As with other medical disorders, effective treatment of major psychiatric illnesses such as major depression and panic disorder, respectively, require patient access to informed health care practioners, accurate diagnosis, affordable treatment, and safe, effective treatment modalities. Factors hampering well-conducted psychiatric (psychotherapeutic or psychopharmacologic and somatic) treatment include patient reluctance, social stigma regarding psychiatric treatment, managed care restrictions, and a dearth of psychiatrists and psychologists, particularly in rural areas. However, the evidence of the adverse impact of affective and anxiety disorders on relatively young and physically healthy individuals as well as medically ill patients heralds an opportunity and an accompanying incentive to prevent or limit the personal suffering, economic cost, and social disability associated with mental disorders. Although the safety and efficacy of anxiolytic and antidepressant treatment in patients with cardiovascular disease remain to be extensively established in randomized clinical trials, these agents, particularly the newly introduced ones, are prescribed routinely to patients with heart disease. This seems appropriate given the drastic reduction in psychosocial function associated with anxiety or depressive disorders and the extant literature demonstrating the safety and efficacy of these psychotropic agents in generally healthy populations, existing data from psychopharmacologic treatment of medically ill patients, and the paucity of psychiatric practitioners available to patients with severe CVD.
Many heart patients believe that their persistent “worry,”“lack of enjoyment of life,” or “loss of interest” constitutes an understandable (and untreatable) condition. However, given the prevalence of major depression in patients with heart disease, the astute clinician’s index of suspicion should always be heightened. Third-party information (particularly from a spouse or other caregiver) is often more revealing of the true extent of a patient’s symptoms (e.g., irritability, social isolation, or listlessness), including attempts to “self-medicate” through abuse of alcohol, prescription medication, or illicit substances. A thorough evaluation of anxiety, panic attacks (if any), and depressive symptoms should be performed, including queries regarding feelings of pessimism, hopelessness, and the wish not to continue living. While the preferences of cardiac patients, as with any medical disorder, should be respected, cardiac patients and their families should always be gently apprised of the risks of untreated depression (CVD-related morbidity and mortality) versus the options of psychotherapeutic and/or psychopharmacologic treatment. Consultation with a knowledgeable mental health provider can assist in the discrimination of depressive disorders from complicated or pathologic grief, delirium, ascertainment of coexisting anxiety disorders (such as generalized anxiety disorder or social phobia), detection of intoxication or withdrawal syndromes, and appropriate emotional reactions.
The efficacy (and safety) of psychotherapeutic and psychopharmacologic treatment of post-MI patients with comorbid major depression or any of the anxiety disorders is an area undergoing intense investigation. In two large-scale, randomized, multicenter studies, the Montreal Heart Attack Readjustment Trial (M-HART) (n= 1376) and the Enhancing Recovering in Coronary Heart Disease (ENRICHD) Patients Study (n= 2481), sponsored by the National Heart, Lung, and Blood Institute, the psychosocial interventions were not superior to routine care in reducing cardiac events or prolonging survival. Whereas the individual and group cognitive behavior psychotherapy of ENRICHD was effective in reducing depressive symptoms (57 percent reduction in depression in the treatment arm versus 47 percent reduction in the control group) and improving social support (27 percent improvement in social support in the treatment group compared with an 18 percent improvement in the usual care group), the home-based telephone monitoring and psychosocial nursing intervention of M-HART appeared detrimental to women with depression or lack of social support. Older, smaller studies have reported successful psychological interventions with post-MI patients targeted primarily to diminish “psychological distress” or alter type A personality traits.
With the introduction of fluoxetine (Prozac) in the United States and citalopram (Celexa) in Europe in 1989, over a decade of clinical information has been gleaned regarding the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. Furthermore, during the 1990s, the SSRIs and more recently the 5-HT and NE reuptake inhibitor (SSNRI) venlafaxine superseded the benzodiazepines as the first-line treatment of choice for anxiety disorders. These newer antidepressants provide significant reduction of anxiety symptoms in approximately 60 percent of medically healthy patients without having a potential for addiction. SSRIs and SSNRIs have been approved by U.S. Food and Drug Agency for the treatment of panic disorder (paroxetine, Paxil, and sertraline, Zoloft), social anxiety disorder (social phobia, paroxetine), obsessive-compulsive disorder (paroxetine, sertraline, fluoxetine and fluvoxamine, Luvox), and generalized anxiety disorder (paroxetine, venlafaxine, Effexor) (Table 91–7). It is important to note that the SSRIs, although they all are potent 5-HT reuptake inhibitors, also exert unique effects on other neurotransmitter systems. Thus, paroxetine is a very potent inhibitor of NE reuptake, whereas sertraline is a potent inhibitor of dopamine (DA) reuptake. The clinical sequelae of these pharmacologic properties remain obscure.
