W. Victor R. Vieweg, MD

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

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

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

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

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

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

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.

Antipsychotics have long been linked with hyperprolactinemia.¹ This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.

We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.² Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.

Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME

Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.

Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.

Prolactin physiology

Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.³ Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.⁴

Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.⁵ Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.

Serum prolactin concentrations change during various life stages (Figure 1).⁶ Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.

Prolactin secretion

Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.⁵ A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.

Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.

Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.

Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:

• a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
• to a lesser extent, estrogen decreases the number of D2 receptors.

Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.⁵

Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.

For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.

Prolactin’s actions

Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.

The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.⁷

Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.

Table 1

COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA

Diagnosis of hyperprolactinemia

Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.

Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).⁸ Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.

Thirty to 80% of women with hyperprolactinemia develop galactorrhea,⁹ although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.

Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).⁹ In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass

Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.

Table 2

CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA

Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.² Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.

Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.¹⁰

Antipsychotic drugs and hyperprolactinemia

Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.

Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.¹¹ This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.¹²

Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.⁸

Atypical antipsychotics

A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.¹³ The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.

Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.

The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.¹⁴

Risperidone. A study sponsored by Janssen Pharmaceutica¹⁵ reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.

Table 3

HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE

Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:

• adverse events did not correlate with plasma prolactin concentrations
• the incidence of adverse events was dose-related
• the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.

Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).¹⁶

Olanzapine. A study sponsored by Eli Lilly and Co.¹⁷ assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.

Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.

Conclusion

The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.

Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
• Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.

Drug brand names

• Clozapine • Clozaril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Antipsychotics have long been linked with hyperprolactinemia.¹ This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.

We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.² Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.

Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME

Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.

Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.

Prolactin physiology

Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.³ Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.⁴

Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.⁵ Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.

Serum prolactin concentrations change during various life stages (Figure 1).⁶ Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.

Prolactin secretion

Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.⁵ A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.

Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.

Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.

Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:

• a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
• to a lesser extent, estrogen decreases the number of D2 receptors.

Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.⁵

Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.

For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.

Prolactin’s actions

Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.

The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.⁷

Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.

Table 1

COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA

Diagnosis of hyperprolactinemia

Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.

Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).⁸ Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.

Thirty to 80% of women with hyperprolactinemia develop galactorrhea,⁹ although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.

Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).⁹ In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass

Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.

Table 2

CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA

Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.² Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.

Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.¹⁰

Antipsychotic drugs and hyperprolactinemia

Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.

Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.¹¹ This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.¹²

Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.⁸

Atypical antipsychotics

A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.¹³ The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.

Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.

The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.¹⁴

Risperidone. A study sponsored by Janssen Pharmaceutica¹⁵ reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.

Table 3

HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE

Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:

• adverse events did not correlate with plasma prolactin concentrations
• the incidence of adverse events was dose-related
• the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.

Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).¹⁶

Olanzapine. A study sponsored by Eli Lilly and Co.¹⁷ assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.

Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.

Conclusion

The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.

Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
• Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.

Drug brand names

• Clozapine • Clozaril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Antipsychotics have long been linked with hyperprolactinemia.¹ This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.

We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.² Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.

Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME

Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.

Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.

Prolactin physiology

Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.³ Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.⁴

Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.⁵ Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.

Serum prolactin concentrations change during various life stages (Figure 1).⁶ Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.

Prolactin secretion

Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.⁵ A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.

Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.

Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.

Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:

• a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
• to a lesser extent, estrogen decreases the number of D2 receptors.

Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.⁵

Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.

For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.

Prolactin’s actions

Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.

The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.⁷

Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.

Table 1

COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA

Diagnosis of hyperprolactinemia

Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.

Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).⁸ Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.

Thirty to 80% of women with hyperprolactinemia develop galactorrhea,⁹ although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.

Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).⁹ In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass

Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.

Table 2

CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA

Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.² Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.

Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.¹⁰

Antipsychotic drugs and hyperprolactinemia

Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.

Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.¹¹ This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.¹²

Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.⁸

Atypical antipsychotics

A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.¹³ The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.

Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.

The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.¹⁴

Risperidone. A study sponsored by Janssen Pharmaceutica¹⁵ reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.

Table 3

HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE

Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:

• adverse events did not correlate with plasma prolactin concentrations
• the incidence of adverse events was dose-related
• the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.

Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).¹⁶

Olanzapine. A study sponsored by Eli Lilly and Co.¹⁷ assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.

Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.

Conclusion

The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.

Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
• Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.

Drug brand names

• Clozapine • Clozaril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Antipsychotics have long been linked with hyperprolactinemia.¹ This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.

We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.² Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.

Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME

Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.

Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.

Prolactin physiology

Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.³ Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.⁴

Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.⁵ Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.

Serum prolactin concentrations change during various life stages (Figure 1).⁶ Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.

Prolactin secretion

Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.⁵ A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.

Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.

Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.

Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:

• a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
• to a lesser extent, estrogen decreases the number of D2 receptors.

Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.⁵

Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.

For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.

Prolactin’s actions

Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.

The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.⁷

Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.

Table 1

COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA

Diagnosis of hyperprolactinemia

Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.

Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).⁸ Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.

Thirty to 80% of women with hyperprolactinemia develop galactorrhea,⁹ although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.

Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).⁹ In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass

Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.

Table 2

CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA

Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.² Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.

Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.¹⁰

Antipsychotic drugs and hyperprolactinemia

Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.

Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.¹¹ This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.¹²

Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.⁸

Atypical antipsychotics

A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.¹³ The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.

Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.

The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.¹⁴

Risperidone. A study sponsored by Janssen Pharmaceutica¹⁵ reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.

Table 3

HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE

Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:

• adverse events did not correlate with plasma prolactin concentrations
• the incidence of adverse events was dose-related
• the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.

Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).¹⁶

Olanzapine. A study sponsored by Eli Lilly and Co.¹⁷ assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.

Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.

Conclusion

The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.

Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
• Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.

Drug brand names

• Clozapine • Clozaril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Antipsychotics have long been linked with hyperprolactinemia.¹ This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.

We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.² Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.

Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME

Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.

Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.

Prolactin physiology

Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.³ Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.⁴

Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.⁵ Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.

Serum prolactin concentrations change during various life stages (Figure 1).⁶ Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.

Prolactin secretion

Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.⁵ A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.

Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.

Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.

Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:

• a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
• to a lesser extent, estrogen decreases the number of D2 receptors.

Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.⁵

Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.

For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.

Prolactin’s actions

Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.

The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.⁷

Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.

Table 1

COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA

Diagnosis of hyperprolactinemia

Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.

Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).⁸ Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.

Thirty to 80% of women with hyperprolactinemia develop galactorrhea,⁹ although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.

Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).⁹ In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass

Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.

Table 2

CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA

Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.² Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.

Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.¹⁰

Antipsychotic drugs and hyperprolactinemia

Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.

Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.¹¹ This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.¹²

Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.⁸

Atypical antipsychotics

A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.¹³ The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.

Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.

The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.¹⁴

Risperidone. A study sponsored by Janssen Pharmaceutica¹⁵ reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.

Table 3

HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE

Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:

• adverse events did not correlate with plasma prolactin concentrations
• the incidence of adverse events was dose-related
• the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.

Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).¹⁶

Olanzapine. A study sponsored by Eli Lilly and Co.¹⁷ assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.

Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.

Conclusion

The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.

Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
• Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.

Drug brand names

• Clozapine • Clozaril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Antipsychotics have long been linked with hyperprolactinemia.¹ This phenomenon was first considered a drug class effect, but the arrival of clozapine, better deliniation of dopamine receptor subtypes, and identification of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of antipsychotic use.

We now know that most atypical antipsychotics are less likely to induce hyperprolactinemia than older antipsychotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 minimally in the hypothalamic tuberoinfundibular pathway.² Evidence is emerging that atypical agents elevate serum prolactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties.

Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME

Mean serum prolactin concentrations from puberty until menopause. For nursing women, the length of the arrows depicts the increase in serum prolactin concentration associated with each episode of suckling. The Y-axis expresses serum prolactin concentration in both ng/ml and mg/l.

Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Can 1978;11:275-81.

Prolactin physiology

Prolactin—a large peptide containing 198 amino acids—was the first anterior pituitary gland hormone to be isolated in pure form.³ Despite its molecular weight of approximately 23,000, the hormone easily crosses the blood-brain barrier.⁴

Similar to other anterior pituitary hormones, prolactin is secreted episodically. Its secretion is inhibited by dopamine release from the hypothalamus and enhanced by different prolactin-releasing factors. Prolactin is the only anterior pituitary hormone that is produced by tuberoinfundibular neurons governed by dopamine.⁵ Dopamine stimulates lactotrope D2 receptors and inhibits adenylate cyclase, resulting in reduced prolactin synthesis and release.

