Heterogeneity of amygdala response in major depressive disorder: the impact of lifetime subthreshold mania

Background. Patients with major depressive disorder (MDD) present with highly heterogeneous symptom profiles. We aimed to examine whether individual differences in amygdala activity to emotionally salient stimuli were related to heterogeneity in lifetime levels of depressive and subthreshold manic symptoms among adults with MDD. Method. We compared age-and gender-matched adults with MDD (n=26) with healthy controls (HC, n=28). While undergoing functional magnetic resonance imaging, participants performed an implicit emotional faces task : they labeled a color flash superimposed upon initially neutral faces that dynamically morphed into one of four emotions (angry, fearful, sad, happy). Region of interest analyses examined group differences in amygdala activity. For conditions in which adults with MDD displayed abnormal amygdala activity versus HC, within-group analyses examined amygdala activity as a function of scores on a continuous measure of lifetime depression-related and mania-related pathology. Results. Adults with MDD showed significantly greater right-sided amygdala activity to angry and happy conditions than HC (p<0.05, corrected). Multiple regression analyses revealed that greater right-amygdala activity to the happy condition in adults with MDD was associated with higher levels of subthreshold manic symptoms experienced across the lifespan (p=0.002). Conclusions. Among depressed adults with MDD, lifetime features of subthreshold mania were associated with abnormally elevated amygdala activity to emerging happy faces. These findings are a first step toward identifying biomarkers that reflect individual differences in neural mechanisms in MDD, and challenge conventional mood disorder diagnostic boundaries by suggesting that some adults with MDD are characterized by pathophysiological processes that overlap with bipolar disorder.