First Randomized Controlled Trial Shows Promise of a Ketogenic Diet in Psychotic Disorders

First Randomized Controlled Trial Shows Promise of a Ketogenic Diet in Psychotic Disorders

Researchers are exploring the intersection of metabolism and neuroscience to treat serious mental illness, moving toward a field described as metabolic psychiatry. A first-of-its-kind randomized controlled trial (RCT) from the University of California, San Francisco (UCSF) has demonstrated that a ketogenic diet may provide metabolic, psychiatric, and cognitive benefits for individuals with schizophrenia-spectrum or bipolar-1 disorders.

The study, published in Schizophrenia Bulletin and funded in part by the National Institute of Mental Health (NIMH), focused on the feasibility and impact of the diet. Of 58 enrolled participants, 47 completed an initial one-month comparison between a ketogenic intervention and a diet-as-usual control group. Following this, 25 participants entered a four-month single-arm extension.

The intervention proved feasible, as 83% of daily-tested participants maintained ketosis during the one-month RCT, and that figure rose to 94% during the four-month extension. Researchers reported no significant side effects from the diet.

Metabolic and Psychiatric Gains

After one month, participants on the ketogenic diet showed statistically significant improvements in key metabolic markers compared to the control group. Higher ketone levels were associated with lower blood glucose and reduced depression symptoms, measured by PHQ-9. These results remained evident even after accounting for weight loss, suggesting that ketosis itself—rather than weight reduction—contributes to the effects.

The subsequent four-month extension showed sustained metabolic improvements alongside enhanced cognitive performance and significant reductions in schizophrenia and depression symptoms.

"The improvement we saw in cognitive and psychological symptoms is particularly important in people with psychotic disorders, because current medications that address their psychosis don't address their overall mental wellbeing, including cognitive or depressive symptoms, which can be debilitating,"

Judith M. Ford, PhD, Professor of Psychiatry at UCSF and the Weill Institute for Neurosciences, via miragenews.com

Addressing the "Double-Edged Sword" of Medication

The UCSF findings build upon a separate pilot study led by Stanford Medicine, published March 27 in Psychiatry Research. That study addressed a specific challenge: while antipsychotic medications regulate brain chemistry, they often cause metabolic side effects like obesity and insulin resistance, which can lead patients to stop their treatment.

In the Stanford trial, 21 adults with schizophrenia or bipolar disorder followed a ketogenic diet consisting of approximately 60% fat, 30% protein, and 10% carbohydrates. The results showed that participants could reverse metabolic syndrome and obesity even while remaining on antipsychotic drugs. Specifically, 29% of participants met metabolic syndrome criteria before the trial; by the end of four months, none did.

The Stanford group also saw an average body weight loss of 10% and an 11% reduction in waist circumference. Psychiatric improvements were noted as well, with participants improving 31% on the clinical global impressions scale, and three-quarters of the group showing clinically meaningful improvement.

Shebani Sethi, MD, associate professor of psychiatry and behavioral sciences at Stanford, noted that the ketogenic diet may provide ketones as an alternative fuel for a brain experiencing energy dysfunction.

Expanding the Scope of Metabolic Therapy

The research is supported by the Baszucki Group, founded in 2021 by David and Jan Ellison Baszucki. The group has established the nonprofit initiative Metabolic Mind and the funding program ReThink Bipolar: Researching Therapeutic Integration of Nutritional Ketosis in Bipolar Disorder, which has announced $8M in funding for randomized controlled trials at the University of Pittsburgh and McLean Hospital.

While the current results are encouraging, UCSF researchers emphasize that a one-month intervention is insufficient to capture full mental health benefits. They have called for larger, longer, and fully controlled trials to determine if these improvements can be replicated at scale.