Fix Your Brain by Fixing Your Body: Metabolic Psychiatry Explained

Understanding Metabolic Psychiatry

Dr. Sethi begins by defining metabolic psychiatry as a holistic field dedicated to exploring the intricate relationship between metabolism and mental health. This is not just about brain energy metabolism or ketogenic diets but encompasses all systemic and central metabolic dysfunctions that influence psychiatric diseases like schizophrenia, bipolar disorder, and major depression. Unlike traditional psychiatric approaches, which primarily focus on neurotransmitters and symptoms, metabolic psychiatry seeks root causes related to physiological abnormalities in how the body processes energy and nutrients.

She recalls how over a century ago, early psychiatrists observed elevated lactate levels and reduced antioxidants in the brains of those with severe mental illness—markers of bioenergetic dysfunction. However, unlike those early insights, contemporary psychiatry has largely neglected these metabolic mechanisms, focusing instead on mental and chemical symptomology without addressing systemic causes such as insulin resistance, inflammation, oxidative stress, and mitochondrial dysfunction. Metabolic psychiatry, she explains, reconnects psychiatry to the body, emphasizing a bidirectional "body-mind" effect, where bodily metabolic health profoundly impacts brain function, often silently manifesting as mental illness rather than physical pain.

The Role of Insulin Resistance

One of the central themes that Dr. Sethi highlights is how insulin resistance—often thought of primarily as a metabolic condition affecting blood sugar regulation—also exists in the brain and plays a crucial role in mental health disorders. She explains that cerebral glucose hypometabolism, or the brain's impaired ability to utilize glucose for energy, is a hallmark of several psychiatric and neurodegenerative disorders. Brain insulin resistance affects critical areas responsible for neuronal plasticity and brain remodeling, negatively impacting cognition, mood, and overall mental health.

Importantly, insulin resistance in the brain does not always correlate directly with insulin resistance in the peripheral body, complicating diagnosis and treatment. Psychiatric medications, for example, often worsen peripheral insulin resistance, which can structurally damage brain regions such as the hippocampus. This interplay creates a vicious cycle between metabolic dysfunction and psychiatric symptoms, where poor metabolic health exacerbates mental illness and vice versa.

Adding more biological layers, mitochondrial dysfunction—where the cell's energy factories fail to operate efficiently—also contributes to the pathology of these illnesses. Because brain cells have the highest mitochondrial density, even subtle impairments in mitochondrial function can cause energy deficits, increase oxidative stress, and amplify inflammation, thereby worsening psychiatric symptoms. This systemic failure of energy metabolism provides a compelling target for innovative treatment strategies.

Metabolic Psychiatry

Dr. Sethi shares how metabolic psychiatry merges insights from endocrinology, immunology, nutrition, and neurology to develop multi-faceted interventions that address both psychiatric symptoms and metabolic dysfunctions. These interventions include dietary changes such as ketogenic diets, medications like metformin, and supplementation with mitochondrial cofactors or antioxidants. For instance, metformin, commonly used for diabetes, crosses the blood-brain barrier and exerts neuroprotective, anti-inflammatory effects that can enhance antidepressant efficacy in treatment-resistant bipolar disorder.

She emphasizes that these metabolic approaches are not substitute therapies but foundational to enhancing and sometimes enabling the effectiveness of traditional psychiatric medications and psychotherapies. We are moving from a reductionist, symptom-focused model toward a precision medicine framework that personalizes treatment based on an individual's specific metabolic and biochemical profile.

Challenges and Opportunities

Dr. Sethi acknowledges that implementing metabolic interventions poses challenges, especially for patients with severe mental illness who may struggle with lifestyle changes or restrictive diets like ketogenic nutrition. However, she stresses that with proper support systems, caregiver involvement, and reframing these changes from restrictive diets to metabolic therapies aimed at improving quality of life, patients can and do adhere to these regimens successfully. Her pilot clinical trial involving ketogenic diets in bipolar disorder and schizophrenia patients showed remarkable improvements in metabolic health markers alongside reductions in psychiatric symptoms. These "good side effects" motivate patients to continue such therapies long term, contrasting with many psychiatric medications that come with burdensome adverse effects.

Beyond diet, her team is investigating a wide range of metabolic and inflammatory biomarkers—including lipid panels, triglyceride to HDL ratios, insulin resistance scores, neuroinflammatory markers, and mitochondrial metabolites—to better characterize disease severity and progression in mental illness. This biomarker-driven approach aims to deepen understanding and foster targeted treatments. The integration of advanced technologies such as metabolomics, proteomics, epigenetics, and AI-powered data analysis allows the field to move towards personalized psychiatry rooted in metabolic health.

Nutrition, Microbiome, and Mental Health

Both Dr. Sethi and Dr. Hyman reflect on the historical neglect of nutrition and metabolic health in medical education and psychiatric treatment despite overwhelming evidence for their importance. Many patients are "overfed but undernourished," consuming diets rich in ultra-processed foods, sugars, and starches that drive metabolic dysfunction and chronic inflammation, which in turn compromise brain health. Dr. Sethi highlights the need for more routine screening of metabolic biomarkers like fasting insulin, C-reactive protein, and nutrient deficiencies that have direct implications for mental health.

The conversation also touches on the emerging evidence around the gut-brain axis, where microbiome imbalances and gut inflammation can influence psychiatric symptoms. In particular, cases such as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANS/PANDAS) showcase how treating underlying infections and dysbiosis can dramatically improve psychiatric symptoms. These intersections further underscore the body-mind connection central to metabolic psychiatry.

Future Directions

Dr. Sethi expresses excitement about the current momentum in metabolic psychiatry, especially with growing institutional support, interdisciplinary collaboration, and new funding opportunities from entities like the National Institute of Mental Health emphasizing nutritional and metabolic approaches in serious mental illness. She envisions scaling access to metabolic psychiatric care through digital platforms like Metabolic Psychiatry Labs, which provide nationwide virtual care to bridge gaps in conventional mental health services.

She also stresses the importance of combining metabolic psychiatry with emerging treatments such as psychedelic-assisted therapy and trauma-informed care to develop comprehensive, multi-dimensional strategies for mental health. The goal is to overcome psychiatric stigma by legitimatizing mental illnesses as systemic metabolic diseases deserving integrated therapies that treat the whole person.

Ultimately, Dr. Sethi calls for a redefinition of psychiatric diagnostics beyond DSM symptom clusters toward biologically valid, individualized profiles using biomarkers, metabolomics, and genetics. This shift would enable more precise treatments tailored to each person's unique metabolic and neurochemical landscape.

Dr. Hyman reflects on how these advances align with functional medicine's personalized systems approach and calls attention to the vast, largely untapped potential of metabolic psychiatry to revolutionize mental health care. The episode closes with a shared sense of optimism that fixing the body first—through targeted metabolic and nutritional therapies—can unlock healing and transform lives affected by mental illness, proving once again that to fix the brain, we must begin by fixing the body.