Lawson R. Wulsin, MD

In early-stage Alzheimer’s disease, Mrs. P enters a nursing home because her daughter, who usually takes care of her, is hospitalized for cancer chemotherapy. Mrs. P promptly develops paranoid delusions and refuses her medications for high blood pressure and high cholesterol. What are the treatment options? Is any one antipsychotic safer than another?

Writing an antipsychotic prescription for patients such as Mrs. P is no longer a quick scribble. First we learned that atypicals may alter glucose and lipid metabolism in clinically troublesome ways.^1,2 Then we learned that antipsychotics can triple the risk for sudden death in older patients with dementia. (See FDA advisory, Related resources.)

How great are the risks, who is at risk, and how strong is the evidence for these new risks? The debate is not yet settled, but the boundaries of good practice for antipsychotic use in older patients are being redrawn. This is particularly true for those with dementia, in whom antipsychotics’ risk/benefit ratio is higher than for older patients with schizophrenia or bipolar disorder.

Unproven effectiveness

Antipsychotics are not FDA-approved for treating dementia-related psychosis. Though antipsychotics are commonly used off-label to treat behavioral disturbances in the elderly with dementia, no standard of care exists for managing these symptoms with drugs. So far, the evidence for antipsychotics’ effectiveness for dementia’s behavioral and psychological symptoms is spotty at best.

Sink et al (Table 1)³ systematically reviewed 14 randomized, controlled trials and concluded “there is no clear evidence that typical antipsychotics are useful for treating neuropsychiatric symptoms [of dementia].” They concluded from 6 studies of atypicals that only olanzapine and risperidone had shown efficacy, but the effects were “modest and further complicated by risk of stroke.” When the benefits are modest, the risks are more difficult to justify.

When medication is necessary, on the other hand, the Expert Consensus Panel for Using Antipsychotic Drugs in Older Patients reported in 2004 that “for agitated dementia with delusions, the experts’ first-line recommendation is an antipsychotic drug alone…. Risperidone (0.5 to 2.0 mg/day) was first line, followed by quetiapine (50 to 150 mg/day) and olanzapine (5.0 to 7.5 mg/day) as high second-line options.”⁴

CATIE studies. The definitive prospective study of antipsychotics’ effectiveness in dementia has not been completed. The National Institute of Mental Health is sponsoring CATIE—Clinical Antipsychotic Trials of Intervention Effectiveness—a multi-site research program comparing the effectiveness and outcomes of antipsychotics in treating schizophrenia and Alzheimer’s disease. Results of the Alzheimer disease arm⁵ are expected next year.

The schizophrenia arm comparing four atypical antipsychotics (quetiapine, risperidone, ziprasidone, and olanzapine) and one typical antipsychotic (perphenazine) found:

• Typical and atypical antipsychotics were similarly effective in 1,493 patients with chronic schizophrenia
• 74% of patients discontinued assigned medications before 18 months for lack of efficacy, intolerable side effects, or other reasons.⁶

Table 1

Timeline: Evidence on risks, efficacy of atypical antipsychotics

Stroke risk

How strong is the evidence for stroke risk among older patients who take antipsychotics? Wooltorton⁷ first raised concern about increased risk of stroke with risperidone in 2002 in a summary of four clinical trials. Though none was designed to examine stroke risk as the primary outcome, two showed significantly higher incidence of cerebrovascular events with risperidone than with placebo. The stroke rate with risperidone was double that with placebo (4% vs 2%) across the total 1,200 subjects in the four studies.

This preliminary report led to an FDA advisory but surprisingly no definitive studies or systematic reviews. No epidemiologic studies have examined stroke rates in those who take antipsychotics compared with those who don’t, while controlling for common stroke predictors. So we have a warning based on post hoc analyses in two positive and two negative studies, but no sound estimate of how much antipsychotic use in general adds to the risk of stroke.

Atypicals vs. typicals. Are atypicals worse than typicals in their effect on stroke risk?

Herrmann et al^8,9 reviewed a health care database of 11,400 older persons and found no statistically significant increase in stroke rate with risperidone or olanzapine compared with typical antipsychotics. This study did not assess whether patients had dementia or primary psychotic disorders.

In a larger retrospective study of 32,710 older persons with dementia, Herrmann’s group¹⁰ found no greater stroke risk in those who took atypicals than in those who took typical antipsychotics.

So the evidence for the risk of stroke in older patients who take antipsychotics is based on a few reports and no definitive studies.

Risk of early death

What about the risk of early death? After reviewing 17 clinical trials of atypical antipsychotics in older patients with dementia, the FDA issued its warning in April 2005 about increased mortality risk (see Related resources). Fifteen of the trials showed an increased mortality risk, resulting in an estimated 1.6- to 1.7-fold increase in risk of death, mostly by cardiac or infectious causes.

A year earlier, Straus et al¹¹ reported on risk of sudden cardiac death with antipsychotic use in a population-based, case-control study in the Netherlands. In this longitudinal, observational database of 250,000 patients, 75% were age >65 and <1% had dementia. Current use of antipsychotics was associated with a threefold increase in risk of sudden cardiac death (554 cases), after other predictors of sudden death were factored in. This risk increased with higher antipsychotic dosages and was similarly elevated for patients with and without schizophrenia-related disorders.

Mechanisms unknown

By what mechanisms could antipsychotics precipitate stroke, sudden cardiac death, or pneumonia? A clear biological mechanism has not been proposed, much less proven. The risks seen in clinical trials—usually lasting 12 weeks or less—suggest an acute effect rather than the more-gradual consequences of weight gain, altered lipid metabolism, or diabetes.

Speculations range widely. Possibilities awaiting study include postural hypotension, altered platelet aggregation, increased venous thromboembolism, peripheral vasodilation leading to cardiovascular collapse, acute dystonia, acute cardiomyopathy, arrhythmias related to QT prolongation, and other forms of cardiac toxicity.^10,11

Remaining questions

The few studies plus two FDA advisories force clinicians to make complex treatment decisions on insufficient evidence. Here’s what we don’t know:

• The magnitude of stroke or sudden death risk in older patients who take antipsychotics for any diagnosis. (All studies have limitations, and public health policy should not rely on one or two studies, no matter how good they may be.)
• Who is at higher or lower risk with antipsychotic use—men vs women? blacks vs whites?etc.
• Biological mechanisms of an association between antipsychotics and risks of stroke and premature death.

Strategies for reducing risk

We can minimize patients’ clinical risk and our legal risk only by using the limited evidence, expert consensus, and sound clinical judgment. Suggested strategies are listed in Table 2.

Table 2

Strategies to minimize antipsychotic risk in patients age 65 and older

Related resources

• Food and Drug Administration. Advisory on increased risk of mortality with use of atypical antipsychotics to treat behavioral disturbances in older patients with dementia. www.fda.gov/cder/drug/advisory/antipsychotics.htm.

Drug brand names

• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

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

In early-stage Alzheimer’s disease, Mrs. P enters a nursing home because her daughter, who usually takes care of her, is hospitalized for cancer chemotherapy. Mrs. P promptly develops paranoid delusions and refuses her medications for high blood pressure and high cholesterol. What are the treatment options? Is any one antipsychotic safer than another?

