November 2005
Reviewer: Jeff C. Huffman, MD
Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression
Serebruany VL, Suckow RF, Cooper TB, et al
Am J Psychiatry 2005; 162(6):1165-1170
Summary: Sertraline, when prescribed to post-MI patients with major depression, is associated (in a level/dose-dependent manner) with the development of decreased levels of platelet biomarkers compared to those receiving placebo. This supports the argument that sertraline (and possibly other SSRIs) act as platelet inhibitors, and that this is a potentially beneficial cardiovascular effect of this agent in the post-MI period.
Background/Method: The SADHART trial, a large multicenter trial of the safety and efficacy of sertraline in post-MI major depression, found that sertraline was indeed safe and efficacious in this population and that patients receiving sertraline had a nonsignificant reduction in cardiovascular events. Since that time, the ENRICHD trial of post-MI depression also found in a post-hoc analysis that patients receiving sertraline had significantly lower mortality. Such findings have encouraged researcher to investigate possible favorable cardiovascular effects of sertraline above and beyond the effects on depression; many in the field have suggested that platelet inhibition by SSRIs may be playing a role. This study, a substudy of the original SADHART trial, examines the effects of sertraline on platelet and endothelial biomarkers in a total of 55 patients receiving either sertraline (n=23) or placebo (n=32) for post-MI depression. Platelet and endothelial biomarkers and levels of sertraline and n-desmethylsertraline were measured at baseline (biomarkers only), 6 and 16 weeks after sertraline or placebo were initiated.
Results: Levels of three of the eight biomarkers were significantly lower in the sertraline group than the placebo group during at least one of the two time points, and by the final time point all eight biomarker levels were lower than in the placebo group (though only two were statistically significant). In addition, there was a consistent negative correlation between sertraline/N-desmethysertraline levels and the biomarkers, suggesting that both parent compound and active metabolite affected platelet activation in a level-dependent fashion.
Comment: This preliminary study adds further interesting data to support an impact of sertraline on platelet function in the post-MI period. The strength of the study lies in its rigorous original design (e.g., clear diagnosis of DMS-IV major depression and myocardial infarction), though it is very much limited by its small size (23 patients in sertraline group, and only 14 patients in the portion of the study measuring sertraline levels). In addition, it is the first study to correlate platelet biomarker levels with sertraline drug levels, and the article makes a good case that the effects of sertraline on platelet biomarkers are real and dose/level dependent. Clinically, it is not yet clear what these results mean in terms of actual platelet function, and to what extent there should be cause for optimism (that sertraline may have a beneficial cardiovascular impact for both depressed and nondepressed post-MI patients) or concern (related to worry about exacerbation of bleeding risk in selected post-MI patients)—though at this point benefit appears to outweigh risk in the majority of patients.
Overall, given the significant impact of post-MI depression on cardiac morbidity and mortality, and the promising effects of sertraline on both psychiatric and cardiac outcome in the post-MI period, this study prompts researchers to perform larger studies of sertraline to better assess effects on platelet biomarkers and function. Someday soon we may see prophylactic studies of sertraline in the post-MI period for nondepressed patients to prevent the development of depression and for its beneficial effects on platelet activation.