Aberrant amygdala subregion volumes in youth at high risk for bipolar disorder predict antidepressant-induced adverse events.

Youth with familial risk for bipolar disorder (BD) and current depression/anxiety are vulnerable to antidepressant-induced adverse events (AE), including mania. The amygdala, implicated in the pathophysiology of mood disorders, may play a key role in these AE. 105 youth with at least one first-degree relative with BD-I and a current depressive/anxiety disorder (high-risk) and 51 healthy controls (HC) underwent baseline MRI to investigate neurostructural risk factors for antidepressant-induced AE. High-risk youth were randomized to either psychotherapy plus escitalopram or psychotherapy plus placebo (2:1) for up to 16 weeks. Clinical efficacy was assessed using the Children's Depression Rating Scale-Revised and Pediatric Anxiety Rating Scale, and AE were assessed using the Pediatric Adverse Events Rating Scale and Treatment-Emergent Activation and Suicidality Assessment Profile. Baseline amygdala subregion volumes and their associations with the rates of change in clinical symptoms and AE over time were evaluated using linear regression models. Compared to HC, high-risk youth had reduced volumes in left lateral and medial nuclei, bilateral central and cortical nuclei, and bilateral corticoamygdaloid transition area and increased volumes in bilateral basal and accessory basal nuclei. In escitalopram-treated youth, but not those receiving placebo, smaller baseline volumes in bilateral cortical nuclei and left medial nucleus were associated with fewer arousal-related AE. Additionally, larger bilateral basal nuclei volumes at baseline were associated with more arousal-related AE. Widespread amygdala volume abnormalities provide insights into neurobiological mechanisms underlying the development of BD in high-risk youth, and specific subregion volumes may serve as neurostructural markers for predicting antidepressant-induced AE.