From Side Effect to Target: Rethinking Metabolic Dysfunction in Psychiatry

Metabolic psychiatry was defined as the study of how metabolic dysfunction, and the central and peripheral treatments that target it, affected psychiatric outcomes as well as metabolic health outcomes, according to Shebani Sethi, MD.¹ The subfield was relatively new, with scientists worldwide working in the area, and it focused on how nutritional and metabolic drivers of chronic disease intersected with psychiatry. Anti-inflammatory strategies, insulin-sensitizing agents, and nutritional interventions belonged in treatment planning alongside existing tools, not in place of them. Sethi presented this framework in an American Psychiatric Association webinar to establish the scope of the field with other experts.

Sethi described a shift in how the field regarded metabolic problems. "For decades, we've treated metabolic dysfunction in our field like weight gain or insulin resistance as really a side effect that needs to be monitored and not really a target to treat, but that's really being changed," Sethi said. She explained that "Insulin signaling in the brain or chronic low-grade inflammation or mitochondrial function, even immunity, innate and adaptive immunity being affected by the diet, are mechanistically upstream of psychiatric symptoms, not just downstream consequences of medications."

Markers of bioenergetic dysfunction, including lower lactate levels and glutathione, were identified about 100 years ago, and current work revisited how bioenergetic dysfunction in the brain and body influenced mental health outcomes. Drugs and nutritional interventions could act on specific metabolic pathways to potentially improve psychiatric outcomes.

Ketogenic metabolic therapy, a dietary intervention studied for the past 100 years to reduce seizures in epilepsy, was the focus of Sethi's work, including studies in serious mental illness such as schizophrenia and bipolar disorder.² Drug trials of insulin-sensitizing and obesity medications, such as metformin in bipolar disorder, examined effects on psychiatric symptoms rather than only metabolic health. A randomized controlled trial was starting, and next steps included mechanisms of action such as mitochondrial function and deep omic profiling—protein expression and the microbiome—before and after the intervention. The field was moving toward mechanistic questions about what occurred inside the cell and mitochondria, beyond clinical research alone.

Dr Sethi is an associate professor at Stanford University School of Medicine and founder of Metabolic Psychiatry Labs.

References

1. Sethi S, Berk M, Andreazza AC, et al. Metabolic psychiatry targeting metabolic dysregulation in mental health. Nat Ment Health. 2026;4(4):508-520.

2. Sethi S, Wakeham D, Ketter T, et al. Ketogenic diet intervention on metabolic and psychiatric health in bipolar and schizophrenia: a pilot trial. Psychiatry Res. 2024;335:115866.