Building on Decades of Research: Advancing Mental Health Through Metabolic Science
March 11, 2025
Christopher M. Palmer, MD, is a leading voice in exploring the intersection of metabolic science and mental health.
As the founder and director of McLean Hospital’s new Metabolic and Mental Health Program, Palmer is challenging traditional perspectives by suggesting that many mental health disorders may be influenced by metabolic factors. His work emphasizes that while solutions may not be simple, metabolic interventions could represent a promising path forward in treatment.
His clinical research has pioneered the use of the ketogenic diet for individuals with treatment-resistant psychotic disorders such as bipolar and schizophrenia disorders.
Some patients with psychotic disorders who follow the strict ketogenic diet have had fewer symptoms or were able to take fewer medications. Some have even achieved remission of illness.
“In order to understand how the biopsychosocial factors play a role in the development of mental health conditions, you must understand the complex picture of metabolism and mitochondria,” said Palmer. Brain energy is a shorthand way of expressing that complexity.
The new Metabolic and Mental Health Program at McLean Hospital is bringing research, education, and clinical practice together to advance a new and renewed metabolic understanding and theory of mental health, with a goal of improving the lives of people affected by psychiatric conditions.
The program will also have a small consulting service to address the gap in current mental health care offerings.
Funded with a generous $3 million donation from Mr. Lewis Sanders, the new Metabolic and Mental Health Program will be based in McLean’s Division of Psychotic Disorders, where early metabolic treatments have had their greatest impact.
“Metabolic interventions are an exciting new lead in the goal of understanding and treating psychotic disorders, including a range of schizophrenia and bipolar disorders,” said Dost Öngür, MD, PhD, chief of the Division of Psychotic Disorders and director of the Schizophrenia and Bipolar Disorder Research Program at McLean Hospital, and the William P. and Henry B. Test Professor of Psychiatry at Harvard Medical School.
“Recent research from Palmer and others demonstrates that some individuals with psychotic disorders have dramatic improvements on a ketogenic diet,” he continued.
“We know that no one treatment will work for all psychotic disorders or even all types of schizophrenia or bipolar disorders, but some patients have had far better responses to the ketogenic diet than to medications.”
Personal and Patient Experiences Behind the Program
Palmer’s work as a psychiatrist stems from personal experiences, shaped by childhood observations of his mother’s struggle with a psychotic disorder and his own struggles with mental and physical health.
As a young adult, despite healthy habits including exercise, he had metabolic syndrome, a condition which put him at risk for diabetes. He tried a low-carbohydrate diet and noticed a dramatic improvement in his mental health.
Slowly and somewhat reluctantly, he began to support some patients trying the ketogenic diet if their traditional treatments and medications were not working. The ketogenic diet had been established as a therapeutic intervention for epilepsy but not for other disorders.
The final turning point for Palmer came in 2017 when he witnessed a transformation in a long-standing patient with schizoaffective disorder, whose symptoms improved with the ketogenic diet.
The work with patients led Palmer to publish case studies on his work and to look more closely at the history of research on metabolic interventions, cellular metabolism, and mitochondria.
Palmer now believes that many mental health disorders have metabolic drivers and that metabolic interventions can be used as treatment.
Decades of Research Discoveries on Metabolism
In highlighting research into brain metabolism and mitochondria at McLean, Palmer pointed to the influential work of Seymour Kety, MD, on neuroimaging and metabolism.
Metabolism was an active area of research early in the 20th century, but the field changed entirely around 1950 when Kety created a way to study metabolism in the conscious human brain.
This work led to the neuroimaging techniques used in metabolism research today, including the positron emission tomography (PET) scan.
Kety’s subsequent research leadership at Massachusetts General Hospital and then at McLean Hospital in the 1970s and early 1980s, and his return to McLean later in his career, contributed to generations of hospital researchers pursuing an understanding of metabolism in different types of brain cells, in different locations in the brain, and in the cause, course, or treatment of neuropsychiatric disorders.
Advances in Neuroimaging
“Some of the recent advances in our understanding of neurometabolism and mitochondria can be attributed to newer advances in neuroimaging,” said Kerry J. Ressler, MD, PhD, chief scientific officer and James and Patricia Poitras Chair in Psychiatry at McLean.
He points to work led by Fei Du, PhD, director of the Laboratory for High-Field Imaging and Translational Neuroscience and associate professor of psychiatry at Harvard Medical School.