Writing an antipsychotic prescription for patients such as Mrs. P is no longer a quick scribble. First we learned that atypicals may alter glucose and lipid metabolism in clinically troublesome ways.^1,2 Then we learned that antipsychotics can triple the risk for sudden death in older patients with dementia. (See FDA advisory, Related resources.)

How great are the risks, who is at risk, and how strong is the evidence for these new risks? The debate is not yet settled, but the boundaries of good practice for antipsychotic use in older patients are being redrawn. This is particularly true for those with dementia, in whom antipsychotics’ risk/benefit ratio is higher than for older patients with schizophrenia or bipolar disorder.

Unproven effectiveness

Antipsychotics are not FDA-approved for treating dementia-related psychosis. Though antipsychotics are commonly used off-label to treat behavioral disturbances in the elderly with dementia, no standard of care exists for managing these symptoms with drugs. So far, the evidence for antipsychotics’ effectiveness for dementia’s behavioral and psychological symptoms is spotty at best.

Sink et al (Table 1)³ systematically reviewed 14 randomized, controlled trials and concluded “there is no clear evidence that typical antipsychotics are useful for treating neuropsychiatric symptoms [of dementia].” They concluded from 6 studies of atypicals that only olanzapine and risperidone had shown efficacy, but the effects were “modest and further complicated by risk of stroke.” When the benefits are modest, the risks are more difficult to justify.

When medication is necessary, on the other hand, the Expert Consensus Panel for Using Antipsychotic Drugs in Older Patients reported in 2004 that “for agitated dementia with delusions, the experts’ first-line recommendation is an antipsychotic drug alone…. Risperidone (0.5 to 2.0 mg/day) was first line, followed by quetiapine (50 to 150 mg/day) and olanzapine (5.0 to 7.5 mg/day) as high second-line options.”⁴

CATIE studies. The definitive prospective study of antipsychotics’ effectiveness in dementia has not been completed. The National Institute of Mental Health is sponsoring CATIE—Clinical Antipsychotic Trials of Intervention Effectiveness—a multi-site research program comparing the effectiveness and outcomes of antipsychotics in treating schizophrenia and Alzheimer’s disease. Results of the Alzheimer disease arm⁵ are expected next year.

The schizophrenia arm comparing four atypical antipsychotics (quetiapine, risperidone, ziprasidone, and olanzapine) and one typical antipsychotic (perphenazine) found:

• Typical and atypical antipsychotics were similarly effective in 1,493 patients with chronic schizophrenia
• 74% of patients discontinued assigned medications before 18 months for lack of efficacy, intolerable side effects, or other reasons.⁶

Table 1

Timeline: Evidence on risks, efficacy of atypical antipsychotics

Stroke risk

How strong is the evidence for stroke risk among older patients who take antipsychotics? Wooltorton⁷ first raised concern about increased risk of stroke with risperidone in 2002 in a summary of four clinical trials. Though none was designed to examine stroke risk as the primary outcome, two showed significantly higher incidence of cerebrovascular events with risperidone than with placebo. The stroke rate with risperidone was double that with placebo (4% vs 2%) across the total 1,200 subjects in the four studies.

This preliminary report led to an FDA advisory but surprisingly no definitive studies or systematic reviews. No epidemiologic studies have examined stroke rates in those who take antipsychotics compared with those who don’t, while controlling for common stroke predictors. So we have a warning based on post hoc analyses in two positive and two negative studies, but no sound estimate of how much antipsychotic use in general adds to the risk of stroke.

Atypicals vs. typicals. Are atypicals worse than typicals in their effect on stroke risk?

Herrmann et al^8,9 reviewed a health care database of 11,400 older persons and found no statistically significant increase in stroke rate with risperidone or olanzapine compared with typical antipsychotics. This study did not assess whether patients had dementia or primary psychotic disorders.

In a larger retrospective study of 32,710 older persons with dementia, Herrmann’s group¹⁰ found no greater stroke risk in those who took atypicals than in those who took typical antipsychotics.

So the evidence for the risk of stroke in older patients who take antipsychotics is based on a few reports and no definitive studies.

Risk of early death

What about the risk of early death? After reviewing 17 clinical trials of atypical antipsychotics in older patients with dementia, the FDA issued its warning in April 2005 about increased mortality risk (see Related resources). Fifteen of the trials showed an increased mortality risk, resulting in an estimated 1.6- to 1.7-fold increase in risk of death, mostly by cardiac or infectious causes.

A year earlier, Straus et al¹¹ reported on risk of sudden cardiac death with antipsychotic use in a population-based, case-control study in the Netherlands. In this longitudinal, observational database of 250,000 patients, 75% were age >65 and <1% had dementia. Current use of antipsychotics was associated with a threefold increase in risk of sudden cardiac death (554 cases), after other predictors of sudden death were factored in. This risk increased with higher antipsychotic dosages and was similarly elevated for patients with and without schizophrenia-related disorders.

Mechanisms unknown

By what mechanisms could antipsychotics precipitate stroke, sudden cardiac death, or pneumonia? A clear biological mechanism has not been proposed, much less proven. The risks seen in clinical trials—usually lasting 12 weeks or less—suggest an acute effect rather than the more-gradual consequences of weight gain, altered lipid metabolism, or diabetes.

Speculations range widely. Possibilities awaiting study include postural hypotension, altered platelet aggregation, increased venous thromboembolism, peripheral vasodilation leading to cardiovascular collapse, acute dystonia, acute cardiomyopathy, arrhythmias related to QT prolongation, and other forms of cardiac toxicity.^10,11

Remaining questions

The few studies plus two FDA advisories force clinicians to make complex treatment decisions on insufficient evidence. Here’s what we don’t know:

• The magnitude of stroke or sudden death risk in older patients who take antipsychotics for any diagnosis. (All studies have limitations, and public health policy should not rely on one or two studies, no matter how good they may be.)
• Who is at higher or lower risk with antipsychotic use—men vs women? blacks vs whites?etc.
• Biological mechanisms of an association between antipsychotics and risks of stroke and premature death.

Strategies for reducing risk

We can minimize patients’ clinical risk and our legal risk only by using the limited evidence, expert consensus, and sound clinical judgment. Suggested strategies are listed in Table 2.

Table 2

Strategies to minimize antipsychotic risk in patients age 65 and older

Related resources

• Food and Drug Administration. Advisory on increased risk of mortality with use of atypical antipsychotics to treat behavioral disturbances in older patients with dementia. www.fda.gov/cder/drug/advisory/antipsychotics.htm.

Drug brand names

• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

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

In early-stage Alzheimer’s disease, Mrs. P enters a nursing home because her daughter, who usually takes care of her, is hospitalized for cancer chemotherapy. Mrs. P promptly develops paranoid delusions and refuses her medications for high blood pressure and high cholesterol. What are the treatment options? Is any one antipsychotic safer than another?

