Between 20% and 60% of people with mental illness don’t respond to psychotropic medications. For this population, one promising intervention is a ketogenic diet.
“There are many studies underway, but the most evidence [for ketogenic diets] is in bipolar, schizophrenia and depression,” said Deanna L. Kelly, PharmD, BCPP, the Dr. William and Carol Carpenter Professor of Psychiatry for Mental Illness Research at the University of Maryland School of Medicine, in Baltimore. She reviewed the history of the ketogenic diet, its mechanisms of action and outcomes data during a session at the AAPP 2025 Annual Meeting, in Salt Lake City.
Mitochondria are primarily responsible for generating energy in cells in the form of adenosine triphosphate, usually from glucose utilization. Mitochondrial dysfunction may play a role in mental illness. “If we can bypass glucose and use a different source of fuel, which is fat, we may be able to overcome some of that dysfunction,” Dr. Kelly said in an interview with Pharmacy Practice News after the AAPP meeting.
The ketogenic diet—defined as low carbohydrate, moderate protein and high fat (Box)—induces ketosis, which occurs when the body lacks sufficient carbohydrates to use for energy and begins to break down fat for fuel, producing ketones as a byproduct, she noted.
An Early Track Record in Epilepsy
The ketogenic diet has a long clinical history, with experts first noting benefits for those with epilepsy in the 1920s.
More recent research has confirmed the ability of the ketogenic diet to help alleviate psychiatric symptoms. In a four-month, 23-patient pilot study, Sethi and co-authors investigated the effects of a ketogenic diet on individuals with schizophrenia or bipolar disorder with existing metabolic abnormalities. Across cohorts, the researchers noted improved psychiatric symptoms, improved life satisfaction (17%) and enhanced sleep quality (19%). Participants also lost 12% of their weight, and their waist circumference decreased by 13% (Psychiatry Res 2024;335:115866). “This pilot trial underscores the potential advantages of adjunctive ketogenic dietary treatment in individuals grappling with serious mental illness,” the investigators concluded.
Dr. Kelly noted that patients on the ketogenic diet are monitored for ketosis, with additional lab tests typically ordered for lipids and glucose levels. She added that in clinical trials for people with mental health conditions, adherence to the ketogenic diet has been “impressive” and resulted in improvements in hemoglobin A1c levels, insulin resistance, high-density lipoprotein levels and triglyceride levels.
For instance, in the aforementioned four-month pilot study, 14 of the 23 participants were fully adherent to the diet (defined as >80% of ketone measures >0.5), six participants were semiadherent (defined as ketones >0.5 >60%-80% of the time) and one participant was nonadherent. The participants experienced a 27% drop in insulin resistance and a 25% drop in triglyceride levels.
Not a Cure-All
High Fats and Drug Absorption
Dr. Kelly explained that the ketogenic diet is certainly not a cure-all for the psychiatric conditions for which it is used. And it may have some adverse effects that both patients and clinicians need to keep in mind. For example, “it’s important for people to understand that a high-fat meal and high-fat diet can impact the absorption of certain medications and the pharmacokinetics of those medications,” she said.
Examples include antiepileptic drugs, mood stabilizers and antipsychotics—in particular, xanomeline and trospium chloride (Cobenfy, Bristol Myers Squibb), for the latter class. According to the prescribing information for the combination therapy, a high-fat diet reduced the maximum concentration of trospium by up to 75%, with similar pharmacokinetic adverse effects documented for xanomeline.
Dr. Kelly thus recommended that providers work closely with nutritionists and pharmacists to monitor diet and potential interactions with food. In such deliberations, it is important to be vigilant of the carbohydrate content in certain medications. As noted, carbohydrate levels need to be low enough to induce ketosis. The website ketomeds.com, for example, is a source to view the carbohydrate content of certain medications.
Another consideration is cost, Dr. Kelly noted. “It’s often cheaper and easier to buy processed food and ultra-processed food, and many people with mental health conditions buy fast food and inexpensive processed foods,” she explained.
‘Keto Flu’
In those who can adhere to a keto diet, transitioning into ketosis may be challenging, with “keto flu” being an adverse effect, although the syndrome is not well documented in controlled studies (Front Nutr 2025;12:1538266). Keto flu can happen within the first week of following a keto diet, according to Dr. Kelly, and a slower entry into ketosis can help avoid this effect. For those who can overcome this hump, however, improvements in mood and cognition can be swift—in as little as two weeks in some, she said. Keeping well hydrated with electrolytes can also help with this transition, she added.
Although the ketogenic diet may have profound improvements in mental health, it is “not for everybody, because it’s not something everyone can adhere to,” she stressed. “It’s going to be [easier] for those who have support.” She added that there are packaged meals available to help patients while they are still learning to prepare their own ketogenic diet foods.
Prescriber Perspectives
A number of psychiatrists have had much success in starting their patients on the keto diet. “Ketogenic diets have demonstrated unparalleled therapeutic capacity across a diversity of psychiatric conditions, from autism spectrum disorder to major mood disorders to Alzheimer dementia,” said Georgia Ede, MD, a board-certified psychiatrist specializing in nutritional and metabolic psychiatry and the author of “Change Your Diet, Change Your Mind,” in an interview with PPN. “While ketogenic diets certainly do not work for everyone, a growing number of case reports and small clinical trials document its ability to bring unprecedented relief and sometimes full remission of mental health symptoms in some cases—even in chronic cases of serious mental illnesses previously considered ‘treatment resistant.’”
A systematic review found some evidence for the efficacy of ketogenic diets in those with bipolar disorder, schizoaffective disorder and possibly unipolar depression/anxiety. Furthermore, relapse in mental illness following the discontinuation of the diet was reported in some participants (BJPsych Open 2023;9[3]:e70).
More specifically, seven case reports in the review documented possible efficacy with diet durations between one month and three years, and three described substantial improvements in symptoms in individuals with bipolar disorder (n=4), including improved mood stability, decreased frequency of mood episodes and reduced anxiety. Overall, four patients discontinued or decreased their dosages of antipsychotic or mood stabilizer medication.
Christopher M. Palmer, MD, the founder and director of the Metabolic and Mental Health Program at McLean Hospital, in Belmont, Mass., and an assistant professor of psychiatry at Harvard Medical School, in Boston, has been employing the ketogenic diet in his practice for 25 years for patients with a variety of psychiatric diseases.
“The most important tip I have for clinicians considering using this in their practice is to learn about the science and art of this medical intervention. It’s not just ‘a diet,’ and it’s not something to have your patients do on their own without guidance or support. Many patients will do it incorrectly and assume it doesn’t work for them when, in fact, they simply aren’t doing it right,” Dr. Palmer said in an interview with PPN.
Future Research
To help healthcare practitioners become more competent with the keto diet, Dr. Kelly will soon begin the “Live It: Launch It” study. This study will have providers first take a mastery class where they learn more about the diet, followed by a practical portion where providers spend four weeks on the diet themselves. This trial aims to help build a knowledgeable workforce and help providers better troubleshoot issues given their own experiences, she noted. The study has yet to be assigned an NCT number because it is in the process of being registered with ClinicalTrials.gov.
Dr. Ede reported that she is a medical advisor for Metabolic Mind, a nonprofit metabolic psychiatry advocacy organization, as well as for MetPsy and Owna Health, which are app-based services that combine education, coaching and wearables to make access to metabolic psychiatry care easier, more affordable and more accessible. Drs. Kelly and Palmer reported no relevant financial disclosures.
This article is from the August 2025 print issue.