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Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus

Molecular Psychiatry volume 27, pages 2061–2067 (2022)Cite this article

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Abstract

Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abundant differences in gene expression. These gene expression differences are overall quite similar to gene expression differences between schizophrenia cases and controls. Interestingly, gene expression differences based on antipsychotic toxicology are different between brain regions, potentially due to affected cell type differences. We finally assess similarities with effects in a mouse model, which finds some overlapping effects but many differences as well. As a first look at the molecular effects of antipsychotics in the human brain, the lack of epigenetic effects is unexpected, possibly because long term treatment effects may be relatively stable for extended periods.

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Fig. 1: Gene expression differences by antipsychotic toxicology data.
Fig. 2: Comparison of antipsychotic-based differential gene expression in the caudate nucleus and the DLPFC.

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Data availability

Raw and processed nucleic acid sequencing data generated to support the findings of this study are available via the PsychENCODE Knowledge Portal (https://psychencode.synapse.org/). The PsychENCODE Knowledge Portal is a platform for accessing data, analyses and tools generated through grants funded by the National Institute of Mental Health (NIMH) PsychENCODE program. Data are available for general research use according to the following requirements for data access and data attribution: (https://psychencode.synapse.org/DataAccess). For access to WGBS content described in this paper see access Synapse ID syn23318163. RNA-seq data used was generated by Benjamin et al. [17], who provide the relevant data availability information.

Code availability

Analysis code can be found at https://github.com/LieberInstitute/caudate_antipsychotics/.

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Acknowledgements

The authors would like to express their gratitude to our colleagues whose tireless efforts have led to the donation of postmortem tissue to advance these studies: the Office of the Chief Medical Examiner of the District of Columbia; the Office of the Chief Medical Examiner for Northern Virginia, Fairfax Virginia; and the Office of the Chief Medical Examiner of the State of Maryland, Baltimore, Maryland. We would also like to acknowledge Llewellyn B. Bigelow, MD, for his diagnostic expertise. This project was supported by The Lieber Institute for Brain Development and by NIH grants R01MH112751 and T32GM781437. Finally, we are indebted to the generosity of the families of the decedents, who donated the brain tissue used in these studies.

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Authors and Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA

    Kira A. Perzel Mandell, Nicholas J. Eagles, Amy Deep-Soboslay, Ran Tao, Shizhong Han, Thomas M. Hyde, Joel E. Kleinman, Andrew E. Jaffe & Daniel R. Weinberger

  2. Department of Genetic Medicine, Johns Hopkins University School of Medicine (JHSOM), Baltimore, MD, 21205, USA

    Kira A. Perzel Mandell, Andrew E. Jaffe & Daniel R. Weinberger

  3. Department of Psychiatry and Behavioral Sciences, JHSOM, Baltimore, MD, USA

    Shizhong Han, Thomas M. Hyde, Joel E. Kleinman, Andrew E. Jaffe & Daniel R. Weinberger

  4. Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD, USA

    Richard Wilton & Alexander S. Szalay

  5. Department of Computer Science, JHSOM, Baltimore, MD, USA

    Alexander S. Szalay

  6. Department of Neurology, JHSOM, Baltimore, MD, USA

    Thomas M. Hyde & Daniel R. Weinberger

  7. Department of Neuroscience, JHSOM, Baltimore, MD, USA

    Andrew E. Jaffe & Daniel R. Weinberger

  8. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health (JHBSPH), Baltimore, MD, 21205, USA

    Andrew E. Jaffe

  9. Department of Biostatistics, JHBSPH, Baltimore, MD, USA

    Andrew E. Jaffe

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  1. Kira A. Perzel Mandell
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Contributions

KAPM, AEJ and DRW conceptualised the project and methodology, investigated and analysed the data and wrote the paper. ASS, RW and NJE provided software support. ADS, NJE, RT, TMH and RW curated data. SH, JEK, RT and TMH provided resources. ADS, JEK, AEJ and DRW reviewed and edited the paper. All authors read and approved the final paper.

Corresponding author

Correspondence to Daniel R. Weinberger.

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Competing interests

AEJ is a current employee and shareholder of Neumora Therapeutics. DRW is on the Scientific Advisory Board of Sage Therapeutics. The remaining authors declare no competing interests.

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Perzel Mandell, K.A., Eagles, N.J., Deep-Soboslay, A. et al. Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus. Mol Psychiatry 27, 2061–2067 (2022). https://doi.org/10.1038/s41380-022-01453-6

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