amoxapine, maprotiline, and trazodone), tend to have a more favorable profile;20 however, prescrib- ing is generally a "mix and match" situation. For ex- ample ...
Behavioral Aspects of Heart Disease
Francisco Fernandez, MD
Depression and Its Treatment in Cardiac Patients In general medical-surgical hospital services, depression is the most common reason for seeking psychiatric consultation in behalf of patients with cardiovascular disease. The nontreatment of depression or the use of a psychotropic agent mismatched to a patient's particular cardiac condition or individual sensitivities has considerable negative impact. Therefore, a systematic approach should be used in the differential diagnosis of depression in cardiac patients, to eliminate other psychiatric disorders and to assure the correct treatment strategy. Physicians can develop an appropriate rationale for the use of a psychopharmacologic regimen in cardiovascular settings through recognition of the diagnostic criteria for depression and through comprehensive knowledge of the pharmacologic properties and possible cardiovascular effects of these vital treatments. Standard and alternative pharmacotherapies for depression in cardiac patients are reviewed. (Texas Heart Institute Journal 1993;20:188-97)
epression, whether alone or in company with cardiovascular disease, is often seen by nonpsychiatrists. Frequently it remains untreated. In cardiology, as many as 88% of patients recovering during the acute period after myocardial infarction report symptoms of mixed anxiety and depressive states on self-report instruments.' Yet, psychiatric consultation is too often reserved for patients whose episodes of depression are so severe that they warrant specialized pharmacologic intervention or other somatic therapy, such as electroconvulsive treatments. Depressive symptoms frequently have an adverse effect on recovery after infarction2'3 or post-cardiac surgery.4 Because many physicians still misdiagnose depression or under-utilize effective biologic treatments, this article provides a guide to diagnosing depression and a rationale for the use of various antidepressant medications within the context of cardiovascular disease. D
Key words: Antidepressive
agents/adverse effects! therapeutic use; coronary disease/psychology; depressive disorder/diagnosis/drug
therapy/psychology
From: The Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Psychiatric Consultation Service, Department of Internal Medicine, St. Luke's Episcopal Hospital; and the Texas Heart Institute; Houston, Texas
Section editors: Francisco Fernandez, MD Virendra S. Mathur, MD Address for reprints: Francisco Fernandez, MD, MC 2-199, St. Luke's Episcopal Hospital, PO. Box 20269, Houston, TX 77225-0269 188
Historical Perspective Depression is often considered to be the major psychiatric complication of cardiovascular disease. Recent surveys have indicated that presumed depression is one of the most common reasons for psychiatric referral in coronary care units5 (2nd only to anxiety) and that anywhere between 18% to 44% of cardiac patients suffer from a depression severe enough to warrant psychiatric intervention.2'3'6 In fact, psychosocial correlates of morbidity and mortality in cardiovascular disease reveal that depression is one of the best predictors of significant recurrent complications (e.g., re-infarction, need for angioplasty or surgery, or death),23 of poor adherence to lifestyle and rehabilitative strategies,7 and of poor medical compliance.8 Conversely, a review of death rates from cardiac dysfunction among depressed patients with no underlying cardiac disease indicates similar serious medical complications of depression.9"10 Among these patients, those who were receiving active and optimal medical treatment for their depression had a significantly lower mortality rate from myocardial infarction than did those who received inadequate or suboptimal medication for their depressive disorders.9 Therefore, untreated and undertreated depressed patients have a higher than expected rate of sudden cardiac death, specifically from myocardial infarction. Other investigators" have reported that depressed patients may be at significantly greater risk for sudden death from cardiac arrhythmias secondary to decreased parasympathetic tone that independently increases vulnerability to ventricular fibrillation (for additional information, see the contribution by A.M. Davis and B. Natelson in this
Depression and Its Treatment in Cardiac Patients
Volume 20, Number 3, 1993
issue). Regardless of the mechanisms through which depression affects cardiovascular physiology, the bulk of the evidence suggests that morbidity and mortality from heart disease increase within the context of depression, whether in the presence or absence of preexisting cardiovascular disease.
