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Imaging brain energetics to advance metabolic psychiatry

Neuropsychopharmacology (2025)Cite this article

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Brain physiology requires high energy expenditure. The energetic demands of neurotransmission and the tight control of membrane potentials for electrical signaling explain why, despite representing only 2% of body mass, the brain accounts for a quarter of basal energy utilization. Converging evidence from imaging, mitochondrial ultrastructural analysis, genetics, transcriptomics, and proteomics implicates impaired brain energetic metabolism, and specifically a shift from higher efficiency oxidative phosphorylation to glycolysis, as a shared feature of neuropsychiatric conditions [1,2,3,4]. The extent, anatomical localization, and cell-type specificity of these impairments, as well as the varying vulnerability of neural circuits to metabolic stress, may help explain how this dysregulation contributes to psychiatric symptomatology. Because brain energetics also constrain neurotransmitter signaling, this metabolic perspective integrates into a unifying framework linking molecular, cellular, and network-level abnormalities across psychiatric disorders.

Currently available treatments for mood and psychotic disorders do not improve symptoms in a substantial subset of patients. This has prompted a search for new therapeutic approaches, including those that enhance brain energetics. Studies of treatments targeting brain energetics including pharmacological (creatine, exogenous ketones), device-based (transcranial photobiomodulation) and dietary (ketogenic diet), have shown early promise [5, 6]. Recent pilot trials indicate that ketogenic interventions improve symptom severity in individuals with mood disorders and schizophrenia [4]. Imaging findings suggest that ketogenic interventions enhance brain energy metabolism and mitochondrial function, aligning with improved clinical outcomes in mood stabilization and cognitive performance [5]. Transcranial photobiomodulation, a neuromodulation strategy that delivers near-infrared light to the cortex and enhances metabolism by activating components of the mitochondrial electron transport chain, demonstrated antidepressant properties with a medium to large effect size in patients with major depressive disorder [7]. A recent expert perspective [8] advocating a metabolic psychiatry research agenda [9], identified the need for imaging tools that can track changes in brain energetics as critical to this work. Here, we advocate for the expanded use of functional neuroimaging as a tool to advance a fail-fast clinical research program for studying therapeutics and identifying likely responders.

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Funding

The authors received no funding with respect to the publication, research, or authorship of this commentary.

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Authors and Affiliations

  1. New York University Grossman School of Medicine, Department of Psychiatry New York, New York, NY, USA

    Naomi L. Gaggi & David T. Liebers

  2. Nathan S. Kline Institute for Psychiatric Research, Department of Clinical Research Orangeburg, New York, NY, USA

    Naomi L. Gaggi & David T. Liebers

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  1. Naomi L. Gaggi
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  2. David T. Liebers
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Contributions

NLG conceived the idea for the commentary, submitted the manuscript to NPP, and was involved in all journal correspondence. DTL and NLG contributed equally to the original draft of the manuscript, edited the final version of the manuscript, and created the table. Both contributed equally to manuscript revisions and approval.

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Correspondence to Naomi L. Gaggi.

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Gaggi, N.L., Liebers, D.T. Imaging brain energetics to advance metabolic psychiatry. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02304-y

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