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Antipsychotics cause reversible structural brain changes within one week

Neuropsychopharmacology volume 50, pages 1275–1283 (2025)Cite this article

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Abstract

Determining the effects of antipsychotics on MRI brain structural metrics without the potential confounding effects related to the natural course of a psychotic illness is challenging. However, it is crucial to understand these effects to interpret the results of cross-sectional and longitudinal studies in medicated patients and, ultimately, to understand better the biological mechanisms driving antipsychotics’ effects. In this work, we aim to determine whether exposure to antipsychotics is associated with alterations in brain MRI structural metrics in the absence of disease effects. A randomized, double-blind, counter-balanced order, crossover, placebo-controlled study in healthy volunteers was performed. The study comprised two arms. Within arms, participants were randomized to receive daily doses of either the active compound (Arm 1= amisulpride 400 mg/day, N = 24; Arm 2= aripiprazole 10 mg/day, N = 24) for one week, followed by placebo or vice versa. We found increased MRI volume estimates in the left putamen and in the right caudate in the amisulpride condition as compared to placebo and increased right putamen volume estimates after aripiprazole compared to placebo. No other effects were found in cortical volume estimates, cortical thickness, cortical surface area, and T1-relaxation time. Striatal changes reversed within weeks of drug withdrawal. Short-term exposure to either one of two different antipsychotics results in a transient increase in striatal volume measured with T1-weighted MRI that normalizes rapidly on stopping treatment without cortical changes. Our findings suggest that striatal volumetric MRI differences detected in people with schizophrenia taking antipsychotics are, at least in part, attributable to pharmacological effects.

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Fig. 1: A 3D rendering showing the statistical map for pairwise comparisons between active and placebo sessions (i.e., AMISULPRIDE > PLACEBO and ARIPIPRAZOLE > PLACEBO) on subcortical MRI volume estimates.
Fig. 2: Plots showing group-level and individual putamen volumes.
Fig. 3: Descriptive plots showing the results of the withdrawal analysis.

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Data availability

The ethical approval conditions for this study do not permit unrestricted access to the raw data. De-identified individual participant data are available for research purposes from the corresponding authors from the publication date, subject to a data-sharing agreement, except data from a minority of subjects who did not consent to de-identified data being used to support future research. Requests will be responded to within 15 working days. The conditions of the ethical approval of the study stipulate that access to data that may allow the identification of volunteers will only be permitted for research that an ethics committee has independently reviewed.

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Acknowledgements

We thank all the volunteers who took part in this challenging study. We also thank the staff at the Robert Steiner MRI Unit Imperial College London and at the Maudsley Pharmacy South London and Maudsley NHS Foundation Trust for their crucial support in this study. The authors wish to thank the reviewers for their insightful comments and constructive suggestions, which greatly contributed to improving the quality and clarity of this manuscript. We also sincerely appreciate their positive evaluation of the study.

Funding

This study was funded by Medical Research Council-UK (no. MC_U120097115), Maudsley Charity (no. 666), and Wellcome Trust (no. 094849/Z/10/Z) grants to Prof. Howes. This paper represents an independent research part funded by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London that supported Pierluigi Selvaggi, Ottavia Dipasquale, and Mitul A Mehta. Pierluigi Selvaggi has been supported by a Ph.D. studentship jointly funded by the NIHR-BRC at SLaM and the Department of Neuroimaging, King’s College London. Pierluigi Selvaggi is currently supported by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No. 964874 (REALMENT). George Chapman is currently a National Institute for Health and Care Research (NIHR) Academic Clinical Fellow. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

    Pierluigi Selvaggi, Ottavia Dipasquale, Tobias C. Wood & Mitul A. Mehta

  2. Department of Translational Biomedicine and Neuroscience, University of Bari “Aldo Moro”, Bari, Italy

    Pierluigi Selvaggi

  3. MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom

    Pierluigi Selvaggi, Martin Osugo, Uzma Zahid, Thomas Whitehurst, Ellis Onwordi, George Chapman, Valeria Finelli, Ben Statton, Robin Murray, Tiago Reis Marques & Oliver D. Howes

  4. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

    Martin Osugo, Uzma Zahid, Thomas Whitehurst, Ellis Onwordi, Tiago Reis Marques & Oliver D. Howes

  5. Camden and Islington NHS Foundation Trust, London, United Kingdom

    George Chapman

  6. Division of Psychiatry, Faculty of Brain Sciences, University College London, London, United Kingdom

    George Chapman

  7. Invicro, London, UK

    Matthew B. Wall

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Contributions

Conceptualization: PS, TRS, MAM, ODH, Methodology: PS, OD, BS, TCW, MBW, MAM, ODH; Investigation: PS, MO, UZ, TW, EO, GC, VF; Visualization: PS, MO, UZ, TCW, MBW, RM, MAM, TRM, ODH; Funding acquisition: ODH; Project administration: TRM, ODH; Supervision: RM, MAM, TRM, ODH; Writing – original draft: PS, ODH; Writing – review & editing: PS, MO, UZ, OD, TW, EO, GC, VF, BS, TCW, MBW, RM, MAM, TRM, ODH. All authors approved the manuscript and are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Pierluigi Selvaggi or Oliver D. Howes.

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Competing interests

In the past three years, MAM has been an advisory board member for Lundbeck and Forum Pharmaceuticals. He also received research funding from Lundbeck, Takeda, and Johnson & Johnson. O.D.H. has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/Mylan. He was previously a part-time employee of Lundbeck A/v. Neither O.D.H. nor his family have holdings/a financial stake in any pharmaceutical company. ODH has a patent for the use of dopaminergic imaging. PS participated in advisory/speaker meetings organized by Angelini and Lundbeck. M.B.W. is an employee of Perceptive Inc., London. T.R.M. is an employee and founder of Pasithea Therapeutics. Other authors have reported no biomedical financial interests or potential conflicts of interest.

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Selvaggi, P., Osugo, M., Zahid, U. et al. Antipsychotics cause reversible structural brain changes within one week. Neuropsychopharmacol. 50, 1275–1283 (2025). https://doi.org/10.1038/s41386-025-02120-4

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