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  • Systematic Review
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DNA methylation and histone modifications associated with antipsychotic treatment: a systematic review

Molecular Psychiatry (2024)Cite this article

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Abstract

Antipsychotic medications are essential when treating schizophrenia spectrum and other psychotic disorders, but the efficacy and tolerability of these medications vary from person to person. This interindividual variation is likely mediated, at least in part, by epigenomic processes that have yet to be fully elucidated. Herein, we systematically identified and evaluated 65 studies that examine the influence of antipsychotic drugs on epigenomic changes, including global methylation (9 studies), genome-wide methylation (22 studies), candidate gene methylation (16 studies), and histone modification (18 studies). Our evaluation revealed that haloperidol was consistently associated with increased global hypermethylation, which corroborates with genome-wide analyses, mostly performed by methylation arrays. In contrast, clozapine seems to promote hypomethylation across the epigenome. Candidate-gene methylation studies reveal varying effects post-antipsychotic therapy. Some genes like Glra1 and Drd2 are frequently found to undergo hypermethylation, whereas other genes such as SLC6A4, DUSP6, and DTNBP1 are more likely to exhibit hypomethylation in promoter regions. In examining histone modifications, the literature suggests that clozapine changes histone methylation patterns in the prefrontal cortex, particularly elevating H3K4me3 at the Gad1 gene and affecting the transcription of genes like mGlu2 by modifying histone acetylation and interacting with HDAC2 enzymes. Risperidone and quetiapine, however, exhibit distinct impacts on histone marks across different brain regions and cell types, with risperidone reducing H3K27ac in the striatum and quetiapine modifying global H3K9me2 levels in the prefrontal cortex, suggesting antipsychotics demonstrate selective influence on histone modifications, which demonstrates a complex and targeted mode of action. While this review summarizes current knowledge, the intricate dynamics between antipsychotics and epigenetics clearly warrant more exhaustive exploration with the potential to redefine our understanding and treatment of psychiatric conditions. By deciphering the epigenetic changes associated with drug treatment and therapeutic outcomes, we can move closer to personalized medicine in psychiatry.

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Fig. 1: PRISMA Diagram.
Fig. 2: Summary of global methylation studies results.
Fig. 3: Summary of genome-wide methylation studies results.

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Acknowledgements

This project was funded, in part, by Alberta Innovates Doctoral Scholarship (DM). The authors would like to thank Dr. Myriam Hemberger and Dr. Wendy Dean for constructive criticism.

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Authors and Affiliations

  1. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Diogo Marques, Nazanin Vaziri & Chad Bousman

  2. Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Diogo Marques, Nazanin Vaziri, Steven C. Greenway & Chad Bousman

  3. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Diogo Marques, Nazanin Vaziri & Chad Bousman

  4. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Diogo Marques, Nazanin Vaziri & Steven C. Greenway

  5. Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  6. Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  7. Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  8. Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Chad Bousman

  9. Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Chad Bousman

  10. Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Chad Bousman

Authors
  1. Diogo Marques
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  2. Nazanin Vaziri
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  3. Steven C. Greenway
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  4. Chad Bousman
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Contributions

DM, CB, and SG contributed to the study conception. The retrieved records were independently reviewed by two authors (DM, NV). If there was a disagreement, a third author (CB) reviewed the article, and a consensus was reached. The initial draft of the manuscript was written by DM. CB and SG helped in the revisions. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chad Bousman.

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Competing interests

CB is the founder of Sequence2Script Inc. All other authors have nothing to disclose.

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Marques, D., Vaziri, N., Greenway, S.C. et al. DNA methylation and histone modifications associated with antipsychotic treatment: a systematic review. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02735-x

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  • DOI: https://doi.org/10.1038/s41380-024-02735-x

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