A Primer on How to Critically Read an Observational Study on Adverse Medical Outcomes Associated With Long-Term Antidepressant Drug Use

Abstract

Whether long-term antidepressant use predisposes to or protects against adverse medical outcomes is unclear. In this context, a recent retrospective cohort study found that, for example, at a 10-year follow-up, selective serotonin reuptake inhibitors lowered the risk of diabetes mellitus and hypertension but raised the risk of cerebrovascular disease, cardiovascular mortality, and all-cause mortality. The findings of this study were widely and uncritically covered in the lay and medical media with potential to adversely impact opinions about antidepressant treatment among patients, caregivers, and health care professionals. This article critically evaluates the study with a view to discuss its limitations and, more importantly, to arm the reader with skills to critically appraise other, similar studies. Concepts explained include confounding by indication, regression, and approaches to deal with confounding. Problems with the study identified and explained are incomplete adjustment for confounding, failure to correct for multiple hypothesis testing, the use of backward stepwise regression as a method of analysis, failure to consider reverse causation, and failure to remove death by suicide from analyses of all-cause mortality. Other limitations of the study are also discussed. A take-home message is that it is well established that depression is associated with substantial disability and risk of suicide and that antidepressant drugs treat depression and prevent relapse and remission; in contrast, no causal role for antidepressants in long-term adverse medical outcomes is established. Therefore, known long-term benefits with antidepressants must be weighed against unproven predispositions to long-term medical adverse effects in shared decision-making processes.