“Fei is one of the national leaders in translational imaging, particularly with a technique called ‘magnetic resonance spectroscopy’ (MRS). He has combined imaging techniques that have become essential in understanding neurometabolism generally,” said Ressler.
“He has also developed novel neuroimaging techniques to measure markers of metabolic and mitochondrial function in both psychotic and neurodegenerative disorders.”
An “Uninterrupted Chain” of Metabolism Research at McLean
In highlighting research into brain metabolism and mitochondria at McLean, Palmer also pointed to Bruce Cohen, MD, PhD, founding director of the McLean Brain Imaging Center and president and psychiatrist in chief emeritus at McLean Hospital, Öngür, Virginie-Anne Chouinard, MD, a staff psychiatrist and director of research at McLean OnTrack™, a program for individuals who are experiencing psychosis for the first time, and others.
“McLean has an uninterrupted chain of research into metabolism that extends across laboratories,” explained Öngür.
He recognized Kety, Cohen, and Chouinard, as well as others including Anne M. Cataldo, best known for her work to understand and treat Alzheimer’s disease. Cataldo and Cohen worked together frequently.
In one set of studies, Cataldo and Cohen looked at mitochondrial size and distribution in the cells of people with bipolar disorders when compared to cells of people without bipolar disorders, noting that differences may be linked to energy requirements, plasticity, and resilience.
Their work led to a number of patent applications and grants relating to mitochondrial replacement therapy.
Öngür’s own early work with neurometabolism dates back to 1995 when he determined that a type of brain cell called glia contributes to regulating glucose storage and metabolism, which are necessary for normal neuronal activity.
It was an early glimpse of a biomarker that might be associated with the pathogenesis of psychiatric disorders of the brain.
Chouinard, Öngür, Cohen, and others at McLean have also studied how drug treatments for neuropsychiatric disorders can contribute to metabolic disorders, including diabetes and heart disease.
Palmer expressed concern, as have others, about current treatments that provide symptom reduction rather than remission or recovery, but he also emphasized that a metabolic approach to mental health could help discover why a medication that can increase the risk of metabolic disorders might reduce other metabolically related symptoms.
Metabolism Gaining Momentum With Clinical Trials
“There are decades of research linking metabolism to neuropsychiatric disorders, but there are not decades of research looking at how metabolic interventions can help patients,” said Öngür. “Chris’s new program and current work at McLean is helping to change that.”
Several clinical trials underway at McLean Hospital about brain metabolism are led by Chouinard. Her research has identified mechanisms involved in energy metabolism that are active early in psychosis. Her hope and goal is to find early interventions.
The newest of her clinical trials will assess the benefits of a ketogenic diet in combination with treatment as usual compared to a standard diet for individuals with early-stage bipolar disorder and related psychotic disorders.
The 12-week study will measure the effects of the ketogenic diet on energy metabolism in the brain using magnetic resonance spectroscopy.
This study is funded by a $2 million gift to McLean Hospital from the Baszucki Group, the philanthropy of Roblox founder David Baszucki and his wife, best-selling author Jan Ellison Baszucki.
Another clinical trial on energy metabolism is being led by Fei Du, renowned for his imaging work, who is investigating the effects of a co-enzyme on brain energy metabolism, oxidative stress, and cognitive function in individuals with mild cognitive impairment and mild Alzheimer’s dementia.
A New and Renewed Theory of Metabolic Psychiatry
Given the history of research, Palmer noted that his theory of metabolic and mitochondrial dysfunction is not new, per se, but is instead creating a coherent and integrated approach for the research done over the past century, including imaging, genetics, psychological, social, and basic science studies.
“It’s about seeing the forest, instead of the trees,” he said, also noting transformations in the last decades on the role of mitochondria.
Mitochondria had been thought of as an engine in our cells: Oxygen and food in, energy out. Scientific research has discovered that mitochondria have more dynamic roles in cellular function.
They have their own DNA and their own mutations, can alter gene expression, and are involved in cell signaling pathways, which have been associated with the development of metabolic disorders.
“There’s no doubt that metabolic interventions will become increasingly important over the next 25 years,” said Öngür. “Our goal with the Metabolic and Mental Health Program is to find new ways to improve the lives of people affected by psychiatric conditions.”