Writing an antipsychotic prescription for patients such as Mrs. P is no longer a quick scribble. First we learned that atypicals may alter glucose and lipid metabolism in clinically troublesome ways.^1,2 Then we learned that antipsychotics can triple the risk for sudden death in older patients with dementia. (See FDA advisory, Related resources.)

How great are the risks, who is at risk, and how strong is the evidence for these new risks? The debate is not yet settled, but the boundaries of good practice for antipsychotic use in older patients are being redrawn. This is particularly true for those with dementia, in whom antipsychotics’ risk/benefit ratio is higher than for older patients with schizophrenia or bipolar disorder.

Unproven effectiveness

Antipsychotics are not FDA-approved for treating dementia-related psychosis. Though antipsychotics are commonly used off-label to treat behavioral disturbances in the elderly with dementia, no standard of care exists for managing these symptoms with drugs. So far, the evidence for antipsychotics’ effectiveness for dementia’s behavioral and psychological symptoms is spotty at best.

Sink et al (Table 1)³ systematically reviewed 14 randomized, controlled trials and concluded “there is no clear evidence that typical antipsychotics are useful for treating neuropsychiatric symptoms [of dementia].” They concluded from 6 studies of atypicals that only olanzapine and risperidone had shown efficacy, but the effects were “modest and further complicated by risk of stroke.” When the benefits are modest, the risks are more difficult to justify.

When medication is necessary, on the other hand, the Expert Consensus Panel for Using Antipsychotic Drugs in Older Patients reported in 2004 that “for agitated dementia with delusions, the experts’ first-line recommendation is an antipsychotic drug alone…. Risperidone (0.5 to 2.0 mg/day) was first line, followed by quetiapine (50 to 150 mg/day) and olanzapine (5.0 to 7.5 mg/day) as high second-line options.”⁴

CATIE studies. The definitive prospective study of antipsychotics’ effectiveness in dementia has not been completed. The National Institute of Mental Health is sponsoring CATIE—Clinical Antipsychotic Trials of Intervention Effectiveness—a multi-site research program comparing the effectiveness and outcomes of antipsychotics in treating schizophrenia and Alzheimer’s disease. Results of the Alzheimer disease arm⁵ are expected next year.

The schizophrenia arm comparing four atypical antipsychotics (quetiapine, risperidone, ziprasidone, and olanzapine) and one typical antipsychotic (perphenazine) found:

• Typical and atypical antipsychotics were similarly effective in 1,493 patients with chronic schizophrenia
• 74% of patients discontinued assigned medications before 18 months for lack of efficacy, intolerable side effects, or other reasons.⁶

Table 1

Timeline: Evidence on risks, efficacy of atypical antipsychotics

Stroke risk

How strong is the evidence for stroke risk among older patients who take antipsychotics? Wooltorton⁷ first raised concern about increased risk of stroke with risperidone in 2002 in a summary of four clinical trials. Though none was designed to examine stroke risk as the primary outcome, two showed significantly higher incidence of cerebrovascular events with risperidone than with placebo. The stroke rate with risperidone was double that with placebo (4% vs 2%) across the total 1,200 subjects in the four studies.

This preliminary report led to an FDA advisory but surprisingly no definitive studies or systematic reviews. No epidemiologic studies have examined stroke rates in those who take antipsychotics compared with those who don’t, while controlling for common stroke predictors. So we have a warning based on post hoc analyses in two positive and two negative studies, but no sound estimate of how much antipsychotic use in general adds to the risk of stroke.

Atypicals vs. typicals. Are atypicals worse than typicals in their effect on stroke risk?

Herrmann et al^8,9 reviewed a health care database of 11,400 older persons and found no statistically significant increase in stroke rate with risperidone or olanzapine compared with typical antipsychotics. This study did not assess whether patients had dementia or primary psychotic disorders.

In a larger retrospective study of 32,710 older persons with dementia, Herrmann’s group¹⁰ found no greater stroke risk in those who took atypicals than in those who took typical antipsychotics.

So the evidence for the risk of stroke in older patients who take antipsychotics is based on a few reports and no definitive studies.

Risk of early death

What about the risk of early death? After reviewing 17 clinical trials of atypical antipsychotics in older patients with dementia, the FDA issued its warning in April 2005 about increased mortality risk (see Related resources). Fifteen of the trials showed an increased mortality risk, resulting in an estimated 1.6- to 1.7-fold increase in risk of death, mostly by cardiac or infectious causes.

A year earlier, Straus et al¹¹ reported on risk of sudden cardiac death with antipsychotic use in a population-based, case-control study in the Netherlands. In this longitudinal, observational database of 250,000 patients, 75% were age >65 and <1% had dementia. Current use of antipsychotics was associated with a threefold increase in risk of sudden cardiac death (554 cases), after other predictors of sudden death were factored in. This risk increased with higher antipsychotic dosages and was similarly elevated for patients with and without schizophrenia-related disorders.

Mechanisms unknown

By what mechanisms could antipsychotics precipitate stroke, sudden cardiac death, or pneumonia? A clear biological mechanism has not been proposed, much less proven. The risks seen in clinical trials—usually lasting 12 weeks or less—suggest an acute effect rather than the more-gradual consequences of weight gain, altered lipid metabolism, or diabetes.

Speculations range widely. Possibilities awaiting study include postural hypotension, altered platelet aggregation, increased venous thromboembolism, peripheral vasodilation leading to cardiovascular collapse, acute dystonia, acute cardiomyopathy, arrhythmias related to QT prolongation, and other forms of cardiac toxicity.^10,11

Remaining questions

The few studies plus two FDA advisories force clinicians to make complex treatment decisions on insufficient evidence. Here’s what we don’t know:

• The magnitude of stroke or sudden death risk in older patients who take antipsychotics for any diagnosis. (All studies have limitations, and public health policy should not rely on one or two studies, no matter how good they may be.)
• Who is at higher or lower risk with antipsychotic use—men vs women? blacks vs whites?etc.
• Biological mechanisms of an association between antipsychotics and risks of stroke and premature death.

Strategies for reducing risk

We can minimize patients’ clinical risk and our legal risk only by using the limited evidence, expert consensus, and sound clinical judgment. Suggested strategies are listed in Table 2.

Table 2

Strategies to minimize antipsychotic risk in patients age 65 and older

Related resources

• Food and Drug Administration. Advisory on increased risk of mortality with use of atypical antipsychotics to treat behavioral disturbances in older patients with dementia. www.fda.gov/cder/drug/advisory/antipsychotics.htm.

Drug brand names

• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

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

Medical history

• No other significant medical or psychiatric problems
• Married, with 2 teenaged children
• Employed as an administrator for an insurance company (>50 hrs/wk)
• Drinks 3 to 4 alcoholic beverages/wk
• Does not smoke
• Enjoys fishing and other outdoor activities
• Both parents had hypertension; father also had peripheral vascular disease

Examination

• Patient is in no acute distress
• Approximately 30 pounds over ideal body weight
• Other vital signs are normal
• Normal retinal examination, no carotid bruits, and clear lungs. Cardiac rate and rhythm are regular; no abdominal bruits
• Laboratory studies reveal normal renal function; cholesterol, 184 mg/dL; low-density lipoprotein (LDL) cholesterol, 129 mg/dL; high-density lipoprotein (HDL) cholesterol, 55 mg/dL; triglycerides, 163 mg/dL. Electrocardiogram shows no current or prior evidence of ischemia or left-ventricular strain.

