Depression With Coronary Disease: Therapy Adds No Benefit to SSRI

June 1, 2007

In what was billed as the first randomized controlled study to simultaneously evaluate antidepressant therapy and short-term psychotherapy for depressed patients with coronary artery disease (CAD), treatment with an SSRI led to significant improvement, while addition of interpersonal psychotherapy provided no added benefit.

In what was billed as the first randomized controlled study to simultaneously evaluate antidepressant therapy and short-term psychotherapy for depressed patients with coronary artery disease (CAD), treatment with an SSRI led to significant improvement, while addition of interpersonal psychotherapy provided no added benefit.

With evidence increasing over 2 decades that major depression worsens the prognosis in patients with CAD, the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial was conducted to examine the safety and efficacy of the 2 treatment strategies for depression in a group of outpatients with CAD.1

The study's lead investigators, Francois Lespérance, MD, and Nancy Frasure-Smith, PhD, both from the department of psychiatry, University of Montreal, argued that although there is not yet clear evidence that effective treatment of depression can reduce the morbidity and mortality of CAD, the "available data are more than sufficient to justify developing and evaluating better treatments for depression in patients [with CAD] as well as in those at risk for its development."2

The largest previous investigation of depression treatment in CAD was the Sertraline Antidepressant Heart Attack Trial (SADHART),3 which, according to the CREATE investigators, provided some evidence of the safety of the SSRI sertraline (Zoloft) in patients with CAD. The CREATE investigators note, however, that the "overall efficacy results were less convincing."1

The CREATE trial also used an SSRI (citalopram [Celexa]), chosen because of its relatively low propensity to adversely interact with cardiac medications and the absence of noradrenergic or anticholinergic activity (which can affect cardiac function) that is characteristic of an SSRI. The CREATE trial differed from SADHART by including a psychotherapeutic intervention and widening the study population beyond those hospitalized with acute coronary syndrome. Their inclusion criteria, the CREATE investigators indicated, "help ensure the applicability of results to a wide group of cardiac patients."1

The CREATE investigators identified 284 patients at 9 Canadian academic medical centers who were at least 1 week post-myocardial infarction (MI), cardiac revascularization, or coronary angiography with substantial blockage, and had at least 4 weeks of depressive symptoms rated 20 or higher on the 24-item Hamilton Depression Rating Scale (HAM-D). The patients were randomized into 4 groups, to receive: (1) 12 weekly sessions of interpersonal therapy (IPT) plus clinical management and citalopram; (2) 12 weeks of IPT plus clinical management and placebo pill; (3) clinical management and citalopram; or (4) clinical management and placebo pill.

Citalopram was initiated at 10 mg daily for the first week, then increased to 20 mg. If the HAM-D score was not 8 or lower by the 6th week, the dosage was increased to 40 mg daily and maintained, if tolerated, through the remaining 6 weeks. The clinical management protocol, previously used in the NIMH Treatment of Depression Collaborative Research Program,4 involved weekly 20- to 25-minute sessions along with monitoring of both mood and physical symptoms.

IPT was chosen over cognitive- behavioral therapy (CBT)-the only other psychotherapeutic intervention recommended in depression treatment guidelines-in part because of a previous study finding it superior to CBT for treating depression in patients with comorbid medical illness.5

"Interpersonal psychotherapy deals with problems common in patients with CAD, including interpersonal conflicts, life transitions, grief, and loss," the CREATE investigators explained. "It also addresses social isolation, a factor that has been linked to increased mortality and morbidity in some studies of patients with CAD."1

The investigators reported in the Journal of the American Medical Association (JAMA) that the antidepressant was superior to placebo in reducing depressive symptoms from baseline to the 12-week end point, by a mean 3.3 points on the HAM-D, a small to medium effect size of 0.33. Patients improved with both IPT and clinical management, with no statistical evidence of superiority for IPT. All treatments were well tolerated by the patients with CAD, with the antidepressant similar to placebo in blood pressure and ECG measures.

