On antidepressants and still feeling low

Abstract

Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.amygdala | early life stress | human brain imaging | predictive biomarkers | antidepressant remission A mygdala reactivity and exposure to early life stress (ELS) are both strongly implicated in depression mechanisms in both animal and human models (1-6). The amygdala plays an important role in emotion processing, including evaluating biologically salient emotional stimuli, generating emotional states and potentiating emotional memories (7). It also plays a central role in the stress response, both promoting downstream hypothalamic-pituitaryadrenal (HPA) axis stimulation and receiving HPA axis feedback (8). Engagement of the stress system can fundamentally change amygdala structure and function, especially as a result of ELS (2, 9-11). Moreover, the amygdala is likely a component of the neural circuit involved in antidepressant action (12, 13), and the antidepressant response is modified by prior stress exposure (10,14). Despite these mechanistic foundations, amygdala-stress interactions have not been investigated as a prognostic biobehavioral therapeutic target for depression.Human neuroimaging investigations have demonstrated strong links between depression and amygdala abnormalities in both structure and function (1,(15)(16)(17)(18)(19)(20)(21). Structurally, decreased amygdala volumes were found in unmedicated depressed individuals relative to ...