Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants
- PMID: 27791054
- PMCID: PMC5081583
- DOI: 10.1073/pnas.1606671113
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.
Trial registration: ClinicalTrials.gov NCT00693849.
Keywords: amygdala; antidepressant remission; early life stress; human brain imaging; predictive biomarkers.
Conflict of interest statement
L.M.W. received research funding from Brain Resource Pty Ltd. as an investigator at International Study to Predict Optimized Treatment in Depression sites. A.F.S. has speaking fees from Merck, GSK, and Roche; consultant fees from BrainCells, CeNeRx, CNS Response, Eli Lilly, Forest Labs, Genetech, Gilead, GSK, Jazz, Lundbeck, Merck, Neuronetics, Novadel, Novartis, Pathway Diagnostics, Pfizer, PharmaNeuroBoost, Quintiles, Sanofi-Aventis, Sunovion, Synosia, Takeda, Xytis, Wyeth; equity in Amnestix, BrainCells, CeNeRx, Corcept (co-founder), Delpor, Forest, Merck, Neurocrine, Novadel, Pfizer, PharaNeuroBoost, Somaxon, Synosis, and Titan; and patents on glucocorticoid antagonists and antidepressant response. T.S. has received research funding, from 2015 to the present, from the National Institute of Mental Health, Sunovion Pharmaceuticals, Inc., Elan Pharma International Limited, VA Cooperative Studies Program, Pathway Genomics, and Stanley Medical Research Institute. She has received consultant speaker fees from A/S Lundbeck, Sunovion, and Merck & Co; continuing medical education honoraria from Medscape Education, Global Medical Education, and CMEology; and royalties from Jones and Bartlett and UptoDate. C.B.N. has consultant fees from Xhale, Takeda, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Lundbeck, Prismic Pharmaceuticals, Bracket (Clintara), Total Pain Solutions (TPS), and Gerson Lehrman Group (GLG) Healthcare & Biomedical Council. He has equity in Xhale, Celgene, Seattle Genetics, Abbvie, Titan Pharmaceuticals, OPKO Health, Inc., and Bracket Intermediate Holding Corp; a Scientific Advisory Board/Board of Directors fee from Skyland Trail, Bracket (Clintara), and RiverMend Health LLC; and patents for Methods and devices for transdermal delivery of lithium (US 6,375,990 BI) and Method to estimate antidepressant drug therapy by ex vivo assay (US 7,148,027B2). L.M.W. has consult fees from Humana and Advisor Board Fees from Psyberguide.
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