During the time (often 6 to 8 weeks) before the onset of an antidepressant’s anxiolytic effect, benzodiazepines such as lorazepam, alprazolam, and clonazepam may be utilized. These agents are rapidly effective but should be used only for short-term treatment (6- to 8-week duration) of disabling anxiety symptoms. Benzodiazepines are sedating, produce gait instability, impair memory, may induce behavioral disinhibition, are ineffective in the treatment of coexisting depressive syndromes, and place patients at risk of physiologic (and psychologic) dependence.
The use of tricyclic and structurally related antidepressants should be limited in patients with CVD because of the myriad of side effects of these drugs on the cardiovascular system, including orthostatic hypotension, tachycardia, reduction in HRV, and slowing of intraventricular conduction (as a result of quinidine-like effects; see Table 91–7). These antidepressants should never be prescribed for patients with bifascicular and left fascicular block. As might be expected, examination of prescription databases has revealed an increased risk of MI with administration of TCAs in comparison to SSRIs and atypical antidepressants. Monoamine oxidase inhibitors and trazodone are generally free of effects on cardiac conduction but, like the TCAs, may cause postural hypotension. Because of their fewer potential adverse effects on the cardiovascular system and the lack of lethality from an overdose, pharmacotherapeutic treatment with SSRIs, the SSNRI venlafaxine, or other “atypical” antidepressants (such as bupropion, nefazodone, and mirtazapine) may offer significant advantages in depressed or anxious patients with CVD.
The only known cardiac effect of SSRIs is severe sinus node slowing, which to date has been reported in only a few cases. 5-HT has been implicated in both platelet aggregation and coronary artery vasoconstriction; the SSRIs, which are widely used to treat major depression, produce effects on platelet function. The case reports of altered hemostasis with SSRI treatment, combined with findings of in vivo clinical studies indicate that SSRIs reduce platelet activation in patients with major depression, without and with, CAD. Though potentially advantageous in patients with heightened platelet activation (e.g., smokers), retrospective examinations of large-scale medication databases have revealed no such cardioprotective effective or even an increased risk of upper gastrointestinal bleeding with SSRI antidepressants, especially when coprescribed with nonsteroidal anti-inflammatory drugs. Conversely, other investigators have not documented an increased risk of upper gastrointestinal bleeding in SSRI-treated patients, or a propensity for intracranial hemorrage.
Because of inhibition of some cytochrome P450 isoenzymes, certain SSRIs may alter the metabolism of medications often used in patients with heart disease. The SSRIs that inhibit the P450 2D6 isoenzyme (fluoxetine, paroxetine, fluvoxamine, and higher doses of sertraline) should be used with caution in patients receiving medications metabolized by the P450 2D6 (e.g., lipophilic beta blockers and type 1C antiarrhythmics: flecainide, mexiletine, propafenone). SSRIs that inhibit the P450 3A4 isoenzyme (fluoxetine, fluvoxamine, nefazodone) may increase the plasma concentrations of calcium channel blockers and warfarin. Although the antidepressants venlafaxine, bupropion, citalopram, and mirtazapine exhibit minimal hepatic P450 enzyme inhibition, their safety remains to be established in patients with CVD who have comorbid depression or anxiety disorders.
