SchizophreniaNCT06748950
Ketogenic Metabolic Therapy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder: Deep Omic Profiling
A study testing LCHF Ketogenic Diet and Diet-as-Usual (DAU) in people with Schizophrenia and Schizophrenia and Related Disorders, run by Stanford University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Schizophrenia, Schizophrenia and Related Disorders, Bipolar Disorder
- What is being tested?
- LCHF Ketogenic Diet and Diet-as-Usual (DAU)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2025to Jul 2028
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- diagnosed with bipolar disorder (BD), major depressive disorder (MDD), and or schizophrenia
- 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)
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- For individuals diagnosed with major depressive disorder (MDD):
- Not mild
- PHQ-9 > 10
- clinically stable (with no hospitalization for past 3 months)
- 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)
- 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.
- willing and able to give informed consent for participation in English.
- live within the United States.
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Who cannot join
- has started the ketogenic diet or was in ketosis within 3 months of wanting to enroll
- pregnant or nursing
- insulin dependent
- comorbidity of developmental delay
- in a current severe mood or psychotic state when entering the study that would prohibit compliance with study visits or dietary programs.
- any one who has been hospitalized or taken clozapine at doses above 550mg over the past 3 months
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- inability to complete baseline measurements
- severe renal or hepatic insufficiency
- cardiovascular dysfunction, including diagnosis of:
- Congestive heart failure
- Angina
- Arrhythmias
- Cardiomyopathy
- Valvular heart disease
- 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
- active suicidal and considered at significant risk for suicide during course of study
- 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
- mild BPRS at screening or baseline visits
- history of TBI
- 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.
- any medical condition that physicians or the PI believe would interfere with study participation or evaluation of results
- history of familial hypercholesterolemia
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Stanford University
Palo Alto, California, 94304
Study Coordinators, 650-725-0169, jessili@stanford.edu
About this study
Official title: A Randomized Controlled Trial of a Ketogenic Metabolic Therapy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder: Deep Omic Profiling
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.
Read the 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
- Being tested
- LCHF Ketogenic Diet, Diet-as-Usual (DAU)
- Keywords
- Mental Illness, Multiomics, Multi-omics, Omics Profiling
- Medical subject headings
- Schizophrenia, Bipolar Disorder, Bipolar and Related Disorders, Depressive Disorder, Major, Ketosis, Metabolic Diseases, Metabolic Syndrome, Mental Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LCHF Ketogenic DietOther
Low Carbohydrate, Moderate Protein, High Fat (LCHF) Ketogenic Dietary Intervention for 12 weeks
Diet-as-Usual (DAU)Other
Participant's usual diet
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: Ketogenic Diet Only | Experimental | Participants will follow 12 weeks of the ketogenic diet, with monitoring of physical and psychological health and coaching support. Receives: Other: LCHF Ketogenic Diet |
| Arm 2: DAU- Ketogenic Diet Crossover | Experimental | 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. Receives: Other: LCHF Ketogenic Diet; Other: Diet-as-Usual (DAU) |
What is being measured
The primary outcome is the main question the study is designed to answer.
WHO-5 Well-being Index
Change in general well-being from baseline. Self reported to measure quality of life. Assessed on 5-items, scored from 0-5 on each item, with higher scores indicating better quality of life.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Functioning Assessment Short Test (FAST)
Change in quality of life from baseline. Self reported and assessed on 24-items regarding difficulties in the experiences described. Scored from 0-3 on each item, with lower composite scores indicating better quality of life.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Quality of Life Scale (QIDS)
Change in severity of depression from baseline. Self reported on 16 items with a composite score range of 0-27 (0= no depression, 27 = very severe depression).
