A pilot study by Stanford Medicine researchers suggests a promising new adjunct treatment for individuals with serious mental illnesses such as schizophrenia or bipolar disorder who experience metabolic side effects from standard antipsychotic medications. The study, published in Psychiatry Research, reports that a ketogenic diet not only improves metabolic health but also enhances psychiatric outcomes for these patients, offering a dual benefit that could potentially encourage better adherence to treatment.
The ketogenic diet, commonly referred to as the “keto diet,” is a high-fat, low-carbohydrate eating plan that has been used for decades, primarily to treat epilepsy, especially in children who do not respond to conventional medications. By drastically reducing carbohydrate intake and replacing it with fat, the body is forced into a state of ketosis, where it burns fat instead of carbohydrates for energy.
The classic ketogenic diet follows a strict ratio of fats to carbohydrates and proteins, often around 4:1 by weight. This means that about 80-90% of the caloric intake comes from fats, with the remainder provided by a combination of proteins and very limited carbohydrates. Foods such as bread, pasta, grains, and sugary snacks are replaced with fats like nuts, cream, butter, and healthy oils, as well as sufficient protein sources.
Research into the ketogenic diet’s effect on brain chemistry suggests that ketone bodies produced during ketosis can provide a more efficient and steady energy source for the brain, potentially stabilizing neuronal activity and reducing inflammation. This has led scientists to explore its benefits beyond epilepsy, including its potential effects on mental health disorders such as depression and anxiety.
Given that metabolic dysfunction could be contributing to the exacerbation of psychiatric symptoms, and knowing the ketogenic diet’s capacity to alter metabolic processes, the researchers saw an opportunity to explore its use as a complementary treatment. They hypothesized that the ketogenic diet might help mitigate the metabolic side effects of psychiatric medications while potentially enhancing their therapeutic effects on mental health.
“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain. We thought it would be worth exploring this treatment in psychiatric condition,” said Shebani Sethi, an associate professor of psychiatry and behavioral sciences and the first author of the new paper.
The researchers conducted a four-month, single-arm pilot study with 23 participants. Participants were selected nationwide, involving individuals aged 18 to 75 who had been diagnosed with either schizophrenia or bipolar disorder as defined by the DSM-V, the Diagnostic and Statistical Manual of Mental Disorders.
Candidates were eligible if they were experiencing metabolic side effects from their psychiatric medications, such as being overweight or having insulin resistance, among other criteria. All participants were required to continue their psychiatric medications without any changes, unless directed by their doctor.
Throughout the four-month study, participants’ adherence to the diet was closely monitored using blood ketone meters. Ketone levels were checked at least weekly to ensure participants maintained nutritional ketosis — a key indicator of strict adherence to the ketogenic diet. Adherence was classified into three categories: fully adherent, semi-adherent, and non-adherent, based on the percentage of time participants’ ketone levels were within the target range.
Regular follow-up visits were scheduled for medical monitoring, which included repeated blood tests and assessments of weight, blood pressure, and other metabolic indicators. Psychiatric assessments were also conducted at baseline, two months, and at the end of the study, using standardized psychiatric scales to measure symptoms of depression, anxiety, and overall psychiatric state.
A subset of the cohort met the criteria for metabolic syndrome, a cluster of conditions that elevate the risk of heart disease, stroke, and diabetes. By the end of the four-month period, none of the participants continued to meet these criteria, marking a substantial improvement in metabolic health.
On average, participants experienced a 10% reduction in body weight and an 11% decrease in waist circumference. Additionally, the researchers observed reductions in blood pressure, body mass index, triglycerides, blood sugar levels, and insulin resistance.
Furthermore, the researchers reported improvements in several metabolic biomarkers. Participants saw improvements in insulin resistance measured by HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and a notable decrease in hemoglobin A1c levels, which reflects better blood sugar control.
These changes are critical because they directly contribute to lowering the risk of cardiovascular diseases, which are notably higher in individuals with serious mental illnesses due to both their condition and the metabolic side effects of their medications.
“We’re seeing huge changes,” Sethi said. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”
The improvements were not limited to physical health; significant enhancements in psychiatric conditions were also observed. Participants demonstrated reductions in depression, anxiety, and the overall severity of mental illness.
“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”
Fourteen participants were fully adherent, consistently maintaining ketone levels above 0.5 for over 80% of the time. Six participants were semi-adherent, with ketone levels above 0.5 for 60-80% of the time, while one participant was non-adherent, keeping ketone levels above 0.5 less than 50% of the time. Participants who were fully adherent to the diet showed greater improvements compared to those who were less strict. This finding suggests a potential dose-response relationship between diet adherence and psychiatric relief.
Despite these promising results, the study has several limitations, including its small sample size and lack of a control group, which makes it difficult to definitively conclude that the observed benefits were solely due to the diet rather than other factors like increased medical attention. The study’s short duration also leaves open questions about the long-term viability and safety of a ketogenic diet in this patient population.
Future research is needed to build on these findings through larger, randomized controlled trials that can provide more definitive evidence of the diet’s effectiveness and safety over longer periods. The researchers also suggest exploring the mechanisms through which the ketogenic diet affects both metabolism and psychiatric symptoms, to better understand how this dietary intervention could be optimized and personalized for individuals with serious mental illnesses.
“These findings underscore the importance of further exploration of evidence based approach in neurology to individuals with serious mental illness in psychiatry,” the researchers concluded. “Mental health and physical health are interconnected, and addressing metabolic issues can complement psychiatric treatment to enhance overall well-being. Understanding the mechanisms and potential synergies between psychiatric treatment and metabolic improvements can also inform the development of more effective interventions.”
The study, “Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial,” was authored by Shebani Sethi, Diane Wakeham, Terence Ketter, Farnaz Hooshmand, Julia Bjornstad, Blair Richards, Eric Westman, Ronald M Krauss, and Laura Saslow.
