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The ketogenic diet has long been known for its use in treatment-resistant epilepsy, but attention is now turning to its potential benefits in mental illness as well.

Could something as simple as a diet actually improve notoriously difficult-to-treat conditions including major depressive disorder, bipolar disorder, and schizophrenia?

The evidence to date has been less rigorous than gold-standard randomized controlled trials. But new studies are underway, and more clinicians are keen to explore whose psychiatric conditions improved when they adhered to a ketogenic diet.

Nonetheless, there are challenges inherent to dietary intervention trials that must be mitigated, and broader buy-in from the medical community at large remains to be seen.

"There have to be randomized trials before we can make enthusiastic and evidence-based treatment recommendations," Drew Ramsey, MD, a nutritional psychiatrist and member of the American Psychiatric Association, told MedPage Today. "That said, I'm hopeful and optimistic that patients are going to have more tools to treat their mental health disorders."

What Does the Evidence Say?

Ramsey noted that some randomized controlled trials have shown that dietary interventions -- albeit not specifically the ketogenic diet -- can help improve depression. For instance, the showed better symptomatic improvement and remission rates with a dietary intervention compared with a control social support group, and the showed greater improvements in symptoms and quality of life for young men on the Mediterranean diet compared with controls.

As for the ketogenic diet specifically, Georgia Ede, MD, a nutritional psychiatrist based in Massachusetts, told MedPage Today that the body of research for its use in psychiatric conditions "is really starting to grow."

Ede co-authored a French study in 2022 entitled, "The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients."

Patients with severe and persistent mental illness (major depressive disorder, bipolar disorder, and schizoaffective disorder), with poorly controlled symptoms were admitted to a psychiatric hospital and placed on a ketogenic diet as an adjunct to conventional care.

Though 3 patients were unable to adhere to the diet for more than 14 days, the researchers concluded that following the ketogenic diet for treatment-refractory mental illness was "feasible, well-tolerated, and associated with significant and substantial improvements in depression and psychosis symptoms and multiple markers of metabolic health."

More than 40% of patients experienced remission from their diagnosis, Ede said, and 64% left the hospital on less psychiatric medication than when they entered.

Among other recent research, a feasability pilot study of the ketogenic diet in bipolar disorder was recently completed in the U.K.

Findings of the study, last October, found that of 27 participants, 20 completed 6 to 8 weeks of the ketogenic diet. A majority of participants reached and maintained ketosis, indicating adherence to the diet, and adverse events were generally mild and modifiable, the researchers found.

What Studies Are Underway?

In an email, a spokesperson for the National Institute of Mental Health (NIMH) pointed MedPage Today to two trials that it is supporting in an investigation of the effects of the ketogenic diet on mental illness -- one led by researchers based in Maryland, and another by a team in California.

Deanna Kelly, PharmD, of the Maryland Psychiatric Research Center -- a joint program between the University of Maryland School of Medicine and state Department of Health -- is leading an inpatient randomized controlled trial of a gluten-free diet in a subgroup of people with schizophrenia.

These patients were found to have high levels of IgG anti-gliadin antibodies. The goal of the trial is to determine whether participants benefit from a gluten-free diet, predicted to result in .

The inpatient setting enables complete control over what the participants eat, she said. Lending another layer of stringency to the trial is that individuals performing the psychiatric ratings are blinded.

Judith Ford, PhD, of the University of California San Francisco, who also received NIMH funding, and her team will look at whether neural network instability in schizophrenia can be improved by a ketogenic diet. Particularly, they are exploring whether deficient glucose metabolism -- at least partially mediated by insulin resistance -- , a mechanism underlying accelerated aging and cognitive impairment in patients.

"So far, it's helping people's overall intellectual function," Ford said.

As for current funding opportunities available through NIMH, the agency told MedPage Today that there are not any that "specifically focus on diet and mental health," but that it would "consider relevant applications submitted under broader funding opportunity announcements."

What Challenges Remain?

A number of researchers pursuing work pertaining to ketogenic diets and mental health have turned to a private organization .

Securing federal funding can be difficult, in part because of the need to show targets of engagement, Kelly said. Even if someone had a cure for depression, she explained, they would have to show, for instance, what links the outcome, improvement in depression, to the brain.

"People have to spend their lives [in order to] understand the target," Kelly said. "Not everybody can afford that. Sometimes, it's not really even that clear."

"That's why we need other funding agencies to step up and take risks," she added.

Other hurdles for researchers include added costs for inpatient stays during clinical trials, and the lack of pharmaceutical funding for dietary interventions, Kelly said.

Mackenzie Cervenka, MD, medical director of the Adult Epilepsy Diet Center at Johns Hopkins Hospital in Baltimore and a member of the American Epilepsy Society, noted that potential interest in and promise of ketogenic diets for mental health is due in part to a more than 100-year history of the use of such diets for epilepsy patients.

However, Cervenka also noted that "awareness that there can be long-term side effects of the diet is important."

If patients no longer see their doctor for prescription medications, they may not be monitored for potential areas of concern like kidney stones, hyperlipidemia, and bone health, she said.

Cervenka also noted that short-term studies "might not be sufficient to indicate what the benefits could be in real-world applications." For instance, "in our experience about 50% [of individuals] will stop the diet within 6 months, whether they are responders or not," she said.

This can be due to adherence difficulties, she said, or in the case of patients with epilepsy, not achieving sufficient seizure control, for instance, for the purpose of driving.

Ramsey also cautioned that it's important to remember that "not everything works for everybody."

Ultimately, regarding randomized controlled trials, "we need more," Ede said. "Many clinicians will not feel comfortable until we have more."

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