Ketogenic Metabolic Therapy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder: Deep Omic Profiling

NCT ID: NCT06748950

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-31
• Study Completion Date: 2028-07-31

Brief Summary

The goal of this randomized clinical trial is to be adequately powered to evaluate the effect of ketogenic metabolic therapy on the quality of life in serious mental illness, schizophrenia, bipolar disorder, major depressive disorder.

Detailed Description

The ketogenic diet is a low carbohydrate, moderate protein, higher fat diet to help individuals improve energy and mood and to obtain nutrients from fats and protein. Schizophrenia, bipolar disorder, and major depressive disorder, collectively affect about 344 million individuals worldwide, (24 million with schizophrenia, 40 million people with BD, and 280 million with depression World Health Organization). These illnesses are debilitating psychiatric conditions characterized by a chronic pattern of emotional, behavioral, and cognitive disturbances. Shared psychopathology includes the pre-eminence of altered affective states, disorders of thoughts, and behavioral control. Additionally, those conditions share epidemiological traits, including significant cardiovascular, metabolic, infectious, and respiratory comorbidities, resulting in reduced life expectancy of up to 25 years (Xie et al., 2023). Reductions in cerebral glucose uptake are seen in both schizophrenia and bipolar disorder. While glucose is the brain's default fuel, ketone bodies are 27% more efficient, improve brain metabolism, and promote neural stability, as seen in childhood epilepsy (Sethi & Ford, 2022). The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy (Sethi et al., 2024, Liu et al., 2018, Martin-McGill et al., 2020). Nutritional ketosis has been successfully used to treat a range of neurological disorders. Metabolic disorders, which include conditions such as obesity and metabolic syndrome, more commonly occur in individuals with severe mental illness (between 40-60%). The investigators aim to study the effect of ketogenic metabolic therapy on various markers including:

• Metabolic health measurements and cardiovascular risk factors including: insulin resistance, advanced lipid analysis, weight, glucose regulation, dyslipidemia, absolute body fat chang, inflammation, waist circumference, blood pressure, skeletal muscle mass, and omega index
• Psychiatric symptom measures include: mood, psychosis, cognition, and quality of life
• Deep omic profiling including metabolic and proteomic data. Through identifying patterns, changes, and pathways of molecular, psychiatric, physiologic, and metabolic markers, the investigators aim to assess how this intervention may impact individuals with serious mental illnesses and symptoms/conditions related to serious mental illnesses.

Conditions

Schizophrenia; Schizophrenia and Related Disorders; Bipolar Disorder; Bipolar and Related Disorders; Major Depressive Disorder; Major Depression Severe; Ketogenic Dieting; Ketosis; Metabolic Disease; Metabolic Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1: Ketogenic Diet Only

Participants will follow 12 weeks of the ketogenic diet, with monitoring of physical and psychological health and coaching support.

Group Type: EXPERIMENTAL

LCHF Ketogenic Diet

Intervention Type: OTHER

Low Carbohydrate, Moderate Protein, High Fat (LCHF) Ketogenic Dietary Intervention for 12 weeks

Arm 2: DAU- Ketogenic Diet Crossover

Participants will follow 12 weeks of their usual diet (Diet-as-Usual, DAU). Then, participants will crossover and follow 12 weeks of the ketogenic diet. Monitoring of physical and psychological health and coaching support will occur throughout participation.

Group Type: EXPERIMENTAL

LCHF Ketogenic Diet

Intervention Type: OTHER

Low Carbohydrate, Moderate Protein, High Fat (LCHF) Ketogenic Dietary Intervention for 12 weeks

Diet-as-Usual (DAU)

Intervention Type: OTHER

Participant's usual diet

Interventions

LCHF Ketogenic Diet

Low Carbohydrate, Moderate Protein, High Fat (LCHF) Ketogenic Dietary Intervention for 12 weeks

Intervention Type: OTHER

Diet-as-Usual (DAU)

Participant's usual diet

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. diagnosed with bipolar disorder (BD), major depressive disorder (MDD), and or schizophrenia

1. For individuals diagnosed with bipolar disorder (BD):

• Meet DSM V criteria for BD (any subtype)
• Not mild
• >40 on BPRS
• clinically stable (with no hospitalization for past 3 months)

2. For individuals diagnosed with major depressive disorder (MDD):

• Not mild
• PHQ-9 > 10
• clinically stable (with no hospitalization for past 3 months)

3. For individuals diagnosed with schizophrenia:

• Meet DSM V criteria for schizophrenia (any subtype)
• Not mild
• >40 on BPRS
• clinically stable (with no hospitalization for past 3 months)

2. Participants may currently be on a stable and adequate dose of SSRI antidepressant therapy or other psychiatric medication. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, or trazodone) will be allowed if the therapy has been stable for at least four weeks prior to screening and if it is expected to remain stable. Participants may be switched from other classes of medication to another medication class by their psychiatrist or primary care doctor, but need to be stable enough to enroll and adhere to study procedures.

3. willing and able to give informed consent for participation in English.

4. live within the United States.

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Exclusion Criteria

1. has started the ketogenic diet or was in ketosis within 3 months of wanting to enroll

2. pregnant or nursing

3. insulin dependent

4. comorbidity of developmental delay

5. in a current severe mood or psychotic state when entering the study that would prohibit compliance with study visits or dietary programs.

6. any one who has been hospitalized or taken clozapine at doses above 550mg over the past 3 months

7. inability to complete baseline measurements

8. severe renal or hepatic insufficiency

9. cardiovascular dysfunction, including diagnosis of:

• Congestive heart failure
• Angina
• Arrhythmias
• Cardiomyopathy
• Valvular heart disease

10. active substance abuse with illicit drugs or alcohol and/or current diagnosis of a Substance Use Disorder (Abuse or Dependence, as defined by DSM-IV-TR), with the exception of nicotine or cannabis dependence

11. active suicidal and considered at significant risk for suicide during course of study

12. participation in any clinical trial- within the past month or concurrent to study participation- with an investigational drug/device and/or intervention that may interfere with study participation/evaluation of results

13. mild BPRS at screening or baseline visits

14. history of TBI

15. any other medical condition that may make diet intervention dangerous as determined by the study medical team (e.g. anorexia nervosa) or assessed by study team to have insufficient control over their food intake to adhere to study diets.

16. any medical condition that physicians or the PI believe would interfere with study participation or evaluation of results

17. history of familial hypercholesterolemia

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanford University

OTHER

Sponsor Role: lead

Responsible Party

Shebani Sethi

Clinical Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Shebani Sethi, MD, ABOM

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Michael Snyder, PhD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

Stanford University

Palo Alto, California, United States

Countries

United States

Central Contacts

Study Coordinator

Role: CONTACT

jessili@stanford.edu

(650) 725-0169

Facility Contacts

Study Coordinators

Role: primary

jessili@stanford.edu

650-725-0169

References

Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel R. Clinical implications of Brief Psychiatric Rating Scale scores. Br J Psychiatry. 2005 Oct;187:366-71. doi: 10.1192/bjp.187.4.366.

Reference Type: BACKGROUND

PMID: 16199797 (View on PubMed)

Other Identifiers

76425

Identifier Type: -

Identifier Source: org_study_id