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

doi:10.1016/j.bpsgos.2023.01.005

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

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	867-874
Number of pages	8
Journal	Biological Psychiatry Global Open Science
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.bpsgos.2023.01.005
State	Published - Oct 2023

Bibliographical note

Funding Information:
This work was supported by the National Institute of Mental Health (Grant Nos. R01MH105355 and R01MH072833 [to YN]); by an Independent Investigator Grant from the Brain and Behavior Research Foundation (to IH-R); by the Clinical Neurosciences Division of the National Center for PTSD (to IH-R); a donation from the American Brain Society (to IH-R); and by the Yale Center for Clinical Investigation supported by a Clinical and Translational Science Awards grant from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (to IH-R). The authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Brain Circuitry and Psychosocial Predictors of PTSD; https://clinicaltrials.gov/ct2/show/NCT01576510; NCT01576510. ClinicalTrials.gov: Combining Neurobiology and New Learning: Ketamine and Prolonged Exposure: A Potential Rapid Treatment for Post Traumatic Stress Disorder (PTSD); https://clinicaltrials.gov/ct2/show/NCT02727998; NCT02727998.

Funding Information:
This work was supported by the National Institute of Mental Health (Grant Nos. R01MH105355 and R01MH072833 [to YN]); by an Independent Investigator Grant from the Brain and Behavior Research Foundation (to IH-R); by the Clinical Neurosciences Division of the National Center for PTSD (to IH-R); a donation from the American Brain Society (to IH-R); and by the Yale Center for Clinical Investigation supported by a Clinical and Translational Science Awards grant from the National Center for Advancing Translational Sciences , a component of the National Institutes of Health (to IH-R).

Publisher Copyright:
© 2023 The Authors

Keywords

Hippocampal volume
Hippocampus
Ketamine
Neural mechanisms
PTSD
Prolonged exposure therapy

ASJC Scopus subject areas

Clinical Neurology
Psychiatry and Mental health
Biological Psychiatry
Psychiatric Mental Health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bpsgos.2023.01.005

Cite this

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title = "Underlying Hippocampal Mechanism of Posttraumatic Stress Disorder Treatment Outcome: Evidence From Two Clinical Trials",

abstract = "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.",

keywords = "Hippocampal volume, Hippocampus, Ketamine, Neural mechanisms, PTSD, Prolonged exposure therapy",

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

note = "Funding Information: This work was supported by the National Institute of Mental Health (Grant Nos. R01MH105355 and R01MH072833 [to YN]); by an Independent Investigator Grant from the Brain and Behavior Research Foundation (to IH-R); by the Clinical Neurosciences Division of the National Center for PTSD (to IH-R); a donation from the American Brain Society (to IH-R); and by the Yale Center for Clinical Investigation supported by a Clinical and Translational Science Awards grant from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (to IH-R). The authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Brain Circuitry and Psychosocial Predictors of PTSD; https://clinicaltrials.gov/ct2/show/NCT01576510; NCT01576510. ClinicalTrials.gov: Combining Neurobiology and New Learning: Ketamine and Prolonged Exposure: A Potential Rapid Treatment for Post Traumatic Stress Disorder (PTSD); https://clinicaltrials.gov/ct2/show/NCT02727998; NCT02727998. Funding Information: This work was supported by the National Institute of Mental Health (Grant Nos. R01MH105355 and R01MH072833 [to YN]); by an Independent Investigator Grant from the Brain and Behavior Research Foundation (to IH-R); by the Clinical Neurosciences Division of the National Center for PTSD (to IH-R); a donation from the American Brain Society (to IH-R); and by the Yale Center for Clinical Investigation supported by a Clinical and Translational Science Awards grant from the National Center for Advancing Translational Sciences , a component of the National Institutes of Health (to IH-R). Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

doi = "10.1016/j.bpsgos.2023.01.005",

language = "English",

volume = "3",

pages = "867--874",

journal = "Biological Psychiatry Global Open Science",

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T1 - Underlying Hippocampal Mechanism of Posttraumatic Stress Disorder Treatment Outcome

T2 - Evidence From Two Clinical Trials

AU - Zilcha-Mano, Sigal

AU - Duek, Or

AU - Suarez-Jimenez, Benjamin

AU - Zhu, Xi

AU - Lazarov, Amit

AU - Helpman, Liat

AU - Korem, Nachshon

AU - Malka, Michal

AU - Harpaz-Rotem, Ilan

AU - Neria, Yuval

N1 - Funding Information: This work was supported by the National Institute of Mental Health (Grant Nos. R01MH105355 and R01MH072833 [to YN]); by an Independent Investigator Grant from the Brain and Behavior Research Foundation (to IH-R); by the Clinical Neurosciences Division of the National Center for PTSD (to IH-R); a donation from the American Brain Society (to IH-R); and by the Yale Center for Clinical Investigation supported by a Clinical and Translational Science Awards grant from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (to IH-R). The authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Brain Circuitry and Psychosocial Predictors of PTSD; https://clinicaltrials.gov/ct2/show/NCT01576510; NCT01576510. ClinicalTrials.gov: Combining Neurobiology and New Learning: Ketamine and Prolonged Exposure: A Potential Rapid Treatment for Post Traumatic Stress Disorder (PTSD); https://clinicaltrials.gov/ct2/show/NCT02727998; NCT02727998. Funding Information: This work was supported by the National Institute of Mental Health (Grant Nos. R01MH105355 and R01MH072833 [to YN]); by an Independent Investigator Grant from the Brain and Behavior Research Foundation (to IH-R); by the Clinical Neurosciences Division of the National Center for PTSD (to IH-R); a donation from the American Brain Society (to IH-R); and by the Yale Center for Clinical Investigation supported by a Clinical and Translational Science Awards grant from the National Center for Advancing Translational Sciences , a component of the National Institutes of Health (to IH-R). Publisher Copyright: © 2023 The Authors

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

KW - Hippocampal volume

KW - Hippocampus

KW - Ketamine

KW - Neural mechanisms

KW - PTSD

KW - Prolonged exposure therapy

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JO - Biological Psychiatry Global Open Science

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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