Additional information is required in a number of domains. Blood pressure readings should be repeated to make an accurate diagnosis of hypertension. While the patient may have hypertension, only a single blood pressure reading is elevated. The Joint National Committee on Blood Pressure (JNC 7) specifications¹ state that 2 such readings on different days are needed to confirm a diagnosis of hypertension. The symptoms of claudication should be investigated. Physical examination should focus on auscultation for bruits and on the examination of eye grounds to further investigate the possibility of peripheral vascular disease (PVD). In addition, a lipid profile should be drawn. While guidelines are conflicting, consideration should be given to assessing a fasting glucose, potassium, and renal function. Other tests, such as a C-reactive protein, are more controversial.²

The patient opts for drug treatment of his hypertension, and begins taking atenolol 50 mg/d (in addition to aspirin 81 mg/d). He is scheduled to follow-up by phone in 1 week to assure compliance and in 3 months in the office.

On further questioning he reports that he initially tolerated the beta-blocker without problem, but more recently has experienced low energy and poor sleep (with early morning awakening); he acknowledges decreases in libido, interest in pleasurable activities (eg, hunting, fishing), and his ability to concentrate. He has gained 5 to 10 pounds in the last month.

Although he denies feeling “sad,” he says his emotions seem “flat.” He denies having thoughts of suicide, increased anxiety, symptoms of hypomania, or psychotic symptoms. He describes a mild increase in stress at work, and he feels that the process of preparing for his son to go to college had been “a big burden.” He says there are no other stressors.

The patient’s alcohol use has not changed significantly, and he reports being compliant with his new medication regimen.

When his father died 6 years earlier, he experienced similar symptoms; at no other time have such symptoms occurred. The patient reports no other new physical symptoms, and his physical examination is essentially unchanged from the exam conducted 3 months earlier. His vital signs are normal, including a blood pressure of 128/84 mm Hg.

Consider the differential diagnosis of the patient’s abnormal mood and neurovegetative symptoms. In the primary care setting, the differential diagnosis of depressed mood is broad (Table 1 ), including medical disorders and a variety of psychiatric syndromes.

Medical conditions to consider include a medication induced side effect, hypothyroidism (a metabolic masquerader of depression), anemia, sleep disorder (eg, sleep apnea), and alcohol abuse. PVD should also be considered—his symptoms may be secondary to poor perfusion of the cerebral cortex.

TABLE 1

Partial differential diagnosis of depressed mood and neurovegetative symptoms

Psychiatrist’s comments

It is important to distinguish major depression from other, less severe depressive syndromes. In major depression, 5 out of 9 symptoms (including depressed mood or anhedonia) are present most of the day nearly every day for 2 weeks.

With adjustment disorder and so-called minor depression, symptoms are fewer or less persistent (Table 2).

This distinction is important, as antidepressants are effective for major depression, but they have not yet been shown effective for adjustment disorders or minor depression. Major depression is the “hypertension of mental illness in primary care”—common, often undiagnosed, and associated with poor outcomes. Therefore, accurate diagnosis and appropriate treatment for major depression are essential.

Given the possibility of a depressive syndrome, gather further information to determine the duration of ongoing symptoms, and obtain answers to a short questionnaire (eg, the Beck Depression Inventory [BDI]³ or the PHQ-9⁴). Elicit a family history of mood disorder, or personal history suggestive of thyroid dysfunction, a sleep disorder, or alcohol or drug abuse. Order a complete blood count (CBC) to evaluate for anemia, a thyroid-stimulating hormone (TSH) to evaluate for hypothyroidism, and, if indicated by history, a sleep study.

Beta-blockers and depression. The patient’s symptoms developed in the context of beta-blocker therapy. From the 1970s through the 1990s, the lore was that beta-blockers caused depression and should be avoided in patients with a history of depression. Because of this, many patients with myocardial infarction (MI) and congestive heart failure (CHF) have been denied treatment with beta-blockers when otherwise indicated.

Fortunately, a recent rigorous academic study of this issue was conducted by Ko and colleagues⁵ to rationally guide treatment. This study involved a meta-analysis of 15 randomized controlled trials of beta-blocker therapy in patients with MI, CHF, or hypertension; the authors found that beta-blockers were associated with a slight (though statistically significant) increase in fatigue and sexual dysfunction, and that their use was not associated with depressive symptoms. This is the best review to date of beta-blockers and depression, and it debunks the myth that beta-blockers cause depression—a myth that has prevented many post-MI patients from receiving much-needed beta-blocker therapy. In short, although idiosyncratic reactions are possible, it is unlikely the patient’s use of atenolol caused his apparent depressive symptoms.

TABLE 2

Major depression, minor depression, and adjustment disorder

Further primary care evaluation

The patient has no cold intolerance or other symptoms of thyroid dysfunction. He does report a long history of snoring, confirmed by his wife. However, he did not notice feeling more fatigued after starting atenolol.Nonetheless, you switch his antihypertensive medication from atenolol to hydrochlorothiazide. In addition, you order a CBC, serum chemistries, a thyroid panel, and a sleep study. The patient is told to return for a follow-up appointment in 2 weeks and to call before that if symptoms worsen.

In this situation, the evidence (depressive symptoms in the context of good blood-pressure control) was insufficient to justify a switch from a beta-blocker to hydrochlorothiazide. One could argue that the switch was reasonable regardless of his depressive symptoms; the most recent guidelines from JNC 7¹ indicate that thiazide diuretics are first-line therapy for hypertension in patients without CAD, and that beta-blockers are not the first-line agent in the patient’s clinical situation.

But discontinuing atenolol because of ongoing depressive symptoms is not supported. The patient may well need a beta-blocker in the future (eg, if he were to develop CAD). By prematurely concluding that the beta-blocker caused adverse effects, we may be denying him an important treatment down the road.

Option 1: 2-week drug holiday

If there was concern that the patient was having an idiosyncratic reaction to atenolol, or if he developed substantial fatigue or sexual dysfunction, a 2-week drug holiday could be conducted while carefully monitoring blood pressure and depressive symptoms. Atenolol could then be restarted to identify a temporal relationship between the symptoms and the medication.

Option 2: Treat for depression

Another option would be to treat the patient as if his symptoms represented depression. Exhibiting 4 of the necessary diagnostic criteria, the patient nearly qualifies for a diagnosis of current major depression. An antidepressant could be started, exercise could be prescribed, or a referral could be made for psychotherapy. However, again there is insufficient evidence that his subsyndromal depression will respond to standard treatments designed for major depressive disorder.

The patient returns as scheduled 2 weeks later. He has tolerated the change in blood pressure medications without difficulty, but he is experiencing persistent anhedonia, terminal insomnia, and low levels of concentration, energy, and libido. He has felt increasingly hopeless and worthless over the past 2 weeks, though he denies having thoughts of suicide. Results on CBC, serum chemistries, thyroid panel, and sleep study are all unremarkable.

