psychopharmacology and ancillary treatments lags decades behind evidence-based treatment in adults.

Table 2

Efficacy of SSRIs and other newer antidepressants in short-term, placebo-controlled pediatric studies in major depressive disorder

Drug	Age range	Outcome* (drug vs. placebo)
Paroxetine
Study 1  Study 2  Study 3	12 to 18 13 to 18 7 to 17	Negative† Negative Negative
Fluoxetine
Study 1  Study 2	8 to 17 8 to 17	Positive Positive
Sertraline
Study 1  Study 2	6 to 17 6 to 17	Trend Negative§
Venlafaxine
Study 1  Study 2	7 to 17 7 to 17	Negative Negative
Citalopram
Study 1  Study 2	7 to 17 13 to 18	Positive Negative
Nefazodone
Study 1  Study 2	12 to 18 7 to 17	Trend Negative
Mirtazapine
Study 1  Study 2	7 to 17 7 to 17	Negative Negative
* Positive (P 0.05); Negative (P >0.10; Trend (0.05
† Positive on most secondary endpoints
§ Positive on pooling of 2 studies
Source: Adapted and reprinted from Laughren TP. Memorandum: Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee. Appendix I. Center for Drug Evaluation and Research. Food and Drug Administration, Public Health Service, Department of Health and Human Services.

From tricyclics to SSRIS

Tricyclic antidepressants (TCAs) were the mainstay in treating childhood depression two decades ago, based on clinical and anecdotal evidence. However, double blind, placebo-controlled studies failed to show that TCAs were effective in treating depressed children and adolescents. The few controlled studies included small samples of children and adolescents, and the methodologies were often flawed.

In the late 1980s, TCA use in children dropped precipitously because of:

• episodes of sudden death in pediatric patients taking desipramine
• introduction of SSRIs as safer alternatives.

The causal link between sudden death and desipramine was tenuous; Biederman’s article comparing children exposed versus not exposed to TCAs did not demonstrate a statistically significant difference in sudden death.⁸ Even so, fear of cardiotoxicity in children curtailed TCAs’ use.

SSRIs are now are now usually considered firstline antidepressants for children and adolescents because they are presumed to be safer than TCAs. SSRIs are associated with minimal cardiotoxicity and anticholinergic effects, a wider margin of safety in overdose than TCAs, and demonstrated efficacy.

A 12-week, double-blind study compared paroxetine, 20 to 40 mg/d, imipramine, up to 300 mg/d, and placebo in 275 adolescents with major depression.⁹ Patients receiving paroxetine improved significantly more than patients receiving placebo, as measured by reductions in the Hamilton Rating Scale for Depression (HAM-D) total scores and other scales. Response to imipramine was not significantly different from placebo.

Discontinuation rates because of side effects were 9.7% for paroxetine and 31.5% (nearly one-third because of cardiovascular side effects) for imipramine. The average imipramine dosage of 200 mg/d was higher than usual, however.

Table 3

Recommended antidepressant dosages for children and adolescents

Selective serotonin reuptake inhibitors
Drug	Dosage	Comments
Citalopram	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Antianxiety component Limited pediatric data Less effect on P-450 isoenzyme systems than other SSRIs, with fewer drug-drug interactions claimed
Escitalopram	Once-daily Children: 5 to 10 mg Adolescents: 10 mg	L-isomer of citalopram, purported to have lesser side effects than parent compound No data in children
Fluoxetine	Once-daily Children: 5 to 20 mg Adolescents: 10 to 60 mg	Antianxiety properties More effective than placebo in trials of adolescent depression11-12 Long half-life; watch for drug-drug interactions
Fluvoxamine	Divided Children: 50 to 100 mg/d Adolescents: 50 to 200 mg/d	Useful in depression with comorbid obsessive-compulsive symptoms No data for pediatric depression
Paroxetine	Once-daily Children: 10 to 20 mg Adolescents: 10 to 40 mg	Similar profile as fluoxetine but shorter half-life Not recommended in pediatric patients (FDA advisory)
Sertraline	Divided Children: 25 to100 mg/d Adolescents: 50 to 200 mg/d	Less activating and shorter half-life than fluoxetine
Other reuptake inhibitors
Drug	Dosage	Comment
Bupropion	Divided Children: 75 to 250 mg/d Adolescents: 75 to 400 mg/d	Useful in depression with comorbid attention- deficit/hyperactivity disorder No controlled data in children
Nefazodone	Divided Children: 100 to 300 mg/d Adolescents: 200 to 600 mg/d	5HT2-receptor and serotonin-reuptake blocker
Venlafaxine	Divided or once-daily Children: 18.75 to 75 mg/d Adolescents: 37.5 to 150 mg/d	Noradrenergic and serotonergic effects Limited pediatric data; not recommended in depressed pediatric patients (manufacturer advisory)
Source: Adapted and reprinted with permission from Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000:244.

 

Head-to-head studies of children with obsessive-compulsive disorder have shown fewer side effects with paroxetine compared with clomipramine. Paroxetine’s side effects included anxiety and headaches; clomipra-ALmine’s included headache, tremor, nausea, insomnia, dry mouth and anxiety.¹⁰

Efficacy data. Two double-blind, placebo-controlled studies have shown fluoxetine to be more effective than placebo in treating children and adolescents with depression.^11-13 In general, however, not all SSRIs have shown consistent efficacy in placebo-controlled trials of pediatric major depression. Among 15 such trials submitted to the FDA, three (20%) showed positive results (Table 2). The success rate of drug therapy trials for adult major depression is about 50%.

The FDA’s Feb. 2 hearing memorandum notes several reasons why the agency does not view these findings as proof that SSRIs lack benefit for pediatric patients. For one, the FDA’s program allowing drug companies to apply for pediatric marketing exclusivity—for which the 15 studies were submitted—did not require positive efficacy results.

Clearly, more research is needed to demonstrate the benefits and risks of SSRIs in children and adolescents with major depression and other disorders.

Using SSRIs safely in youth

During its inquiry, the FDA recommended that prescribers observe standard antidepressant labeling language:

• Be cautious when using SSRIs or related antidepressants in major depressive disorder in children and adolescents.
• Supervise high-risk patients, especially during initial drug therapy.

Monitor suicidality. When treating depressed youth with SSRIs and other antidepressants, ask about suicide attempts, suicidal thinking, and plans for suicide. As part of informed consent, discuss with parents the potential for suicidal behavior in youth with untreated depression.

Discuss antidepressant side effects, which may include disinhibition and impulsivity. Individualize treatment plans; for example, aggressive and impulsive children require especially careful monitoring for risky or suicidal behavior.

Rule out bipolar depression and mixed episodes that are often characterized by marked irritability before prescribing antidepressants to depressed children and adolescents. Early-onset depression is a marker for bipolar disorder in pediatric populations, and bipolar illness may be a possible explanation for behavioral activation and dysphoria when antidepressants are prescribed.

Minimize side effects. Children can tolerate moderately high SSRI dosages but are usually started on lower dosages than are used in adolescents and adults (Table 3). SSRIs do not show a clear dose-response relationship, but their side effects are considered dose-dependent.¹⁴

Most-frequent SSRI side effects are nausea, diarrhea, decreased or increased appetite, headaches, restlessness, tremor, and insomnia or hypersomnia. Rare side effects include ecchymoses.¹⁵ Reduced growth, possibly related to growth hormone suppression, has been reported in four boys treated with SSRIs.¹⁶

Prevent drug interactions. SSRIs are rarely used as monotherapy in pediatric patients because of the high rates of comorbidity and severity of mental illness that presents in childhood. Using two or more medications is the rule, not the exception.¹⁷

SSRIs are highly protein-bound and are metabolized by the cytochrome P-450 isoenzyme system, which increases the likelihood of drug-drug interactions. Thus, be aware of the potential impact of combining SSRIs with other agents.