Serum prolactin concentrations change during various life stages (Figure 1).⁶ Estrogen’s effects on prolactin gene expression regulate prolactin synthesis, resulting in higher prolactin levels in premenopausal women than in men.

Prolactin secretion

Normally, prolactin is secreted in pulses—approximately 14 in a 24-hour period, with an interpulse interval of about 80 minutes.⁵ A bimodal daily pattern of secretion is superimposed upon this pattern, with peak levels at night and trough levels at noon. Stress—including surgery and general anesthesia, exercise, and hypoglycemia—may transiently increase prolactin levels.

Endocrine regulation. Estrogen modulates the response of hypothalamic factors that control prolactin production. It stimulates decreased prolactin response to dopamine and increased response to thyrotropic-releasing hormone.

Insulin also stimulates prolactin secretion—probably by inducing hypoglycemia. Serum insulin level changes within physiologic ranges appear to affect prolactin regulation.

Neuroendocrine regulation. The hypothalamus blunts prolactin secretion primarily via dopamine release. This modulation occurs principally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine receptor in the anterior pituitary gland:

• a decrease in dopamine levels reaching the anterior pituitary gland increases the number of D2 receptors
• to a lesser extent, estrogen decreases the number of D2 receptors.

Dopamine-modulated reductions in action potential discharge from lactotrophs and in calcium flux leads to decreased intracellular calcium and decreased prolactin secretion.⁵

Most hormones are target-organ agents and are regulated via a feedback loop that includes the peripheral circulation. Prolactin, however, is not considered to have a specific target organ. It is its own inhibiting factor, using an autoregulatory, pituitary-to-hypothalamus short-loop feedback circuit.

For example, prolactin-secreting tumors or drugs that elevate hormone levels lead to an increase in dopamine. In contrast, hypophysectomy decreases dopamine. In this setting, prolactin injections will restore normal dopamine levels. Prolactin-releasing factors include thyrotropic-releasing hormone, vasoactive intestinal peptide, and serotonin.

Prolactin’s actions

Many tissues—including breast, liver, ovary, testis, and prostate—have prolactin receptors. These receptors are stimulated with equal potency by prolactin and growth hormone.

The principal site of prolactin action is the mammary gland, where the hormone initiates and maintains lactation after childbirth. Major stimuli for breast development are estrogen, progesterone, prolactin, and placental mammotropic hormones. Other stimuli include insulin, cortisol, and thyroid hormone.⁷

Gonadotropin secretion is influenced by prolactin via the hypothalamus. Prolactin-mediated inhibition of luteinizing hormone-releasing hormone secretion impairs gonadotropin release and inhibits gonadal function.

Table 1

COMMON CLINICAL EFFECTS IN PATIENTS WITH HYPERPROLACTINEMIA

Diagnosis of hyperprolactinemia

Pathologic hyperprolactinemia is defined as consistently elevated serum prolactin concentration (>20 ng/ml) in the absence of pregnancy or postpartum lactation. Because of the pulsatile nature of prolactin secretion, a definitive diagnosis of hyperprolactinemia requires three serum prolactin levels taken on different mornings.

Clinical presentation. Hyperprolactinemia—the most common hypothalamic-pituitary disturbance—usually presents with clinical features of gonadal dysfunction (Table 1).⁸ Symptoms and signs related to a brain mass—headache, visual field disturbances, ophthalmoplegia, and reduced visual acuity—may predominate with a large pituitary tumor. The patient may first present to a primary care physician or to a clinical specialist, such as a gynecologist, neurologist, ophthalmologist, pediatrician, psychiatrist, or urologist.

Thirty to 80% of women with hyperprolactinemia develop galactorrhea,⁹ although some women with galactorrhea have normal prolactin levels. Men with hyperprolactinemia usually have gonadal dysfunction, which unfortunately is often attributed to “psychogenic” causes. Particularly in men, prolactin is implicated in the control of libido.

Causes. Hyperprolactinemia may be caused by any process that inhibits dopamine synthesis, the neurotransmitter’s transport to the anterior pituitary gland, or its action at the lactotrope dopamine receptors ( Table 2).⁹ In this article, we will limit our discussion to antipsychotic drugs. have long-term effects on bone density. Trabecular bone mass

Estrogen and prolactin. During pregnancy, the rise in estrogen levels probably stimulates an increase in prolactin. Increased prolactin levels are also found in women taking estrogen-containing oral contraceptives, although this effect is very small with low-estrogen formulations.

Table 2

CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA

Functions of the pituitary lactotrophs regulated by estrogen include prolactin gene expression, release, storage, and cellular expression.² Estradiol inhibition of dopamine synthesis in the tuberoinfundibular dopaminergic neurons may contribute to some gender differences in neurocognitive function and to psychiatric conditions’ clinical features.

Hyperprolactinemia and bone density. Besides causing galactorrhea and sexual dysfunction, hyperprolactinemia may has been found to be reduced in young women with amenorrhea secondary to hyperprolactinemia. This trabecular osteopenia is reversible—spinal bone density decreases progressively without treatment and improves when hyperprolactinemia is treated. Menstrual function appears to best predict risk of progressive spinal osteopenia in women with hyperprolactinemia. Estradiol level is a stronger predictor of clinical course than is the prolactin level.¹⁰

Antipsychotic drugs and hyperprolactinemia

Among the four principal dopamine pathways in the brain, the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that releases dopamine into the portal veins of the pituitary gland. Terminals in the median eminence of the hypothalamus release dopamine that travels down the pituitary stalk in the portal veins.

Typical antipsychotics block dopamine receptors both in the striatum and in the hypothalamus.¹¹ This finding suggests that the older drugs lack specificity of dopamine blockade. Prolactin elevations in patients treated with older antipsychotics may be associated with sexual dysfunction—a common cause of drug noncompliance, particularly in men.¹²

Antipsychotics and sexual side effects. Patients taking antipsy-chotics often complain—spontaneously or after focused questioning—of sexual side effects caused by drug-induced hyperprolactinemia. Assessing antipsychotic-induced sexual dysfunction may be confounded by the psychoses being treated, patient compliance, and sexuality’s complexities. Antipsychotics are generally believed to reduce desire, cause orgasmic dysfunction, and lead to difficulties during sexual performance.⁸

Atypical antipsychotics

A recent study designed to assess the effect of three atypical antipsychotics on serum prolactin levels enrolled 18 men with schizophrenia (mean age 32) taking clozapine, 300 to 400 mg/d; risperidone, 1 to 3 mg/d; or olanzapine, 10 to 20 mg/d, for at least 8 weeks.¹³ The study participants were instructed not to take their antipsychotics the night before the study. Baseline prolactin levels were measured in the morning, the men took the full daily dose of their medications, and prolactin levels were measured every 60 minutes over the next 8 hours and again at 24 hours.

Mean baseline prolactin values of clozapine (9 ng/ml, SD=5) and olanzapine (9 ng/ml, SD=5) were in the normal range (<20 ng/ml), compared with those of risperidone (27 ng/ml, SD=14). Three of the six patients taking risperidone had hyperprolactinemia at baseline. Prolactin values doubled within 6 hours of administration of all three medications. There was no comparable increase in prolactin levels in five control subjects not taking antipsychotics.

The authors concluded that these atypical antipsychotics raise prolactin levels but more transiently than typical antipsychotics. They suggested that the differences among the three drugs may be attributed to each drug’s binding properties to pituitary dopamine D2 receptors. A similar study in four patients with first-episode schizophrenia found serum prolactin levels increased from <10 ng/ml at baseline to peak levels of 80 to 120 ng/ml within 60 to 90 minutes after patients took a full daily dose of quetiapine, 700 to 800 mg/d.¹⁴

Risperidone. A study sponsored by Janssen Pharmaceutica¹⁵ reviewed the manufacturer’s experience with prolactin and its potential to induce side effects, using data from premarketing studies comparing risperidone with haloperidol. Amenorrhea and galactorrhea were assessed in women; ejaculatory dysfunction, erectile dysfunction, and gynecomastia were assessed in men.

