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This article is the author's final published version in Frontiers in Psychiatry, Volume 12, December 2021, Article number 718539.

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Copyright © 2021 Tai, Cha, Vedaei, Dunlop, Craighead, Mayberg and Choi.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


Background: Hippocampal atrophy has been consistently reported in major depressive disorder with more recent focus on subfields. However, literature on hippocampal volume changes after antidepressant treatment has been limited. The first-line treatments for depression include antidepressant medication (ADM) or cognitive-behavior therapy (CBT). To understand the differential effects of CBT and ADM on the hippocampus, we investigated the volume alterations of hippocampal subfields with treatment, outcome, and chronicity in treatment-naïve depression patients. Methods: Treatment-naïve depressed patients from the PReDICT study were included in this analysis. A total of 172 patients who completed 12 weeks of randomized treatment with CBT (n = 45) or ADM (n = 127) were included for hippocampal subfield volume analysis. Forty healthy controls were also included for the baseline comparison. Freesurfer 6.0 was used to segment 26 hippocampal substructures and bilateral whole hippocampus from baseline and week 12 structural MRI scans. A generalized linear model with covariates of age and gender was used for group statistical tests. A linear mixed model for the repeated measures with covariates of age and gender was used to examine volumetric changes over time and the contributing effects of treatment type, outcome, and illness chronicity. Results: Of the 172 patients, 85 achieved remission (63/127 ADM, 22/45 CBT). MDD patients showed smaller baseline volumes than healthy controls in CA1, CA3, CA4, parasubiculum, GC-ML-DG, Hippocampal Amygdala Transition Area (HATA), and fimbria. Over 12 weeks of treatment, further declines in the volumes of CA1, fimbria, subiculum, and HATA were observed regardless of treatment type or outcome. CBT remitters, but not ADM remitters, showed volume reduction in the right hippocampal tail. Unlike ADM remitters, ADM non-responders had a decline in volume in the bilateral hippocampal tails. Baseline volume of left presubiculum (regardless of treatment type) and right fimbria and HATA in CBT patients were correlated with a continuous measure of clinical improvement. Chronicity of depression had no effect on any measures of hippocampal subfield volumes. Conclusion: Two first-line antidepressant treatments, CBT and ADM, have different effects on hippocampal tail after 12 weeks. This finding suggests that remission achieved via ADM may protect against progressive hippocampal atrophy by altering neuronal plasticity or supporting neurogenesis. Studies with multimodal neuroimaging, including functional and structural analysis, are needed to assess further the impact of two different antidepressant treatments on hippocampal subfields.

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