Clinical trial NCT06748950: Ketogenic Metabolic Therapy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder: Deep Omic Profiling
Official title: A Randomized Controlled Trial of a Ketogenic Metabolic Therapy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder: Deep Omic Profiling
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
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
Keywords: Mental Illness
Multiomics
Multi-omics
Omics Profiling
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2024-12-27
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: WHO-5 Well-being Index
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Functioning Assessment Short Test (FAST)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Quality of Life Scale (QIDS)
timeFrame: 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:
measure: Cambridge Cognition (CANTAB Assessment)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Quality of Life in Neurological Disorders (Neuro-QOL, Cognitive Function)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Brief Psychiatric Assessment Scale (BPRS)
timeFrame: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Clinical Global Impressions Scale (CGI)/ Clinical Mood Monitoring
timeFrame: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Perceived Stress Scale 4 (PSS-4)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Generalized Anxiety Disorder Scale (GAD-7)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Epigenome
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Mitochondrial Function
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Metabolome
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Proteome
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Microbiome
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Transcriptome
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Lipidome
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Blood pressure
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Heart Rate Variability
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Heart Rate
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Weight
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Waist Circumference
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Total Cholesterol
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Low Density Lipoprotein Cholesterol (LDL-C)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: High Density Lipoprotein Cholesterol (HDL-C)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Triglycerides (TG)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Inflammatory Marker (hs-CRP)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Insulin Resistance Measure (HOMA-IR)
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Glucose
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
measure: Hemoglobin A1c
timeFrame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Shebani Sethi, MD, ABOM
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Michael Snyder, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.