Ketogenic and Nutritional Interventions for First Episode Bipolar Disorder

A Randomized Controlled Clinical Trial of Ketogenic and Nutritional Interventions for Brain Energy Metabolism and Psychiatric Symptoms in First Episode Bipolar Disorder.

This is a randomized, controlled clinical trial to assess the effects of the ketogenic diet in combination with treatment as usual on brain energy metabolism and psychiatric symptoms in individuals with first episode bipolar disorder and schizoaffective disorder.

Study Overview

• Status: Recruiting
• Conditions: Schizoaffective Disorder; Psychosis; Bipolar I Disorder
• Intervention / Treatment: Other: Ketogenic diet; Other: Dietary Guidelines for Americans

Detailed Description

Several lines of evidence show energy metabolism and redox dysregulation in bipolar disorder and psychotic disorders. Ketogenic interventions targeting energy metabolism are promising therapeutic approaches to improve mood and psychosis in bipolar disorder and other psychotic disorders. Early intervention is also critical to helping people achieve their goals for recovery after a first episode. Investigators aim to use multimodal imaging and metabolic measures to study the effects of a ketogenic diet intervention on energy metabolism and psychiatric symptoms in individuals with first episode bipolar disorder and schizoaffective disorder. This 12-week randomized controlled trial will assess the benefits of a ketogenic diet in combination with treatment as usual compared to a standard diet. Investigators will measure the effects of nutritional ketosis on brain redox and energy metabolism and other neurometabolic markers using magnetic resonance spectroscopy. Furthermore, investigators will measure the effects of the ketogenic diet on mood and psychotic symptoms and metabolic measures such as insulin resistance.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jacey Anderson, B.A.; Phone Number: 617-855-3988; Email: janderson75@mclean.harvard.edu
• Study Contact Backup: Name: Virginie-Anne Chouinard, MD; Email: vchouinard@mclean.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Belmont, Massachusetts, United States, 02478
      • Recruiting
      • McLean Hospital
      • Principal Investigator: Virginie-Anne Chouinard, MD
      • Contact: Jacey Anderson, B.A.; Email: janderson75@mclean.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Between the ages of 18 and 45.
• Ability to adhere to study diets.
• Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) diagnosis of bipolar I disorder or schizoaffective disorder with onset of illness in the last 7 years.
• Must have a stable psychiatric disorder with no change in psychiatric medications within the past 2 weeks of screening
• Must not be expected to require addition of any new psychiatric medications during the 12-week duration of the study.

Exclusion Criteria:

