Impact of a Ketogenic Diet on Metabolic and Psychiatric Health in Patients With Bipolar or Schizophrenia Illness

• ClinicalTrials.gov Identifier: NCT03935854
• Recruitment Status: Completed
• First Posted: May 2, 2019
• Last Update Posted: December 8, 2022
• Sponsor: Stanford University
• Information provided by (Responsible Party): Shebani Sethi, Stanford University

Tracking Information

• First Submitted Date: April 30, 2019
• First Posted Date: May 2, 2019
• Last Update Posted Date: December 8, 2022
• Actual Study Start Date: February 13, 2019
• Actual Primary Completion Date: August 11, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2022)

• Change in heart rate from baseline [ Time Frame: Baseline, 16 weeks ]
  Heart rate recorded at 9 visits during study
• Change in blood pressure from baseline [ Time Frame: Baseline, 16 weeks ]
  Blood pressure recorded at 9 visits during study
• Change in weight from baseline [ Time Frame: Baseline, 16 weeks ]
  Weight recorded at 9 visits during study
• Change in waist circumference from baseline [ Time Frame: Baseline, 16 weeks ]
  waist circumference measured at 9 visits during study
• Change in visceral fat mass from baseline [ Time Frame: Baseline, 16 weeks ]
  Body composition (SECA) recorded at 5 visits during study
• Change in body fat mass from baseline [ Time Frame: Baseline, 16 weeks ]
  Body composition (SECA) recorded at 5 visits during study
• Percent Change in Hemoglobin A1c from baseline [ Time Frame: Baseline, 16 weeks ]
  Hemoglobin A1c recorded at initial and final visits
• Change in insulin resistance measure (HOMA-IR) from baseline [ Time Frame: Baseline, 16 weeks ]
  HOMA-IR measured at initial and final visits
• Change in inflammatory marker (hsCRP) from baseline [ Time Frame: Baseline, 16 weeks ]
  hsCRP measured at initial and final visits
• Change in lipid profile TG (triglycerides) from baseline [ Time Frame: Baseline, 16 weeks ]
  Lipid profile TG measured at initial and final visits
• Change in lipid profile small LDL (small dense LDL) from baseline [ Time Frame: Baseline, 16 weeks ]
  Lipid profile small LDL measured at initial and final visits
• Change in lipid profile (HDL) from baseline [ Time Frame: Baseline,16 weeks ]
  Lipid profile HDL measured at initial and final visits

Original Primary Outcome Measures (submitted: April 30, 2019)

• Change in heart rate from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in blood pressure from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in weight from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in body fat mass from baseline [ Time Frame: Baseline, 16 weeks ]
• Percent Change in Hemoglobin A1c from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in insulin resistance measure (HOMA-IR) from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in inflammatory marker (hsCRP) from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in lipid profile (triglycerides) from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in lipid profile (small dense LDL) from baseline [ Time Frame: Baseline, 16 weeks ]
• Change in lipid profile (HDL) from baseline [ Time Frame: Baseline,16 weeks ]

Current Secondary Outcome Measures (submitted: August 19, 2022)

