title: Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants.
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.
authors: Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305; Sierra-Pacific Mental Illness Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors: Andrea N
authors: AN
authors: Goldstein-Piekarski
authors: Brain Dynamics Center, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW 2145, Australia; Discipline of Psychiatry, Sydney Medical School, Westmead, NSW 2145, Australia.
authors: Mayuresh S
authors: MS
authors: Korgaonkar
authors: Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors: Erin
authors: E
authors: Green
authors: Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors: Trisha
authors: T
authors: Suppes
authors: Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305.
authors: Alan F
authors: AF
authors: Schatzberg
authors: Statistics Department, Stanford University, Stanford, CA 94305; Biomedical Data Science Department, Stanford University, Stanford, CA 94305.
authors: Trevor
authors: T
authors: Hastie
authors: Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136.
authors: Charles B
authors: CB
authors: Nemeroff
authors: Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305; Sierra-Pacific Mental Illness Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; leawilliams@stanford.edu.
authors: Leanne M
authors: LM
authors: Williams
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology*; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001519:Behavior / Q000187:drug effects*; D003863:Depression / Q000209:etiology / Q000503:physiopathology* / Q000534:rehabilitation*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D008960:Models, Psychological; D015233:Models, Statistical; D011379:Prognosis; D012372:ROC Curve; D015203:Reproducibility of Results; D013315:Stress, Psychological; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents
keywords: amygdala; antidepressant remission; early life stress; human brain imaging; predictive biomarkers