Distinguishing between unipolar depression and bipolar depression: current and future clinical and neuroimaging perspectives

Abstract

Differentiating bipolar disorder (BD) from recurrent unipolar depression (UD) is a major clinical challenge. Main reasons for this include the higher prevalence of depressive relative to hypo/manic symptoms during the course of BD illness and the high prevalence of subthreshold manic symptoms in both BD and UD depression. Identifying objective markers of BD might help improve accuracy in differentiating between BD and UD depression, to ultimately optimize clinical and functional outcome for all depressed individuals. Yet, only eight neuroimaging studies to date have directly compared UD and BD depressed individuals. Findings from these studies suggest more widespread abnormalities in white matter connectivity and white matter hyperintensities in BD than UD depression, habenula volume reductions in BD but not UD depression, and differential patterns of functional abnormalities in emotion regulation and attentional control neural circuitry in the two depression types. These findings suggest different pathophysiologic processes, especially in emotion regulation, reward, and attentional control neural circuitry in BD versus UD depression. This review thereby serves as a call to action to highlight the pressing need for more neuroimaging studies, using larger samples sizes, comparing BD and UD depressed individuals. These future studies should also include dimensional approaches, studies of at-risk individuals, and more novel neuroimaging approaches, such as connectivity analysis and machine learning. Ultimately, these approaches might provide biomarkers to identify individuals at future risk for BD versus UD and biological targets for more personalized treatment and new treatment developments for BD and UD depression.

Figure 1. Current and future perspectives in the classification of affective disorders

Panel A: Left: The present categorical dichotomization of bipolar versus unipolar depression. Right: The clinical overlap between bipolar and unipolar depression, with subthreshold hypomanic symptoms (subM) evident in both disorders during a depressive episode. Panel B: A dimensional perspective for mood disorder classification. Symptoms reflect a spectrum varying from lower to higher severity of hypo/manic symptoms. Panel C: Periods during development for early detection of hypomanic/mixed symptoms and diagnosis of bipolar disorder during the course of the disorder. Panel D: The potential of dimensional approaches, including the RDoC initiative to redefine “bipolarity” in terms of different underlying pathophysiological dimensions (labeled with Roman numerals in the figure) that cut across conventionally defined diagnostic categories of affective disorders, leading to the construction of disease profiles. Such approaches may facilitate identification of biomarkers reflecting relationships among genetic, molecular neural circuitry-level, and behavioral-level abnormalities that underlie different dimensions of psychopathology across the affective disorder spectrum.