Bipolar Depression: A Historical Perspective of the Current Concept, with a Focus on Future Research

The aim of this narrative review is to trace the origin of the concept of bipolar depression and to expose some of its limitations. Bipolar depression is a broad clinical construct including experiences ranging from traditional melancholic and psychotic episodes ascribed to "manic-depressive insanity," to another heterogeneous group of depressive episodes originally described in the context of binary models of unipolar depression (e.g., psychogenic depression, neurotic depression). None of the available empirical evidence suggests, however, that these subsets of "bipolar" depression are equivalent in terms of clinical course, disability, family aggregation, and response to treatment, among other relevant diagnostic validators. Therefore, the validity of the current concept of bipolar depression should be a matter of concern. Here, we discuss some of the potential limitations that this broad construct might entail in terms of pathophysiological, clinical, and therapeutic aspects. Finally, we propose a clinical research program for bipolar depression in order to delimit diagnostic entities based on empirical data, with subsequent validation by laboratory or neuroimaging biomarkers. This process will then aid in the development of more specific treatments.