Dominic D’Agostino: Examining the Overlooked Metabolic Link Behind Bipolar Disorder

Dominic D’Agostino is a tenured associate professor at the University of South Florida Morsani College of Medicine, where he teaches medical neuroscience, physiology, nutrition, and neuropharmacology within the Department of Molecular Pharmacology and Physiology. He also serves as a senior visiting research scientist at the Institute for Human and Machine Cognition in Ocala, Florida, contributing to efforts that optimize the safety, health, and resilience of warfighters and astronauts. D’Agostino’s laboratory develops and tests nutritional and metabolic-based therapies, including ketone technologies and nutritional ketosis protocols, using methods such as electrophysiology, radio-telemetry, and confocal microscopy. His research has addressed biomarkers tied to type 2 diabetes, obesity, insulin resistance, and cancer-specific metabolism, work that connects directly to the following discussion of how metabolic health, including ketogenic approaches, may influence bipolar disorder.

Bipolar disorder is a serious psychiatric condition characterized by recurring changes in mood, energy, and activity, including episodes of mania or hypomania and depression. It affects millions of people worldwide and is associated with substantial disability, impaired functioning, and a considerable social and economic burden.

The global burden of bipolar disorder has increased in absolute terms. A Global Burden of Disease analysis published in the British Journal of Psychiatry found that the number of prevalent and incident cases rose between 1990 and 2019, although age-standardized trends varied across regions and populations. By 2019, an estimated 3.5 million new cases were occurring worldwide each year.

The causes of bipolar disorder remain complex and incompletely understood, but research has identified important associations with metabolic abnormalities such as insulin resistance, diabetes, hypertension, and dyslipidemia.

In a 2026 study, researchers assessed 81 people with bipolar disorder and 78 with major depressive disorder using blood biomarkers, structural brain imaging, and cognitive testing to examine relationships among metabolism, brain structure, and cognition. The study found that insulin-resistance markers and leptin were strongly associated with the metabolic pattern linked to reduced gray-matter volume and poorer cognition in the bipolar group.

Leptin is a hormone involved in appetite and energy regulation, but the findings do not establish that insulin or leptin abnormalities cause bipolar mood episodes. More broadly, a 2025 meta-analysis estimated that about 33 percent of people with bipolar disorder worldwide met criteria for metabolic syndrome, although rates varied substantially among studies.

More metabolic psychiatry studies are coming out linking metabolic disorders with mental health conditions like bipolar disorder. Together, they emphasize what scientists have long suspected – metabolic health is not a peripheral concern when it comes to mental health conditions. Rather, it is a primary factor influencing the brain’s structure, cognitive functioning, and moods.

These findings highlight the importance of considering metabolic health alongside established treatments for bipolar disorder. Doctors, therefore, should go beyond prescribing medications for the illnesses to guiding patients on metabolic health improvements that will correct insulin resistance and improve mood regulation.

A dietary change that is showing promise in helping people with bipolar disorder is the ketogenic diet. The ketogenic diet is a high-fat, low-carbohydrate diet.

People on this diet severely reduce their intake of carbohydrates and sugar, prompting their bodies to rely on fat for energy. This puts their body in a metabolic state of ketosis, in which the liver converts fat into ketone bodies that the body uses for energy.

Early evidence included a 2019 analysis of self-reported comments from online bipolar forums. Of 165 ketogenic-diet reports, 141 described some improvement in mood stabilization, including fewer depressive episodes, clearer thinking or speech, and greater energy.

Positive reports were more frequent than for the other diets examined, and some users described benefits lasting months or years. Because the data came from self-selected online posts rather than clinically assessed participants, however, the findings could not establish that the diet caused those improvements.

This preliminary investigation, despite its inherent limitations, supports the hypothesis that a ketogenic diet can be beneficial to people with bipolar disorder. A more comprehensive controlled trial is necessary to investigate this hypothesis. And scientists are moving in that direction.

A 2023 pilot study put 26 people with bipolar disorder on the ketogenic diet for six to eight weeks. Of the 26 who started, 20 completed the trial.

A majority of the participants were able to reach and maintain ketosis, and adverse events were mostly mild (fatigue, drowsiness, hunger, and constipation). This feasibility study showed the diet could be implemented in a group of people, opening the path for a larger, randomized, controlled trial.

About Dominic D’Agostino

Dominic D’Agostino is a tenured associate professor at the University of South Florida Morsani College of Medicine’s Department of Molecular Pharmacology and Physiology, where he teaches medical neuroscience, physiology, nutrition, and neuropharmacology. He also serves as a senior visiting research scientist at the Institute for Human and Machine Cognition in Ocala, Florida. His laboratory develops and tests nutritional and metabolic-based therapies, including ketogenic and nutritional ketosis protocols, with research spanning diabetes, obesity, insulin resistance, and cancer metabolism.