The patient now clearly meets criteria for a major depressive episode. As a first step, he should be educated about depression. An excellent self-help book is Getting Your Life Back by Wright and Basco.⁶ The patient should be taught to monitor his symptoms with the BDI³ or the PHQ-9⁴ to better assess the severity of the current episode, to monitor changes in his symptoms, and to rapidly identify relapses.

Most physicians would start an antidepressant, unless the patient had significant objections. Other treatment options, alone or in concert with antidepressant treatment, include exercise or psychotherapy. The patient is an excellent candidate for exercise, given that he has 3 risk factors for CAD: hypertension, a sedentary lifestyle, and obesity (4, if you include depression). Exercising for at least 30 minutes, 2 to 3 times per week, would likely benefit his physical and mental health. In addition to its cardiac benefits, exercise 3 times weekly was found in at least one trial to be as effective as sertraline in treating major depression in outpatients.⁷

Choosing an antidepressant. A number of factors should be considered in choosing antidepressants, including efficacy, side effect profile, and cost. Table 3 outlines some of the main considerations in the choice of antidepressants for this patient. Note that tricyclic antidepressants are not listed, being contraindicated in CAD because of their tendency to contribute to arrhythmias in the post-MI period. In this patient’s case, mirtazapine should be avoided because of the possibility of weight gain; venlafaxine should be avoided because of hypertension. Sertraline would be an appropriate choice, given that it has been relatively well-studied in persons with CAD.

The patient begins treatment with fluoxetine (10 mg/d, which is then increased to 20 mg/d after several days). His depressive symptoms gradually diminish; he achieves a “50%” reduction of symptoms at follow-up visit 3 weeks later. Two months after fluoxetine was initiated, the patient is nearly euthymic, reporting only 2 depressive symptoms, and is again engaging in usual recreational activities.

TABLE 3

A comparison of antidepressants in the treatment of depressed patients in cardiac populations

Whether depression is a risk factor for CAD depends on how one defines a risk factor and whether one is discussing “major” or “minor” risk factors. At least 15 narrative reviews have been written on the relationship between depression and heart disease, but none has examined the epidemiologic evidence for depression as a major risk factor for CAD (Table 4).⁸

In looking at the 7 main epidemiologic criteria for a risk factor, depression does very well on 4: strength of association, consistency, dose-response effect, and predictability. Numerous studies have shown that depression is clearly and consistently associated with the development of CAD, and that clinical depression appears to predict CAD more robustly than does depressed mood alone.^9-12

On 2 of the criteria, specificity and biological plausibility, there is fair evidence for depression as a CAD risk factor. We do not yet know the relative importance of recurrent major depression, dysthymia, BDI scores of 10 or greater, or some other marker of depression as predictors of CAD.

Because mild depressive symptoms may predict CAD, it is unclear what levels of depression increase the risk of CAD and require intervention. Excellent work exists regarding the development of plausible mechanisms by which depression may lead to CAD; however, these mechanisms have yet to be proven. Therefore, the evidence in this domain can only be rated as fair.

Finally, the evidence is incomplete for one important criterion: response to treatment. Only one study has been designed to examine the effect of depression treatments on cardiac risk reduction. This study (the ENRICHD trial¹³) was a treatment study of post-MI depression that found that cognitive-behavioral therapy did not have a significant impact on reducing recurrent cardiac events.

Based on the most stringent epidemiologic criteria, depression is almost, but not quite, a risk factor for CAD. However, depression is a minor risk factor for CAD, and may someday be considered a major risk factor. While the mechanisms by which depression may lead to CAD have not yet been established, the association between depression and subsequent CAD likely occurs via 2 pathways.

The first pathway is behavioral. Patients with depression have diminished self-care, possibly increasing other CAD risk factors such as smoking, poor diet/hyperlipidemia, diabetes, physical inactivity, and obesity.

The second pathway by which depression may lead to CAD is neuroendocrine. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and hyperactive sympathomedullary activity may result in elevated cytokine levels, platelet activation, and vascular damage, thereby contributing to CAD.⁸

TABLE 4

Depression as a risk factor for CAD: a “report card”⁸

· Acknowledgments ·

Portions of this article were presented at the Association of Medicine and Psychiatry Annual Meeting, San Diego, California, November 19, 2003.

Medical history

• No other significant medical or psychiatric problems
• Married, with 2 teenaged children
• Employed as an administrator for an insurance company (>50 hrs/wk)
• Drinks 3 to 4 alcoholic beverages/wk
• Does not smoke
• Enjoys fishing and other outdoor activities
• Both parents had hypertension; father also had peripheral vascular disease

Examination

• Patient is in no acute distress
• Approximately 30 pounds over ideal body weight
• Other vital signs are normal
• Normal retinal examination, no carotid bruits, and clear lungs. Cardiac rate and rhythm are regular; no abdominal bruits
• Laboratory studies reveal normal renal function; cholesterol, 184 mg/dL; low-density lipoprotein (LDL) cholesterol, 129 mg/dL; high-density lipoprotein (HDL) cholesterol, 55 mg/dL; triglycerides, 163 mg/dL. Electrocardiogram shows no current or prior evidence of ischemia or left-ventricular strain.

Additional information is required in a number of domains. Blood pressure readings should be repeated to make an accurate diagnosis of hypertension. While the patient may have hypertension, only a single blood pressure reading is elevated. The Joint National Committee on Blood Pressure (JNC 7) specifications¹ state that 2 such readings on different days are needed to confirm a diagnosis of hypertension. The symptoms of claudication should be investigated. Physical examination should focus on auscultation for bruits and on the examination of eye grounds to further investigate the possibility of peripheral vascular disease (PVD). In addition, a lipid profile should be drawn. While guidelines are conflicting, consideration should be given to assessing a fasting glucose, potassium, and renal function. Other tests, such as a C-reactive protein, are more controversial.²

The patient opts for drug treatment of his hypertension, and begins taking atenolol 50 mg/d (in addition to aspirin 81 mg/d). He is scheduled to follow-up by phone in 1 week to assure compliance and in 3 months in the office.

On further questioning he reports that he initially tolerated the beta-blocker without problem, but more recently has experienced low energy and poor sleep (with early morning awakening); he acknowledges decreases in libido, interest in pleasurable activities (eg, hunting, fishing), and his ability to concentrate. He has gained 5 to 10 pounds in the last month.

Although he denies feeling “sad,” he says his emotions seem “flat.” He denies having thoughts of suicide, increased anxiety, symptoms of hypomania, or psychotic symptoms. He describes a mild increase in stress at work, and he feels that the process of preparing for his son to go to college had been “a big burden.” He says there are no other stressors.

The patient’s alcohol use has not changed significantly, and he reports being compliant with his new medication regimen.

When his father died 6 years earlier, he experienced similar symptoms; at no other time have such symptoms occurred. The patient reports no other new physical symptoms, and his physical examination is essentially unchanged from the exam conducted 3 months earlier. His vital signs are normal, including a blood pressure of 128/84 mm Hg.

