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Schizophrenia: a disorder of broken brain bioenergetics

Molecular Psychiatry volume 27, pages 2393–2404 (2022)Cite this article

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Abstract

A substantial and diverse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.

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Fig. 1: Overview of the major reported perturbations of bioenergetic deficits in schizophrenia.
Fig. 2: Hypothesized therapeutics for schizophrenia that exploit perturbed metabolic functioning in the brain.

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Acknowledgements

This work was supported by NIMH MH107487 and MH121102.

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Authors and Affiliations

  1. Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Nicholas D. Henkel, Xiajoun Wu, Sinead M. O’Donovan, Emily A. Devine, Jessica M. Jiron & Robert E. McCullumsmith

  2. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Laura M. Rowland

  3. Laboratory of Psychiatric Neuroscience, Australian Institute for Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia

    Zoltan Sarnyai

  4. Department of Pharmacology and Toxicology, Department of Physiology, University of Toronto, Toronto, ON, Canada

    Amy J. Ramsey

  5. Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA

    Zhexing Wen

  6. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Margaret K. Hahn

  7. Neurosciences Institute, ProMedica, Toledo, OH, USA

    Robert E. McCullumsmith

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Contributions

NDH, XW, SMOD, JMJ, EAD, and REM wrote the paper. ZS, MKH, and NDH wrote the portion of the paper related to the ketogenic diet. NDH designed and made the figures and tables for the paper. SMOD, LMR, ZS, AJR, ZW, MKH, and REM provided critical feedback, major editorial feedback, and organized the contents of the paper. NDH, XW, SMOD, LMR, ZS, AJR, ZW, MKH, and REM conceptualized the contents of the paper.

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Correspondence to Nicholas D. Henkel.

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MKH discloses an interest with Alkermes, for which she receives consultation fees. NDH, Xiaojun Wu, SMOD, EAD, JMJ, LMR, AJR, ZS, ZW, and REMC have neither financial nor competing interests to disclose.

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Henkel, N.D., Wu, X., O’Donovan, S.M. et al. Schizophrenia: a disorder of broken brain bioenergetics. Mol Psychiatry 27, 2393–2404 (2022). https://doi.org/10.1038/s41380-022-01494-x

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