Table 3

HYPERPROLACTINEMIA-RELATED SIDE EFFECTS REPORTED BY PATIENTS TAKING RISPERIDONE AND OLANZAPINE

Both risperidone and haloperidol were associated with dose-related increases in plasma prolactin concentration in men and women. In women, neither risperidone dosage nor end-point prolactin concentrations were correlated with adverse events. In men:

• adverse events did not correlate with plasma prolactin concentrations
• the incidence of adverse events was dose-related
• the incidence of adverse events associated with risperidone, 4 to 10 mg/d, was not significantly greater than in patients taking placebo.

Another Janssen-sponsored study compared potential hyperprolactinemia-related side effects of risperidone and olanzapine but did not report prolactin concentrations. The authors found no significant differences between the drugs, based on breast features/menstrual changes in women and chest features/sexual dysfunction in men (Table 3).¹⁶

Olanzapine. A study sponsored by Eli Lilly and Co.¹⁷ assessed the effects of olanzapine on prolactin concentration in women previously treated with risperidone. The authors enrolled 20 Korean women with schizophrenia treated with risperidone (mean dosage 3.5 mg/d) and complaining of menstrual disturbances, galactorrhea, and/or sexual dysfunction. The mean serum prolactin concentration with risperidone was 132.2 ng/ml.

Over 2 weeks, patients were switched from risperidone to olanzapine (mean dosage 9.1 mg/d). After 8 weeks, the mean serum prolactin concentration was measured at 23.4 ng/ml. The authors noted improved menstrual function and reduced sexual side effects with olanzapine.

Conclusion

The package inserts of all atypical antipsychotics list hyperprolactinemia as a potential risk in patients taking these medications. The clinical significance of hyperprolactinemia associated with antipsychotic use is being explored but requires further elucidation.

Based on our understanding of the long-term course of untreated hyperprolactinemia—derived largely from patients not taking antipsychotics—it seems reasonable to ask patients taking atypical antipsychotics at least once a year about chest/breast complaints and sexual dysfunction. This recommendation would seem particularly relevant in patients taking risperidone at dosages >6 mg/d for sustained periods. In the absence of specific complaints, hyperprolactinemia associated with risperidone should be evaluated case by case, including perhaps endocrinology consultation.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;63(suppl 4):56-62.
• Smith S, Wheeler MJ, Murray R, O’Keane V. The effects of antipsychotic-induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002;22(2):109-14. Available at: http://www.psychiatry.wustl.edu/Resources/LiteratureList/2002/May/Smith.PDF.

Drug brand names

• Clozapine • Clozaril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Vieweg reports that he is on the speakers bureau of Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Before approving the antipsychotic agent ziprasidone last year, the Food and Drug Administration required specific safety data on whether the drug might cause the life-threatening arrhythmia known as torsade de pointes.

The FDA’s action, which delayed the drug’s approval for 3 years, underscores growing concern about the risk of cardiovascular effects with the use of antipsychotic and other agents known to prolong the cardiac QT interval. This concern has led to withdrawal of some drugs before reaching the market (e.g., the atypical neuroleptic sertindole), the addition of “black box” warnings in the labeling of some antipsychotics, and withdrawal from the market of antihistamines terfenadine and astemizole and the GI stimulant cisapride.

Torsade de pointes is a polymorphic ventricular tachycardia (VT), a rare arrhythmia that can cause sudden death. Because torsade can occur with the use of some antipsychotics, the psychiatrist needs to consider cardiovascular safety when selecting among available agents. To help with these decisions, here is information about the documented and potential electrocardiographic features of commonly prescribed antipsychotic drugs, as well as background on QT interval prolongation and torsade de pointes.

Torsade de pointes

Named for a ballet movement, torsade de pointes describes bursts of “twisting of the points,” a variation of the morphology of the QRS vector about the isoelectric axis from positive to net negative and back again. As seen on an ECG (Figure 1), the first beat of torsade de pointes is a normal ventricular complex preceded by a P wave. This is followed by a premature ventricular contraction (PVC) with a short coupling interval. After a compensatory pause, a second normal beat is followed by a second PVC, which is the first beat of a polymorphic VT. We know tachycardia is present because the ventricular beats appear close together. We know the arrhythmia is ventricular in origin because the ventricular complexes are wide. Finally, we note the ventricular complexes vary in configuration—that is, the shape (morphology) varies from beat to beat.

Figure 1 Typical ECG features of torsade de pointes

Sinus beat with normal ventricular complex (1) followed by premature ventricular contraction (PVC) (2) with short coupling interval. After a long pause (long refractory period), another sinus beat (3) is followed by another PVC (4) with a short coupling interval. The second PVC (4) is the first beat of polymorphic ventricular tachycardiaIn torsade, the stimulus for the VT moves within the ventricle, changing its shape from beat to beat. This multifocal VT differs from the more common unifocal VT, in which all the QRS complexes appear the same.

Drug-induced torsade de pointes

Although the term torsade de pointes was first described in 1966,¹ the drug-induced form of this arrhythmia has been recognized for nearly a century.

Quinidine Around 1920, cardiologists first used quinidine to help restore normal sinus rhythm in patients with atrial fibrillation, most commonly due to rheumatic heart disease.²

In 1964, Selzer and Wray³ studied the use of quinidine to convert atrial fibrillation to normal sinus rhythm in more than 200 patients seen during 4 years in a cardiopulmonary clinic. In a subgroup of eight patients, these researchers documented 10 reactions (including five documented episodes of ventricular fibrillation/ventricular flutter) among 36 syncopal episodes that developed within 1 to 6.5 hours of quinidine administration. Symptoms were nonspecific and included nausea, faintness, and feeling ill. It is now recognized that torsade de pointes was the principal rhythm disturbance in those eight patients. Syncope usually occurs early in treatment and may be found in 5% to 10% of patients taking quinidine.

TCAs and antipsychotics Tricyclic antidepressants (TCAs) and antipsychotics that have quinidine-like properties (e.g., thioridazine) also may be associated with QT interval prolongation and torsade de pointes.^4-9 In high doses (particularly in overdose), TCAs may induce widening of the QRS complex. Fowler et al reported episodes of VT in five patients taking thioridazine—one of whom died.¹⁰

Mehtonen et al reported sudden unexpected deaths associated with antipsychotic or antidepressant drugs among 31 women and 18 men in a survey of autopsies performed from 1985 to 1988 in Finland. The authors documented therapeutic use of phenothiazines in all but 3 of the 49 cases. Thioridazine was involved in more than half the deaths. In 15 of the deaths, thioridazine was the only antipsychotic drug taken. Drugs other than thioridazine were documented in only 5 of the 49 sudden cardiac deaths.¹¹

Figure 2 Normal ECG in sinus rhythm

In this typical lead II of a surface ECG, the P wave (atrial depolarization) leads to right and left atrial contraction and the QRS complex (ventricular depolarization) leads to left and right ventricular contraction. The ST segment represents isoelectric ventricular repolarization, and the T wave represents directional repolarization. The QT interval includes both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval, or ST segment plus T wave).

QT interval as a marker for torsade

The incidence of torsade is unknown, but it is an uncommon cardiac abnormality. In the United States, torsade probably accounts for less than 5% of the 300,000 sudden cardiac deaths that occur each year. Because torsade de pointes is rare, regulatory agencies and clinicians use the QT interval as a surrogate ECG marker for risk of torsade de pointes. Heart rate can affect the QT interval, so various formulae are used to correct the QT interval for heart rate (QTc).

What is the QT interval? In a normal ECG (Figure 2), the P wave derives from right and left atrial electrical depolarization. The pacemaker of the heart is located in the sino-atrial node (SAN) in the superior portion of the right atrium. From the SAN, electrical signals travel down three intra-atrial pathways, activating the right atrium, then travel to the atrioventricular node (AVN). Bachmann’s bundle—a fourth atrial pathway—passes from the SAN to depolarize the left atrium. From the AVN, the electrical signal travels through the left and right bundle branches to activate their respective ventricles.

Electrical depolarization of the left and right ventricles produces the QRS complex. Most of the electrical forces making up this complex arise in the left ventricle, which is much larger than the right ventricle.

