The present findings confirm and extend our previous observations by showing that symptoms of depression are associated with adverse clinical outcomes, including cardiovascular (or all-cause) hospitalization and death, over a median of five years of follow-up from baseline (with range of 4 to 7 years and no losses to follow-up), even after controlling for the severity of HF disease and other established risk factors, and that worsening of depression was additionally associated with such adverse events compared to patients whose depressive symptoms remained relatively stable over the initial 1-year follow up period. To our knowledge, this is the first study to evaluate prospectively the clinical impact of changing depression symptoms in HF patients, and our observations demonstrate that such changes do indeed affect clinical outcomes. Specifically, a one-point change in BDI score was associated with a 7% alteration in risk (per unit of time) for cardiovascular hospitalizations and mortality. Importantly, the effects of change in depression symptoms were independent of baseline depression symptoms, and HF disease severity biomarkers, as well as hospitalizations occurring during the year over which depression symptoms were monitored. Exploratory analyses designed to better understand the latter finding suggest that worsening symptoms of depression in HF patients may be of particular concern; an increase in depressive symptoms of three or more BDI points over a 1-year follow-up period was associated with over a two-fold increased risk of cardiovascular hospitalization or death compared to minimal change (<2 BDI points). Our findings are consistent with observations in post-MI patients, in whom worsening symptoms of depression have been associated with greater risk of subsequent mortality (9
Our study found no association between antidepressant use and clinical outcomes. However, because the study was not designed to assess the impact of antidepressant treatment on outcomes, the significance of this observation is unclear. There are currently no published data from randomized clinical trials (RCTs) of HF patients indicating whether interventions designed to modify depression symptoms may alter long-term clinical outcomes. Although the SADHART trial (18
) was designed to be a safety and efficacy trial and was not powered to evaluate adverse clinical outcomes, the incidence of cardiovascular events in a subgroup of more severely depressed patients with acute coronary syndromes randomized to sertraline treatment was 14.5% compared to 22.4% among those receiving a placebo. In the ENRICHD trial, the rates of non-fatal MI and all cause mortality were similar between post-MI patients randomized to cognitive behavior therapy (CBT) and education controls (19
), although a post-hoc analysis revealed that patients who received anti-depressant medication had improved survival compared to similar patients not receiving anti-depressants (20
). Moreover, patients randomized to the CBT condition who exhibited an increase in depressive symptoms had higher event rates compared to those patients who showed an improvement in depressive symptoms (9
). In a recently completed RCT in HF patients with depression (22
), no antidepressant benefit of sertraline compared to placebo was observed, although remitting depression symptoms were found to be associated with improved health status and quality of life (23
It is important to note that the observational data reported in the present study do not lend themselves to causal inferences nor to insights into the potential effects of interventions designed to modify symptoms of depression. Other limitations of the present study include absence of changes in depression during the follow-up period. However, changes in depression symptoms during the follow-up period would be difficult to interpret since such changes would be concomitant with changing HF disease severity. The reported analyses evaluate the role of change in depressive symptoms prior to the onset of the follow-up period and are therefore explanatory. The sample size of the present study also was relatively small, but a significant relationship between 1-year change in depression symptoms and subsequent clinical outcomes was observed despite this limitation. It also should be noted that the HF disease severity biomarkers (NT-proBNP and LVEF) were assessed only at baseline, not at the time of the reassessment of depressive symptoms, one year later; however, our inclusion of hospitalizations during that one year period was designed to minimize this potential limitation.
In summary, elevated depression symptoms, and worsening depression symptoms, were found to be explanatory risk factors for adverse clinical outcomes in HF patients, independent of HF disease severity. Our findings support the recent American Heart Association's position encouraging depression screening (24
), and would further suggest that it may be prudent for clinicians to routinely reassess symptoms of depression in HF patients, in order to better determine appropriate medical management of these patients who are at increased risk for adverse clinical outcomes and impaired quality of life.