Some researchers suggest that paroxetine, sertraline, and citalopram’s relatively short half-lives (14 to 16 hours) in children may be a rationale for giving the medications twice daily.¹⁸

Avoid withdrawal. The withdrawal syndrome following abrupt cessation of paroxetine, venlafaxine, or fluvoxamine is well known, and its irritability and depression-like symptoms can be quite distressing for patients. Thus, make decisions thoughtfully when discontinuing SSRIs, and plan to taper for 1 to 2 weeks.

Related resources

• Food and Drug Administration. Report prepared for public hearing Feb. 2, 2004. www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm (click on “Background Memorandum”)
• Preliminary report of the task force on SSRIs and suicidal behavior in youth, Jan. 21, 2004. American College of Neuropsychopharmacology. www.acnp.org/exec_summary.pdf
• Sood B, Sood R. Depression in children and adolescents. In: Levenson JL (ed). Depression: key diseases series. Philadelphia: American College of Physicians, 2000.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Sood is a speaker for AstraZeneca, Shire Pharmaceutical Group, and Eli Lilly and Co.

Dr. Elizabeth Weller has received research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis, AstraZeneca, and Otsuka Pharmaceutical.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.

When depression fails to respond to initial therapy—as it commonly does—we have many options but little evidence to guide our choices. We often wonder:

• Is this patient’s depression treatment-resistant?
• Would switching medications or augmenting the initial drug be more likely to achieve an adequate response?
• How effective is psychotherapy compared with medication for treatment-resistant depression?

This article offers insights into each question, based on available trial data, algorithmic approaches to major depressive disorder, and clinical experience. Included is a preview of an ongoing multicenter, treatment-resistant depression study that mimics clinical practice and a look at vagus nerve stimulation (VNS)—a novel somatic therapy being considered by the FDA.

Measuring treatment response

Sustained symptom remission—with normalization of function—is the aim of treating major depressive disorder. Outcomes are categorized as:

• remission (virtual absence of depressive symptoms)
• response with residual symptoms (>50% reduction in baseline symptom severity that does not qualify for remission)
• partial response (>25% but <50% decrease in baseline symptom severity)
• nonresponse (<25% reduction in baseline symptoms).

Box

In 8-week acute-phase trials, 7% to 15% of patients do not tolerate the initial medication, 25% show no response, 15% show partial response, 10% to 20% exhibit response with residual symptoms, and 30% to 40% achieve remission. Complicated depressions that may not respond as well include those concurrent with Axis I conditions—such as panic disorder or substance abuse—or Axis II or III conditions.¹

Time-limited psychotherapies targeted at depressive symptoms (such as cognitive, interpersonal, and behavioral therapies) also typically achieve a 50% response rate in uncomplicated depression that is not treatment-resistant.

Recommendation. When treating depression, assess response at least every 4 weeks (preferably at each visit), using a self-report or clinician rating such as:

• Quick Inventory of Depressive Symptomatology² (see Related resources)
• Beck Depression Inventory^3,4
• Patient Health Questionnaire.⁵

Defining treatment resistance

A patient may not achieve remission for a variety of reasons, including poor adherence, inadequate medication trial or dosing, occult substance abuse, undiagnosed medical conditions (Box),^6-8 concurrent Axis I or II disorders, or treatment resistance.

The general consensus is to consider depression “treatment-resistant” when at least two adequately delivered treatments do not achieve at least a response. A stricter definition—failure to achieve sustained remission with two or more treatments—has also been suggested.

Several schemes have proposed treatment resistance levels, such as the five stages identified in the Table. Recent studies^9,10 suggest that increasing treatment resistance is associated with decreasing response or remission rates.

Therefore, when a patient’s treatment resistance is high, two appropriate strategies are to:

• persist with and use maximally tolerated dosages of the treatment you select
• aim for response because high resistance lowers the likelihood of remission.

Predicting response. A major clinical issue is determining whether remission will occur during an acute treatment trial. It is important to not declare treatment resistance unless there has been:

• adequate exposure (dosing and duration) to the treatment
• and adequate adherence.

Patients often have apparent but not actual resistance, meaning that the agent was not used long enough (at least 6 weeks) or at high enough doses. Remission typically follows response by several weeks or even 1 to 2 months for more-chronic depressions.¹¹ Thus, treatment trials should continue at least 12 weeks to determine whether remission will occur.

On the other hand, not obtaining at least a signal of minimal benefit (at least a 20% reduction in baseline symptom severity) in 4 to 6 weeks often portends a low likelihood of response in the long run.^12,13 Thus, continue a treatment at least 6 weeks before you decide that it will not achieve a response.

 

Recommendation. Measure symptoms at key decision points. If modest improvement (such as 20% reduction in baseline symptoms) is found at 4 to 6 weeks, continue treating another 4 to 6 weeks, increasing the dosage as tolerated.

Table

Simple system for staging antidepressant resistance

Stage	Definition
I	Failure of at least one adequate trial of one major antidepressant class
II	Stage I resistance plus failure of an adequate trial of an antidepressant in a distinctly different class from that used in Stage I
III	Stage II resistance plus failure of an adequate trial of a tricyclic antidepressant
IV	Stage III resistance plus failure of an adequate trial of a monoamine oxidase inhibitor
V	Stage IV resistance plus failure of a course of bilateral electroconvulsive therapy
Source: Reprinted with permission from Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58(suppl 13):24.

Treatment options

When initial antidepressant treatment fails to achieve an adequate response—as it does in more than onehalf of major depression cases—the next step is to add a second agent or switch to another agent.

Available evidence¹⁴ relies almost exclusively on open, uncontrolled trials, which do not provide definitive answers. Even so, these trials indicate that nonresponse (or nonremission) with one agent does not predict nonresponse/nonremission with another.

Switching strategies. When a selective serotonin reuptake inhibitor (SSRI) is the first treatment, several open trials reveal an approximately 50% response rate to a second SSRI. However, opentrial evidence and retrospective chart review reports also indicate that switching out of class (such as from an SSRI to bupropion) is also approximately 50% effective.¹⁵

Some post hoc analyses of acute 8-week trials indicate that the dual-action agent venlafaxine at higher dosages (up to 225 mg/d of venlafaxine XR) is associated with higher remission rates than the more-selective SSRIs.^16,17 On the other hand, unpublished data indicate that escitalopram, 10 mg/d, and venlafaxine XR, up to 150 mg/d, did not differ in efficacy among outpatients treated by primary care physicians.¹⁸

On the other hand, sertraline and imipramine (a dual-action agent) were equally effective in a 12-week acute-phase trial.¹⁹ Furthermore, response and remission rates were similar when nonresponders in each group switched to the other antidepressant.²⁰ This suggests that the dual-action agent (imipramine) was not more effective than the more selective agent (sertraline) in this population.

Well-controlled trials show that monoamine oxidase inhibitors (MAOIs) can be effective when tricyclic antidepressants (TCAs) are not. Switches among the TCAs are associated with a 30% response rate, whereas switching from a TCA to an MAOI typically results in a 50% response rate.²¹

Controlled prospective comparisons of two or more alternate switch or augment treatments are needed to establish comparative efficacy and tolerability.

