This analysis of the SADHART-CHF trial demonstrated an association of depression remission during the 12-week active intervention and significantly reduced fatal and non-fatal cardiovascular events. Such findings support the hypothesis that successful depression treatment may be associated with a cardiac benefit in HF patients. Carney et al. performed a post hoc analysis in ENRICHD study to examine whether depression improvement at 6-months from baseline was associated with survival11
. They found that patients who were randomized into the intervention arm and remained depressed at the 6-month follow-up had significantly worse survival than those patients whose depression improved, though there was no survival difference between the intervention group and the control group. Furthermore, Glassman et al. 12
examined a 7-year survival difference between the SADHART trial participants whose depression significantly improved and whose depression remained based on Clinical Global Impression-Improvement subscale score (CGI) during the 24-week sertraline or placebo trial intervention. The authors demonstrated that depressed ischemic heart disease patients whose CGI score were reduced to 1 or 2 had significant higher survival than those patients whose CGI score >2, irrespective of the treatment assignment.
The SADHART-CHF study design followed the traditional phase II–III clinical trial model of randomized and placebo controlled, and it focused primarily on examining differences between active treatment assignments, i.e. drug or psychotherapy, vs. placebo or usual care. Sertraline, compared to placebo, did not result in a statistically significant higher rate of remission in the SADHART-CHF study (54.1% vs. 49.5%, P
= .36) 10
. Several factors may have contributed to this finding, including the placebo effect; the therapeutic impact of the NFS, or the uniqueness of co-morbid depression in HF patients. Therapeutic response to placebo has been recognized in research as well as in clinical practice 15–16
. Several meta-analyses have demonstrated a placebo response in depression trials exceeding 50%, a finding that was particularly evident among non-published trials 17–19
. In recent years, an increase in scientific attention to the placebo effect has yielded evidence that the effect may have a neurobiological foundation 20–21
. However, the potential impact of the NFS on treatment response cannot be overlooked. One of the major predisposing factors for depression is a weak social support network. Persistent and negative life stressors coupled with limited supportive structures are believed to result in reduction of mental function in patients with chronic illnesses. The NFS fostered relationship may have replaced ineffective or insufficient social networks, and established an alliance that contributed to functional improvement22–24
. Specific evidence to support the therapeutic impact of the NFS includes the maintenance of remission in these participants after 4–6 weeks when placebo effects tend to diminish25
. The majority of the study population was naive to psychological and psychiatric interventions; therefore, these participants may have been innately more responsive to psychosocial supportive measures. Additionally, the fact that a large proportion of study participants had a mild baseline depression in severity (i.e. HDRS total score 8–17) at study entry may have contributed to the high remission rate for those participants. Other studies of this type had failed to demonstrate survival or prognostic benefit of active treatment compared to controls11,26–27
. Trials that failed to show treatment benefit of pharmacological agents hypothesized that the lack of a statistically significant difference in outcomes was due to insufficient power 27–30
SADHART-CHF had a similar design to other studies in patients with heart disease and co-morbid depression. In SADHART-CHF, the sample size was believed to be adequate to evaluate differences in depression and clinical outcome, however there was no benefit observed with antidepressant treatment over placebo10
. In contrast, in the ENRICHD trial, open label treatment of SSRIs showed a statistically significant 40% reduction in death or nonfatal MI, with a crude HR of 0.61 (95% CI, 0.41–0.90) and an adjusted HR of 0.53 (95% CI, 0.38–0.84)28
. In this study, because antidepressant prescription was at the discretion of the study physicians and not randomized nor controlled, the impact of the finding is controversial. Whether or not a survival benefit was associated with depression improvement was not reported in the primary analysis. However, in the subgroup analysis for ENRICHD, successful treatment of depression appeared to reduce the risk of cardiovascular events11
The present findings of the SADHART-CHF studies raise several important questions, including the need to determine whose depression is easier to remit versus those who are more resistant to interventions, to examine whether or not subsets of depressed HF patients may be at higher risk for cardiovascular events, and to identify effective antidepressant(s) for this particular population. Our research indicates that male HF patients with mild depression (HDRS ≤17) have nearly a 2.5 fold chance to remit compared to the rest of the study population. On the other hand, patients who had greater somatic affective symptoms were less likely to remit. This data suggest that future trials testing therapeutics may need to focus on patients whose depression is more severe and do not respond to general supportive measures. This information may be useful for clinical practice as well. Nevertheless, future studies are needed to confirm the observed association between depression remission and cardiovascular outcomes. NFS appears to be a powerful therapeutic modality that results in depression remission in certain patients with HF. A more sophisticated study design, along with refinement of the support measures, will be needed to fully evaluate the effects of an NFS among patients with HF or other medical conditions. Etiology of depression in patients with cardiac disease or other chronic medical conditions may be more heterogeneous than populations studied in traditional trials that test the antidepressant efficacy. Therefore, outcome studies testing the association between depression treatment and prognosis may need to be aligned with real-world clinical practice techniques, such as employing a naturalistic approach in the acclimatization of individual differences and identifying characteristics of populations who respond differently to various anti-depressive treatments.
The results of this analysis should be interpreted in the context of limitations. This was a secondary analysis of a trial, which was originally designed to assess treatment response to sertraline vs. placebo, examining subgroups that are defined by changes in measures over the course of the trial. Therefore, any changes in depression and cardiovascular outcomes between the remission group and non-remission group may be considered to be due to pre-existing baseline characteristic differences between those who do and do not respond to sertraline or other interventional measures. Whether these participants received depression treatment after the 12-week acute phase of trial were not further evaluated, similar to the studies of Carney and Glassman11–12
. Although the analysis was adjusted for differences in baseline variables and baseline depression severity was not associated with the prognosis, the fact that participants who remitted had a baseline lower depressive score, especially by the self-administered test, might have reflected a sub-population who had perceived their illness milder and/or were more receptive to psycho-supportive intervention. In addition, this study had limited statistical power to evaluate survival.