Researchers find how ketogenic diet improves severe mental illness

Stanford, April 2

The common antipsychotic medication used for severe mental illnesses such as schizophrenia and bipolar disorder might have unintended consequences. Although these medications aid in the regulation of brain chemistry, they frequently result in metabolic adverse effects, such as obesity and insulin resistance, which are so upsetting that many patients cease taking them.

According to a recent pilot study conducted by doctors at Stanford Medicine, a ketogenic diet helps these individuals’ mental health in addition to restoring their metabolic health while they continue their drug regimen. The findings, which were released in Psychiatry Research, indicate that nutritional interventions can be quite effective in addressing mental health conditions.

“It’s very promising and encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi, MD, associate professor of psychiatry and behavioural sciences and the first author of the new paper.

The senior author of the paper is Laura Saslow, PhD, associate professor of health behaviour and biological sciences at the University of Michigan.

Sethi, who is board certified in obesity and psychiatry, remembers when she first noticed the connection. As a medical student working in an obesity clinic, she saw a patient with treatment-resistant schizophrenia whose auditory hallucinations quieted on a ketogenic diet.

That prompted her to dig into the medical literature. There were only a few, decades-old case reports on using the ketogenic diet to treat schizophrenia, but there was a long track record of success in using ketogenic diets to treat epileptic seizures.

“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” Sethi said. “We thought it would be worth exploring this treatment in psychiatric conditions.” A few years later, Sethi coined the term metabolic psychiatry, a new field that approaches mental health from an energy conversion perspective.

In the four-month pilot trial, Sethi’s team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality—such as weight gain, insulin resistance, hypertriglyceridemia, dyslipidaemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10 per cent of the calories from carbohydrates, 30 per cent from protein and 60 per cent from fat. They were not told to count calories.

“The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats,” said Sethi, who shared keto-friendly meal ideas with the participants. They were also given keto cookbooks and access to a health coach.

The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels. (Ketones are acids produced when the body breaks down fat—instead of glucose—for energy.) By the end of the trial, 14 patients had been fully adherent, six were semi-adherent and only one was non-adherent.

The participants underwent a variety of psychiatric and metabolic assessments throughout the trial.

Before the trial, 29 per cent of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. After four months on a ketogenic diet, none of the participants had metabolic syndrome.

On average, the participants lost 10 per cent of their body weight; reduced their waist circumference by 11 percent; and had lower blood pressure, body mass index, triglycerides, blood sugar levels and insulin resistance.

“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 psychiatric benefits were also striking. On average, the participants improved 31 per cent on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. Overall, the participants also reported better sleep and greater life satisfaction.

“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.” The researchers were impressed that most of the participants stuck with the diet. “We saw more benefit with the adherent group compared with the semi-adherent group, indicating a potential dose-response relationship,” Sethi said.

There is increasing evidence that psychiatric diseases such as schizophrenia and bipolar disorder stem from metabolic deficits in the brain, which affect the excitability of neurons, Sethi said.

The researchers hypothesize that just as a ketogenic diet improves the rest of the body’s metabolism, it also improves the brain’s metabolism.

“Anything that improves metabolic health in general is probably going to improve brain health anyway,” Sethi said. “But the ketogenic diet can provide ketones as an alternative fuel to glucose for a brain with energy dysfunction.”

Likely there are multiple mechanisms at work, she added, and the main purpose of the small pilot trial is to help researchers detect signals that will guide the design of larger, more robust studies.