Diagnosing Depression Depression is a concept that easily generates confusion in most physicians. This may be because the term "depression" has been used loosely to describe a wide spectrum of behaviors, ranging from a mild and transient mood disturbance (such as sadness in reaction to life events, or uncomplicated bereavement) to a major affective disorder. Making the diagnosis of depression in the context of cardiovascular disease presents obvious difficulties. For instance, it is uncommon to find a cardiac patient who is not suffering from 1 or more of the somatic symptoms that overlap with depression. Consequently, many investigators12"13 have advocated relying on indicators of cognitive and psychological symptoms of depression, as opposed to somatic signs and symptoms; but there is no evidence to suggest that the latter should not be used as well.'1314 When the diagnosis of depression is made according to the nomenclature set forth in the Diagnostic and Statistical Manual ofMental Disorders, 3rd Edition Revised, of the American Psychiatric Association (DSM-III-R),'5 the prevalence of clinically significant depression among cardiac patients is 18% to 44%,236 which is a rate not very different from that reported in other medically ill populations.'4 Unfortunately, the significance of these findings is often overlooked because of nonchalance regarding depression in cardiac patients (e.g., "wouldn't you be depressed if you'd had a heart attack or bypass surgery?"). This misconception often leads to misdiagnosis or undertreatment and underscores the need for reliance on explicit and reliable diagnostic criteria, so that true depression (i.e., the syndrome, not the symptom) can be recognized and readily treated in cardiac patients. Crteria for Depression. The DSM-III-R diagnostic criteria for major depression'5 include dysphoric mood and loss of interest or pleasure in usual activities that is prominent, pervasive, and persistent. At least 4 of the following symptoms must also be present: significantly decreased or increased appetite, or a weight loss or gain (amounting to 1 pound per week or 10 pounds per year); sleep disturbance (too much sleep or too little); loss of energy, fatigability, or tiredness; psychomotor agitation or retardation; loss of interest or pleasure in usual activities, or decreased sexual drive; feelings of self-reproach or guilt (along with feelings of hopelessness, helplessness, and worthlessness); decreased ability to conTexas Hearl Institutejournal
centrate (indecisiveness); and recurrent thoughts of death or of the wish to be dead, including death by suicide. The duration of these symptoms must be at least 2 weeks, and the symptoms must not be secondary to either an organic mental disorder or schizophrenia. Given current trends toward brief hospitalization for uncomplicated myocardial infarction and coronary artery bypass grafting, patients who have exhibited depressive signs and symptoms will often require careful follow-up observation on an outpatient basis for approximately 2 months, in order to make a definitive diagnosis of a mood disorder. When using these criteria with cardiac patients, it is best to conceptualize depression as an acute illness superimposed on a more chronic one.* This is not a novel idea to those who subscribe to the medical model in psychiatry. An example would be a subacute bacterial endocarditis (SBE) as a complication of rheumatic heart disease. The acute illness (i.e., SBE) is the focus of attention and the one that requires immediate attention. Yet, reluctance to apply this analogy to depression typically occurs in the clinical setting, where health professionals often insist that "depression" is an appropriate reaction to a cardiovascular event. Others argue that one cannot apply the same criteria to the diagnosis of depression in a seriously disabled patient (such as a patient with end-stage heart disease, awaiting transplant) that one would apply to a physically healthy psychiatric patient.12 Because the somatic symptoms of major depression, such as appetite disturbance, weight loss, insomnia, impaired cognition, and loss of energy are attributed to the underlying cardiac disease rather than to the depressive illness, clinicians might exclude these patients from antidepressant treatment, even though their symptoms meet the full criteria for major depression. This concern is as relevant for those engaged in research as for clinicians who are immersed in the differential diagnostic and therapeutic process. However, we advocate the use of an inclusive"3 rather than an exclusive approach in the clinical evaluation of the depressed cardiac patient. By "inclusive" we mean that any pertinent symptoms of depression (regardless of cause or presumed cause) must be counted toward "ruling in" rather than "ruling out" the diagnosis of major depression. The drawback of the few false positive diagnoses that could result from this approach would be offset by the benefits of accurately diagnosing those patients most in need of treatment, who might otherwise suffer significant morbidity and mortality due to an undiagnosed true depression. The following clinical guidelines'6 should also be considered in the evaluation of depressed cardiac patients: *Murray GB. Personal communication, September 1983.