Augmentation strategies may include lithium, buspirone, thyroid hormone (T3), stimulants, or atypical antipsychotics. Although head-to-head comparisons are rare, a randomized, controlled trial found that combining olanzapine (mean 50 mg/d), with fluoxetine (mean 15 mg/d) was more effective than each agent used alone.²²

Risperidone augmentation is supported by open trials, as is the use of modafinil, other stimulants, and bupropion. An important unanswered question with most augmentation strategies is how long to continue them if they are successful.

Psychotherapy may also play a key role in augmenting medication’s effects. Keller et al²³ found in chronically depressed outpatients that 12 weeks of nefazodone, up to 600 mg/d, plus cognitive behavioral analytic system psychotherapy (CBASP) produced higher response and remission rates compared with either treatment alone. A subsequent report²⁴ found that 50% of nefa-zodone and CBASP monotherapy nonresponders did respond when switched to the alternate treatment.

Thus, CBASP may be useful at least in chronic depression to augment medication or as a “switch” to monotherapy if medication alone fails. Interestingly, Nemeroff et al²⁵ found CBASP more effective than nefazodone for patients with chronic major depression who had a childhood history of parental loss or physical, sexual, or emotional abuse.

Antidepressant tachyphylaxis—commonly referred to as “poop-out”—is reported with all antidepressants. That is, even while apparently taking their medications for 6 to 18 months, some patients lose the antidepressant effect, such that some symptoms return or a full relapse/recurrence ensues. Mechanisms of this phenomenon are unknown.

Clinically, some believe that “poop out” is more common with SSRIs than with other antidepressant classes, but no long-term comparative data support or challenge this view. Treatment options include a dosage increase, dosage reduction (especially for long half-life SSRIs such as fluoxetine), or augmentation with the options noted above (such as bupropion, buspirone, etc.).

Benefit of using algorithms

Algorithms (such as the Texas Medication Algorithm Project²⁶ ) have suggested multiple treatment steps for major depression after initial treatment fails, with several options available at each step. Using medication algorithms has been found more effective than treatment-as-usual in outpatients with major depressive disorder.²⁷ No studies have compared different algorithms.

 

STAR*D trial. The ongoing National Institute of Mental Health (NIMH) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial may offer a new algorithmic approach to treating major depression.^14,28 NIMH launched STAR*D in 1999, enrollment began in 2001, and results are expecte by May 2005 (see Related resources).

STAR*D—of which I am the study director—is a randomized, controlled, raterblinded, multisite trial of outpatients ages 18 to 75 with nonpsychotic major depression (17-item Hamilton Rating Scale for Depression score 14). The trial design includes four treatment levels and numerous antidepressant options (Figure).

The study’s aim is to enroll 4,000 patients into level 1, with 1,500 entering level 2. Patients who achieve an adequate response based on clinician judgment may continue the effective treatment for 12 months, during which their symptoms and other relevant information are monitored monthly by telephone. Patients who do not achieve an acceptable response in level 1 (or in subsequent levels) may proceed to the next level, which involves a randomized assignment.

STAR*D has an innovative design that mimics clinical practice and ensures high levels of patient participation. When patients agree to randomization, they may elect to exclude groups of treatments but may not pick a particular treatment (they must accept randomization to stay in the study).

Figure STAR*D treatment levels for major depressive disorder

For example, patient A entering level 2 may exclude switch treatments and elect to accept randomization to citalopram plus bupropion SR, citalopram plus buspirone, or citalopram and cognitive therapy. Conversely, patient B may exclude all augment options at level 2, and accept randomization to the four switch options.

Patients may exclude cognitive psychotherapy as an augment and/or switch option as long as they accept randomization to all available medication switches, or augments, or both. They may also choose cognitive therapy and exclude all medication switch and augment options. These patients must accept randomization to either cognitive therapy switch or cognitive therapy augmentation.

This so-called equipoise stratified randomized design²⁹ allows us to compare all participants randomized to the treatments being compared. To date, only 1% of subjects have accepted randomization to all seven level-2 treatments. About one-half elect only the switch options, and about one-half elect only the augment options.

STAR*D’s goal is to determine whether there is a preferred next step for varying types and degrees of treatment-resistant repression.

Vagus nerve stimulation

Somatic therapies being investigated to expand our therapeutic options for major depressive disorder include magnetic seizure therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation (VNS).

VNS—now indicated for treatment-resistant epilepsy—is being investigated as a potential augmentation for treatment-resistant depression. An application for this supplemental indication was submitted to the FDA in October 2003.

With VNS, a device implanted in the patient’s chest provides intermittent stimulation to the left vagus nerve (typically 30 seconds on and 5 minutes off, 24 hours a day). In an open trial¹⁰ and follow-up report,³⁰ VNS was associated with a 30% to 45% response rate in 59 depressed patients with high levels of treatment resistance (inadequate response to an average of 16 treatment trials).

VNS is well tolerated, though it has not been prospectively studied in patients with diagnosed cardiovascular disease. Side effects that may occur when the stimulation is “on” include:

• voice alteration in about 60% of patients (the voice becomes more hoarse when the left recurrent laryngeal nerve is activated)
• paresthesias in the neck
• shortness of breath on heavy exertion.

These effects are usually absent in the 5-minute “off” phase.

Related resources

• National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Includes the Quick Inventory of Depressive Symptomatology. www.star-d.org
• HealthyPlace.Com Depression Community. Vagus nerve stimulation for treating depression. www.healthyplace.com/communities/depression/treatment/vns

Drug brand names

• Bupropion • Wellbutrin, Wellbutrin SR
• Buspirone • BuSpar
• Citalopram • Celexa
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Modafinil • Provigil
• Nefazodone • Serzone
• Nortriptyline • Pamelor, Aventyl
• Olanzapine • Zyprexa
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tranylcypromine • Parnate
• Venlafaxine • Effexor, Effexor XR

Disclosure

Dr. Rush receives grant/research support from the Robert Wood Johnson Foundation, National Institute of Mental Health, and The Stanley Foundation. He is a consultant to Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, and GlaxoSmithKline, and a speaker for Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.

When depression fails to respond to initial therapy—as it commonly does—we have many options but little evidence to guide our choices. We often wonder:

• Is this patient’s depression treatment-resistant?
• Would switching medications or augmenting the initial drug be more likely to achieve an adequate response?
• How effective is psychotherapy compared with medication for treatment-resistant depression?

This article offers insights into each question, based on available trial data, algorithmic approaches to major depressive disorder, and clinical experience. Included is a preview of an ongoing multicenter, treatment-resistant depression study that mimics clinical practice and a look at vagus nerve stimulation (VNS)—a novel somatic therapy being considered by the FDA.

Measuring treatment response

Sustained symptom remission—with normalization of function—is the aim of treating major depressive disorder. Outcomes are categorized as:

• remission (virtual absence of depressive symptoms)
• response with residual symptoms (>50% reduction in baseline symptom severity that does not qualify for remission)
• partial response (>25% but <50% decrease in baseline symptom severity)
• nonresponse (<25% reduction in baseline symptoms).