The electrical circuitry of the heart activates the left and right atria in such a fashion that these chambers eject blood into their respective ventricles just before these chambers contract. Optimal ventricular filling maximizes ventricular ejection of blood (Starling’s law). Ventricular repolarization (JT interval—electrical recovery) follows ventricular depolarization. On the surface ECG, the JT interval consists of an isoelectric event—the ST segment running from the end of the QRS complex to the beginning of the T wave—and the T wave itself (directional electrical recovery).

The QT interval, then, consists of both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval). Ventricular repolarization makes up by far the greater portion of the QT interval.

Correcting the QT interval (QTc) In 1920, Bazett noted that as the heart rate slowed, the QT interval lengthened.¹² From personal and reported observations, he derived an equation called the Bazett formula that corrects (or normalizes) the QT interval to a heart rate of 60 beats/min (QTc). In the Bazett formula, the QTc interval is the measured QT interval divided by the square root of the RR interval (time between sequential QRS complexes—the determinant of heart rate) measured in seconds (QTc = QT/RR).

The Bazett formula is most widely used to estimate the QTc interval, although at least 20 other formulae have been developed in response to the original’s perceived inadequacies.^13-15 Bazett’s formula is used in most automated interpretations of the ECG.

Up to age 55, the normal QTc interval ranges from 350 to 430 msec for men and 350 to 450 msec for women, and it tends to increase with age. Most cases of torsade occur when the QT or QTc interval is greater than 500 msec.¹⁴ A QTc interval between 450 and 500 msec is cause for concern; a QTc interval that exceeds 500 msec is cause for alarm.

Factors that cause variations in QTc

Factors that can affect the QTc interval and increase the risk of torsade de pointes include electrolyte imbalances, medication use and overdose, cardiac disease, liver disease, endocrine disorders such as diabetes and hypothyroidism, and CNS injury (Table 1).

Table 1

Risk factors contributing to QTc interval prolongation

Circadian patterns The QTc interval varies throughout the 24-hour day, with nocturnal values about 20 msec greater than daytime measurements. These differences are driven by changes in autonomic (sympathetic and parasympathetic) tone.^16,17 In 20 normal subjects, circadian variability was 76 ± 19 msec (range 35 to 108 msec) from day to night.¹⁷ This circadian variation may be accentuated in patients with cardiovascular disease.

Sex. At birth, QTc interval measurements do no vary by sex.¹⁸ At puberty, however, the male QTc interval shortens and remains shorter than its female counterpart by about 20 msec until age 50 to 55, coincident with a decline in male testosterone levels. This sex difference appears to be androgen driven. About 70% of torsade de pointes cases occur in women.¹⁸

Menstrual cycle QTc interval measurements are stable throughout the menstrual cycle if quinidine-like drugs are not given.

Variations were seen, however, when Rodriguez et al studied the effect of IV low-dose ibutilide (an antiarrhythmic agent known to prolong the QT interval) on the QTc intervals of 58 healthy subjects (38 men and 20 women, ages 21 to 40). During 1 month, men were studied once and women studied three times, coincident with the three phases of the menstrual cycle. The greatest increase in QTc intervals measurements occurred in women during the first half of their menstrual cycles.¹⁹

Age and cardiovascular disease Two congenital long QT syndromes may be associated with sudden death, mostly in children and young adults:

• The Jervell and Lange-Nielsen syndrome is marked by severe congenital deafness and autosomal recessive inheritance.
• The Romano-Ward syndrome has normal hearing and autosomal dominant inheritance.²⁰

Congenital long QT syndrome (LQTS) occurs in about one in 5,000 births and accounts for about 3,000 to 4,000 deaths per year in the United States. Nine percent of pediatric LQTS subjects present with sudden cardiac death. More than 71% of patients will die before age 15 if not treated.

Elderly persons tend to have longer QTc intervals than do younger subjects, even when both groups are free of cardiovascular disease.²¹ Also, age-matched subjects with cardiovascular disease tend to have longer QTc intervals than do those free of cardiovascular disease.

Electrolytes Electrolyte disturbances, particularly hypokalemia and hypomagnesemia, may contribute to or even cause QT interval prolongation.²²

Hypokalemia prolongs the cardiac action potential and may cause early afterdepolarization, leading to torsade.²³ Low potassium levels reduce the net outward potassium current during phase 3 of the cardiac action potential. Hypomagnesemia may contribute to gross U wave alternans, lengthening the cardiac action potential and setting the stage for torsade.²⁴ Various factors may contribute to electrolyte disturbances, including use of diuretics and excessive vomiting and diarrhea. Even postprandial states may induce hypokalemia.

Intensive exercise and agitation may be associated with hypokalemia.²⁵ Serum potassium may be lower in severely agitated patients (3.59 mmol/L) than in mildly agitated patients (3.79 mmol/L). The mean QTc interval of psychiatric emergency patients may be prolonged (453±40 msec),⁵ with QTc intervals of psychiatric inpatients longer than those of psychiatric outpatients. Altered potassium states probably explain these observations. Mechanisms that link exercise and agitation with hypokalemia remain to be elucidated.

Metabolic factors Drugs may alter phase 3 potassium flow, thereby disrupting the synchrony of action of individual cardiac cells during repolarization. This change may induce early afterdepolarizations and torsade.²³

Five percent to 10% of Americans of European descent have genetic profiles that make them poor metabolizers of drugs that are metabolized by the cytochrome P-450 isoenzyme 2D6. The Pfizer Inc. 054 study assessed the potential for metabolic inhibitors such as paroxetine to raise antipsychotic drug levels in these patients and induce QTc interval prolongation.²⁶

In response to FDA concerns about QTc interval prolongation associated with the use of ziprasidone, Pfizer studied the potential for QTc interval prolongation when antipsychotics are given with and without metabolic inhibitors of cytochrome P-450 isoenzymes 2D6 (paroxetine), 3A4 (ketoconazole), and 1A2 (fluvoxamine). The study population of 183 subjects (mean age:men, 37.1 years, women 38.8 years) was three-quarters young men with schizophrenia, in good health otherwise and possessing normal ECGs—i.e., patients with a low risk of developing cardiac arrhythmias.

Figure 3 Antipsychotic drugs and QTc interval changes

Six antipsychotic drugs and QTc interval changes from baseline when given with and without metabolic inhibitors. QTc interval changes (in msec) when given without a metabolic inhibitor were ziprasidone, 20.3; risperidone, 11.6; olanzapine, 6.8; quetiapine, 14.5; thioridazine, 35.6; and haloperidol 4.7.

Reprinted from: “FDA Psychopharmacological Drugs Advisory Committee. 19 July 2000. Briefing Documents for Zeldox Capsules (Ziprasidone HCL). Pfizer.” Available from Central Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, (860) 441-4100.Over the course of about 1 week, daily doses were escalated to ziprasidone, 160 mg; risperidone, 8 mg and 16 mg; olanzapine, 20 mg; quetiapine, 750 mg; thioridazine, 300 mg; and haloperidol, 15 mg. Thioridazine (35.6 msec) and ziprasidone (20.3 msec) showed the greatest QTc interval increase following drug administration (Figure 3). Co-administration of a metabolic inhibitor did not further prolong the QTc interval for these two drugs.

Of the six drugs studied, only thioridazine and ziprasidone showed QTc interval increases 5% compared with baseline measurements.

Co-administration of a metabolic inhibitor caused the greatest increase in QTc intervals for quetiapine (from 14.5 to 19.7 msec). This value closely approached the steady-state ziprasidone measurement (20.3 msec). Because quetiapine is more likely than the other antipsychotic drugs studied to increase heart rate, it may be argued that the Bazett formula’s limitations in estimating the QTc interval at higher heart rates contributed to the quetiapine study findings.

Table 2

Relative risk of QTc interval prolongation with common antipsychotic agents

Recommendations

Taking a careful history is key to cardiovascular assessment before prescribing an antipsychotic. An ECG is indicated for patients with:

• Personal or family history of syncope or sudden death;
• Personal history of angina pectoris, myocardial infarction, congestive heart failure, cardiac arrhythmias, hypokalemia, hypomagnesemia, or significant cardiac risk factors.

The relative cardiovascular risks associated with antipsychotic agents are shown in Table 2.

An ECG also is required or strongly recommended before prescribing the antipsychotic drugs most commonly associated with QT prolongation and torsade de pointes—droperidol, haloperidol in large doses IV (commonly 100 mg/d), mesoridazine, pimozide, and thioridazine.