Consider the differential diagnosis of the patient’s abnormal mood and neurovegetative symptoms. In the primary care setting, the differential diagnosis of depressed mood is broad (Table 1 ), including medical disorders and a variety of psychiatric syndromes.

Medical conditions to consider include a medication induced side effect, hypothyroidism (a metabolic masquerader of depression), anemia, sleep disorder (eg, sleep apnea), and alcohol abuse. PVD should also be considered—his symptoms may be secondary to poor perfusion of the cerebral cortex.

TABLE 1

Partial differential diagnosis of depressed mood and neurovegetative symptoms

Psychiatrist’s comments

It is important to distinguish major depression from other, less severe depressive syndromes. In major depression, 5 out of 9 symptoms (including depressed mood or anhedonia) are present most of the day nearly every day for 2 weeks.

With adjustment disorder and so-called minor depression, symptoms are fewer or less persistent (Table 2).

This distinction is important, as antidepressants are effective for major depression, but they have not yet been shown effective for adjustment disorders or minor depression. Major depression is the “hypertension of mental illness in primary care”—common, often undiagnosed, and associated with poor outcomes. Therefore, accurate diagnosis and appropriate treatment for major depression are essential.

Given the possibility of a depressive syndrome, gather further information to determine the duration of ongoing symptoms, and obtain answers to a short questionnaire (eg, the Beck Depression Inventory [BDI]³ or the PHQ-9⁴). Elicit a family history of mood disorder, or personal history suggestive of thyroid dysfunction, a sleep disorder, or alcohol or drug abuse. Order a complete blood count (CBC) to evaluate for anemia, a thyroid-stimulating hormone (TSH) to evaluate for hypothyroidism, and, if indicated by history, a sleep study.

Beta-blockers and depression. The patient’s symptoms developed in the context of beta-blocker therapy. From the 1970s through the 1990s, the lore was that beta-blockers caused depression and should be avoided in patients with a history of depression. Because of this, many patients with myocardial infarction (MI) and congestive heart failure (CHF) have been denied treatment with beta-blockers when otherwise indicated.

Fortunately, a recent rigorous academic study of this issue was conducted by Ko and colleagues⁵ to rationally guide treatment. This study involved a meta-analysis of 15 randomized controlled trials of beta-blocker therapy in patients with MI, CHF, or hypertension; the authors found that beta-blockers were associated with a slight (though statistically significant) increase in fatigue and sexual dysfunction, and that their use was not associated with depressive symptoms. This is the best review to date of beta-blockers and depression, and it debunks the myth that beta-blockers cause depression—a myth that has prevented many post-MI patients from receiving much-needed beta-blocker therapy. In short, although idiosyncratic reactions are possible, it is unlikely the patient’s use of atenolol caused his apparent depressive symptoms.

TABLE 2

Major depression, minor depression, and adjustment disorder

Further primary care evaluation

The patient has no cold intolerance or other symptoms of thyroid dysfunction. He does report a long history of snoring, confirmed by his wife. However, he did not notice feeling more fatigued after starting atenolol.Nonetheless, you switch his antihypertensive medication from atenolol to hydrochlorothiazide. In addition, you order a CBC, serum chemistries, a thyroid panel, and a sleep study. The patient is told to return for a follow-up appointment in 2 weeks and to call before that if symptoms worsen.

In this situation, the evidence (depressive symptoms in the context of good blood-pressure control) was insufficient to justify a switch from a beta-blocker to hydrochlorothiazide. One could argue that the switch was reasonable regardless of his depressive symptoms; the most recent guidelines from JNC 7¹ indicate that thiazide diuretics are first-line therapy for hypertension in patients without CAD, and that beta-blockers are not the first-line agent in the patient’s clinical situation.

But discontinuing atenolol because of ongoing depressive symptoms is not supported. The patient may well need a beta-blocker in the future (eg, if he were to develop CAD). By prematurely concluding that the beta-blocker caused adverse effects, we may be denying him an important treatment down the road.

Option 1: 2-week drug holiday

If there was concern that the patient was having an idiosyncratic reaction to atenolol, or if he developed substantial fatigue or sexual dysfunction, a 2-week drug holiday could be conducted while carefully monitoring blood pressure and depressive symptoms. Atenolol could then be restarted to identify a temporal relationship between the symptoms and the medication.

Option 2: Treat for depression

Another option would be to treat the patient as if his symptoms represented depression. Exhibiting 4 of the necessary diagnostic criteria, the patient nearly qualifies for a diagnosis of current major depression. An antidepressant could be started, exercise could be prescribed, or a referral could be made for psychotherapy. However, again there is insufficient evidence that his subsyndromal depression will respond to standard treatments designed for major depressive disorder.

The patient returns as scheduled 2 weeks later. He has tolerated the change in blood pressure medications without difficulty, but he is experiencing persistent anhedonia, terminal insomnia, and low levels of concentration, energy, and libido. He has felt increasingly hopeless and worthless over the past 2 weeks, though he denies having thoughts of suicide. Results on CBC, serum chemistries, thyroid panel, and sleep study are all unremarkable.

The patient now clearly meets criteria for a major depressive episode. As a first step, he should be educated about depression. An excellent self-help book is Getting Your Life Back by Wright and Basco.⁶ The patient should be taught to monitor his symptoms with the BDI³ or the PHQ-9⁴ to better assess the severity of the current episode, to monitor changes in his symptoms, and to rapidly identify relapses.

Most physicians would start an antidepressant, unless the patient had significant objections. Other treatment options, alone or in concert with antidepressant treatment, include exercise or psychotherapy. The patient is an excellent candidate for exercise, given that he has 3 risk factors for CAD: hypertension, a sedentary lifestyle, and obesity (4, if you include depression). Exercising for at least 30 minutes, 2 to 3 times per week, would likely benefit his physical and mental health. In addition to its cardiac benefits, exercise 3 times weekly was found in at least one trial to be as effective as sertraline in treating major depression in outpatients.⁷

Choosing an antidepressant. A number of factors should be considered in choosing antidepressants, including efficacy, side effect profile, and cost. Table 3 outlines some of the main considerations in the choice of antidepressants for this patient. Note that tricyclic antidepressants are not listed, being contraindicated in CAD because of their tendency to contribute to arrhythmias in the post-MI period. In this patient’s case, mirtazapine should be avoided because of the possibility of weight gain; venlafaxine should be avoided because of hypertension. Sertraline would be an appropriate choice, given that it has been relatively well-studied in persons with CAD.

The patient begins treatment with fluoxetine (10 mg/d, which is then increased to 20 mg/d after several days). His depressive symptoms gradually diminish; he achieves a “50%” reduction of symptoms at follow-up visit 3 weeks later. Two months after fluoxetine was initiated, the patient is nearly euthymic, reporting only 2 depressive symptoms, and is again engaging in usual recreational activities.