• Psychiatric Indices - Mood [ Time Frame: Baseline, 16 weeks ]
  Change in Mood Qualitative Score (Clinical Mood Monitoring) from baseline
• Psychiatric Indices- Clinical Global Impression [ Time Frame: Baseline, 16 weeks ]
  Change in Clinical Global Impression Scales (CGI) from baseline 1-7 scale. 1= not at all ill, 7= among the most extremely ill patients)
• Generalized Anxiety Disorder - GAD-7 Anxiety [ Time Frame: Baseline, 16 weeks ]
  Change in Generalized Anxiety Symptom (GAD-7) scale from baseline. 0-15+ scale. (0= no anxiety, 15+= severe anxiety)
• Patient Health Questionnaire - PHQ-9 Depression [ Time Frame: Baseline, 16 weeks ]
  Change in Patient Health Questionnaire (PHQ-9) from baseline. Score range 0-27 (0= no depression, 27= severe depression)
• Psychiatric Indices- Global Assessment of Functioning [ Time Frame: Baseline, 16 weeks ]
  Change in Global Assessment of Functioning (GAF) Scale from baseline. 1-100 scale (1= persistent danger of hurting self or others, 100= superior functioning)
• Psychiatric Indices- Quality of Life [ Time Frame: Baseline, 16 weeks ]
  Change in Manchester Quality of Life Scale (MANSA) from baseline. Range 12-84 (each of 12 outcomes rated from 1= could not be worse to 7= could not be better; <4= dissatisfied with QoL, >4= satisfied with QoL)
• Psychiatric Indices- BPRS [ Time Frame: Baseline, 16 weeks ]
  Change in Brief Psychiatric Rating Scale (BPRS) from baseline. Score range 18-126. (For each of 18 symptoms, 1=symptom not present, 7= extremely severe)
• Pittsburgh Sleep Quality Index - PSQI [ Time Frame: Baseline, 16 weeks ]
  Change in Pittsburgh Sleep Quality Index from baseline. 0-21 scale (<5=good sleeper; 5+= meaningfully disturbed sleep or poor sleeper)

Original Secondary Outcome Measures (submitted: April 30, 2019)

• Psychiatric Indices - Mood [ Time Frame: Baseline, 16 weeks ]
  Change in Mood Score (Clinical Mood Monitoring) from baseline
• Psychiatric Indices- Clinical Global Impression [ Time Frame: Baseline, 16 weeks ]
  Change in Clinical Global Impression Scales (CGI) from baseline
• Psychiatric Indices- Global Assessment of Functioning [ Time Frame: Baseline, 16 weeks ]
  Change in Global Assessment of Functioning (GAF) Scale from baseline
• Psychiatric Indices- Quality of Life [ Time Frame: Baseline, 16 weeks ]
  Change in Manchester Quality of Life Scale (MANSA) from baseline
• Psychiatric Indices- BPRS [ Time Frame: Baseline, 16 weeks ]
  Change in Brief Psychiatric Rating Scale (BPRS) from baseline

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Impact of a Ketogenic Diet on Metabolic and Psychiatric Health in Patients With Bipolar or Schizophrenia Illness
• Official Title: Impact of A Low-Carbohydrate, High-Fat, Ketogenic Diet on Obesity, Metabolic Abnormalities and Psychiatric Symptoms in Patients With Bipolar or Schizophrenia Illness: A Pilot Trial
• Brief Summary: To initiate a low-carbohydrate, high-fat (LCHF) or ketogenic dietary (KD) intervention among a cohort of outpatients with either schizophrenia or bipolar illness who also have metabolic abnormalities, overweight/obesity, and/or are currently taking psychotropic medications experiencing metabolic side effects.
• Detailed Description: Adults with mental illness represent a high-risk, marginalized group in the current metabolic and obesity epidemic. Among US adults with severe mental illness, metabolic syndrome are highly prevalent conditions having severe consequences, with patients estimated to die on average 25 years earlier than the general population largely of premature cardiovascular disease. Many psychiatric medications, particularly neuroleptics and mood stabilizers, may, in addition, contribute to metabolic side effects and weight gain. Low-carbohydrate high-fat (LCHF) or ketogenic diets (KD) have been shown to reduce cardiovascular risk in those with insulin resistance. Recent findings support the idea that bipolar disorder, along with other psychiatric diseases schizophrenia, may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction which has downstream effects on synapse connections. A KD diet provides alternative fuel to the brain aside from glucose and is believed to contain beneficial neuroprotective effects, including stabilization of brain networks, reduction of inflammation and oxidative stress. The purpose of this study is to evaluate both the metabolic and psychiatric outcomes with a KD diet in this psychiatric population.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Obesity
• Ketogenic Dieting
• Metabolic Syndrome
• Bipolar Disorder
• Schizophrenia
• Weight Gain
• Psychotropic Agents Causing Adverse Effects in Therapeutic Use
• Brain Metabolic Disorder

Intervention

Other: LCHF, Ketogenic Diet

Low Carbohydrate, Moderate Protein, High Fat Ketogenic Dietary Intervention 16 weeks