The FDA has strengthened the warning labels required for these agents, adding “black box” warnings about the risks of prolonged QTc intervals, torsade de pointes, and sudden death for droperidol, mesoridazine, and thioridazine. Thioridazine, for example, is indicated only for patients with schizophrenia who fail to show an acceptable response to other antipsychotic drugs. Its use is contraindicated in patients who take:

• fluvoxamine, propranolol, and pindolol;
• any drug that inhibits the cytochrome P-450 2D6 isoenzyme (e.g., fluoxetine, paroxetine);
• agents known to prolong the QTc interval.

Use of thioridazine also is contraindicated in patients known to have reduced levels of the cytochrome P450 2D6 isozyme, as well as in patients with congenital LQTS or a history of cardiac arrhythmias. Psychiatrists are advised to read the warnings and prescribing information in the labeling of all antipsychotics for potential cardiovascular side effects.

When the psychiatrist receives a report of suspected QTc interval prolongation on a patient’s ECG, the following steps are recommended:

• Obtain another ECG.
• Assess serum potassium, magnesium, calcium, and thyroid hormone levels.

In patients with confirmed QTc interval prolongation, any complaint of palpitations, presyncope, or syncope are grounds for urgent referral to a cardiologist.

Related resources

• European Society of Cardiology guidelines: www.escardio.org/scinfo/Guidelines/Haverkamp.pdf
• Sudden Arrhythmia Death Syndromes Foundation (SADSF): www.sads.org (800) 786-7723.
• Drugs that prolong the QT interval and/or induce torsade de pointes. Georgetown Center for Education and Research Therapeutics: www.torsades.org

Before approving the antipsychotic agent ziprasidone last year, the Food and Drug Administration required specific safety data on whether the drug might cause the life-threatening arrhythmia known as torsade de pointes.

The FDA’s action, which delayed the drug’s approval for 3 years, underscores growing concern about the risk of cardiovascular effects with the use of antipsychotic and other agents known to prolong the cardiac QT interval. This concern has led to withdrawal of some drugs before reaching the market (e.g., the atypical neuroleptic sertindole), the addition of “black box” warnings in the labeling of some antipsychotics, and withdrawal from the market of antihistamines terfenadine and astemizole and the GI stimulant cisapride.

Torsade de pointes is a polymorphic ventricular tachycardia (VT), a rare arrhythmia that can cause sudden death. Because torsade can occur with the use of some antipsychotics, the psychiatrist needs to consider cardiovascular safety when selecting among available agents. To help with these decisions, here is information about the documented and potential electrocardiographic features of commonly prescribed antipsychotic drugs, as well as background on QT interval prolongation and torsade de pointes.

Torsade de pointes

Named for a ballet movement, torsade de pointes describes bursts of “twisting of the points,” a variation of the morphology of the QRS vector about the isoelectric axis from positive to net negative and back again. As seen on an ECG (Figure 1), the first beat of torsade de pointes is a normal ventricular complex preceded by a P wave. This is followed by a premature ventricular contraction (PVC) with a short coupling interval. After a compensatory pause, a second normal beat is followed by a second PVC, which is the first beat of a polymorphic VT. We know tachycardia is present because the ventricular beats appear close together. We know the arrhythmia is ventricular in origin because the ventricular complexes are wide. Finally, we note the ventricular complexes vary in configuration—that is, the shape (morphology) varies from beat to beat.

Figure 1 Typical ECG features of torsade de pointes

Sinus beat with normal ventricular complex (1) followed by premature ventricular contraction (PVC) (2) with short coupling interval. After a long pause (long refractory period), another sinus beat (3) is followed by another PVC (4) with a short coupling interval. The second PVC (4) is the first beat of polymorphic ventricular tachycardiaIn torsade, the stimulus for the VT moves within the ventricle, changing its shape from beat to beat. This multifocal VT differs from the more common unifocal VT, in which all the QRS complexes appear the same.

Drug-induced torsade de pointes

Although the term torsade de pointes was first described in 1966,¹ the drug-induced form of this arrhythmia has been recognized for nearly a century.

Quinidine Around 1920, cardiologists first used quinidine to help restore normal sinus rhythm in patients with atrial fibrillation, most commonly due to rheumatic heart disease.²

In 1964, Selzer and Wray³ studied the use of quinidine to convert atrial fibrillation to normal sinus rhythm in more than 200 patients seen during 4 years in a cardiopulmonary clinic. In a subgroup of eight patients, these researchers documented 10 reactions (including five documented episodes of ventricular fibrillation/ventricular flutter) among 36 syncopal episodes that developed within 1 to 6.5 hours of quinidine administration. Symptoms were nonspecific and included nausea, faintness, and feeling ill. It is now recognized that torsade de pointes was the principal rhythm disturbance in those eight patients. Syncope usually occurs early in treatment and may be found in 5% to 10% of patients taking quinidine.

TCAs and antipsychotics Tricyclic antidepressants (TCAs) and antipsychotics that have quinidine-like properties (e.g., thioridazine) also may be associated with QT interval prolongation and torsade de pointes.^4-9 In high doses (particularly in overdose), TCAs may induce widening of the QRS complex. Fowler et al reported episodes of VT in five patients taking thioridazine—one of whom died.¹⁰

Mehtonen et al reported sudden unexpected deaths associated with antipsychotic or antidepressant drugs among 31 women and 18 men in a survey of autopsies performed from 1985 to 1988 in Finland. The authors documented therapeutic use of phenothiazines in all but 3 of the 49 cases. Thioridazine was involved in more than half the deaths. In 15 of the deaths, thioridazine was the only antipsychotic drug taken. Drugs other than thioridazine were documented in only 5 of the 49 sudden cardiac deaths.¹¹

Figure 2 Normal ECG in sinus rhythm

In this typical lead II of a surface ECG, the P wave (atrial depolarization) leads to right and left atrial contraction and the QRS complex (ventricular depolarization) leads to left and right ventricular contraction. The ST segment represents isoelectric ventricular repolarization, and the T wave represents directional repolarization. The QT interval includes both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval, or ST segment plus T wave).

QT interval as a marker for torsade

The incidence of torsade is unknown, but it is an uncommon cardiac abnormality. In the United States, torsade probably accounts for less than 5% of the 300,000 sudden cardiac deaths that occur each year. Because torsade de pointes is rare, regulatory agencies and clinicians use the QT interval as a surrogate ECG marker for risk of torsade de pointes. Heart rate can affect the QT interval, so various formulae are used to correct the QT interval for heart rate (QTc).

What is the QT interval? In a normal ECG (Figure 2), the P wave derives from right and left atrial electrical depolarization. The pacemaker of the heart is located in the sino-atrial node (SAN) in the superior portion of the right atrium. From the SAN, electrical signals travel down three intra-atrial pathways, activating the right atrium, then travel to the atrioventricular node (AVN). Bachmann’s bundle—a fourth atrial pathway—passes from the SAN to depolarize the left atrium. From the AVN, the electrical signal travels through the left and right bundle branches to activate their respective ventricles.

Electrical depolarization of the left and right ventricles produces the QRS complex. Most of the electrical forces making up this complex arise in the left ventricle, which is much larger than the right ventricle.

The electrical circuitry of the heart activates the left and right atria in such a fashion that these chambers eject blood into their respective ventricles just before these chambers contract. Optimal ventricular filling maximizes ventricular ejection of blood (Starling’s law). Ventricular repolarization (JT interval—electrical recovery) follows ventricular depolarization. On the surface ECG, the JT interval consists of an isoelectric event—the ST segment running from the end of the QRS complex to the beginning of the T wave—and the T wave itself (directional electrical recovery).

The QT interval, then, consists of both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval). Ventricular repolarization makes up by far the greater portion of the QT interval.

Correcting the QT interval (QTc) In 1920, Bazett noted that as the heart rate slowed, the QT interval lengthened.¹² From personal and reported observations, he derived an equation called the Bazett formula that corrects (or normalizes) the QT interval to a heart rate of 60 beats/min (QTc). In the Bazett formula, the QTc interval is the measured QT interval divided by the square root of the RR interval (time between sequential QRS complexes—the determinant of heart rate) measured in seconds (QTc = QT/RR).