Depression and Its Treatment in Cardiac Patients
189
1) Are the overlapping somatic signs and symptoms of depression judged to be in excess of those effects typically associated with the underlying disease? If so, have all attempts to correct the possible underlying abnormalities of these symptoms been exhausted? When all the correctables have been clinically pursued and treated, the residual signs and symptoms should be counted toward making the diagnosis of major depression. 2) Are there signs and symptoms judged to be psychological (e.g., excessive self-reproach, worthlessness, or suicidal ideation) that are not specifically related to the underlying cardiovascular disease? If so, they should be applied in making the diagnosis of major depression. 3) Are there few or no areas of key interest to the patient (including sex) that bring about affective brightening in the interview? If not, and the person sustains a relatively flat or blunted interpersonal style, the diagnosis of major depression should be considered. 4) Is cognition impaired? Is the patient unable to pay attention and concentrate? Is he or she unable to comprehend written materials and to follow commands, whether simple or complex? If so, major depression should be considered and a mental status examination should be mandatory, to rule out the effects of medications and the possibility of encephalopathy masquerading as a depressive illness but in fact secondary to another medical condition-particularly in criti-
cally ill or hospitalized patients (see Tables IA and IB). Unfortunately, there are currently no reliable laboratory examinations that can be used to substantiate the diagnosis of major depression. Neuroendocrine markers such as the dexamethasone suppression test17 or the thyroid-releasing hormone stimulation test,'8 which reveal the disordered function of major depression in relatively homogeneous populations, often result in false-positive tests in medically ill patients. Therefore, their use in cardiac patients should not be advocated. Likewise, other biologic markers,18 such as electrophysiologic studies (e.g., shortened REM latency), neuroimaging studies (e.g., single photon emission computed tomography scanning of the brain), and platelet [3H1-imipramine binding,19 cannot be interpreted unambiguously in the cardiac patient. When the diagnostic criteria for the syndrome of major depression are not met, the clinician should continue to assess the patient's symptom complex for subsyndromal states.14"6 Depressive symptoms may also be the consequence of a psychological reaction to the cardiac disease. The differential diagnosis must consider the presence of states such as despondency and demoralization. The patient may also exhibit uncomplicated bereavement, which is a normal psychological response to the actual or perceived loss of function or lifestyle. A more serious and pervasive psychological response to such a loss is the inability or refusal to accept the usual limita-
TABLE IA. Common Medical Conditions that Masquerade as Depression Cardiovascular
Autoimmune
Others
Congestive heart failure Myocardial infarction Cardiac arrhythmias Hyperlipidemia
Systemic lupus erythematosus
Infectious diseases Malnutrition Metabolic abnormalities Anemias Deficiency states Malignancies Pulmonary embolus Pulmonary insufficiency Pancreatic diseases Chronic pain syndrome Personality disorders
Central Nervous System Cerebral anoxia Cerebrovascular accident Meningiomas Subdural hematoma Multiple sclerosis Huntington's chorea Parkinson's disease Alzheimer's disease AIDS dementia Epilepsy Carotid stenosis
190
Rheumatoid arthritis Polyarteritis nodosa Anticardiolipin/antiphospholipid antibody disease Temporal arteritis Endocrine
Hypothyroidism Apathetic hyperthyroidism Hyperparathyroidism Hypoparathyroidism Diabetes mellitus Cushing's disease Addison's disease
Depression and Its Treatment in Cardiac Patients
Volume 20, Number 3, 1993
TABLE IB. Selected Agents that Can Precipitate Depression Cardiovascular & Antihypertensive Agents Atropine Digitalis Procainamide Quinidine Reserpine Methyldopa Guanethidine Clonidine Hydralazine Propranolol Indapamide Prazosin Pravastatin Simvastatin Analgesics Indomethacin Phenacetin Phenylbutazone Opiates
Central Nervous System Agents L-Dopa Carbidopa Amantadine Diazepam (and other benzodiazepines) Barbiturates Chloral hydrate Alcohol Phenothiazines Haloperidol Metoclopramide Carbamazepine Valproic acid Phenytoin Succinimide derivatives Cocaine Amphetamines Lithium carbonate
tions imposed by the underlying illness, as in the case of an adjustment disorder with depressed mood. Typically, such patients may have difficulty adapting to the knowledge of their disease or to the prospect of an indeterminate period of dependency on others (including their physicians) and may regress into a depressed state characterized by feelings of helplessness, hopelessness, worthlessness, or haplessness. Strong emotional support that includes coping-enhancing strategies is essential for these patients.
