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Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics

Molecular Psychiatry (2024)Cite this article

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Abstract

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

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Fig. 1: Steps 1-3: Discovery, Prioritization and Validation of Biomarkers for Hallucinations and Delusions.
Fig. 2: Best single biomarkers predictors for state and trait.
Fig. 3: Example of prototype report for physicians.

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Data availability

Additional data are available in Supplementary Information and upon request to the corresponding author.

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Acknowledgements

We would like to acknowledge our gratitude for the work and results of the many other groups, cited in our paper, who have conducted and published studies (clinical, genetic, and biological) in schizophrenia and related disorders. Combining their work with ours makes a convergent approach possible. We also would particularly like to thank the subjects in these studies and their families. Without their contribution, such work to advance the understanding of psychotic disorders would not be possible. This work was supported by NIH grants (R01MH117431) and a VA Merit Award (2I01CX000139) to ABN.

Author information

Author notes

  1. H. D. Dainton

    Present address: Department of Neurology, Medical University of South Carolina, Charleston, SC, USA

  2. S. K. Wolf

    Present address: Department of Neurology, Ohio State University Medical Center, Columbus, OH, USA

  3. A. Shekhar

    Present address: Office of the Dean, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

  4. These authors contributed equally: M. D. Hill, S. S. Gill, H. Le-Niculescu, O. MacKie.

Authors and Affiliations

  1. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    M. D. Hill, S. S. Gill, H. Le-Niculescu, O. MacKie, R. Bhagar, K. Roseberry, O. K. Murray, H. D. Dainton, S. K. Wolf, A. Shekhar & A. B. Niculescu

  2. Indianapolis VA Medical Center, Indianapolis, IN, USA

    M. D. Hill, O. MacKie & A. B. Niculescu

  3. Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

    H. Le-Niculescu & A. B. Niculescu

  4. Scripps Health, La Jolla, CA, USA

    S. M. Kurian

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Contributions

ABN designed the study and wrote the manuscript. MH, SSG, HLN, OM, RB, KR, OKM, HDD, SKW analyzed the data. MH and OM organized, conducted, and scored testing in psychiatric subjects. SSG assisted with sample report generation. AS assisted with data interpretation. SMK conducted microarray experiments. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to A. B. Niculescu.

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Competing interests

ABN is listed as inventor on a patent application filed by Indiana University. ABN and AS are co-founders, SMK is a consultant, and SSG is a part-time employee of MindX Sciences.

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Hill, M.D., Gill, S.S., Le-Niculescu, H. et al. Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02433-8

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