Metabolic psychiatry targeting metabolic dysregulation in mental health
Sethi S, Berk M, Andreazza A C, Mujica-Parodi L R, Campbell I, Campbell H, Longhitano C, Rasgon N, Volek J, Calkin C V, Ford J, McCullumsmith R, Cunnane S, Liwinski T, D’Agostino D, Frye M, Sarnyai Z (2026) Nat. Mental Health https://doi.org/10.1038/s44220-026-00609-5
Abstract:
Systemic metabolic abnormalities including insulin resistance, lipid dysregulation, mitochondrial dysfunction and inflammation are highly prevalent in psychiatric illness and may contribute to increased mortality, illness severity and treatment resistance.This Review synthesizes current evidence linking systemic and central metabolic dysfunction with mental health outcomes across disorders. We highlight bidirectional interactions between brain function and metabolic state, and examine how psychotropic medications, stressors and disease mechanisms contribute to metabolic burden. In turn, we discuss how systemic dysfunction may impair brain structure and function. We review emerging metabolism-based interventions used in psychiatry, including pharmacologic agents (metformin, glucagon-like peptide-1 agonists and pioglitazone), lifestyle strategies (intermittent fasting, ketogenic metabolic therapy and exercise) and theoretical models (mitochondrial dysfunction, ‘allostatic load model’ and ‘selfish brain hypothesis’).
We summarize the interventions, their observed outcomes, and a ranked assessment of the current level of evidence and class of recommendation. This reflects that some metabolic-based approaches show promising results from clinical studies while other emerging strategies remain too preliminary or inconsistent to draw conclusions, underscoring the need for further trials in humans.
We conclude by briefly discussing practical and safety considerations, identifying limitations in the current literature, and propose future directions for building a more integrated model of mental and metabolic health.
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