Box

In 8-week acute-phase trials, 7% to 15% of patients do not tolerate the initial medication, 25% show no response, 15% show partial response, 10% to 20% exhibit response with residual symptoms, and 30% to 40% achieve remission. Complicated depressions that may not respond as well include those concurrent with Axis I conditions—such as panic disorder or substance abuse—or Axis II or III conditions.¹

Time-limited psychotherapies targeted at depressive symptoms (such as cognitive, interpersonal, and behavioral therapies) also typically achieve a 50% response rate in uncomplicated depression that is not treatment-resistant.

Recommendation. When treating depression, assess response at least every 4 weeks (preferably at each visit), using a self-report or clinician rating such as:

• Quick Inventory of Depressive Symptomatology² (see Related resources)
• Beck Depression Inventory^3,4
• Patient Health Questionnaire.⁵

Defining treatment resistance

A patient may not achieve remission for a variety of reasons, including poor adherence, inadequate medication trial or dosing, occult substance abuse, undiagnosed medical conditions (Box),^6-8 concurrent Axis I or II disorders, or treatment resistance.

The general consensus is to consider depression “treatment-resistant” when at least two adequately delivered treatments do not achieve at least a response. A stricter definition—failure to achieve sustained remission with two or more treatments—has also been suggested.

Several schemes have proposed treatment resistance levels, such as the five stages identified in the Table. Recent studies^9,10 suggest that increasing treatment resistance is associated with decreasing response or remission rates.

Therefore, when a patient’s treatment resistance is high, two appropriate strategies are to:

• persist with and use maximally tolerated dosages of the treatment you select
• aim for response because high resistance lowers the likelihood of remission.

Predicting response. A major clinical issue is determining whether remission will occur during an acute treatment trial. It is important to not declare treatment resistance unless there has been:

• adequate exposure (dosing and duration) to the treatment
• and adequate adherence.

Patients often have apparent but not actual resistance, meaning that the agent was not used long enough (at least 6 weeks) or at high enough doses. Remission typically follows response by several weeks or even 1 to 2 months for more-chronic depressions.¹¹ Thus, treatment trials should continue at least 12 weeks to determine whether remission will occur.

On the other hand, not obtaining at least a signal of minimal benefit (at least a 20% reduction in baseline symptom severity) in 4 to 6 weeks often portends a low likelihood of response in the long run.^12,13 Thus, continue a treatment at least 6 weeks before you decide that it will not achieve a response.

 

Recommendation. Measure symptoms at key decision points. If modest improvement (such as 20% reduction in baseline symptoms) is found at 4 to 6 weeks, continue treating another 4 to 6 weeks, increasing the dosage as tolerated.

Table

Simple system for staging antidepressant resistance

Stage	Definition
I	Failure of at least one adequate trial of one major antidepressant class
II	Stage I resistance plus failure of an adequate trial of an antidepressant in a distinctly different class from that used in Stage I
III	Stage II resistance plus failure of an adequate trial of a tricyclic antidepressant
IV	Stage III resistance plus failure of an adequate trial of a monoamine oxidase inhibitor
V	Stage IV resistance plus failure of a course of bilateral electroconvulsive therapy
Source: Reprinted with permission from Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58(suppl 13):24.

Treatment options

When initial antidepressant treatment fails to achieve an adequate response—as it does in more than onehalf of major depression cases—the next step is to add a second agent or switch to another agent.

Available evidence¹⁴ relies almost exclusively on open, uncontrolled trials, which do not provide definitive answers. Even so, these trials indicate that nonresponse (or nonremission) with one agent does not predict nonresponse/nonremission with another.

Switching strategies. When a selective serotonin reuptake inhibitor (SSRI) is the first treatment, several open trials reveal an approximately 50% response rate to a second SSRI. However, opentrial evidence and retrospective chart review reports also indicate that switching out of class (such as from an SSRI to bupropion) is also approximately 50% effective.¹⁵

Some post hoc analyses of acute 8-week trials indicate that the dual-action agent venlafaxine at higher dosages (up to 225 mg/d of venlafaxine XR) is associated with higher remission rates than the more-selective SSRIs.^16,17 On the other hand, unpublished data indicate that escitalopram, 10 mg/d, and venlafaxine XR, up to 150 mg/d, did not differ in efficacy among outpatients treated by primary care physicians.¹⁸

On the other hand, sertraline and imipramine (a dual-action agent) were equally effective in a 12-week acute-phase trial.¹⁹ Furthermore, response and remission rates were similar when nonresponders in each group switched to the other antidepressant.²⁰ This suggests that the dual-action agent (imipramine) was not more effective than the more selective agent (sertraline) in this population.

Well-controlled trials show that monoamine oxidase inhibitors (MAOIs) can be effective when tricyclic antidepressants (TCAs) are not. Switches among the TCAs are associated with a 30% response rate, whereas switching from a TCA to an MAOI typically results in a 50% response rate.²¹

Controlled prospective comparisons of two or more alternate switch or augment treatments are needed to establish comparative efficacy and tolerability.

Augmentation strategies may include lithium, buspirone, thyroid hormone (T3), stimulants, or atypical antipsychotics. Although head-to-head comparisons are rare, a randomized, controlled trial found that combining olanzapine (mean 50 mg/d), with fluoxetine (mean 15 mg/d) was more effective than each agent used alone.²²

Risperidone augmentation is supported by open trials, as is the use of modafinil, other stimulants, and bupropion. An important unanswered question with most augmentation strategies is how long to continue them if they are successful.

Psychotherapy may also play a key role in augmenting medication’s effects. Keller et al²³ found in chronically depressed outpatients that 12 weeks of nefazodone, up to 600 mg/d, plus cognitive behavioral analytic system psychotherapy (CBASP) produced higher response and remission rates compared with either treatment alone. A subsequent report²⁴ found that 50% of nefa-zodone and CBASP monotherapy nonresponders did respond when switched to the alternate treatment.

Thus, CBASP may be useful at least in chronic depression to augment medication or as a “switch” to monotherapy if medication alone fails. Interestingly, Nemeroff et al²⁵ found CBASP more effective than nefazodone for patients with chronic major depression who had a childhood history of parental loss or physical, sexual, or emotional abuse.

Antidepressant tachyphylaxis—commonly referred to as “poop-out”—is reported with all antidepressants. That is, even while apparently taking their medications for 6 to 18 months, some patients lose the antidepressant effect, such that some symptoms return or a full relapse/recurrence ensues. Mechanisms of this phenomenon are unknown.

Clinically, some believe that “poop out” is more common with SSRIs than with other antidepressant classes, but no long-term comparative data support or challenge this view. Treatment options include a dosage increase, dosage reduction (especially for long half-life SSRIs such as fluoxetine), or augmentation with the options noted above (such as bupropion, buspirone, etc.).

Benefit of using algorithms

Algorithms (such as the Texas Medication Algorithm Project²⁶ ) have suggested multiple treatment steps for major depression after initial treatment fails, with several options available at each step. Using medication algorithms has been found more effective than treatment-as-usual in outpatients with major depressive disorder.²⁷ No studies have compared different algorithms.

 

STAR*D trial. The ongoing National Institute of Mental Health (NIMH) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial may offer a new algorithmic approach to treating major depression.^14,28 NIMH launched STAR*D in 1999, enrollment began in 2001, and results are expecte by May 2005 (see Related resources).

STAR*D—of which I am the study director—is a randomized, controlled, raterblinded, multisite trial of outpatients ages 18 to 75 with nonpsychotic major depression (17-item Hamilton Rating Scale for Depression score 14). The trial design includes four treatment levels and numerous antidepressant options (Figure).

