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

NCT05268809 | Completed

• 1 other identifier: 613338789
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Schizophrenia; Bipolar Disorder

Keywords

ketogenic diet; metabolic syndrome; fMRI; functional connectivity

Outcome Measures

Primary Outcomes (5)

• Change in network stabilization after 4 weeks

  Will measure dynamic connectivity by assessing how long a network of independent nodes, within and between brain regions, maintains a stable connection. Instability or dynamic connectivity quantifies stochastic processes or other potential heterogeneity in connectivity over time at baseline and at 4 weeks (post-treatment).

  Baseline (0 weeks) and posttreatment (4 weeks)

• Change in body composition after 4 weeks

  Body composition will be determined by calculating the waist-hip ratio.

  Baseline (0 weeks) and posttreatment (4 weeks)

• Change in systemic inflammation after 4 weeks

  Systemic inflammation will be assayed by plasma C-Reactive Protein levels (VA Clinical Lab).

  Baseline (0 weeks) and posttreatment (4 weeks)

• Change in insulin resistance after 4 weeks

  Insulin resistance will be indirectly determined from fasting glucose and insulin levels using the homeostasis model assessment of insulin resistance (HOMA-IR). Plasma glucose and insulin levels will be determined by the VA Clinical Lab.

  Baseline (0 weeks) and posttreatment (4 weeks)

• Cognition Battery

  Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). This will enable the direct assessment of the relationship between network stability at baseline and cognition using the MATRICS battery to determine if the known relationship with general cognition in neuro-typical adults is also seen in SZ and BD.

  Baseline (0 weeks)

Study Arms (2)

Ketogenic Diet

EXPERIMENTAL

The ketogenic diet is a normo-caloric diet composed of high-fat (70%), low-carbohydrate (10%), and adequate protein (20%) that induces fasting-like effects and the production of ketone bodies. Metabolic Meals will be delivered to KETO subjects' homes via courier, consisting of 3 meals a day plus snacks, targeting 70% fat, 20% protein, 10% carbohydrates.

Other: Ketogenic diet

Diet as usual

NO INTERVENTION

The Diet As Usual (DAU) participants will be asked to maintain their current dietary habits and will be discouraged from starting new diets during the 4-week study.

Interventions

Ketogenic diet OTHER

The ketogenic diet is a normo-caloric diet composed of high-fat (70%), low-carbohydrate (10%), and adequate protein (20%) that induces fasting-like effects and the production of ketone bodies.

Ketogenic Diet

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Northern California Institute of Research and Education: lead

Study Sites (1)

San Francisco VA Medical Center

San Francisco, California, 94121, United States

Location

MeSH Terms

Conditions

Schizophrenia; Bipolar Disorder; Metabolic Syndrome

Interventions

Diet, Ketogenic

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Bipolar and Related Disorders; Mood Disorders; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diet, Carbohydrate-Restricted; Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: We will randomize 70 overweight/obese SZ and BD participants to receive either a ketogenic or Diet as Usual.

Study Record Dates

• First Submitted: January 6, 2022
• First Posted: March 7, 2022
• Study Start: April 21, 2022
• Primary Completion: August 1, 2025
• Study Completion: August 31, 2025
• Last Updated: January 12, 2026

Record last verified: 2025-03

Locations

US (1)