The Bazett formula is most widely used to estimate the QTc interval, although at least 20 other formulae have been developed in response to the original’s perceived inadequacies.^13-15 Bazett’s formula is used in most automated interpretations of the ECG.

Up to age 55, the normal QTc interval ranges from 350 to 430 msec for men and 350 to 450 msec for women, and it tends to increase with age. Most cases of torsade occur when the QT or QTc interval is greater than 500 msec.¹⁴ A QTc interval between 450 and 500 msec is cause for concern; a QTc interval that exceeds 500 msec is cause for alarm.

Factors that cause variations in QTc

Factors that can affect the QTc interval and increase the risk of torsade de pointes include electrolyte imbalances, medication use and overdose, cardiac disease, liver disease, endocrine disorders such as diabetes and hypothyroidism, and CNS injury (Table 1).

Table 1

Risk factors contributing to QTc interval prolongation

Circadian patterns The QTc interval varies throughout the 24-hour day, with nocturnal values about 20 msec greater than daytime measurements. These differences are driven by changes in autonomic (sympathetic and parasympathetic) tone.^16,17 In 20 normal subjects, circadian variability was 76 ± 19 msec (range 35 to 108 msec) from day to night.¹⁷ This circadian variation may be accentuated in patients with cardiovascular disease.

Sex. At birth, QTc interval measurements do no vary by sex.¹⁸ At puberty, however, the male QTc interval shortens and remains shorter than its female counterpart by about 20 msec until age 50 to 55, coincident with a decline in male testosterone levels. This sex difference appears to be androgen driven. About 70% of torsade de pointes cases occur in women.¹⁸

Menstrual cycle QTc interval measurements are stable throughout the menstrual cycle if quinidine-like drugs are not given.

Variations were seen, however, when Rodriguez et al studied the effect of IV low-dose ibutilide (an antiarrhythmic agent known to prolong the QT interval) on the QTc intervals of 58 healthy subjects (38 men and 20 women, ages 21 to 40). During 1 month, men were studied once and women studied three times, coincident with the three phases of the menstrual cycle. The greatest increase in QTc intervals measurements occurred in women during the first half of their menstrual cycles.¹⁹

Age and cardiovascular disease Two congenital long QT syndromes may be associated with sudden death, mostly in children and young adults:

• The Jervell and Lange-Nielsen syndrome is marked by severe congenital deafness and autosomal recessive inheritance.
• The Romano-Ward syndrome has normal hearing and autosomal dominant inheritance.²⁰

Congenital long QT syndrome (LQTS) occurs in about one in 5,000 births and accounts for about 3,000 to 4,000 deaths per year in the United States. Nine percent of pediatric LQTS subjects present with sudden cardiac death. More than 71% of patients will die before age 15 if not treated.

Elderly persons tend to have longer QTc intervals than do younger subjects, even when both groups are free of cardiovascular disease.²¹ Also, age-matched subjects with cardiovascular disease tend to have longer QTc intervals than do those free of cardiovascular disease.

Electrolytes Electrolyte disturbances, particularly hypokalemia and hypomagnesemia, may contribute to or even cause QT interval prolongation.²²

Hypokalemia prolongs the cardiac action potential and may cause early afterdepolarization, leading to torsade.²³ Low potassium levels reduce the net outward potassium current during phase 3 of the cardiac action potential. Hypomagnesemia may contribute to gross U wave alternans, lengthening the cardiac action potential and setting the stage for torsade.²⁴ Various factors may contribute to electrolyte disturbances, including use of diuretics and excessive vomiting and diarrhea. Even postprandial states may induce hypokalemia.

Intensive exercise and agitation may be associated with hypokalemia.²⁵ Serum potassium may be lower in severely agitated patients (3.59 mmol/L) than in mildly agitated patients (3.79 mmol/L). The mean QTc interval of psychiatric emergency patients may be prolonged (453±40 msec),⁵ with QTc intervals of psychiatric inpatients longer than those of psychiatric outpatients. Altered potassium states probably explain these observations. Mechanisms that link exercise and agitation with hypokalemia remain to be elucidated.

Metabolic factors Drugs may alter phase 3 potassium flow, thereby disrupting the synchrony of action of individual cardiac cells during repolarization. This change may induce early afterdepolarizations and torsade.²³

Five percent to 10% of Americans of European descent have genetic profiles that make them poor metabolizers of drugs that are metabolized by the cytochrome P-450 isoenzyme 2D6. The Pfizer Inc. 054 study assessed the potential for metabolic inhibitors such as paroxetine to raise antipsychotic drug levels in these patients and induce QTc interval prolongation.²⁶

In response to FDA concerns about QTc interval prolongation associated with the use of ziprasidone, Pfizer studied the potential for QTc interval prolongation when antipsychotics are given with and without metabolic inhibitors of cytochrome P-450 isoenzymes 2D6 (paroxetine), 3A4 (ketoconazole), and 1A2 (fluvoxamine). The study population of 183 subjects (mean age:men, 37.1 years, women 38.8 years) was three-quarters young men with schizophrenia, in good health otherwise and possessing normal ECGs—i.e., patients with a low risk of developing cardiac arrhythmias.

Figure 3 Antipsychotic drugs and QTc interval changes

Six antipsychotic drugs and QTc interval changes from baseline when given with and without metabolic inhibitors. QTc interval changes (in msec) when given without a metabolic inhibitor were ziprasidone, 20.3; risperidone, 11.6; olanzapine, 6.8; quetiapine, 14.5; thioridazine, 35.6; and haloperidol 4.7.

Reprinted from: “FDA Psychopharmacological Drugs Advisory Committee. 19 July 2000. Briefing Documents for Zeldox Capsules (Ziprasidone HCL). Pfizer.” Available from Central Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, (860) 441-4100.Over the course of about 1 week, daily doses were escalated to ziprasidone, 160 mg; risperidone, 8 mg and 16 mg; olanzapine, 20 mg; quetiapine, 750 mg; thioridazine, 300 mg; and haloperidol, 15 mg. Thioridazine (35.6 msec) and ziprasidone (20.3 msec) showed the greatest QTc interval increase following drug administration (Figure 3). Co-administration of a metabolic inhibitor did not further prolong the QTc interval for these two drugs.

Of the six drugs studied, only thioridazine and ziprasidone showed QTc interval increases 5% compared with baseline measurements.

Co-administration of a metabolic inhibitor caused the greatest increase in QTc intervals for quetiapine (from 14.5 to 19.7 msec). This value closely approached the steady-state ziprasidone measurement (20.3 msec). Because quetiapine is more likely than the other antipsychotic drugs studied to increase heart rate, it may be argued that the Bazett formula’s limitations in estimating the QTc interval at higher heart rates contributed to the quetiapine study findings.

Table 2

Relative risk of QTc interval prolongation with common antipsychotic agents

Recommendations

Taking a careful history is key to cardiovascular assessment before prescribing an antipsychotic. An ECG is indicated for patients with:

• Personal or family history of syncope or sudden death;
• Personal history of angina pectoris, myocardial infarction, congestive heart failure, cardiac arrhythmias, hypokalemia, hypomagnesemia, or significant cardiac risk factors.

The relative cardiovascular risks associated with antipsychotic agents are shown in Table 2.

An ECG also is required or strongly recommended before prescribing the antipsychotic drugs most commonly associated with QT prolongation and torsade de pointes—droperidol, haloperidol in large doses IV (commonly 100 mg/d), mesoridazine, pimozide, and thioridazine.

The FDA has strengthened the warning labels required for these agents, adding “black box” warnings about the risks of prolonged QTc intervals, torsade de pointes, and sudden death for droperidol, mesoridazine, and thioridazine. Thioridazine, for example, is indicated only for patients with schizophrenia who fail to show an acceptable response to other antipsychotic drugs. Its use is contraindicated in patients who take:

• fluvoxamine, propranolol, and pindolol;
• any drug that inhibits the cytochrome P-450 2D6 isoenzyme (e.g., fluoxetine, paroxetine);
• agents known to prolong the QTc interval.

Use of thioridazine also is contraindicated in patients known to have reduced levels of the cytochrome P450 2D6 isozyme, as well as in patients with congenital LQTS or a history of cardiac arrhythmias. Psychiatrists are advised to read the warnings and prescribing information in the labeling of all antipsychotics for potential cardiovascular side effects.