The study’s aim is to enroll 4,000 patients into level 1, with 1,500 entering level 2. Patients who achieve an adequate response based on clinician judgment may continue the effective treatment for 12 months, during which their symptoms and other relevant information are monitored monthly by telephone. Patients who do not achieve an acceptable response in level 1 (or in subsequent levels) may proceed to the next level, which involves a randomized assignment.

STAR*D has an innovative design that mimics clinical practice and ensures high levels of patient participation. When patients agree to randomization, they may elect to exclude groups of treatments but may not pick a particular treatment (they must accept randomization to stay in the study).

Figure STAR*D treatment levels for major depressive disorder

For example, patient A entering level 2 may exclude switch treatments and elect to accept randomization to citalopram plus bupropion SR, citalopram plus buspirone, or citalopram and cognitive therapy. Conversely, patient B may exclude all augment options at level 2, and accept randomization to the four switch options.

Patients may exclude cognitive psychotherapy as an augment and/or switch option as long as they accept randomization to all available medication switches, or augments, or both. They may also choose cognitive therapy and exclude all medication switch and augment options. These patients must accept randomization to either cognitive therapy switch or cognitive therapy augmentation.

This so-called equipoise stratified randomized design²⁹ allows us to compare all participants randomized to the treatments being compared. To date, only 1% of subjects have accepted randomization to all seven level-2 treatments. About one-half elect only the switch options, and about one-half elect only the augment options.

STAR*D’s goal is to determine whether there is a preferred next step for varying types and degrees of treatment-resistant repression.

Vagus nerve stimulation

Somatic therapies being investigated to expand our therapeutic options for major depressive disorder include magnetic seizure therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation (VNS).

VNS—now indicated for treatment-resistant epilepsy—is being investigated as a potential augmentation for treatment-resistant depression. An application for this supplemental indication was submitted to the FDA in October 2003.

With VNS, a device implanted in the patient’s chest provides intermittent stimulation to the left vagus nerve (typically 30 seconds on and 5 minutes off, 24 hours a day). In an open trial¹⁰ and follow-up report,³⁰ VNS was associated with a 30% to 45% response rate in 59 depressed patients with high levels of treatment resistance (inadequate response to an average of 16 treatment trials).

VNS is well tolerated, though it has not been prospectively studied in patients with diagnosed cardiovascular disease. Side effects that may occur when the stimulation is “on” include:

• voice alteration in about 60% of patients (the voice becomes more hoarse when the left recurrent laryngeal nerve is activated)
• paresthesias in the neck
• shortness of breath on heavy exertion.

These effects are usually absent in the 5-minute “off” phase.

Related resources

• National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Includes the Quick Inventory of Depressive Symptomatology. www.star-d.org
• HealthyPlace.Com Depression Community. Vagus nerve stimulation for treating depression. www.healthyplace.com/communities/depression/treatment/vns

Drug brand names

• Bupropion • Wellbutrin, Wellbutrin SR
• Buspirone • BuSpar
• Citalopram • Celexa
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Modafinil • Provigil
• Nefazodone • Serzone
• Nortriptyline • Pamelor, Aventyl
• Olanzapine • Zyprexa
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tranylcypromine • Parnate
• Venlafaxine • Effexor, Effexor XR

Disclosure

Dr. Rush receives grant/research support from the Robert Wood Johnson Foundation, National Institute of Mental Health, and The Stanley Foundation. He is a consultant to Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, and GlaxoSmithKline, and a speaker for Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.

When depression fails to respond to initial therapy—as it commonly does—we have many options but little evidence to guide our choices. We often wonder:

• Is this patient’s depression treatment-resistant?
• Would switching medications or augmenting the initial drug be more likely to achieve an adequate response?
• How effective is psychotherapy compared with medication for treatment-resistant depression?

This article offers insights into each question, based on available trial data, algorithmic approaches to major depressive disorder, and clinical experience. Included is a preview of an ongoing multicenter, treatment-resistant depression study that mimics clinical practice and a look at vagus nerve stimulation (VNS)—a novel somatic therapy being considered by the FDA.

Measuring treatment response

Sustained symptom remission—with normalization of function—is the aim of treating major depressive disorder. Outcomes are categorized as:

• remission (virtual absence of depressive symptoms)
• response with residual symptoms (>50% reduction in baseline symptom severity that does not qualify for remission)
• partial response (>25% but <50% decrease in baseline symptom severity)
• nonresponse (<25% reduction in baseline symptoms).

Box

In 8-week acute-phase trials, 7% to 15% of patients do not tolerate the initial medication, 25% show no response, 15% show partial response, 10% to 20% exhibit response with residual symptoms, and 30% to 40% achieve remission. Complicated depressions that may not respond as well include those concurrent with Axis I conditions—such as panic disorder or substance abuse—or Axis II or III conditions.¹

Time-limited psychotherapies targeted at depressive symptoms (such as cognitive, interpersonal, and behavioral therapies) also typically achieve a 50% response rate in uncomplicated depression that is not treatment-resistant.

Recommendation. When treating depression, assess response at least every 4 weeks (preferably at each visit), using a self-report or clinician rating such as:

• Quick Inventory of Depressive Symptomatology² (see Related resources)
• Beck Depression Inventory^3,4
• Patient Health Questionnaire.⁵

Defining treatment resistance

A patient may not achieve remission for a variety of reasons, including poor adherence, inadequate medication trial or dosing, occult substance abuse, undiagnosed medical conditions (Box),^6-8 concurrent Axis I or II disorders, or treatment resistance.

The general consensus is to consider depression “treatment-resistant” when at least two adequately delivered treatments do not achieve at least a response. A stricter definition—failure to achieve sustained remission with two or more treatments—has also been suggested.

Several schemes have proposed treatment resistance levels, such as the five stages identified in the Table. Recent studies^9,10 suggest that increasing treatment resistance is associated with decreasing response or remission rates.

Therefore, when a patient’s treatment resistance is high, two appropriate strategies are to:

• persist with and use maximally tolerated dosages of the treatment you select
• aim for response because high resistance lowers the likelihood of remission.

Predicting response. A major clinical issue is determining whether remission will occur during an acute treatment trial. It is important to not declare treatment resistance unless there has been:

• adequate exposure (dosing and duration) to the treatment
• and adequate adherence.

Patients often have apparent but not actual resistance, meaning that the agent was not used long enough (at least 6 weeks) or at high enough doses. Remission typically follows response by several weeks or even 1 to 2 months for more-chronic depressions.¹¹ Thus, treatment trials should continue at least 12 weeks to determine whether remission will occur.

On the other hand, not obtaining at least a signal of minimal benefit (at least a 20% reduction in baseline symptom severity) in 4 to 6 weeks often portends a low likelihood of response in the long run.^12,13 Thus, continue a treatment at least 6 weeks before you decide that it will not achieve a response.

 

Recommendation. Measure symptoms at key decision points. If modest improvement (such as 20% reduction in baseline symptoms) is found at 4 to 6 weeks, continue treating another 4 to 6 weeks, increasing the dosage as tolerated.

Table

Simple system for staging antidepressant resistance

Stage	Definition
I	Failure of at least one adequate trial of one major antidepressant class
II	Stage I resistance plus failure of an adequate trial of an antidepressant in a distinctly different class from that used in Stage I
III	Stage II resistance plus failure of an adequate trial of a tricyclic antidepressant
IV	Stage III resistance plus failure of an adequate trial of a monoamine oxidase inhibitor
V	Stage IV resistance plus failure of a course of bilateral electroconvulsive therapy
Source: Reprinted with permission from Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58(suppl 13):24.