TABLE 3

A comparison of antidepressants in the treatment of depressed patients in cardiac populations

Whether depression is a risk factor for CAD depends on how one defines a risk factor and whether one is discussing “major” or “minor” risk factors. At least 15 narrative reviews have been written on the relationship between depression and heart disease, but none has examined the epidemiologic evidence for depression as a major risk factor for CAD (Table 4).⁸

In looking at the 7 main epidemiologic criteria for a risk factor, depression does very well on 4: strength of association, consistency, dose-response effect, and predictability. Numerous studies have shown that depression is clearly and consistently associated with the development of CAD, and that clinical depression appears to predict CAD more robustly than does depressed mood alone.^9-12

On 2 of the criteria, specificity and biological plausibility, there is fair evidence for depression as a CAD risk factor. We do not yet know the relative importance of recurrent major depression, dysthymia, BDI scores of 10 or greater, or some other marker of depression as predictors of CAD.

Because mild depressive symptoms may predict CAD, it is unclear what levels of depression increase the risk of CAD and require intervention. Excellent work exists regarding the development of plausible mechanisms by which depression may lead to CAD; however, these mechanisms have yet to be proven. Therefore, the evidence in this domain can only be rated as fair.

Finally, the evidence is incomplete for one important criterion: response to treatment. Only one study has been designed to examine the effect of depression treatments on cardiac risk reduction. This study (the ENRICHD trial¹³) was a treatment study of post-MI depression that found that cognitive-behavioral therapy did not have a significant impact on reducing recurrent cardiac events.

Based on the most stringent epidemiologic criteria, depression is almost, but not quite, a risk factor for CAD. However, depression is a minor risk factor for CAD, and may someday be considered a major risk factor. While the mechanisms by which depression may lead to CAD have not yet been established, the association between depression and subsequent CAD likely occurs via 2 pathways.

The first pathway is behavioral. Patients with depression have diminished self-care, possibly increasing other CAD risk factors such as smoking, poor diet/hyperlipidemia, diabetes, physical inactivity, and obesity.

The second pathway by which depression may lead to CAD is neuroendocrine. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and hyperactive sympathomedullary activity may result in elevated cytokine levels, platelet activation, and vascular damage, thereby contributing to CAD.⁸

TABLE 4

Depression as a risk factor for CAD: a “report card”⁸

· Acknowledgments ·

Portions of this article were presented at the Association of Medicine and Psychiatry Annual Meeting, San Diego, California, November 19, 2003.

Medical history

• No other significant medical or psychiatric problems
• Married, with 2 teenaged children
• Employed as an administrator for an insurance company (>50 hrs/wk)
• Drinks 3 to 4 alcoholic beverages/wk
• Does not smoke
• Enjoys fishing and other outdoor activities
• Both parents had hypertension; father also had peripheral vascular disease

Examination

• Patient is in no acute distress
• Approximately 30 pounds over ideal body weight
• Other vital signs are normal
• Normal retinal examination, no carotid bruits, and clear lungs. Cardiac rate and rhythm are regular; no abdominal bruits
• Laboratory studies reveal normal renal function; cholesterol, 184 mg/dL; low-density lipoprotein (LDL) cholesterol, 129 mg/dL; high-density lipoprotein (HDL) cholesterol, 55 mg/dL; triglycerides, 163 mg/dL. Electrocardiogram shows no current or prior evidence of ischemia or left-ventricular strain.

Additional information is required in a number of domains. Blood pressure readings should be repeated to make an accurate diagnosis of hypertension. While the patient may have hypertension, only a single blood pressure reading is elevated. The Joint National Committee on Blood Pressure (JNC 7) specifications¹ state that 2 such readings on different days are needed to confirm a diagnosis of hypertension. The symptoms of claudication should be investigated. Physical examination should focus on auscultation for bruits and on the examination of eye grounds to further investigate the possibility of peripheral vascular disease (PVD). In addition, a lipid profile should be drawn. While guidelines are conflicting, consideration should be given to assessing a fasting glucose, potassium, and renal function. Other tests, such as a C-reactive protein, are more controversial.²

The patient opts for drug treatment of his hypertension, and begins taking atenolol 50 mg/d (in addition to aspirin 81 mg/d). He is scheduled to follow-up by phone in 1 week to assure compliance and in 3 months in the office.

On further questioning he reports that he initially tolerated the beta-blocker without problem, but more recently has experienced low energy and poor sleep (with early morning awakening); he acknowledges decreases in libido, interest in pleasurable activities (eg, hunting, fishing), and his ability to concentrate. He has gained 5 to 10 pounds in the last month.

Although he denies feeling “sad,” he says his emotions seem “flat.” He denies having thoughts of suicide, increased anxiety, symptoms of hypomania, or psychotic symptoms. He describes a mild increase in stress at work, and he feels that the process of preparing for his son to go to college had been “a big burden.” He says there are no other stressors.

The patient’s alcohol use has not changed significantly, and he reports being compliant with his new medication regimen.

When his father died 6 years earlier, he experienced similar symptoms; at no other time have such symptoms occurred. The patient reports no other new physical symptoms, and his physical examination is essentially unchanged from the exam conducted 3 months earlier. His vital signs are normal, including a blood pressure of 128/84 mm Hg.

Consider the differential diagnosis of the patient’s abnormal mood and neurovegetative symptoms. In the primary care setting, the differential diagnosis of depressed mood is broad (Table 1 ), including medical disorders and a variety of psychiatric syndromes.

Medical conditions to consider include a medication induced side effect, hypothyroidism (a metabolic masquerader of depression), anemia, sleep disorder (eg, sleep apnea), and alcohol abuse. PVD should also be considered—his symptoms may be secondary to poor perfusion of the cerebral cortex.

TABLE 1

Partial differential diagnosis of depressed mood and neurovegetative symptoms

Psychiatrist’s comments

It is important to distinguish major depression from other, less severe depressive syndromes. In major depression, 5 out of 9 symptoms (including depressed mood or anhedonia) are present most of the day nearly every day for 2 weeks.

With adjustment disorder and so-called minor depression, symptoms are fewer or less persistent (Table 2).

This distinction is important, as antidepressants are effective for major depression, but they have not yet been shown effective for adjustment disorders or minor depression. Major depression is the “hypertension of mental illness in primary care”—common, often undiagnosed, and associated with poor outcomes. Therefore, accurate diagnosis and appropriate treatment for major depression are essential.

Given the possibility of a depressive syndrome, gather further information to determine the duration of ongoing symptoms, and obtain answers to a short questionnaire (eg, the Beck Depression Inventory [BDI]³ or the PHQ-9⁴). Elicit a family history of mood disorder, or personal history suggestive of thyroid dysfunction, a sleep disorder, or alcohol or drug abuse. Order a complete blood count (CBC) to evaluate for anemia, a thyroid-stimulating hormone (TSH) to evaluate for hypothyroidism, and, if indicated by history, a sleep study.

Beta-blockers and depression. The patient’s symptoms developed in the context of beta-blocker therapy. From the 1970s through the 1990s, the lore was that beta-blockers caused depression and should be avoided in patients with a history of depression. Because of this, many patients with myocardial infarction (MI) and congestive heart failure (CHF) have been denied treatment with beta-blockers when otherwise indicated.

