Metabolic approach aims to mimic ketosis without strict keto diet

—Researchers at the University of Michigan have designed a pilot study to see whether a simplified plan that boosts ketones—without a strict keto diet—can steady brain networks and improve mood in people with bipolar disorder. The protocol blends a ketone ester supplement with a few low-glycemic eating rules over about 90 days.

The study matters because many patients struggle with medication side effects and adherence, and strict ketogenic diets are hard to start during mood episodes. 

The ketogenic diet is a high-fat, low-carbohydrate dietary pattern that aims to induce a metabolic state called ketosis. In it, the liver increases ketone bodies for cellular energy, while reducing production of glucose.

The team’s approach aims to mimic two core features of therapeutic ketosis—high circulating ketones and minimal blood-sugar spikes—using an over-the-counter ketone ester plus basic diet tweaks. 

The trial appears in the science journal Nutrients and is framed as a target-engagement pilot, not a treatment recommendation.

The rationale links bipolar disorder to patterns also seen in epilepsy, where ketogenic therapy has a long history. Overlapping drug classes for seizures and mood stabilization suggest shared biology. 

The authors highlight evidence that mitochondria—the cell’s power plants—may falter in bipolar disorder, and that ketones can bolster cellular energy, calm inflammation, and stabilize neural firing. 

Prior case reports and small analyses hinted at mood benefits on strict keto; this study tests whether a lighter “ketogenic-mimicking” strategy can move key brain and clinical markers.

Here’s how it will work: The open-label study plans to enroll 34 adults with any bipolar subtype. Participants will take a ketone ester (bis-hexanoyl (R)-1,3-butanediol; 19 grams twice daily) and follow four simple rules: avoid soda; avoid candy and sweets; skip white grains and rice in favor of whole grains; and, if eating fruit, have it at the end of meals to blunt glucose spikes. The intervention lasts roughly 90 days.

The primary outcome is “neural network stability,” measured by functional MRI before and after the intervention. Secondary measures include brain ketone uptake via MR spectroscopy; mania and depression ratings (YMRS, PHQ-9, BDI); anxiety (STAI); and quality of life (SF-36). 

Participants will also wear a continuous glucose monitor to track sugar swings, use a finger-stick device to check beta-hydroxybutyrate (a ketone), and wear an Oura ring to monitor sleep. The team will explore whether steadier glucose, higher ketones, and improved network stability line up with better mood and functioning.

What’s novel is the middle-path design. Rather than require a high-fat, ultra-low-carb diet, the protocol pairs a ketone ester with minimal diet changes that many patients may tolerate even during stressful periods. The study is also mechanistic. By focusing on brain-network stability and metabolic markers, the researchers hope to learn whether this approach engages the right targets—an early step before any larger, controlled trials.

The authors outline testable predictions: stronger brain uptake of ketones should track with greater network stability; bigger glucose spikes should predict weaker responses; and a lower “glucose-ketone index” should associate with better outcomes. If results are negative, they argue, future work may need stricter dietary ketosis; if positive, it could justify randomized trials of ketone-based strategies for bipolar disorder.

The paper cautions that this is an exploratory design, not a clinical guideline. Still, it underscores a growing push to study metabolism in psychiatry and to develop practical tools patients can use. 

If the pilot shows target engagement in the brain and meaningful symptom signals, it could open the door to larger studies and add a new option to the bipolar care toolbox. 

Nutrients, July 7, 2023