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Effect of olanzapine exposure on relapse and brain structure in patients with major depressive disorder with psychotic features

Molecular Psychiatry (2024)Cite this article

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Abstract

Some data suggest that antipsychotics may adversely affect brain structure. We examined the relationship among olanzapine exposure, relapse, and changes in brain structure in patients with major depressive disorder with psychotic features. We analyzed data from the Study of the Pharmacotherapy of Psychotic Depression II trial (STOP-PD II), a randomized, placebo-controlled trial in patients with psychotic depression who attained remission on sertraline and olanzapine and were randomized to continue sertraline plus olanzapine or placebo for 36 weeks. Olanzapine steady state concentration (SSC) were calculated based on sparsely-sampled levels. Rates of relapse and changes in brain structure were assessed as outcomes. There were significant associations between dosage and relapse rates (N = 118; HR = 0.94, 95% CI [0.897, 0.977], p = 0.002) or changes in left cortical thickness (N = 44; B = −2.0 × 10−3, 95% CI [−3.1 × 10−3, −9.6 × 10−4], p < 0.001) and between SSC and changes in left cortical thickness (N = 44; B = −8.7 × 10−4, 95% CI [−1.4 × 10−3, −3.6 × 10−4], p = 0.001). Similar results were found for the right cortex. These associations were no longer significant when the analysis was restricted to participants treated with olanzapine. Our findings suggest that, within its therapeutic range, the effect of olanzapine on relapse or cortical thickness does not depend on its dosage or SSC. Further research is needed on the effect of olanzapine and other antipsychotics on mood symptoms and brain structure.

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Fig. 1: Distribution of dosages and steady state concentrations.
Fig. 2: Change in cortical thickness with olanzapine treatment.

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Data available upon request.

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Acknowledgements

We thank the members of the STOP-PD II Study Group for their contributions. Members of the STOP-PD II Study Group are listed in the Supplementary Information.

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Author notes

  1. These authors contributed equally: George S. Alexopoulos, Kathleen S. Bingham, Alastair J. Flint, Patricia Marino, Anthony J. Rothschild, Ellen M. Whyte.

Authors and Affiliations

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

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

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

    Aristotle N. Voineskos, Nicholas H. Neufeld & Benoit H. Mulsant

  3. Department of Psychiatry, Weill Cornell Medicine of Cornell University and New York Presbyterian Hospital, Westchester Division, New York, NY, USA

    George S. Alexopoulos & Patricia Marino

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

    Kathleen S. Bingham & Alastair J. Flint

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

    Anthony J. Rothschild

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

    Ellen M. Whyte

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Contributions

All authors made substantial contributions to the design of the study, data acquisition, data analysis, interpretation, and/or preparation of the manuscript. All authors participated in drafting and revising of the manuscript and approved the final version to be published.

Corresponding author

Correspondence to Benoit H. Mulsant.

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Competing interests

HKK has no financial relationships with commercial interests. ANV receives funding from the National Institute of Mental Health (NIMH), Canadian Institutes of Health Research, Canada Foundation for Innovation, Centre for Addiction and Mental Health (CAMH) Foundation, and the University of Toronto. NHN receives grant support from the Canadian Institutes of Health Research, Physicians’ Services Incorporated Foundation, and the University of Toronto. GA has served on an advisory board of Otsuka and has been on the speakers bureau of Otsuka. KSB receives grant support from the University of Toronto. AJF has received grant support from the US National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and Alzheimer’s Association. PM has no financial relationships with commercial interests. 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, Lupin Pharmaceuticals, Zydus Pharmaceuticals (USA), Inc., 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. Dr. Mulsant 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 from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, and the US National Institutes of Health (NIH); research support from Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli-Lilly (medications for an NIH-funded clinical trial), Pfizer (medications for an NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada).

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Kim, H.K., Voineskos, A.N., Neufeld, N.H. et al. Effect of olanzapine exposure on relapse and brain structure in patients with major depressive disorder with psychotic features. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02523-7

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