Ketogenic Therapy for Schizophrenia: Evidence, Mechanisms, and Clinical Perspectives

Cristiano Chaves^1,2*Jennifer Fabe³Fabiano Gomes¹Heather McNeely¹Massimo Tusconi⁴Mauro G Carta⁴Serdar M Dursun⁵Jaime Eduardo Hallak⁶Benicio N Frey¹Elisa Brietzke²

• ¹Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
• ²Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
• ³McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
• ⁴University of Cagliari, Cagliari, Sardinia, Italy
• ⁵Neurochemical Research Unit, Department of Psychiatry University of Alberta, Edmonton, Alberta, Canada
• ⁶Department of Neurosciences and Behavioral Sciences, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirao Preto, Sao Paulo, Brazil

Introduction: Schizophrenia is a chronic psychiatric disorder marked by significant cognitive and functional impairments. Current antipsychotic treatments offer limited benefit for negative symptoms and cognitive dysfunction while often exacerbating metabolic comorbidities. Emerging evidence implicates impaired glucose metabolism and mitochondrial dysfunction in the pathophysiology of schizophrenia, suggesting a role for metabolic interventions.Methods: This article reviews and synthesizes clinical, preclinical, and mechanistic evidence supporting the use of ketogenic therapy-a high-fat, low-carbohydrate intervention that induces ketosis-as a potential adjunctive treatment in schizophrenia.Results: Preliminary clinical findings, including case reports and small trials, suggest that ketogenic therapy may improve positive and negative symptoms, cognitive performance, and metabolic outcomes in individuals with schizophrenia spectrum disorders. Preclinical studies using NMDA antagonist models demonstrate that ketogenic interventions can normalize behavioral and neurophysiological deficits. Mechanistically, ketone bodies enhance mitochondrial function, modulate neurotransmitter systems (GABA, glutamate, dopamine), and reduce inflammation and oxidative stress. These effects may address core dysfunctions in schizophrenia that are unresponsive to dopamine-targeting pharmacotherapies.Discussion: Ketogenic therapy holds potential for addressing unmet clinical needs in schizophrenia, including negative and cognitive symptoms, treatment-resistant cases, and antipsychotic-induced metabolic syndrome. It may also be explored as a preventive strategy in high-risk populations. However, larger controlled trials are needed to establish efficacy, safety, and feasibility in psychiatric settings.Ketogenic therapy offers a novel, mechanistically informed intervention that targets metabolic and neurochemical pathways implicated in schizophrenia. If validated, it could pave the way for more integrative and personalized treatment strategies.