When the psychiatrist receives a report of suspected QTc interval prolongation on a patient’s ECG, the following steps are recommended:

• Obtain another ECG.
• Assess serum potassium, magnesium, calcium, and thyroid hormone levels.

In patients with confirmed QTc interval prolongation, any complaint of palpitations, presyncope, or syncope are grounds for urgent referral to a cardiologist.

Related resources

• European Society of Cardiology guidelines: www.escardio.org/scinfo/Guidelines/Haverkamp.pdf
• Sudden Arrhythmia Death Syndromes Foundation (SADSF): www.sads.org (800) 786-7723.
• Drugs that prolong the QT interval and/or induce torsade de pointes. Georgetown Center for Education and Research Therapeutics: www.torsades.org

Before approving the antipsychotic agent ziprasidone last year, the Food and Drug Administration required specific safety data on whether the drug might cause the life-threatening arrhythmia known as torsade de pointes.

The FDA’s action, which delayed the drug’s approval for 3 years, underscores growing concern about the risk of cardiovascular effects with the use of antipsychotic and other agents known to prolong the cardiac QT interval. This concern has led to withdrawal of some drugs before reaching the market (e.g., the atypical neuroleptic sertindole), the addition of “black box” warnings in the labeling of some antipsychotics, and withdrawal from the market of antihistamines terfenadine and astemizole and the GI stimulant cisapride.

Torsade de pointes is a polymorphic ventricular tachycardia (VT), a rare arrhythmia that can cause sudden death. Because torsade can occur with the use of some antipsychotics, the psychiatrist needs to consider cardiovascular safety when selecting among available agents. To help with these decisions, here is information about the documented and potential electrocardiographic features of commonly prescribed antipsychotic drugs, as well as background on QT interval prolongation and torsade de pointes.

Torsade de pointes

Named for a ballet movement, torsade de pointes describes bursts of “twisting of the points,” a variation of the morphology of the QRS vector about the isoelectric axis from positive to net negative and back again. As seen on an ECG (Figure 1), the first beat of torsade de pointes is a normal ventricular complex preceded by a P wave. This is followed by a premature ventricular contraction (PVC) with a short coupling interval. After a compensatory pause, a second normal beat is followed by a second PVC, which is the first beat of a polymorphic VT. We know tachycardia is present because the ventricular beats appear close together. We know the arrhythmia is ventricular in origin because the ventricular complexes are wide. Finally, we note the ventricular complexes vary in configuration—that is, the shape (morphology) varies from beat to beat.

Figure 1 Typical ECG features of torsade de pointes

Sinus beat with normal ventricular complex (1) followed by premature ventricular contraction (PVC) (2) with short coupling interval. After a long pause (long refractory period), another sinus beat (3) is followed by another PVC (4) with a short coupling interval. The second PVC (4) is the first beat of polymorphic ventricular tachycardiaIn torsade, the stimulus for the VT moves within the ventricle, changing its shape from beat to beat. This multifocal VT differs from the more common unifocal VT, in which all the QRS complexes appear the same.

Drug-induced torsade de pointes

Although the term torsade de pointes was first described in 1966,¹ the drug-induced form of this arrhythmia has been recognized for nearly a century.

Quinidine Around 1920, cardiologists first used quinidine to help restore normal sinus rhythm in patients with atrial fibrillation, most commonly due to rheumatic heart disease.²

In 1964, Selzer and Wray³ studied the use of quinidine to convert atrial fibrillation to normal sinus rhythm in more than 200 patients seen during 4 years in a cardiopulmonary clinic. In a subgroup of eight patients, these researchers documented 10 reactions (including five documented episodes of ventricular fibrillation/ventricular flutter) among 36 syncopal episodes that developed within 1 to 6.5 hours of quinidine administration. Symptoms were nonspecific and included nausea, faintness, and feeling ill. It is now recognized that torsade de pointes was the principal rhythm disturbance in those eight patients. Syncope usually occurs early in treatment and may be found in 5% to 10% of patients taking quinidine.

TCAs and antipsychotics Tricyclic antidepressants (TCAs) and antipsychotics that have quinidine-like properties (e.g., thioridazine) also may be associated with QT interval prolongation and torsade de pointes.^4-9 In high doses (particularly in overdose), TCAs may induce widening of the QRS complex. Fowler et al reported episodes of VT in five patients taking thioridazine—one of whom died.¹⁰

Mehtonen et al reported sudden unexpected deaths associated with antipsychotic or antidepressant drugs among 31 women and 18 men in a survey of autopsies performed from 1985 to 1988 in Finland. The authors documented therapeutic use of phenothiazines in all but 3 of the 49 cases. Thioridazine was involved in more than half the deaths. In 15 of the deaths, thioridazine was the only antipsychotic drug taken. Drugs other than thioridazine were documented in only 5 of the 49 sudden cardiac deaths.¹¹

Figure 2 Normal ECG in sinus rhythm

In this typical lead II of a surface ECG, the P wave (atrial depolarization) leads to right and left atrial contraction and the QRS complex (ventricular depolarization) leads to left and right ventricular contraction. The ST segment represents isoelectric ventricular repolarization, and the T wave represents directional repolarization. The QT interval includes both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval, or ST segment plus T wave).

QT interval as a marker for torsade

The incidence of torsade is unknown, but it is an uncommon cardiac abnormality. In the United States, torsade probably accounts for less than 5% of the 300,000 sudden cardiac deaths that occur each year. Because torsade de pointes is rare, regulatory agencies and clinicians use the QT interval as a surrogate ECG marker for risk of torsade de pointes. Heart rate can affect the QT interval, so various formulae are used to correct the QT interval for heart rate (QTc).

What is the QT interval? In a normal ECG (Figure 2), the P wave derives from right and left atrial electrical depolarization. The pacemaker of the heart is located in the sino-atrial node (SAN) in the superior portion of the right atrium. From the SAN, electrical signals travel down three intra-atrial pathways, activating the right atrium, then travel to the atrioventricular node (AVN). Bachmann’s bundle—a fourth atrial pathway—passes from the SAN to depolarize the left atrium. From the AVN, the electrical signal travels through the left and right bundle branches to activate their respective ventricles.

Electrical depolarization of the left and right ventricles produces the QRS complex. Most of the electrical forces making up this complex arise in the left ventricle, which is much larger than the right ventricle.

The electrical circuitry of the heart activates the left and right atria in such a fashion that these chambers eject blood into their respective ventricles just before these chambers contract. Optimal ventricular filling maximizes ventricular ejection of blood (Starling’s law). Ventricular repolarization (JT interval—electrical recovery) follows ventricular depolarization. On the surface ECG, the JT interval consists of an isoelectric event—the ST segment running from the end of the QRS complex to the beginning of the T wave—and the T wave itself (directional electrical recovery).

The QT interval, then, consists of both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval). Ventricular repolarization makes up by far the greater portion of the QT interval.

Correcting the QT interval (QTc) In 1920, Bazett noted that as the heart rate slowed, the QT interval lengthened.¹² From personal and reported observations, he derived an equation called the Bazett formula that corrects (or normalizes) the QT interval to a heart rate of 60 beats/min (QTc). In the Bazett formula, the QTc interval is the measured QT interval divided by the square root of the RR interval (time between sequential QRS complexes—the determinant of heart rate) measured in seconds (QTc = QT/RR).

The Bazett formula is most widely used to estimate the QTc interval, although at least 20 other formulae have been developed in response to the original’s perceived inadequacies.^13-15 Bazett’s formula is used in most automated interpretations of the ECG.

Up to age 55, the normal QTc interval ranges from 350 to 430 msec for men and 350 to 450 msec for women, and it tends to increase with age. Most cases of torsade occur when the QT or QTc interval is greater than 500 msec.¹⁴ A QTc interval between 450 and 500 msec is cause for concern; a QTc interval that exceeds 500 msec is cause for alarm.

Factors that cause variations in QTc

Factors that can affect the QTc interval and increase the risk of torsade de pointes include electrolyte imbalances, medication use and overdose, cardiac disease, liver disease, endocrine disorders such as diabetes and hypothyroidism, and CNS injury (Table 1).