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Secondary outcomes (28)
Cambridge Cognition (CANTAB Assessment)
Change in cognition and brain health assessment from baseline. Scored by assessment's algorithm that compares scores within the established benchmark by age group and test. (≥ 1.5 SD below normative means = insufficient performance, ≥1 SD below normative means = subtle impaired performance in task)
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Quality of Life in Neurological Disorders (Neuro-QOL, Cognitive Function)
Change in quality of life related to cognitive function from baseline. T-score 17.3- 38.9 (high scores indicate better/desirable self-reported health).
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Brief Psychiatric Assessment Scale (BPRS)
change in severity of psychopathy; 18 conditions scored by clinician. Each of the 18 conditions/outcomes rated from 0-7 (0= not assessed, 7 = extremely severe).
Measured: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Patient Health Questionnaire (PHQ-9)
Change in Depression; 9-10 items scored on composite score range 0-27 (0= no depression, 27= severe depression).
Measured: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Clinical Global Impressions Scale (CGI)/ Clinical Mood Monitoring
Change in Clinical Global Impression (CGI) Psychiatric Index; 1-7 scale. (1= not at all ill, 7= among the most extremely ill patients).
Measured: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Perceived Stress Scale 4 (PSS-4)
Change in perceived stress from baseline measured by PSS-4 biweekly, a 4-item scale providing a 0-16 point composite score, with higher scores indicating greater perceived stress.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Generalized Anxiety Disorder Scale (GAD-7)
Change in General Anxiety Disorder (GAD-7) scale from Baseline. 0-15+ scale. (0= no anxiety, 15+= severe anxiety).
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Pittsburgh Sleep Quality Index (PSQI)
Change in sleep quality from baseline; 0-21 scale (<5=good sleeper; 5+= meaningfully disturbed sleep or poor sleeper).
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Epigenome
Profiling of epigenome measured in biospecimen collected.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Mitochondrial Function
Change in mitochondrial function from baseline measured in biospecimen.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Metabolome
Change in metabolites from baseline measured in biospecimen.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Proteome
Change in proteins from baseline measured in biospecimen.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Microbiome
Change in microbes/microorganisms from baseline measured in biospecimen.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Transcriptome
Change in mRNA-based expression from baseline measured in biospecimen.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Lipidome
Change in lipids from baseline measured in biospecimen.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Blood pressure
Change in blood pressure measured continuously by wearable devices and recorded weekly/biweekly during study visits.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Heart Rate Variability
Change in heart rate variability measured continuously by wearable devices and recorded weekly/biweekly during study visits.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Heart Rate
Change in heart rate measured continuously by wearable devices and recorded. weekly/biweekly during study visits.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Weight
Change in Weight from Baseline, recorded weekly/biweekly during study visits.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Waist Circumference
Change in waist circumference from Baseline, recorded weekly/biweekly during study visits.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Total Cholesterol
Blood measurement of change in Lipid Profile (total cholesterol) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Low Density Lipoprotein Cholesterol (LDL-C)
Blood measurement of change in Lipid Profile (LDL-C) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
High Density Lipoprotein Cholesterol (HDL-C)
Blood measurement of change in Lipid Profile (HDL-C) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Triglycerides (TG)
Blood measurement of change in Lipid Profile (TG) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Inflammatory Marker (hs-CRP)
Blood measurement of change in Inflammatory Marker (hs-CRP) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Insulin Resistance Measure (HOMA-IR)
Blood measurement of change in insulin resistance from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Glucose
Blood measurement of change in Metabolic Marker (Glucose) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Hemoglobin A1c
Blood measurement of change in Metabolic Marker (hemoglobin A1c) from baseline.
Measured: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2024
- Study startJul 2025 (estimated)
- Primary completionJul 2028 (estimated)
- Study completionJul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Shebani Sethi, Stanford University
- Investigators
- Shebani Sethi, MD, ABOM, Principal investigator, Stanford UniversityMichael Snyder, PhD, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06748950
- Sponsor's protocol ID
- 76425
- Status last verified
- May 2025
- First submitted
- 14 Dec 2024
- Last updated
- 16 May 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No current plan to share data.
Publications
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.
PubMed 16199797