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Effects of antipsychotic medication on functional connectivity in major depressive disorder with psychotic features

Molecular Psychiatry volume 28, pages 3305–3313 (2023)Cite this article

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Abstract

The effect of antipsychotic medication on resting state functional connectivity in major depressive disorder (MDD) is currently unknown. To address this gap, we examined patients with MDD with psychotic features (MDDPsy) participating in the Study of the Pharmacotherapy of Psychotic Depression II. All participants were treated with sertraline plus olanzapine and were subsequently randomized to continue sertraline plus olanzapine or be switched to sertraline plus placebo. Participants completed an MRI at randomization and at study endpoint (study completion at Week 36, relapse, or early termination). The primary outcome was change in functional connectivity measured within and between specified networks and the rest of the brain. The secondary outcome was change in network topology measured by graph metrics. Eighty-eight participants completed a baseline scan; 73 completed a follow-up scan, of which 58 were usable for analyses. There was a significant treatment X time interaction for functional connectivity between the secondary visual network and rest of the brain (t = −3.684; p = 0.0004; pFDR = 0.0111). There was no significant treatment X time interaction for graph metrics. Overall, functional connectivity between the secondary visual network and the rest of the brain did not change in participants who stayed on olanzapine but decreased in those switched to placebo. There were no differences in changes in network topology measures when patients stayed on olanzapine or switched to placebo. This suggests that olanzapine may stabilize functional connectivity, particularly between the secondary visual network and the rest of the brain.

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Fig. 1: CONSORT Chart.
Fig. 2: Brain Networks and Changes in Functional Connectivity.

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Code availability

Code used for these analyses can be found here: https://github.com/loliver4/STOPPD_Long_FC

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Acknowledgements

This study was funded by the National Institute of Mental Health (NIMH) R01MH099167 grant. The STOP-PD II clinical trial from which participants were recruited was funded by US Public Health Service grants MH 62446, MH 62518, MH 62565, and MH 62624 from the NIMH. In that trial, Eli Lilly provided olanzapine and matching placebo pills and Pfizer provided sertraline; neither company provided funding for the study. ClinicalTrials.gov Identifier: NCT01427608. We thank the members of the STOP-PD II Study Group for their contributions. Members of the STOP-PD II Study Group were: Peter Giacobbe, M.D. and Brenda Swampillai B.Sc. at the University Health Network, Toronto and James Kennedy, M.D. and Bruce Pollock M.D., Ph.D. at the Centre for Addiction and Mental Health, Toronto; Kristina Deligiannidis, M.D., Chelsea Kosma, M.A., Wendy Marsh, M.D. at the University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, MA; Ariel Gildengers M.D., Joelle Kincman Ph.D., Meryl Butters Ph.D., and Michelle Zmuda M.A. at the University of Pittsburgh School of Medicine, Pittsburgh, PA; and Judith English, M.A., James Kocsis, M.D., Barbara Ladenheim, Ph.D., Vassilios Latoussakis, M.D., and Nikhil Palekar, M.D. at Weill Cornell Medicine of Cornell University and New York Presbyterian Hospital, NY. We additionally thank Cristina Pollari, MPH, for her help with data management, Matthew Rudorfer, MD, who represented the NIMH on the STOP-PD II trial, and Judy Kwan, BSc, for her help with participant recruitment and assessment. We also thank all study participants.

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Authors and Affiliations

  1. Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Nicholas H. Neufeld, Benoit H. Mulsant, Kathleen S. Bingham, Alastair J. Flint & Aristotle N. Voineskos

  2. Centre for Addiction and Mental Health, Toronto, ON, Canada

    Nicholas H. Neufeld, Lindsay D. Oliver, Benoit H. Mulsant, Hideaki Tani & Aristotle N. Voineskos

  3. Department of Psychiatry, Weill Cornell Medicine, Weill Cornell Medical College, Westchester Behavioral Health Center, White Plains, NY, USA

    George S. Alexopoulos, Patricia Marino & Barnett S. Meyers

  4. Division of Clinical Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Matthew J. Hoptman

  5. Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA

    Matthew J. Hoptman

  6. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

    Hideaki Tani

  7. Department of Psychiatry, University of Massachusetts Chan Medical School and UMass Memorial Health Care, Worcester, MA, USA

    Anthony J. Rothschild

  8. Department of Psychiatry, University of Pittsburgh School of Medicine and UPMC Western Psychiatric Hospital, Pittsburgh, PA, USA

    Ellen M. Whyte

  9. Centre for Mental Health, University Health Network, Toronto, ON, Canada

    Kathleen S. Bingham & Alastair J. Flint

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  1. Nicholas H. Neufeld
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Contributions

NHN, LDO, BHM, GSA, BSM, AJR, EMW, AJF, and ANV conceived and designed the study. All authors were involved in the acquisition, analysis, or interpretation of data. NHN, LDO, BHM, GSA, BSM, AJR, EMW, AJF, and ANV drafted the manuscript. All authors were involved in the critical revision of the manuscript for important intellectual content. NHN, LDO, and ANV contributed to statistical analyses. BHM, GSA, BSM, AJR, EMW, AJF, and ANV obtained funding. NHN, LDO, MJH, HT, PM, KSB, AJF, and ANV provided administrative, technical, or material support. ANV provided supervision.

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Correspondence to Aristotle N. Voineskos.

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Competing interests

NHN receives grant support from the Brain and Behavior Research Foundation (BBRF), Canadian Institutes of Health Research (CIHR), Physicians’ Services Incorporated Foundation, Labatt Family Network for Research on the Biology of Depression, and the University of Toronto; this work was supported in part by an Academic Scholars Award from the Department of Psychiatry, University of Toronto. Dr Oliver receives grant support from the BBRF. BHM holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received research support during the past three years from Brain Canada, CIHR, CAMH Foundation, Patient-Centered Outcomes Research Institute (PCORI), US National Institutes of Health (NIH), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). Within the past three years, he has also been an unpaid consultant to Myriad Neuroscience. He directly owns stocks of General Electric (less than $5000). GSA has received National Institute of Mental Health (NIMH) grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, and Sunovion. MJH has received an American Foundation for Suicide Prevention grant and NIMH subcontract funding during the conduct of this study. HT was supported by a Postdoctoral Fellowship from CIHR. He has received manuscript or speaker fees from Dainippon Sumitomo Pharma, Janssen Pharmaceutical, Otsuka Pharmaceutical, Takeda, Wiley Japan, and Yoshitomi Yakuhin. PM received research support from the NIMH at the time this work was done. BSM received research support from the NIMH at the time this work was done. AJR has received grant or research support from Janssen, Otsuka, and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry; is a consultant to Daiichi Sankyo, Inc., Sage Therapeutics, Xenon Pharmaceuticals, and Neumora Therapeutics; and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®, Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012, and from UpToDate®. EMW receives grant support from the NIMH and Health Resources and Services Administration. KSB receives grant support from the University of Toronto. AJF has received grant support from the US NIH, PCORI, CIHR, Brain Canada, Ontario Brain Institute, Alzheimer’s Association, AGE-WELL, Canadian Foundation for Healthcare Improvement, and University of Toronto. ANV receives funding from the NIMH, CIHR, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto.

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Neufeld, N.H., Oliver, L.D., Mulsant, B.H. et al. Effects of antipsychotic medication on functional connectivity in major depressive disorder with psychotic features. Mol Psychiatry 28, 3305–3313 (2023). https://doi.org/10.1038/s41380-023-02118-8

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