The CREATE trial found, as did SADHART, a greater benefit of the SSRI for patients with recurrent rather than first episode depression. This emerged from both more pronounced drug effect and reduced response to placebo in patients with a history of depression.

"It is . . . possible that SSRIs may actually have less impact in comparison with placebo among persons experiencing first episodes of major depression late in life, in the context of CAD or other cardiovascular diseases," the CREATE investigators suggested.

Although IPT did not evidence superiority over clinical management, the investigators pointed out that the clinical management protocol is not an "inert intervention." Clinical management involved semistructured 20- to 25-minute visits including information about depression and medication use, reassurance, and encouragement of adherence to medication and the study protocol.

The investigators suggested that clinical management may be particularly useful for this population. "CAD patients with low levels of support or poor daily functioning may have difficulty in dealing directly with the combination of cardiac and interpersonal issues that IPT sessions entail, and may do better with the lower demands of regular medical management," the investigators suggested.

Recognizing depression as cardiac risk factor

Lespérance and Frasure-Smith were among the first researchers to associate depression with increased mortality from MI6 and have understandably taken exception to the omission of major depression from recent lists of cardiac risk factors. "Are cardiologists particularly hard to convince, or is there something wrong with the data that has led many behavioral medicine specialists to believe that depression is a cardiac risk factor?" they asked.6

In their own review of the literature, Frasure-Smith and Lespérance did find great heterogeneity in study designs, definitions of depression, and outcome measures. Their analysis determined, however, that there is compelling evidence from adequately powered prospective etiologic studies, and from prospective studies with objective outcome measures and recognized indices of depression.

These studies, they indicated, "are remarkably consistent in their support of depression as a risk factor for both the development of and the worsening of [coronary heart disease]."2

Despite evidence of the detrimental impact of depression in cardiac patients, only 1 large randomized trial has sought to determine whether treating depression can improve CAD outcomes. The National Heart, Lung, and Blood Institute's ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial demonstrated that a combination of short-term CBT and an SSRI, when necessary, was significantly better than usual care for reducing depressive symptoms.7 The study was insufficiently statistically powered, however, to determine whether the ENRICHD regimen was superior to usual care in reducing all-cause mortality or recurrent MI over a mean 29-month follow-up.

Frasure-Smith and Lespérance credit the ENRICHD trial, however, for breaking necessary ground before the CREATE trial. "The [ENRICHD] study . . . demonstrated that psychologists, psychiatrists, and cardiologists can successfully collaborate to test complicated intervention protocols with large numbers of patients from multiple sites," they pointed out.8 The CREATE trial would follow because, as Frasure-Smith and Lespérance described in a JAMA editorial, the ENRICHD study and others had left major depression as a CAD risk factor in search of a successful intervention.8 They noted further, "Regardless of whether rigorous studies will convincingly show that treating depression can influence cardiac prognosis, more trials are needed to find the best ways to improve care for patients with depression and CAD."

References:

References


1.

Lespérance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial.

JAMA

. 2007;297:367-379.

2.

Frasure-Smith N, Lespérance F. Reflections on depression as a cardiac risk factor.

Psychosom Med

. 2005; 67:S19-S25.

3.

Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina.

JAMA

. 2002;288:701-709.

4.

Fawcett J, Epstein P, Fiester SJ, et al. Clinical management-imipramine/placebo administration manual. NIMH Treatment of Depression Collaborative Research Program.

Psychopharmacol Bull

. 1987;23:309-324.

5.

Markowitz JC, Kocsis JH, Fishman B, et al. Treatment of depressive symptoms in human immunodeficiency virus-positive patients.

Arch Gen Psychiatry

. 1998;55: 452-457.

6.

Frasure-Smith N, Lespérance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival.

JAMA

. 1993;270:1819-1825.

7.

Berkman LF, Blumenthal J, Burg M, et al, and the Enhancing Recovery in Coronary Heart Disease Patients Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial.

JAMA

. 2003;289:3106-3116.

8.

Frasure-Smith N, Lespérance F. Depression-a cardiac risk factor in search of a treatment.

JAMA

. 2003; 289:3171-3173.