Treatment options

When initial antidepressant treatment fails to achieve an adequate response—as it does in more than onehalf of major depression cases—the next step is to add a second agent or switch to another agent.

Available evidence¹⁴ relies almost exclusively on open, uncontrolled trials, which do not provide definitive answers. Even so, these trials indicate that nonresponse (or nonremission) with one agent does not predict nonresponse/nonremission with another.

Switching strategies. When a selective serotonin reuptake inhibitor (SSRI) is the first treatment, several open trials reveal an approximately 50% response rate to a second SSRI. However, opentrial evidence and retrospective chart review reports also indicate that switching out of class (such as from an SSRI to bupropion) is also approximately 50% effective.¹⁵

Some post hoc analyses of acute 8-week trials indicate that the dual-action agent venlafaxine at higher dosages (up to 225 mg/d of venlafaxine XR) is associated with higher remission rates than the more-selective SSRIs.^16,17 On the other hand, unpublished data indicate that escitalopram, 10 mg/d, and venlafaxine XR, up to 150 mg/d, did not differ in efficacy among outpatients treated by primary care physicians.¹⁸

On the other hand, sertraline and imipramine (a dual-action agent) were equally effective in a 12-week acute-phase trial.¹⁹ Furthermore, response and remission rates were similar when nonresponders in each group switched to the other antidepressant.²⁰ This suggests that the dual-action agent (imipramine) was not more effective than the more selective agent (sertraline) in this population.

Well-controlled trials show that monoamine oxidase inhibitors (MAOIs) can be effective when tricyclic antidepressants (TCAs) are not. Switches among the TCAs are associated with a 30% response rate, whereas switching from a TCA to an MAOI typically results in a 50% response rate.²¹

Controlled prospective comparisons of two or more alternate switch or augment treatments are needed to establish comparative efficacy and tolerability.

Augmentation strategies may include lithium, buspirone, thyroid hormone (T3), stimulants, or atypical antipsychotics. Although head-to-head comparisons are rare, a randomized, controlled trial found that combining olanzapine (mean 50 mg/d), with fluoxetine (mean 15 mg/d) was more effective than each agent used alone.²²

Risperidone augmentation is supported by open trials, as is the use of modafinil, other stimulants, and bupropion. An important unanswered question with most augmentation strategies is how long to continue them if they are successful.

Psychotherapy may also play a key role in augmenting medication’s effects. Keller et al²³ found in chronically depressed outpatients that 12 weeks of nefazodone, up to 600 mg/d, plus cognitive behavioral analytic system psychotherapy (CBASP) produced higher response and remission rates compared with either treatment alone. A subsequent report²⁴ found that 50% of nefa-zodone and CBASP monotherapy nonresponders did respond when switched to the alternate treatment.

Thus, CBASP may be useful at least in chronic depression to augment medication or as a “switch” to monotherapy if medication alone fails. Interestingly, Nemeroff et al²⁵ found CBASP more effective than nefazodone for patients with chronic major depression who had a childhood history of parental loss or physical, sexual, or emotional abuse.

Antidepressant tachyphylaxis—commonly referred to as “poop-out”—is reported with all antidepressants. That is, even while apparently taking their medications for 6 to 18 months, some patients lose the antidepressant effect, such that some symptoms return or a full relapse/recurrence ensues. Mechanisms of this phenomenon are unknown.

Clinically, some believe that “poop out” is more common with SSRIs than with other antidepressant classes, but no long-term comparative data support or challenge this view. Treatment options include a dosage increase, dosage reduction (especially for long half-life SSRIs such as fluoxetine), or augmentation with the options noted above (such as bupropion, buspirone, etc.).

Benefit of using algorithms

Algorithms (such as the Texas Medication Algorithm Project²⁶ ) have suggested multiple treatment steps for major depression after initial treatment fails, with several options available at each step. Using medication algorithms has been found more effective than treatment-as-usual in outpatients with major depressive disorder.²⁷ No studies have compared different algorithms.

 

STAR*D trial. The ongoing National Institute of Mental Health (NIMH) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial may offer a new algorithmic approach to treating major depression.^14,28 NIMH launched STAR*D in 1999, enrollment began in 2001, and results are expecte by May 2005 (see Related resources).

STAR*D—of which I am the study director—is a randomized, controlled, raterblinded, multisite trial of outpatients ages 18 to 75 with nonpsychotic major depression (17-item Hamilton Rating Scale for Depression score 14). The trial design includes four treatment levels and numerous antidepressant options (Figure).

The study’s aim is to enroll 4,000 patients into level 1, with 1,500 entering level 2. Patients who achieve an adequate response based on clinician judgment may continue the effective treatment for 12 months, during which their symptoms and other relevant information are monitored monthly by telephone. Patients who do not achieve an acceptable response in level 1 (or in subsequent levels) may proceed to the next level, which involves a randomized assignment.

STAR*D has an innovative design that mimics clinical practice and ensures high levels of patient participation. When patients agree to randomization, they may elect to exclude groups of treatments but may not pick a particular treatment (they must accept randomization to stay in the study).

Figure STAR*D treatment levels for major depressive disorder

For example, patient A entering level 2 may exclude switch treatments and elect to accept randomization to citalopram plus bupropion SR, citalopram plus buspirone, or citalopram and cognitive therapy. Conversely, patient B may exclude all augment options at level 2, and accept randomization to the four switch options.

Patients may exclude cognitive psychotherapy as an augment and/or switch option as long as they accept randomization to all available medication switches, or augments, or both. They may also choose cognitive therapy and exclude all medication switch and augment options. These patients must accept randomization to either cognitive therapy switch or cognitive therapy augmentation.

This so-called equipoise stratified randomized design²⁹ allows us to compare all participants randomized to the treatments being compared. To date, only 1% of subjects have accepted randomization to all seven level-2 treatments. About one-half elect only the switch options, and about one-half elect only the augment options.

STAR*D’s goal is to determine whether there is a preferred next step for varying types and degrees of treatment-resistant repression.

Vagus nerve stimulation

Somatic therapies being investigated to expand our therapeutic options for major depressive disorder include magnetic seizure therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation (VNS).

VNS—now indicated for treatment-resistant epilepsy—is being investigated as a potential augmentation for treatment-resistant depression. An application for this supplemental indication was submitted to the FDA in October 2003.

With VNS, a device implanted in the patient’s chest provides intermittent stimulation to the left vagus nerve (typically 30 seconds on and 5 minutes off, 24 hours a day). In an open trial¹⁰ and follow-up report,³⁰ VNS was associated with a 30% to 45% response rate in 59 depressed patients with high levels of treatment resistance (inadequate response to an average of 16 treatment trials).

VNS is well tolerated, though it has not been prospectively studied in patients with diagnosed cardiovascular disease. Side effects that may occur when the stimulation is “on” include:

• voice alteration in about 60% of patients (the voice becomes more hoarse when the left recurrent laryngeal nerve is activated)
• paresthesias in the neck
• shortness of breath on heavy exertion.

These effects are usually absent in the 5-minute “off” phase.