After short-term treatment with buproprion, fluoxetine, paroxetine, fluvoxamine, or paroxetine, depressed patients exhibit no changes in HRV. A randomized, double-blind, multicenter study compared the efficacy of nortriptyline and paroxetine in depressed patients with IHD. Both antidepressants were effective in the treatment of depression, but not surprisingly, there were more dropouts because of side effects and more cardiac-related effects with the TCA. The SADHART study, a randomized, multicenter, double-blind trial of sertraline (n= 186) versus placebo (n= 183) attempted to determine the safety and efficacy of this SSRI in the treatment of patients hospitalized for unstable angina or index MI. Sertraline exerted no significant effect upon LVEF, in comparison to placebo, or did it exact increases in ventricular premature complex runs or QTc interval, or other cardiac parameters. Moreover, in comparison to placebo-treated patients, depressed individuals with at least one prior episode of depression exhibited a significant improvement in depressive symptoms (72 vs 51 percent; p= .003), especially those who exhibited depressive symptoms of moderate or greater severity (78 vs 45 percent; p= .001). The SADHART sertraline efficacy data are generally congruent with efficacy of other oral antidepressants in “medically healthy” patients with major depression. That is, any of the available oral antidepressants will usually produce a therapeutic response (an improvement in depressive symptoms by 50 percent or more, in comparison to pretreatment severity of depressive symptoms) in 60 to 70 percent of depressed patients, provided that the antidepressant is administered in sufficient dosage over a treatment duration of 5 to 6 weeks. While there is limited, case-control evidence suggesting a role for SSRIs in decreasing the likelihood of MI in smokers, there are as yet no prospective, randomized, controlled trials demonstrating that treatment with SSRIs diminishes future cardiac morbidity or mortality.
Another somatic treatment modality, electroconvulsive therapy (ECT), is effective in up to 80 percent of patients with either unipolar or bipolar depression. ECT has several advantages over medication management of depression. The time to response for ECT is 1 to 3 weeks compared to the 4 to 8 weeks needed for antidepressants, and ECT is clearly the most effective treatment for depression. The most recent trial of ECT in middle-aged and older adults with severe treatment-resistant depression found that more than 80 percent had complete remission of their depressive symptoms. A comparable group of patients treated with antidepressants would be expected to have a remission rate of no better than 30 to 40 percent.
ECT is the treatment of choice in depressed patients who are severely ill (e.g., at nutritional risk from severe calorie loss or dehydration) and require a rapid clinical response. ECT also should be considered for patients who have experienced a previous positive response to ECT, do not respond to oral antidepressants, or cannot tolerate the associated side effects of antidepressants. Patient variables associated with a positive response include increasing age and the presence of psychotic (e.g., hallucinations and delusions) and catatonic symptoms.
The morbidity and mortality associated with ECT have decreased dramatically over the past 60 years. The introduction of curare and, later succinylcholine, decreased the incidence of orthopedic complications from almost 20 percent of cases to being a rare complication. In fact, patients recovering from such orthopedic surgery as that involving the hip can safely be given ECT. Complications related to cognitive dysfunction, such as delirium and amnesia, also have been decreased through the use of brief pulse (versus sine wave) and unilateral (versus bilateral) ECT.
ECT produces a seizure by providing a brief pulse (approximately 1 to 2 s in duration) of electrical charge over the scalp in the area of the right parietal lobe (right unilateral ECT) or over both temples (bilateral ECT). This pulse elicits a generalized convulsive seizure that lasts approximately 30 to 60 s. The patient is anesthetized during the procedure with a short-acting barbiturate (e.g., methohexital), propofol, or etomidate and paralyzed with a muscle relaxant such as succinylcholine. Respirations are controlled by masked ventilation, and intubation is not required unless there have been recurrent episodes of aspiration.
Structural brain studies using magnetic resonance images have shown no evidence of brain damage secondary to ECT. Moreover, most studies of memory problems associated with ECT have reported that patients have transient amnesia. Memory loss is increased with the use of bilateral rather than unilateral ECT and is directly correlated with the number of treatments administered and higher stimulus intensity. Evidence for amnesia should be monitored carefully during ECT as some patients may experience permanent retrograde memory loss. However, more commonly, anterograde and retrograde memory problems occur in a temporal gradient around the time of ECT and clear completely within 6 months of the ECT treatment period.
