Can Neural Network Instability in Schizophrenia be Improved With a Very Low Carbohydrate Ketogenic Diet?
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|ClinicalTrials.gov Identifier: NCT05268809|
Recruitment Status : Recruiting
First Posted : March 7, 2022
Last Update Posted : September 30, 2022
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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.
|Condition or disease||Intervention/treatment||Phase|
|Schizophrenia Bipolar Disorder||Other: Ketogenic diet||Not Applicable|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||70 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||We will randomize 70 overweight/obese SZ and BD participants to receive either a ketogenic or Diet as Usual.|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Can Neural Network Instability in Schizophrenia be Improved With a Very Low Carbohydrate Ketogenic Diet?|
|Actual Study Start Date :||April 21, 2022|
|Estimated Primary Completion Date :||August 31, 2023|
|Estimated Study Completion Date :||August 31, 2023|
Experimental: Ketogenic Diet
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
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.
No Intervention: Diet as usual
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.
- Change in network stabilization after 4 weeks [ Time Frame: Baseline (0 weeks) and posttreatment (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).
- Change in body composition after 4 weeks [ Time Frame: Baseline (0 weeks) and posttreatment (4 weeks) ]Body composition will be determined by calculating the waist-hip ratio.
- Change in systemic inflammation after 4 weeks [ Time Frame: Baseline (0 weeks) and posttreatment (4 weeks) ]Systemic inflammation will be assayed by plasma C-Reactive Protein levels (VA Clinical Lab).
- Change in insulin resistance after 4 weeks [ Time Frame: Baseline (0 weeks) and posttreatment (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.
- Cognition Battery [ Time Frame: Baseline (0 weeks) ]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.
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|Ages Eligible for Study:||18 Years to 65 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Male or female ages 18-65 years old
- SCID-5 Schizophrenia or schizoaffective disorder stable on 2nd generation anti-psychotic (SZ) or bipolar disorder (BD)
- Willing to adhere to 4 wk. KETO diet
- Speak, read, comprehend English
- Access to internet
- Willing and able to heat up KETO meals
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05268809
|Contact: Judith Ford, Ph.D.||email@example.com|
|United States, California|
|San Francisco VA Medical Center||Recruiting|
|San Francisco, California, United States, 94121|
|Contact: Judith Ford, PhD 415-562-4334 firstname.lastname@example.org|
|Principal Investigator: Judith Ford, PhD|
|Responsible Party:||Northern California Institute of Research and Education|
|Other Study ID Numbers:||
|First Posted:||March 7, 2022 Key Record Dates|
|Last Update Posted:||September 30, 2022|
|Last Verified:||September 2022|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
Schizophrenia Spectrum and Other Psychotic Disorders
Bipolar and Related Disorders