Table 1

Risk factors contributing to QTc interval prolongation

Circadian patterns The QTc interval varies throughout the 24-hour day, with nocturnal values about 20 msec greater than daytime measurements. These differences are driven by changes in autonomic (sympathetic and parasympathetic) tone.^16,17 In 20 normal subjects, circadian variability was 76 ± 19 msec (range 35 to 108 msec) from day to night.¹⁷ This circadian variation may be accentuated in patients with cardiovascular disease.

Sex. At birth, QTc interval measurements do no vary by sex.¹⁸ At puberty, however, the male QTc interval shortens and remains shorter than its female counterpart by about 20 msec until age 50 to 55, coincident with a decline in male testosterone levels. This sex difference appears to be androgen driven. About 70% of torsade de pointes cases occur in women.¹⁸

Menstrual cycle QTc interval measurements are stable throughout the menstrual cycle if quinidine-like drugs are not given.

Variations were seen, however, when Rodriguez et al studied the effect of IV low-dose ibutilide (an antiarrhythmic agent known to prolong the QT interval) on the QTc intervals of 58 healthy subjects (38 men and 20 women, ages 21 to 40). During 1 month, men were studied once and women studied three times, coincident with the three phases of the menstrual cycle. The greatest increase in QTc intervals measurements occurred in women during the first half of their menstrual cycles.¹⁹

Age and cardiovascular disease Two congenital long QT syndromes may be associated with sudden death, mostly in children and young adults:

• The Jervell and Lange-Nielsen syndrome is marked by severe congenital deafness and autosomal recessive inheritance.
• The Romano-Ward syndrome has normal hearing and autosomal dominant inheritance.²⁰

Congenital long QT syndrome (LQTS) occurs in about one in 5,000 births and accounts for about 3,000 to 4,000 deaths per year in the United States. Nine percent of pediatric LQTS subjects present with sudden cardiac death. More than 71% of patients will die before age 15 if not treated.

Elderly persons tend to have longer QTc intervals than do younger subjects, even when both groups are free of cardiovascular disease.²¹ Also, age-matched subjects with cardiovascular disease tend to have longer QTc intervals than do those free of cardiovascular disease.

Electrolytes Electrolyte disturbances, particularly hypokalemia and hypomagnesemia, may contribute to or even cause QT interval prolongation.²²

Hypokalemia prolongs the cardiac action potential and may cause early afterdepolarization, leading to torsade.²³ Low potassium levels reduce the net outward potassium current during phase 3 of the cardiac action potential. Hypomagnesemia may contribute to gross U wave alternans, lengthening the cardiac action potential and setting the stage for torsade.²⁴ Various factors may contribute to electrolyte disturbances, including use of diuretics and excessive vomiting and diarrhea. Even postprandial states may induce hypokalemia.

Intensive exercise and agitation may be associated with hypokalemia.²⁵ Serum potassium may be lower in severely agitated patients (3.59 mmol/L) than in mildly agitated patients (3.79 mmol/L). The mean QTc interval of psychiatric emergency patients may be prolonged (453±40 msec),⁵ with QTc intervals of psychiatric inpatients longer than those of psychiatric outpatients. Altered potassium states probably explain these observations. Mechanisms that link exercise and agitation with hypokalemia remain to be elucidated.

Metabolic factors Drugs may alter phase 3 potassium flow, thereby disrupting the synchrony of action of individual cardiac cells during repolarization. This change may induce early afterdepolarizations and torsade.²³

Five percent to 10% of Americans of European descent have genetic profiles that make them poor metabolizers of drugs that are metabolized by the cytochrome P-450 isoenzyme 2D6. The Pfizer Inc. 054 study assessed the potential for metabolic inhibitors such as paroxetine to raise antipsychotic drug levels in these patients and induce QTc interval prolongation.²⁶

In response to FDA concerns about QTc interval prolongation associated with the use of ziprasidone, Pfizer studied the potential for QTc interval prolongation when antipsychotics are given with and without metabolic inhibitors of cytochrome P-450 isoenzymes 2D6 (paroxetine), 3A4 (ketoconazole), and 1A2 (fluvoxamine). The study population of 183 subjects (mean age:men, 37.1 years, women 38.8 years) was three-quarters young men with schizophrenia, in good health otherwise and possessing normal ECGs—i.e., patients with a low risk of developing cardiac arrhythmias.

Figure 3 Antipsychotic drugs and QTc interval changes

Six antipsychotic drugs and QTc interval changes from baseline when given with and without metabolic inhibitors. QTc interval changes (in msec) when given without a metabolic inhibitor were ziprasidone, 20.3; risperidone, 11.6; olanzapine, 6.8; quetiapine, 14.5; thioridazine, 35.6; and haloperidol 4.7.

Reprinted from: “FDA Psychopharmacological Drugs Advisory Committee. 19 July 2000. Briefing Documents for Zeldox Capsules (Ziprasidone HCL). Pfizer.” Available from Central Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, (860) 441-4100.Over the course of about 1 week, daily doses were escalated to ziprasidone, 160 mg; risperidone, 8 mg and 16 mg; olanzapine, 20 mg; quetiapine, 750 mg; thioridazine, 300 mg; and haloperidol, 15 mg. Thioridazine (35.6 msec) and ziprasidone (20.3 msec) showed the greatest QTc interval increase following drug administration (Figure 3). Co-administration of a metabolic inhibitor did not further prolong the QTc interval for these two drugs.

Of the six drugs studied, only thioridazine and ziprasidone showed QTc interval increases 5% compared with baseline measurements.

Co-administration of a metabolic inhibitor caused the greatest increase in QTc intervals for quetiapine (from 14.5 to 19.7 msec). This value closely approached the steady-state ziprasidone measurement (20.3 msec). Because quetiapine is more likely than the other antipsychotic drugs studied to increase heart rate, it may be argued that the Bazett formula’s limitations in estimating the QTc interval at higher heart rates contributed to the quetiapine study findings.

Table 2

Relative risk of QTc interval prolongation with common antipsychotic agents

Recommendations

Taking a careful history is key to cardiovascular assessment before prescribing an antipsychotic. An ECG is indicated for patients with:

• Personal or family history of syncope or sudden death;
• Personal history of angina pectoris, myocardial infarction, congestive heart failure, cardiac arrhythmias, hypokalemia, hypomagnesemia, or significant cardiac risk factors.

The relative cardiovascular risks associated with antipsychotic agents are shown in Table 2.

An ECG also is required or strongly recommended before prescribing the antipsychotic drugs most commonly associated with QT prolongation and torsade de pointes—droperidol, haloperidol in large doses IV (commonly 100 mg/d), mesoridazine, pimozide, and thioridazine.

The FDA has strengthened the warning labels required for these agents, adding “black box” warnings about the risks of prolonged QTc intervals, torsade de pointes, and sudden death for droperidol, mesoridazine, and thioridazine. Thioridazine, for example, is indicated only for patients with schizophrenia who fail to show an acceptable response to other antipsychotic drugs. Its use is contraindicated in patients who take:

• fluvoxamine, propranolol, and pindolol;
• any drug that inhibits the cytochrome P-450 2D6 isoenzyme (e.g., fluoxetine, paroxetine);
• agents known to prolong the QTc interval.

Use of thioridazine also is contraindicated in patients known to have reduced levels of the cytochrome P450 2D6 isozyme, as well as in patients with congenital LQTS or a history of cardiac arrhythmias. Psychiatrists are advised to read the warnings and prescribing information in the labeling of all antipsychotics for potential cardiovascular side effects.

When the psychiatrist receives a report of suspected QTc interval prolongation on a patient’s ECG, the following steps are recommended:

• Obtain another ECG.
• Assess serum potassium, magnesium, calcium, and thyroid hormone levels.

In patients with confirmed QTc interval prolongation, any complaint of palpitations, presyncope, or syncope are grounds for urgent referral to a cardiologist.

Related resources

• European Society of Cardiology guidelines: www.escardio.org/scinfo/Guidelines/Haverkamp.pdf
• Sudden Arrhythmia Death Syndromes Foundation (SADSF): www.sads.org (800) 786-7723.
• Drugs that prolong the QT interval and/or induce torsade de pointes. Georgetown Center for Education and Research Therapeutics: www.torsades.org