ECT-related delirium is relatively rare, however; the risk for delirium increases in patients who are older, have comorbid neurologic disorders with associated brain pathology (e.g., Alzheimer’s disease, Parkinson’s disease, or periventricular white matter changes on magnetic resonance imaging) and/or are receiving more than 8 to 10 treatments. The delirium usually clears within 24 h and can be minimized by changing the treatment parameters (e.g., using unilateral rather than bilateral electrode placement) and treating 2 rather than 3 times a week.
Until recently, the cardiac complications from ECT resulted in the most serious adverse events. As recently as the 1980s, deaths from ECT were estimated to be approximately 1 per 10,000 treatments (most patients receive 6 to 10 treatments per ECT trial), primarily as a result of cardiac complications. Two major cardiac complications occur in relation to the ECT stimulus: an initial asystole secondary to vagal nerve stimulation followed closely by the release of EPI with tachycardia and hypertension. Although the patient is paralyzed, the ECT electrode that conducts up to 100 Joules of energy to stimulate the seizure also produces a direct stimulus of the masseter muscles (a bite block is kept in place during the treatments) and the vagus nerve. The stimulation of the vagus nerve can subsequently cause asystole. Within seconds of vagal stimulation, an adrenergic discharge related to the onset of a generalized seizure causes the release of EPI with tachycardia, hypertension, and the potential for myocardial ischemia or arrhythmias. The tachycardia is relatively brief (1 to 2 min).
Certain clinical situations increase the risk of complications from a course of ECT (i.e., diseases that affect the CNS and/or the cardiothrombovascular system): a cerebral vascular accident (CVA) during the previous 6 months, any illness that increases intracranial pressure (e.g., brain tumor), medical disorders that disrupt the blood-brain barrier (e.g., meningitis), a cerebral or aortic aneurysm, MI, severe valvular heart disease, a high-grade atrioventricular block, symptomatic ventricular arrhythmias, supraventricular arrhythmias with uncontrolled ventricular rate, and coagulation or bleeding disorders. Implanted cardiac pacemakers and defibrillators are usually not problematic during ECT. Some practitioners choose to convert a demand pacemaker to a fixed mode, and an electrophysiologist should be consulted to determine whether the defibrillator’s function should be inhibited during each ECT treatment. Electroconvulsive therapy also is tolerated by cardiac transplant patients who have normal cardiac function.
Electroconvulsive therapy can be conceptualized as a cardiac stress test with peak heart rates of 120 to 140 BPM; however, because of the general anesthesia, the patient cannot report symptoms such as chest pain, and the seizure stimulating the tachycardia cannot be terminated abruptly. Therefore, the pre-ECT workup should include a complete review of systems and a screen for exercise intolerance, angina, evidence of congestive heart failure (patients will receive approximately 1 L of fluid per ECT treatment) or diabetes, extent of smoking history, cholesterol level, and other cardiac risk factors. The basic pre-ECT screening includes measurement of serum electrolytes (with particular attention to hydration status and potassium) and hemoglobin and the obtaining of an electrocardiogram (ECG). Chest x-rays are obtained in case of evidence of CHF or pulmonary disease. Patients with a history of back pain are evaluated with spine films; neuroimaging is used to determine whether there has been a recent CVA or increased intracranial pressure in patients with neurologic dysfunction. Although “beta blockers” are used during ECT treatment (see later), cardiovascular screening should determine whether the patient can tolerate transient tachycardia and hypertension. Patients with evidence for CAD can be screened with a relatively inexpensive treadmill test establishing a peak heart rate of at least 120. ECT patients with severe depression, however, are typically sedentary, elderly, and often unable to tolerate even minimal physical activity. Many would be unable to complete a treadmill test, and more expensive tests such as a persantine thallium stress test can be substituted when appropriate.
