A recent meta-analysis found that when depression is assessed within 2 weeks after ACS, it is less predictive of cardiac events than when it is assessed more than 2 weeks after the event [2
]. This might be due to the prognostic insignificance of transient depressive symptoms that resolve as soon as the patient recovers from the ACS.
A recent study found that of the patients who were depressed after ACS, only those with persistent symptoms, as defined by an elevated BDI score both at baseline and at 12-month follow-up, were at risk of adverse cardiac outcomes. Patients with transient depressive symptoms were not at increased risk [43
]. Interestingly, patients with transient depression actually had higher BDI scores at baseline than did the persistent cases. Although not all studies have found that patients with persistent depression are at higher risk [44
], one form of persistent depression that has been consistently found to be a predictor of cardiac mortality following ACS is depression that has failed to respond to one or more conventional treatments.
In the ENRICHD trial, 2,481 patients with major or minor depression and/or low perceived social support were randomly assigned to usual care or an intervention. The intervention provided up to 6 months of cognitive-behavioral therapy and sertraline for up to 1 year for patients who had severe depression (Hamilton Depression Rating Scale [HAM-D]-17 score >25) at baseline or who did not improve at least 50% on the BDI after 6 sessions of cognitive-behavioral therapy. Six-month mean BDI change scores were −8.6±9.2 among the depressed patients in the intervention group and −5.8±8.1 among those in the usual care group. However, there was no between-group difference in event-free survival over 29 months [13
Among the depressed patients in the ENRICHD intervention arm, treatment nonresponders had a higher risk of death after 6 months of treatment than did the responders [45
]. Patients whose BDI score increased by 10 or more points after 6 months of treatment were 1.6 times more likely to die during the follow-up compared with patients whose BDI scores did not change, and 2.5 times more likely to die than those whose BDI score decreased by 10 or more points. These effects were found after adjusting for baseline BDI score, age, antidepressant use, and major predictors of post-MI mortality, including left ventricular ejection fraction and a prior MI. Although there was a positive relationship between a change in depression and late mortality in the intervention arm, there was no such relationship in the usual care arm. More than 80% of the usual care patients received no treatment for depression. Among those who did receive treatment, usually in the form of an antidepressant, there was a twofold difference in mortality between those with the best and those with the worst response to treatment. However, because relatively few patients in the usual care group received treatment for depression, this difference was not statistically significant.
ENRICHD is the only clinical trial conducted to date that may have been adequately powered to determine whether treating depression improves survival after an MI, but there have been other clinical trials of depression treatment in post-MI or post-ACS patients. The Myocardial Infarction and Depression Intervention Trial (MIND-IT), a study from The Netherlands of 331 depressed post-MI patients, compared 24 weeks of usual care to a complicated treatment regimen that included mirtazapine or placebo followed by open-label citalopram for nonresponders, or a choice of other antidepressants or psychotherapy [46
]. MIND-IT also investigated the effect of treatment on event-free survival. Like the ENRICHD trial, MIND-IT found no difference between the intervention and usual care groups in cardiac event–free survival during an average of 27 months of follow-up [46
In a secondary MIND-IT analysis, de Jonge et al. [47
] classified patients who received the intervention as responders (≥50% improvement on the HAM-D at 24 weeks) or nonresponders (<50% change in HAM-D score), and compared these two groups with patients who received no treatment for depression. After 18 months of follow-up, 26% of the nonresponders, 7% of responders, and 11% of the untreated controls had experienced a cardiac event (P
<0.001). The treatment responders and nonresponders did not differ in age, left ventricular ejection fraction, Killip class, prior revascularization, the Charlson Comorbidity Index, or in the prevalence of specific comorbid conditions (eg, diabetes, cerebrovascular disease, peripheral vascular disease, or hypercholesterolemia).
In the SADHART trial, no difference was noted in depression outcomes between the sertraline and placebo arms. However, treatment did have a statistically significant effect on HAM-D outcomes in the subgroup of patients who had severe, recurrent major depression [48
]. The SADHART investigators also reported the results of a long-term follow-up (median, 6.6 years) of the trial participants [49
]. They found a significant relationship between improvement in depression following treatment and survival in both the sertraline and placebo groups after adjusting for other major risk factors for mortality. The patients in both the placebo and sertraline groups with the most improvement (n
=130) had the lowest rate of mortality (11.5%). Among the patients whose depression improved moderately (n
=80), 22.5% died. In contrast, of those whose depression improved minimally or not at all (n
=148), 28.4% died during the follow-up period (P
Milani and Lavie [50
] reported the results of an exercise training program in 522 CHD patients enrolled in cardiac rehabilitation. Depression was assessed before and after the exercise program. After completion of the exercise training, the mortality rate among the depressed patients who remained depressed was significantly higher (22%) than that of the nondepressed participants (5%) and the patients who had an improvement in depression symptoms following the exercise program (8%; P
=0.0004). In short, patients whose depression did not respond to exercise training had a threefold to fourfold higher risk of dying than depression responders and nondepressed patients.
Thus, the association between improvement in depression and improvement in post-ACS survival seems to be robust as well as independent of the type of treatment for depression. However, residual confounding cannot be ruled out. Whether the failure to respond to treatment identifies a qualitatively different form of depression that is associated with a higher risk of mortality, or whether it is simply remaining depressed that places patients at high risk is not clear from these studies. In ENRICHD, improvement in depression decreased the risk of mortality, but only in patients who received an intervention, not in the untreated usual care patients. This seems to support the possibility that it is poor response to treatment, and not persistent depression per se, that predicts cardiac events and mortality. On the other hand, the SADHART trial found that improvement in depression lowered the risk of mortality in the intervention and placebo groups. However, patients in most drug trials, including SADHART, receive clinical management, which in itself can be therapeutic. Neither MIND-IT nor the Milani and Lavie [50
] exercise study assessed depression after the intervention period in patients who did not receive treatment. Thus, this issue remains to be resolved.
Too few clinical trials have been conducted to resolve this issue, and more are needed. Identifying patients who are treatment resistant, and testing hypotheses regarding high-risk depression subtypes (eg, vascular depression or depression with elevated inflammatory markers) should advance our knowledge in this area.