Underlying Hippocampal Mechanism of Posttraumatic Stress Disorder Treatment Outcome: Evidence From Two Clinical Trials

Sigal Zilcha-Mano*, Or Duek, Benjamin Suarez-Jimenez, Xi Zhu, Amit Lazarov, Liat Helpman, Nachshon Korem, Michal Malka, Ilan Harpaz-Rotem, Yuval Neria

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: The hippocampus plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD) and its prognosis. Accumulating findings suggest that individuals with larger pretreatment hippocampal volume are more likely to benefit from PTSD treatment, but the mechanism underlying this effect is unknown. We investigated whether further increase in hippocampal volume during treatment explains the better prognosis of individuals with greater pretreatment hippocampal volume. Methods: We collected structural magnetic resonance imagesfrom patients with PTSD before and after treatment. We examined whether larger hippocampal volume moderates the effect of increased hippocampal volume during treatment on symptom reduction. Given the relatively small sample sizes of treatment studies with pre- and posttreatment magnetic resonance imaging, we focused on effect sizes and sought to replicate findings in an external sample. We tested our hypothesis in study 1 (N = 38; prolonged exposure therapy) and then tested whether the results could be externally replicated in study 2 (N = 20; ketamine infusion followed by exposure therapy). Results: Findings from study 1 revealed that increased right hippocampal volume during treatment was associated with greater PTSD symptom reduction only in patients with greater pretreatment right hippocampal volume (p = .03; η2 = 0.13, a large effect). Findings were partially replicated in study 2 for depressive symptoms (p = .034; η2 = 0.25, a very large effect) and for PTSD symptoms (p = .15; η2 = 0.15, a large effect). Conclusions: Elucidating increased hippocampal volume as one of the neural mechanisms predictive of therapeutic outcome for individuals with larger pretreatment hippocampal volume may help identify clinical targets for this subgroup.

Original languageEnglish
Pages (from-to)867-874
Number of pages8
JournalBiological Psychiatry Global Open Science
Issue number4
StatePublished - Oct 2023


FundersFunder number
National Institutes of HealthNCT01576510, NCT02727998
National Institute of Mental HealthR01MH072833, R01MH105355
Brain and Behavior Research Foundation
National Center for Advancing Translational Sciences
American Pain Society


    • Hippocampal volume
    • Hippocampus
    • Ketamine
    • Neural mechanisms
    • PTSD
    • Prolonged exposure therapy


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