Related resources

• National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Includes the Quick Inventory of Depressive Symptomatology. www.star-d.org
• HealthyPlace.Com Depression Community. Vagus nerve stimulation for treating depression. www.healthyplace.com/communities/depression/treatment/vns

Drug brand names

• Bupropion • Wellbutrin, Wellbutrin SR
• Buspirone • BuSpar
• Citalopram • Celexa
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Modafinil • Provigil
• Nefazodone • Serzone
• Nortriptyline • Pamelor, Aventyl
• Olanzapine • Zyprexa
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tranylcypromine • Parnate
• Venlafaxine • Effexor, Effexor XR

Disclosure

Dr. Rush receives grant/research support from the Robert Wood Johnson Foundation, National Institute of Mental Health, and The Stanley Foundation. He is a consultant to Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, and GlaxoSmithKline, and a speaker for Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.

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

Drug class/agent	Proposed mechanism	Dysfunction
Monoamine oxidase inhibitors	Unknown	ED (rare), retarded ejaculation(rare)
Selective serotonin reuptake inhibitors	Increased serum prolactin (possible) Increased relative dopamine-to-serotonin reuptake inhibition Increased central serotonin	Decreased libido ED Anorgasmia Delayed/retarded ejaculation
Tricyclic antidepressants	CNS depression Anticholinergic activity	Decreased libido ED
Venlafaxine	Increased relative dopamine-to-serotonin reuptake inhibition Increased central serotonin	ED Anorgasmia Delayed/retarded ejaculation
ED: Erectile 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

Drug class/agent	Proposed mechanism	Dysfunction
Amphetamines	Increased relative sympathetic nervous syndrome/parasympathetic nervous system activity	ED
Anticholinergics	Anticholinergic activity	ED
Antipsychotics (typical and atypical)	CNS depression, increased serum prolactin Anticholinergic activity Alpha1-receptor blockade Decreased internal urethral sphincter closure	Decreased libido ED Retarded ejaculation Retrograde ejaculation
Barbiturates, benzodiazepines, CNS depressants	CNS depression	Decreased libido
Carbamazepine, gabapentin	Decreased androgenic activity	Decreased libido, ED, retarded ejaculation
Disulfiram	Unknown	ED
Dopamine-receptor agonists	Unknown	ED
Dopamine-receptor antagonists	Increased serum prolactin	Decreased libido
ED: Erectile 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

Drug	Adverse effects	Drug interactions
Sildenafil	Dyspepsia, flushing, headache, hypotension, myocardial infarction (rare), nasal congestion, rash, visual disturbances	CYP-2C9 inducers and inhibitors (minor alterations in sildenafil plasma concentration) CYP-3A4 inducers and inhibitors (major alterations in sildenafil plasma concentration) Dihydrocodeine (rare priapism) Nitrates (severe hypotension)
Tadalafil*	Headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, pain in limb, visual disturbances	CYP-3A4 inhibitors (increase tadalafil exposure) Alpha blockers other than tamsulosin (hypotension) Nitrates (severe hypotension)
Vardenafil*	Dizziness, dyspepsia, headache, hypotension	CYP-3A4 inducers and inhibitors (altered vardenafil plasma concentration) Nitrates (severe hypotension)
* Tadalafil and vardenafil are still undergoing post-marketing surveillance. This explains in part why fewer adverse effects and drug-drug interactions have been reported with these agents than with sildenafil.

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

Drug	Adverse effects	Drug interactions
Amantadine	Aggression, altered mentation, anxiety, heart failure (rare), insomnia, leukopenia (rare), nausea Livedo reticularis (with extended use), neuroleptic malignant syndrome (upon discontinuation), orthostatic hypotension, psychoses	Bupropion (increased adverse events) Triamterene (may increase amantadine plasma concentration)
Bethanechol	Cholinergic effects (increased GI motility, lacrimation, miosis, urinary frequency) Diaphoresis, flushing, headache, hypotension, tachycardia	Anticholinergics (decreased effects of both agents) Cholinesterase inhibitors (increased cholinergic effects), Ganglionic blockers (severe hypotension)
Bupropion	Agitation, amblyopia, arrhythmias (rare), constipation, diaphoresis, dizziness, extrapyramidal symptoms (rare), headache, hypertension Hypoprolactinemia, insomnia, leukopenia (minor), nausea/vomiting Alcohol psychoses (rare), seizures, serum sickness (rare), taste perversion, tinnitus, tremor, urinary frequency Urticaria, weight gain (rare), weight loss, xerostomia	CYP-2D6 inducers and inhibitors (altered bupropion plasma concentration) Dopamine-receptor agonists (increased adverse effects) MAOIs (increased seizures and psychoses) QT-prolonging agents (increased QT-prolongation) Alcohol, systemic steroids, theophylline (increased seizures)
Mirtazapine	Somnolence, constipation, xerostomia, increased appetite, weight gain, dizziness, abnormal dreams, confusion Hyperlipidemia, flu-like symptoms, back pain	MAO inhibitors, linezolid, CNS depressants (increased sedative effects) Alcohol (may increase CNS depression) St John’s wort (may decrease mirtazapine levels)
Ropinirole	Abdominal pain, anxiety, arthralgias, confusion, constipation, diaphoresis, dyskinesias, dyspepsia, headache Hallucinations, insomnia, nausea/vomiting, orthostatic hypotension, peripheral edema Somnolence, tremor, upper respiratory infection, urinary tract infection, visual disturbances, xerostomia	CYP-1A2 inducers and inhibitors (altered ropinirole plasma concentration) Dopamine-receptor antagonists (decreased efficacy of both 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

Drug class/agent	Proposed mechanism	Dysfunction
Monoamine oxidase inhibitors	Unknown	ED (rare), retarded ejaculation(rare)
Selective serotonin reuptake inhibitors	Increased serum prolactin (possible) Increased relative dopamine-to-serotonin reuptake inhibition Increased central serotonin	Decreased libido ED Anorgasmia Delayed/retarded ejaculation
Tricyclic antidepressants	CNS depression Anticholinergic activity	Decreased libido ED
Venlafaxine	Increased relative dopamine-to-serotonin reuptake inhibition Increased central serotonin	ED Anorgasmia Delayed/retarded ejaculation
ED: Erectile 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

Drug class/agent	Proposed mechanism	Dysfunction
Amphetamines	Increased relative sympathetic nervous syndrome/parasympathetic nervous system activity	ED
Anticholinergics	Anticholinergic activity	ED
Antipsychotics (typical and atypical)	CNS depression, increased serum prolactin Anticholinergic activity Alpha1-receptor blockade Decreased internal urethral sphincter closure	Decreased libido ED Retarded ejaculation Retrograde ejaculation
Barbiturates, benzodiazepines, CNS depressants	CNS depression	Decreased libido
Carbamazepine, gabapentin	Decreased androgenic activity	Decreased libido, ED, retarded ejaculation
Disulfiram	Unknown	ED
Dopamine-receptor agonists	Unknown	ED
Dopamine-receptor antagonists	Increased serum prolactin	Decreased libido
ED: Erectile 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

Drug	Adverse effects	Drug interactions
Sildenafil	Dyspepsia, flushing, headache, hypotension, myocardial infarction (rare), nasal congestion, rash, visual disturbances	CYP-2C9 inducers and inhibitors (minor alterations in sildenafil plasma concentration) CYP-3A4 inducers and inhibitors (major alterations in sildenafil plasma concentration) Dihydrocodeine (rare priapism) Nitrates (severe hypotension)
Tadalafil*	Headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, pain in limb, visual disturbances	CYP-3A4 inhibitors (increase tadalafil exposure) Alpha blockers other than tamsulosin (hypotension) Nitrates (severe hypotension)
Vardenafil*	Dizziness, dyspepsia, headache, hypotension	CYP-3A4 inducers and inhibitors (altered vardenafil plasma concentration) Nitrates (severe hypotension)
* Tadalafil and vardenafil are still undergoing post-marketing surveillance. This explains in part why fewer adverse effects and drug-drug interactions have been reported with these agents than with sildenafil.

