Can Neural Network Instability in Schizophrenia be Improved With a Very Low Carbohydrate Ketogenic Diet?

Trial ID or NCT#



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Wide ranging cognitive deficits are major drivers of functional decline and poor outcomes in people with schizophrenia (SZ) and bipolar disorder (BD). Medications do not target pathophysiological mechanisms thought to underlie these deficits. In the search for interventions targeting underlying cognitive impairment in SZ and BD, we look comprehensively beyond just the brain and to the potential role of dysfunctional systemic metabolism. Disrupted insulin and glucose metabolism are seen in medication-naïve first-episode SZ, suggesting that SZ itself, and not just the medications used to treat it, is associated with risk of Type 2 diabetes, cardiovascular morbidity and mortality, and more generally, accelerated aging. Even young people with SZ have increased risk of metabolic disease and cognitive deficits. Sadly, their life span is shortened by 15-20 years. BD is associated with similar but less severe disruptions in glucose and insulin metabolism and life expectancy. Although the human brain is 2% of the body's volume, it consumes over 20% of its energy, and accordingly, the brain is particularly vulnerable to the dysregulation of glucose metabolism seen in SZ and BD. While glucose is considered to be the brain's default fuel, ketones provide 27% more free energy and are a major source of energy for the brain. Ketones prevent or improve various age-associated diseases, and a ketogenic diet (70% fat, 20% protein, 10% carbohydrates) has been posited as an anti-aging and dementia antidote. The premise of the work is based on recent evidence that ketogenic diets improve dynamic neural network instability, related to cognitive deficits, aging, and Type 2 diabetes (Mujica-Parodi et al., Proc Natl Acad Sci U S A. 2020;117(11):6170-7.). The rigor of the work rests on findings of (1) poor cerebral glucose homeostasis in SZ and BD, (2) neural network instability in SZ and BD, and (3) direct effects of ketosis on network instability. Unknown is whether ketogenic diets can improve network instability in people with SZ and BD.

Official Title

Can Neural Network Instability in Schizophrenia be Improved With a Very Low Carbohydrate Ketogenic Diet?

Eligibility Criteria

Ages Eligible for Study: 18 Years to 65 Years
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Inclusion Criteria:
  1. - Male or female ages 18-65 years old - Able to attend 2 in-person visits at the San Francisco VA Medical Center - SCID-5 Schizophrenia or schizoaffective disorder stable on 2nd generation anti-psychotic (SZ) or bipolar disorder (BD) - Not currently on KETO diet - Willing to adhere to 4 wk. KETO diet or 4 wk. non-KETO diet per random assignment - Speak, read, comprehend English - Access to internet - Willing and able to heat up KETO meals
Exclusion Criteria:
  1. - Current Cancer diagnosis - Other SCID-5 Axis 1 disorder - Pregnancy, breastfeeding, or planned pregnancy - Current diagnosis of type 1 Diabetes Mellitus - Glucose-lowering drugs (other than metformin) or weight loss pills - History of gastric bypass surgery or any weight loss surgery - >10% weight fluctuation in past 2 years


Shebani Sethi MD, ABOM
Clinical Associate Professor, Psychiatry and Behavioral Sciences