Treatment of anxiety and depressive disorders in patients with cardiovascular disease

Safety

Concern surrounds the use of tricyclic antidepressants in patients with cardiovascular disease. This is based on adverse effects on contractility shown in animal studies, dysrhythmias and severe hypotension observed after overdose, and electrocardiographic studies that imply a theoretical risk of a pro-arrhythmic action similar to type I antiarrhythmic drugs.^w9 In contrast, epidemiological and clinical studies, although small, show no worsening of heart failure and no consistent excess of sudden death in normal usage and, if anything, a lower mortality from myocardial infarction than no treatment.^w10-12 Orthostatic hypotension can be a problem, and in one study almost half the patients with significant heart failure had to withdraw owing to this adverse effect.^w13 Nortriptyline may be less likely to cause large falls in blood pressure than other tricyclics.^w14 Concerns about older tricyclics persist and novel tricyclics and selective serotonin reuptake inhibitors might be preferred in patients with pre-existing cardiovascular disease owing to their lower risk potential.

Selective serotonin reuptake inhibitors present fewer concerns over cardiotoxicity as they lack anticholinergic effects, and reports of arrhythmias have been rare. In a double blind comparative study most patients with ischaemic heart disease prescribed the selective serotonin reuptake inhibitor paroxetine or nortriptyline achieved remission of depressive symptoms, but paroxetine was associated with significantly less cardiovascular side effects.12

Patients with cardiovascular disease are likely to be taking other drugs, notably antihypertensives, lipid lowering drugs, and antiarrhythmic drugs, so prescribing selective serotonin reuptake inhibitors is of concern because of possible pharmacokinetic interactions. Many drugs in these classes are metabolised by the cytochrome P-450 enzymes CYP2D6 and CYP3A4. The selective serotonin reuptake inhibitors paroxetine and fluoxetine are potent CYP2D6 inhibitors, whereas fluoxetine and nefazodone are inhibitors of CYP3A4, so these agents can increase plasma concentrations of cardiovascular drugs such as propanolol, metoprolol, flecainide, and encainide metabolised by CYP2D6, and simvastatin, amlodipine, nifedipine, diltiazem, and amiodarone metabolised by CYP3A4, with the potential for more frequent side effects and toxicity. Adverse effects associated with metoprolol occurred five times more frequently in patients with genetically determined low CYP2D6 activity showing that the activity of this enzyme system is clinically important.13 Sertraline, citalopram, and tricyclic agents have considerably less potential to inhibit metabolising enzymes than do paroxetine and fluoxetine.^w15

The serotonin and noradrenaline reuptake inhibitor venlafaxine may be used in patients with coronary heart disease. Caution is needed at high doses ( 300 mg daily) as the drug shows a dose dependent increase in blood pressure averaging 7 mm Hg diastolic at the highest dose.^w16

Efficacy for psychiatric morbidity in patients with cardiovascular disease

Until recently there has been a limited evidence base for the efficacy of antidepressants in treating psychiatric morbidity in patients with cardiovascular problems. Evidence now exists for most selective serotonin reuptake inhibitors in five double blind comparative or placebo controlled studies of patients with myocardial infarction, ischaemic heart disease, or hypertension (table).12 14^–17 In one placebo controlled trial, fluoxetine reduced depression in patients who had had myocardial infarction.16 Paradoxically only in patients with major depression of mild severity was the treatment effect of fluoxetine significantly greater than that of placebo.

The largest study to date in this area is the SADHART (sertraline antidepressant heart attack randomised trial), a randomised, double blind placebo controlled trial of 369 patients within 30 days of admission to hospital for acute myocardial infarction or unstable angina.14 The participants had depression at study entry and were assigned to sertraline daily (50-200 mg) or placebo for 24 weeks. Sertraline was as safe as placebo, with no difference in any cardiac safety parameter, but was significantly more effective in treating patients with severe depression and those who had had previous episodes, and produced significantly greater improvement in patient rated global impression scores in the whole sample.

Five double blind trials have studied selective serotonin reuptake inhibitors in depressed patients with cerebrovascular disease (see table).18^–22 In three, fluoxetine and citalopram were more effective than placebo.19 21 22 In the fourth, fluoxetine was more efficacious than placebo but only in the open label follow up phase.18 In the fifth, nortriptyline was superior to fluoxetine and placebo in remission of depressive symptoms.20 In a prophylactic study of 137 patients after stroke, those given sertraline were significantly less likely to experience subsequent depression than those given placebo.23

Impact of antidepressant treatment on cardiovascular disease

In a case-control study of 5336 patients use of fluoxetine, sertraline, or paroxetine conferred a significantly reduced odds ratio of 0.59 for myocardial infarction.8

In the sertraline antidepressant heart attack randomised trial, there was a trend for fewer serious cardiac events in the sertraline group (22.4%v 14.5%), which might suggest a cardioprotective effect in patients with psychiatric morbidity.14 In an open study, fluoxetine was more effective in lowering blood pressure than the antihypertensive agent moxonidine in hypertensive patients with comorbid panic disorder.24 In contrast, tricyclic agents may increase cardiovascular risk. After adjustment for confounding factors in one observational study, patients who had taken dothiepin were 67% more likely to develop ischaemic heart disease than those who had not used antidepressants.^w17 In a study of depression after stroke, however, both nortriptyline and fluoxetine were associated with significantly lower overall mortality than placebo when patients were followed up at nine years.25

Non-pharmacological treatments

Substantial evidence supports the use of cognitive behaviour therapy for depression and anxiety disorders in the general population. The technique has also been successful in treating chest pain in patients with negative results on angiography and other cardiac investigations.^w18 A recent large study in patients with depression and low perceived social support enrolled within 28 days of myocardial infarction reported that cognitive behaviour therapy improved depression and social isolation but did not reduce subsequent cardiac events.26 Antidepressants were associated with significantly lower mortality or non-fatal myocardial infarction.

Conclusions

Physicians need to recognise psychiatric morbidity, in particular anxiety and depression in patients with coronary heart disease and hypertension. Associations seem to have a biological basis and left untreated psychiatric disorders may worsen the prognosis of patients with cardiovascular problems.

Depression, panic disorder, and generalised anxiety disorder may all be treated effectively with antidepressant drugs. Selective serotonin reuptake inhibitors are safe in patients with cardiovascular disease, but indirect evidence suggests that classic tricyclic agents are best avoided. With recent evidence suggesting that selective serotonin reuptake inhibitors may improve survival after myocardial infarction in patients with depression, diagnosis and treatment of psychiatric morbidity should be incorporated into the clinical management of hypertension and coronary heart disease.

Web references w1-w18 are on bmj.com