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

Drug	Adverse effects	Drug interactions
Amantadine	Aggression, altered mentation, anxiety, heart failure (rare), insomnia, leukopenia (rare), nausea Livedo reticularis (with extended use), neuroleptic malignant syndrome (upon discontinuation), orthostatic hypotension, psychoses	Bupropion (increased adverse events) Triamterene (may increase amantadine plasma concentration)
Bethanechol	Cholinergic effects (increased GI motility, lacrimation, miosis, urinary frequency) Diaphoresis, flushing, headache, hypotension, tachycardia	Anticholinergics (decreased effects of both agents) Cholinesterase inhibitors (increased cholinergic effects), Ganglionic blockers (severe hypotension)
Bupropion	Agitation, amblyopia, arrhythmias (rare), constipation, diaphoresis, dizziness, extrapyramidal symptoms (rare), headache, hypertension Hypoprolactinemia, insomnia, leukopenia (minor), nausea/vomiting Alcohol psychoses (rare), seizures, serum sickness (rare), taste perversion, tinnitus, tremor, urinary frequency Urticaria, weight gain (rare), weight loss, xerostomia	CYP-2D6 inducers and inhibitors (altered bupropion plasma concentration) Dopamine-receptor agonists (increased adverse effects) MAOIs (increased seizures and psychoses) QT-prolonging agents (increased QT-prolongation) Alcohol, systemic steroids, theophylline (increased seizures)
Mirtazapine	Somnolence, constipation, xerostomia, increased appetite, weight gain, dizziness, abnormal dreams, confusion Hyperlipidemia, flu-like symptoms, back pain	MAO inhibitors, linezolid, CNS depressants (increased sedative effects) Alcohol (may increase CNS depression) St John’s wort (may decrease mirtazapine levels)
Ropinirole	Abdominal pain, anxiety, arthralgias, confusion, constipation, diaphoresis, dyskinesias, dyspepsia, headache Hallucinations, insomnia, nausea/vomiting, orthostatic hypotension, peripheral edema Somnolence, tremor, upper respiratory infection, urinary tract infection, visual disturbances, xerostomia	CYP-1A2 inducers and inhibitors (altered ropinirole plasma concentration) Dopamine-receptor antagonists (decreased efficacy of both 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

Drug class/agent	Proposed mechanism	Dysfunction
Monoamine oxidase inhibitors	Unknown	ED (rare), retarded ejaculation(rare)
Selective serotonin reuptake inhibitors	Increased serum prolactin (possible) Increased relative dopamine-to-serotonin reuptake inhibition Increased central serotonin	Decreased libido ED Anorgasmia Delayed/retarded ejaculation
Tricyclic antidepressants	CNS depression Anticholinergic activity	Decreased libido ED
Venlafaxine	Increased relative dopamine-to-serotonin reuptake inhibition Increased central serotonin	ED Anorgasmia Delayed/retarded ejaculation
ED: Erectile 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

Drug class/agent	Proposed mechanism	Dysfunction
Amphetamines	Increased relative sympathetic nervous syndrome/parasympathetic nervous system activity	ED
Anticholinergics	Anticholinergic activity	ED
Antipsychotics (typical and atypical)	CNS depression, increased serum prolactin Anticholinergic activity Alpha1-receptor blockade Decreased internal urethral sphincter closure	Decreased libido ED Retarded ejaculation Retrograde ejaculation
Barbiturates, benzodiazepines, CNS depressants	CNS depression	Decreased libido
Carbamazepine, gabapentin	Decreased androgenic activity	Decreased libido, ED, retarded ejaculation
Disulfiram	Unknown	ED
Dopamine-receptor agonists	Unknown	ED
Dopamine-receptor antagonists	Increased serum prolactin	Decreased libido
ED: Erectile 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

Drug	Adverse effects	Drug interactions
Sildenafil	Dyspepsia, flushing, headache, hypotension, myocardial infarction (rare), nasal congestion, rash, visual disturbances	CYP-2C9 inducers and inhibitors (minor alterations in sildenafil plasma concentration) CYP-3A4 inducers and inhibitors (major alterations in sildenafil plasma concentration) Dihydrocodeine (rare priapism) Nitrates (severe hypotension)
Tadalafil*	Headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, pain in limb, visual disturbances	CYP-3A4 inhibitors (increase tadalafil exposure) Alpha blockers other than tamsulosin (hypotension) Nitrates (severe hypotension)
Vardenafil*	Dizziness, dyspepsia, headache, hypotension	CYP-3A4 inducers and inhibitors (altered vardenafil plasma concentration) Nitrates (severe hypotension)
* Tadalafil and vardenafil are still undergoing post-marketing surveillance. This explains in part why fewer adverse effects and drug-drug interactions have been reported with these agents than with sildenafil.

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

Drug	Adverse effects	Drug interactions
Amantadine	Aggression, altered mentation, anxiety, heart failure (rare), insomnia, leukopenia (rare), nausea Livedo reticularis (with extended use), neuroleptic malignant syndrome (upon discontinuation), orthostatic hypotension, psychoses	Bupropion (increased adverse events) Triamterene (may increase amantadine plasma concentration)
Bethanechol	Cholinergic effects (increased GI motility, lacrimation, miosis, urinary frequency) Diaphoresis, flushing, headache, hypotension, tachycardia	Anticholinergics (decreased effects of both agents) Cholinesterase inhibitors (increased cholinergic effects), Ganglionic blockers (severe hypotension)
Bupropion	Agitation, amblyopia, arrhythmias (rare), constipation, diaphoresis, dizziness, extrapyramidal symptoms (rare), headache, hypertension Hypoprolactinemia, insomnia, leukopenia (minor), nausea/vomiting Alcohol psychoses (rare), seizures, serum sickness (rare), taste perversion, tinnitus, tremor, urinary frequency Urticaria, weight gain (rare), weight loss, xerostomia	CYP-2D6 inducers and inhibitors (altered bupropion plasma concentration) Dopamine-receptor agonists (increased adverse effects) MAOIs (increased seizures and psychoses) QT-prolonging agents (increased QT-prolongation) Alcohol, systemic steroids, theophylline (increased seizures)
Mirtazapine	Somnolence, constipation, xerostomia, increased appetite, weight gain, dizziness, abnormal dreams, confusion Hyperlipidemia, flu-like symptoms, back pain	MAO inhibitors, linezolid, CNS depressants (increased sedative effects) Alcohol (may increase CNS depression) St John’s wort (may decrease mirtazapine levels)
Ropinirole	Abdominal pain, anxiety, arthralgias, confusion, constipation, diaphoresis, dyskinesias, dyspepsia, headache Hallucinations, insomnia, nausea/vomiting, orthostatic hypotension, peripheral edema Somnolence, tremor, upper respiratory infection, urinary tract infection, visual disturbances, xerostomia	CYP-1A2 inducers and inhibitors (altered ropinirole plasma concentration) Dopamine-receptor antagonists (decreased efficacy of both 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.