Study Arms

Experimental: Ketogenic Diet 16 Week Group

Patients follow ketogenic diet for 16 weeks, with monitoring of physical and psychological health and coaching support

Intervention: Other: LCHF, Ketogenic Diet

Publications *

• Sethi S, Sinha A, Gearhardt AN. Low carbohydrate ketogenic therapy as a metabolic treatment for binge eating and ultraprocessed food addiction. Curr Opin Endocrinol Diabetes Obes. 2020 Oct;27(5):275-282. doi: 10.1097/MED.0000000000000571.
• Carmen M, Safer DL, Saslow LR, Kalayjian T, Mason AE, Westman EC, Sethi S. Treating binge eating and food addiction symptoms with low-carbohydrate Ketogenic diets: a case series. J Eat Disord. 2020 Jan 29;8:2. doi: 10.1186/s40337-020-0278-7. eCollection 2020. Erratum In: J Eat Disord. 2023 Sep 29;11(1):171.
• Norwitz NG, Sethi S, Palmer CM. Ketogenic diet as a metabolic treatment for mental illness. Curr Opin Endocrinol Diabetes Obes. 2020 Oct;27(5):269-274. doi: 10.1097/MED.0000000000000564.
• Yu B, Ozveren R, Sethi Dalai S. Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments. Submitted to Journal of Affective Disorders. Research Square preprint March 2020: DOI is: 10.21203/rs.3.rs-334453/v1
• Brietzke E, Mansur RB, Subramaniapillai M, Balanza-Martinez V, Vinberg M, Gonzalez-Pinto A, Rosenblat JD, Ho R, McIntyre RS. Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments. Neurosci Biobehav Rev. 2018 Nov;94:11-16. doi: 10.1016/j.neubiorev.2018.07.020. Epub 2018 Jul 31.
• Sarnyai Z, Kraeuter AK, Palmer CM. Ketogenic diet for schizophrenia: clinical implication. Curr Opin Psychiatry. 2019 Sep;32(5):394-401. doi: 10.1097/YCO.0000000000000535.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 19, 2022): 23
• Original Estimated Enrollment (submitted: April 30, 2019): 20
• Actual Study Completion Date: August 11, 2022
• Actual Primary Completion Date: August 11, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age 18-75 years old
2. Meet DSM V criteria for schizophrenia or bipolar disorder, any subtype, for > 1 year and clinically stable (with no hospitalization for past 3 months)
3. Currently taking psychotropic medication and gained at least 5% weight since starting medication or have a BMI greater than or equal to 26 kg/m2 or presence of at least one metabolic abnormality (hypertriglyceridemia, insulin resistance, dyslipidemia, impaired glucose tolerance)
4. Willing to consent to all study procedures and attend follow-up appointments and motivated to follow the dietary program.
5. Sufficient control over their food intake to adhere to study diets.
6. Willingness to regularly monitor blood pressure, glucose, dietary intake, and body weight over the 4-month trial

Exclusion Criteria:

1. Any subject pregnant or nursing
2. Comorbidity of developmental delay
3. Active substance abuse with illicit drugs or alcohol
4. In a current severe mood or psychotic state when entering the study that would prohibit compliance with study visits or dietary program.
5. Anyone who has been hospitalized or taken clozapine over the past 3 months
6. Inability to complete baseline measurements
7. Severe renal or hepatic insufficiency

8. Cardiovascular dysfunction, including diagnosis of:

   1. Congestive heart failure
   2. Angina
   3. Arrhythmias
   4. Cardiomyopathy
   5. Valvular heart disease
9. Any other medical condition that may make either diet dangerous as determined by the study medical team (e.g. anorexia nervosa)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03935854
• Other Study ID Numbers: 48527
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Shebani Sethi, Stanford University
• Original Responsible Party: Shebani Sethi Dalai, Stanford University, Clinical Instructor
• Current Study Sponsor: Stanford University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Shebani Sethi Dalai, MD; Stanford University

• PRS Account: Stanford University
• Verification Date: December 2022