Modern ECT suites are equipped with continuous ECG and blood pressure and heart rate monitors as well as pulse oximetry and an electroencephalograph to record seizure activity. Patients should continue their pulmonary (except theophylline) and cardiac (except lidocaine) medications during a course of ECT treatment. Theophylline and lidocaine are discontinued because of prolongation and reduction of seizure duration, respectively. As a result of the increase in intraocular pressure during an ECT-induced seizure, glaucoma medications generally are continued, except for acetylcholinesterases. Hypoglycemic agents should not be administered the morning of ECT to prevent hypoglycemia in diabetic patients. Patients must not ingest food or fluids before ECT treatments but may receive intravenous fluids as tolerated. In addition to usual ECT medications (methohexital 1 mg/kg and succinylcholine 0.75 to 1.50 mg/kg), patients with hypertension, CAD, valvular heart disease, and CHF routinely receive prophylactic medication to prevent cardiac complications from the transient hypertension and tachycardia induced by ECT. Such a “cardiac-modified” ECT protocol should be utilized for elderly patients and those with cardiac disease. Usually either of two beta blockers, labetalol or esmolol, is utilized to reduce maximal heart rate, mean arterial pressure, and arrhythmia frequency during ECT. Labetalol, a selective alpha1- and nonselective ß-adrenergic receptor blocker, with an elimination half-life of 5 to 8 h, may induce significant hypotension. Esmolol (beta1 selective at the usual doses, rapid onset, and an elimination half-life of 9 min) may replace labetalol if labetalol induces prolonged bradycardia and hypotension. Esmolol, however, has been associated with shortened seizure duration during ECT. If elderly patients pretreated with a beta blocker continue to exhibit transient increases in blood pressure, a calcium channel blocker may be added. Nicardipine has replaced nifedipine as the calcium channel blocker of choice because nicardepine may be administered intravenously and has a shorter duration of action. The ECT protocol also involves adequate hydration before ECT, discontinuation of psychotropic medication whenever possible, and provision of anticholinergic medication (0.4 to 0.8 mg intravenous atropine or 0.2 mg of glycopyrrolate) to decrease oropharyngeal secretions and prevent bradycardias whenever beta blockers are used. Caffeine sodium benzoate (usual dose = 120 to 140 mg) may be administered intravenously prior to ECT to maintain adequate seizure duration and does not appear to significantly affect peak pulse rates during ECT. Continuous blood pressure monitoring and ECG monitoring should be performed during all treatments, along with monitoring for shortness of breath or chest pain.
The third most common cardiac complication is orthostatic hypotension, which usually occurs in the recovery room, particularly in elderly debilitated patients and patients with medical conditions associated with autonomic dysfunction (e.g., Parkinson’s disease). As was noted earlier, consideration should be given to the utilization of shorter-acting beta blockers that have less alpha-adrenoreceptor blockade (esmolol for labetalol) and/or shorter-acting calcium channel blockers (nicardepine for nifedipine). After each ECT treatment, patients recover for over an hour in a setting similar to an outpatient surgical suite. Patients remain on a cardiac monitor with intravenous fluids and supplemental oxygen provided until they are oriented and exhibit no orthostatic hypotension (approximately 20 to 30 min). They are then dressed and asked to be seated upright in a chair until they are fully alert and able to ingest fluids orally (approximately 20 to 30 min in duration).
In summary, the magnitude of the risks associated with ECT are approximately equivalent to those of general anesthesia. The incidence of delirium during ECT can be reduced to less than 5 percent in elderly patients through the administration of twice-weekly ECT treatments and the use of unilateral electrode placement on the right temporal area in patients at risk (patients with structural brain changes, concomitant medical illness, Alzheimer’s disease, Parkinson’s disease, advanced age, and concomitant administration of psychotropic medications). Cardiac complications are not uncommon with ECT but are reduced significantly with a cardiac ECT protocol. Although generally a safe and effective treatment, ECT in elderly patients with cardiovascular disease requires a multispecialty coordinated effort among a specially trained ECT-nursing service, psychiatrist, anesthesiologist, and cardiologist.
Depression and Comorbid Medical Illness
Depression and Cardiovascular Disease: Clinical Samples
Anxiety Disorders and Cardiovascular Disease
Diminished Heart Rate Variability
Hypothalamic - Pituitary - Adrenocortical and Sympathomedullary Hyperactivity
Alterations in Platelet Receptors and/or Reactivity
Increased Secretion of Proinflammatory Cytokines
Pathophysiology of Anxiety
Treatment of Major Depression and Anxiety Disorders in Patients with Cardiovascular Disease
Effects of Mood and Anxiety Disorders: Future Directions for Research
Revision date: July 3, 2011
Last revised: by Andrew G. Epstein, M.D.