Current Treatment All antidepressants (see Table II) have been reported to have equivalent efficiency. Choosing the most appropriate agent for different clinical situations requires knowledge of the pharmacologic profiles of these agents20'21 and of their cardiovascular effects.'1",6 The focus of this section is upon review of the tricyclic and heterocyclic antidepressants and of the new antidepressants, including serotoninergicspecific reuptake inhibitors (SSRIs). For those depressed cardiac patients whose treatment with such lst-line antidepressant agents has failed, a psychiatric consultation will be necessary before treating with monoamine oxidase inhibitors (MAOIs), lithium carbonate, psychomotor stimulants, electroconvulsive therapy, anticonvulsants, or intravenous antidepressants. The safe and effective use of these other Texas Heart Instituteiournal
Antimicrobial Agents Sulfonamides Ethambutol Aminoglycosides Quinolones Ciprofloxacin Imipenem-cilastatin Hormones Corticosteroids Estrogen Progesterone
Others Disulfiram Physostigmine Cyclosporine Azathioprine Heavy metals Carbon monoxide Cimetidine Bromides
somatic therapies in cardiac patients is carefully considered elsewhere."",6'21'22 Pharmacology. Of all the antidepressants, imipramine has been the most thoroughly investigated among cardiac patients."'2' Unfortunately, imipramine and the structurally-related tricyclic antidepressants (TCAs) have considerable toxicity for cardiac, autonomic, and central nervous system functions, due to their affinities for relevant central neurotransmitter systems (see Table III).112021 The 2nd-generation agents, heterocyclic and atypical drugs (such as amoxapine, maprotiline, and trazodone), tend to have a more favorable profile;20 however, prescribing is generally a "mix and match" situation. For example, trazodone is a serotoninergic agonist that has practically no anticholinergic side effects but carries with it significant potential for a1x-adrenergic blockade,20 which results in moderately severe orthostatic hypotension. Therefore, a careful assessment of receptor profiles20 is required, along with an analysis of the relative-risk-to-relative-benefit.16 The newer non-tricyclic/non-monoamine oxidase-inhibiting agents-bupropion and the SSRIs, such as fluoxetine, sertraline, and paroxetine-have considerably less potential to cause autonomic, cardiac, and central nervous system toxicity.11"16 Pharmacokinetics. The dosage of any antidepressant drug depends largely on the following considerations: Depression and Its Treatment in Cardiac Patients
191
TABLE Il. Dosages and Therapeutic Concentrations of Commonly Used Antidepressants Starting Dose (mg)
Drug
Daily Dosage Range (mg)
Plasma Levels
(ng/mL) Tricyclic Antidepressants Tertiary Amitriptyline (Elavil®, Endeps) Doxepin (Sinequan®, Adapins) Imipramine (Tofranil g, Pertrofanes) Trimipramine (Surmontil®) Clomipramine (Anafranils)
Secondary Desipramine (Norpramines) Nortriptyline (Pamelor®, Aventyl®) Protriptyline (Vivactil®) Heterocyclic Antidepressants Amoxapine (Asendin®) Maprotiline (Ludiomil®)
Monoamine Oxidase Inhibitors Phenelzine (Nardilg) Tranylcypromine (Parnateg) Isocarboxazid (Marplan®) Atypical Trazodone (Desyrel®) Bupropion (Wellbutrin®) Serotoninergic-Specific Reuptake Inhibitors Fluoxetine (Prozac®) Paroxetine (Paxil®) Sertraline (Zoloft®)
25 TID
50-300
25 TID 25 TID 25 TID
75-300 50-300 75-300
25 BID
100-250
25 TID 25 TID 5 TID
50-300 50-200 15-60
50-150** 100-200
50 TID 25 TID
100-600 50-300
180-600* 200-400*
15 BID
10 BID
15-90 10-60
10 BID
20-90
50 TID 75 BID
50-600 300-450
10-20 QAM 20 QAM 50 QAM
10-80
60-200* 110-250 > 180**
125-250* *
800-1600 50-1 00*
10-50 50-200
* Parent and active metabolite sum **Therapeutic plasma level established
1) the half-life of the parent compound and its active metabolites; and, 2) any drug-drug interactions that may cause clinically significant changes in the therapeutic serum drug levels of either the antidepressant itself or any concomitantly prescribed medications.23
The 1st of these considerations (the half-life of the antidepressant drug) determines 2 clinically relevant factors:
1) the amount of time it will take for drug to reach a steady state; and, 192
Depression and Its Treatment
in
any
given
Cardiac Patients
2) the amount of time any antidepressant must be administered before both the parent compound and its active metabolites reach maximal serum drug levels. As an example, Table IV compares the half-lives and dosages of the new SSRIs with those of the commonly prescribed standard therapy imipramine. There may be as much as a 10-fold individual variation in daily dosages for the tricyclic antidepressants,20 so some patients may respond to 25 mg of imipramine while others may require 250 mg. Additionally, fluoxetine may require treatment of up to a full month to reach a steady-state. This is because Volume 20, Nu m ber 3, 1993
TABLE 111. Comparison of Antihistaminic, Orthostatic, Anticholinergic, and Cardiac Conduction Effects of Commonly Used Antidepressants Muscarinic Receptor Affinity Anticholinergic Potencies
H-1 Receptor
Orthostatic
Affinity
Potency
Amitriptyline
770
Moderate
5.5
Yes
Protriptyline
2.9
Low
4.0
Yes
Agent
Cardiac Conduction Effects
Tricyclics
Trimiprammne
1,000
Moderate
1.7
Yes
Doxepin
3,100
Moderate
1.3
Yes
Imipramine
10
High
1.1
Yes
Clomipramine
3.2
High
2.7
Yes
Nortriptyline
14
Low
0.7
Yes
Desipramine
0.4
Low
0.5
Yes
Maprotiline
100
Low
0.2
Yes
Amoxapine
15
Low
0.1
Yes
Trazodone
1.4
Moderate
0.0003
Yes
Bupropion
0.015
None/low
0.0021
No
Fluoxetine
0.016
None/low
0.05
Rare
Sertraline
Low
None/low
Low
Rare
Paroxetine
Low
None/low
Low
Rare
Pheneizine
High
High
