There is evidence from other clinical trials supporting this conclusion. The Myocardial INfarction and Depression Intervention Trial (MIND-IT) compared 24 weeks of UC vs mirtazapine vs placebo, followed by open-label citalopram for treatment nonresponders.(15
) Like ENRICHD, the MIND-IT trial failed to demonstrate the superiority of the study interventions over UC with respect to cardiac event-free survival during an average of 27 months of follow-up.(15
In a recent secondary analysis, de Jonge et al.(16
) classified Tx patients in MIND-IT as responders (≥50% improvement on the HAM-D at 24 weeks) or nonresponders (<50%). They compared these two subgroups to UC patients who did not receive any treatment for depression. The 18-month incidence of cardiac events was 26% in Tx nonresponders, 11% in untreated controls, and 7% in responders (p<.001). These findings are strikingly similar to the ENRICHD outcomes. Also like ENRICHD, the MIND-IT findings could not be explained by between-group differences in the initial severity of medical illness. Specifically, MIND-IT responders and nonresponders did not differ in age, left ventricular ejection fraction (LVEF), Killip class, the Charlson Comorbidity Index, or in the prevalence of diabetes, cerebrovascular disease, peripheral vascular disease, hypercholesterolemia, smoking, or prior revascularization.
The Montreal Heart Attack Readjustment Trial (MHART) tested the efficacy of a 12-month, home-based nursing intervention targeting emotional distress in post MI-patients.(17
) Although depression per-se was not the primary target of the intervention, over 1/3 of the Tx patients had clinically significant depression (BDI >10) at baseline. Like MIND-IT and ENRICHD, the MHART intervention also failed to improve post-MI survival.
A 5-year follow-up of the UC arm of MHART showed that improvement in depression after one year was associated with lower cardiac mortality only in patients who had mild depression at baseline.(18
) There was no relationship between change in depression and subsequent mortality among patients who had moderate to severe depression at baseline, the very patients who may be considered for treatment in clinical settings.
This report did not include comparable analyses of the outcomes within the Tx arm. In unpublished analyses, however, the MHART investigators found a relationship between BDI change from baseline to 3 months and 5-year survival in the Tx (p<.0001) but not in the UC arm (p=.98) (Frasure-Smith, personal communication, 2004). Only 6% of the patients in the Tx arm who were in the highest quintile of improvement on the BDI died within the first year, compared to 17% of patients in the lowest quintile. Thus, there is a striking similarity between the MHART and ENRICHD findings.
The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) was designed to determine the safety and efficacy of sertraline in patients with a recent ACS. At the completion of the trial, the sertraline and placebo arms did not differ on the HAM-D in the overall sample. However, there was a statistically significant difference in HAM-D outcomes in the subgroup with severe, recurrent major depression. There was also a trend toward fewer cardiac events in the sertraline arm.(19
The SADHART investigators recently completed a long-term follow-up (median 6.6 years) of the trial participants. They found a significant relationship between improvement in depression during the 24 weeks of treatment and survival in both the sertraline and placebo arms, even after adjusting for other mortality risk factors (Glassman, personal communication, 2008). Using the Clinical Global Impression (CGI) scale to measure improvement in depression following treatment, they found that the patients in both the placebo and sertraline groups with the most improvement (n=130) had the lowest rate of mortality (11.5%). For those with moderate improvement (n=80), 22.5% died; and for those whose depression minimally improved, worsened, or stayed the same following treatment (n=148), 28.4% died during follow-up (p=0.001).
Unlike ENRICHD and M-HART, the control group in the SADHART trial also showed a relationship between improvement in depression and survival. However, a placebo condition and a usual care or no-treatment control group are not equivalent. A review of the efficacy data reported for placebo controlled antidepressant trials found that the average HAM-D difference between drug and placebo groups is just 2 points (range, 0.89 to 3.21).(20
) Although the placebo is pharmacologically inert, the clinical management that is provided to a patient in a double-blinded study is often perceived as supportive and beneficial. Simply meeting with patients to discuss their depression symptoms, encouraging them to take the pills as prescribed and to return for the next scheduled visit, may be therapeutic. For example, in a study of 248 patients with CHD, Lespérance et al. found greater depression improvement in patients who received only clinical management compared to those who received clinical management plus interpersonal psychotherapy (IPT), a recognized treatment for depression in psychiatric patients.(22
The relationship between treatment-resistant depression and cardiac mortality and morbidity extends beyond traditional treatments for depression. Milani and Lavie(23
) studied 522 CHD patients in a cardiac rehabilitation aerobic exercise program. The participants were assessed for depression symptoms before and after the program. A comparison group (n=179) was assessed at baseline but not at follow-up. The mortality rate among the depressed patients who completed the training but who remained depressed was significantly higher (22%) than that of the nondepressed participants (5%) and of the initially depressed patients whose mood improved following the exercise program (8%; p=.0004). Thus, patients whose depression did not respond to exercise training had a 3–4 fold higher risk of dying than depression responders and nondepressed patients. Exercise training can therefore be added to the list of depression interventions, including sertraline, mirtazapine, citalopram, cognitive behavior therapy, and stress management, in which nonresponse is associated with an increased risk of mortality.
Milani and Lavie’s(23
) findings are consistent with our hypotheses. However, they do not reveal whether patients with persistent, untreated
depression (a subgroup which includes both potential treatment responders and potential nonresponders) are also at increased risk for mortality because they did not assess depression in the comparison patients during follow-up.
Taken together, these findings, especially those from the ENRICHD, MIND-IT, SADHART, and MHART clinical trials, suggest that unsuccessful treatment of depression after hospitalization for ACS identifies a high-risk patient subgroup. This may help to explain the failure of ENRICHD and the other clinical trials to improve survival. Although depression may have improved slightly more on average in the patients who received the intervention than in those who received usual care, the patients who were at the highest risk for cardiac events did not improve despite treatment, and they were at higher risk for cardiac events after treatment than were the responders. Because the participants in these trials were randomly assigned to treatment or control conditions, patients with potentially treatment-resistant depression were probably equally distributed between the groups. In the usual care groups, in which most patients did not receive any non-study treatment for depression, the potential nonresponders cannot be easily distinguished from potential responders who were simply never treated.