Fortunately, a recent rigorous academic study of this issue was conducted by Ko and colleagues⁵ to rationally guide treatment. This study involved a meta-analysis of 15 randomized controlled trials of beta-blocker therapy in patients with MI, CHF, or hypertension; the authors found that beta-blockers were associated with a slight (though statistically significant) increase in fatigue and sexual dysfunction, and that their use was not associated with depressive symptoms. This is the best review to date of beta-blockers and depression, and it debunks the myth that beta-blockers cause depression—a myth that has prevented many post-MI patients from receiving much-needed beta-blocker therapy. In short, although idiosyncratic reactions are possible, it is unlikely the patient’s use of atenolol caused his apparent depressive symptoms.

TABLE 2

Major depression, minor depression, and adjustment disorder

Further primary care evaluation

The patient has no cold intolerance or other symptoms of thyroid dysfunction. He does report a long history of snoring, confirmed by his wife. However, he did not notice feeling more fatigued after starting atenolol.Nonetheless, you switch his antihypertensive medication from atenolol to hydrochlorothiazide. In addition, you order a CBC, serum chemistries, a thyroid panel, and a sleep study. The patient is told to return for a follow-up appointment in 2 weeks and to call before that if symptoms worsen.

In this situation, the evidence (depressive symptoms in the context of good blood-pressure control) was insufficient to justify a switch from a beta-blocker to hydrochlorothiazide. One could argue that the switch was reasonable regardless of his depressive symptoms; the most recent guidelines from JNC 7¹ indicate that thiazide diuretics are first-line therapy for hypertension in patients without CAD, and that beta-blockers are not the first-line agent in the patient’s clinical situation.

But discontinuing atenolol because of ongoing depressive symptoms is not supported. The patient may well need a beta-blocker in the future (eg, if he were to develop CAD). By prematurely concluding that the beta-blocker caused adverse effects, we may be denying him an important treatment down the road.

Option 1: 2-week drug holiday

If there was concern that the patient was having an idiosyncratic reaction to atenolol, or if he developed substantial fatigue or sexual dysfunction, a 2-week drug holiday could be conducted while carefully monitoring blood pressure and depressive symptoms. Atenolol could then be restarted to identify a temporal relationship between the symptoms and the medication.

Option 2: Treat for depression

Another option would be to treat the patient as if his symptoms represented depression. Exhibiting 4 of the necessary diagnostic criteria, the patient nearly qualifies for a diagnosis of current major depression. An antidepressant could be started, exercise could be prescribed, or a referral could be made for psychotherapy. However, again there is insufficient evidence that his subsyndromal depression will respond to standard treatments designed for major depressive disorder.

The patient returns as scheduled 2 weeks later. He has tolerated the change in blood pressure medications without difficulty, but he is experiencing persistent anhedonia, terminal insomnia, and low levels of concentration, energy, and libido. He has felt increasingly hopeless and worthless over the past 2 weeks, though he denies having thoughts of suicide. Results on CBC, serum chemistries, thyroid panel, and sleep study are all unremarkable.

The patient now clearly meets criteria for a major depressive episode. As a first step, he should be educated about depression. An excellent self-help book is Getting Your Life Back by Wright and Basco.⁶ The patient should be taught to monitor his symptoms with the BDI³ or the PHQ-9⁴ to better assess the severity of the current episode, to monitor changes in his symptoms, and to rapidly identify relapses.

Most physicians would start an antidepressant, unless the patient had significant objections. Other treatment options, alone or in concert with antidepressant treatment, include exercise or psychotherapy. The patient is an excellent candidate for exercise, given that he has 3 risk factors for CAD: hypertension, a sedentary lifestyle, and obesity (4, if you include depression). Exercising for at least 30 minutes, 2 to 3 times per week, would likely benefit his physical and mental health. In addition to its cardiac benefits, exercise 3 times weekly was found in at least one trial to be as effective as sertraline in treating major depression in outpatients.⁷

Choosing an antidepressant. A number of factors should be considered in choosing antidepressants, including efficacy, side effect profile, and cost. Table 3 outlines some of the main considerations in the choice of antidepressants for this patient. Note that tricyclic antidepressants are not listed, being contraindicated in CAD because of their tendency to contribute to arrhythmias in the post-MI period. In this patient’s case, mirtazapine should be avoided because of the possibility of weight gain; venlafaxine should be avoided because of hypertension. Sertraline would be an appropriate choice, given that it has been relatively well-studied in persons with CAD.

The patient begins treatment with fluoxetine (10 mg/d, which is then increased to 20 mg/d after several days). His depressive symptoms gradually diminish; he achieves a “50%” reduction of symptoms at follow-up visit 3 weeks later. Two months after fluoxetine was initiated, the patient is nearly euthymic, reporting only 2 depressive symptoms, and is again engaging in usual recreational activities.

TABLE 3

A comparison of antidepressants in the treatment of depressed patients in cardiac populations

Whether depression is a risk factor for CAD depends on how one defines a risk factor and whether one is discussing “major” or “minor” risk factors. At least 15 narrative reviews have been written on the relationship between depression and heart disease, but none has examined the epidemiologic evidence for depression as a major risk factor for CAD (Table 4).⁸

In looking at the 7 main epidemiologic criteria for a risk factor, depression does very well on 4: strength of association, consistency, dose-response effect, and predictability. Numerous studies have shown that depression is clearly and consistently associated with the development of CAD, and that clinical depression appears to predict CAD more robustly than does depressed mood alone.^9-12

On 2 of the criteria, specificity and biological plausibility, there is fair evidence for depression as a CAD risk factor. We do not yet know the relative importance of recurrent major depression, dysthymia, BDI scores of 10 or greater, or some other marker of depression as predictors of CAD.

Because mild depressive symptoms may predict CAD, it is unclear what levels of depression increase the risk of CAD and require intervention. Excellent work exists regarding the development of plausible mechanisms by which depression may lead to CAD; however, these mechanisms have yet to be proven. Therefore, the evidence in this domain can only be rated as fair.

Finally, the evidence is incomplete for one important criterion: response to treatment. Only one study has been designed to examine the effect of depression treatments on cardiac risk reduction. This study (the ENRICHD trial¹³) was a treatment study of post-MI depression that found that cognitive-behavioral therapy did not have a significant impact on reducing recurrent cardiac events.

Based on the most stringent epidemiologic criteria, depression is almost, but not quite, a risk factor for CAD. However, depression is a minor risk factor for CAD, and may someday be considered a major risk factor. While the mechanisms by which depression may lead to CAD have not yet been established, the association between depression and subsequent CAD likely occurs via 2 pathways.

The first pathway is behavioral. Patients with depression have diminished self-care, possibly increasing other CAD risk factors such as smoking, poor diet/hyperlipidemia, diabetes, physical inactivity, and obesity.

The second pathway by which depression may lead to CAD is neuroendocrine. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and hyperactive sympathomedullary activity may result in elevated cytokine levels, platelet activation, and vascular damage, thereby contributing to CAD.⁸

TABLE 4

Depression as a risk factor for CAD: a “report card”⁸

· Acknowledgments ·

Portions of this article were presented at the Association of Medicine and Psychiatry Annual Meeting, San Diego, California, November 19, 2003.

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.