• Unable to sign informed consent
• Contraindication to magnetic resonance (MR) scan (including claustrophobia)
• Unstable medical illness (including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease)
• Current DSM-5 substance use disorder
• Currently pregnant, nursing, or of childbearing potential and not using a medically accepted means of contraception
• Have a body weight of over 350 lbs or a body mass index (BMI) <20
• Score above 15 on the Young Mania Rating Scale (YMRS)
• History of significant head injury
• Current cancer diagnosis
• Current diagnosis of type 1 or type 2 Diabetes Mellitus
• History of gastric bypass surgery or any weight loss surgery
• Concomitant treatment with Propofol
• Familial hypercholesterolemia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ketogenic diet arm; Eligible participants assigned to the ketogenic diet arm will be asked to follow the ketogenic diet (KD) for 12 weeks in addition to any ongoing medications (e.g., mood stabilizers and/or second-generation antipsychotics). Participants will receive weekly and as needed diet counseling from a registered dietician. Participants will be asked to monitor and report their blood ketone levels each day via a finger-prick device provided by the study team.	Other: Ketogenic diet; The ketogenic diet (KD) is a normo-caloric diet composed of high-fat, low carbohydrate, and adequate protein intake. The KD will consist of 3 meals a day plus snacks, targeting 75-80% fat, 13-18% protein, 7% carbohydrates.
Active Comparator: Dietary Guidelines for Americans arm; Eligible participants assigned to the Dietary Guidelines for Americans (DGA) arm will adhere to the Dietary Guidelines for Americans in addition to any ongoing medications (e.g., mood stabilizers and/or second-generation antipsychotics). Participants will receive weekly and as needed diet counseling from a registered dietician. Participants will be asked to monitor and report their blood ketone levels each day via a finger-prick device provided by the study team.	Other: Dietary Guidelines for Americans; Dietary Guidelines for Americans diet is a normo-caloric diet consisting of 3 meals a day plus snacks, emphasizing nutrient dense foods to meet food group needs (85% of calories), and limits foods and beverages higher in added sugars and saturated fat (15% of calories).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in brain redox nicotinamide adenine dinucleotide metabolites ratio (NAD+/NADH)	Change from baseline to week 12 in NAD+/NADH as measured by in vivo phosphorus magnetic resonance spectroscopy (31P-MRS).	12 weeks
Change in brain creatine kinase forward reaction rate (kf)	Change from baseline to week 12 in creatine kinase forward reaction rate (kf) as measured by 31P magnetization transfer (MT) MRS.	12 weeks
Change in insulin resistance	Change from baseline to week 12 of insulin resistance measured using the homeostatic model assessment of insulin resistance (HOMA-IR) using fasting blood glucose and insulin levels.	12 weeks
Change in psychotic symptoms	Change from baseline to week 12 in Positive and Negative Syndrome Scale (PANSS) total score. Scores range from 30-210; a higher score indicates a higher level of psychotic symptoms.	12 weeks
Change in depressive symptoms	Change from baseline to week 12 in Hamilton Rating Scale for Depression (HAM-D) total score. Scores range from 0-52; a higher score indicates a higher level of depression.	12 weeks
Change in mania symptoms	Change from baseline to week 12 in Young Mania Rating Scale (YMRS) total score. Scores range from 0-60. A higher score indicates a more severe illness.	12 weeks
Change in Clinical Global Impression (CGI) Scale	Change from baseline to week 12 in Clinical Global Impression (CGI) Scale. Scores range from 1-7; a higher score indicates higher severity of illness.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body weight	Change from baseline to week 12 in participant body weight in kilograms, as measured using a standing scale.	12 weeks
Change in glycated hemoglobin (Hemoglobin A1c) level	Change from baseline to week 12 in fasting Hemoglobin A1c level.	12 weeks
Change in triglyceride levels	Change from baseline to week 12 in fasting triglyceride levels.	12 weeks
Change in low-density lipoprotein (LDL) levels	Change from baseline to week 12 in fasting LDL levels.	12 weeks
Change in high-density lipoprotein (HDL) levels	Change from baseline to week 12 in fasting HDL levels.	12 weeks
Change in high-sensitivity C-reactive protein (hs-CRP) levels	Change from baseline to week 12 in fasting hs-CRP levels.	12 weeks
Change in brain gamma-aminobutyric acid (GABA) concentration	Change from baseline to week 12 in GABA concentration measured by proton magnetic resonance spectroscopy.	12 weeks
Change in brain glutamate metabolite concentration	Change from baseline to week 12 in glutamate metabolite concentration measured by proton magnetic resonance spectroscopy.	12 weeks
Change in brain Phosphocreatine (PCr)	Changes from baseline to week 12 in PCr concentration as measured by in vivo 31P-MRS.	12 weeks
Change in brain inorganic phosphate concentration	Change from baseline to week 12 in inorganic phosphate (Pi) concentration as measured by in vivo 31P MRS.	12 weeks
Change in adverse events	Change from baseline to week 12 from baseline to week 12 in adverse events.	12 weeks
Change in anxiety symptoms	Change from baseline to week 12 from baseline to week 12 in Hamilton Anxiety Rating Scale (HAM-A) total score. Scores range from 0 - 56; a higher score indicates a higher level of anxiety.	12 weeks
Change in stress symptoms	Change from baseline to week 12 in Depression Anxiety Stress Scales (DASS-42) Stress Subscale score. Scores range from 0-42; a higher score indicates a higher level of stress.	12 weeks
Change in cognitive performance	Change from baseline to week 12 in Matrics Consensus Cognitive Battery (MCCB) Total Score. Scores range from 0.00% - 100.00%; a higher score indicates higher cognition.	12 weeks
Change in Global Functioning Scale (GFS) - Social and Role total score	Change from baseline to week 12 in Global Functioning Scale (GFS) - Social and Role total score. Scores range from 6-60; a lower score indicates worse social and role functioning.	12 weeks
Change in brain glutathione (GSH)	Change from baseline to week 12 in brain GSH measured by proton magnetic resonance spectroscopy.	12 weeks
Change in brain pH	Change from baseline to week 12 in pH as measured by in vivo 31P MRS.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in World Health Organization Disability Assessment Schedule (WHODAS) score	Change from baseline to week 12 in World Health Organization Disability Assessment Schedule (WHODAS) scale. Scores range from 0-144. A higher score indicates greater dysfunction and disability in major life domains.	12 weeks
Change in World Health Organization Quality of Life (WHOQOL) score	Change from baseline to week 12 in World Health Organization Quality of Life (WHOQOL) scale. Scores range from 1-130. A lower score indicates lower perceived quality of life.	12 weeks
Change in Extrapyramidal Symptom Rating Scale (ESRS) total score	Change from baseline to week 12 in Extrapyramidal Symptom Rating Scale (ESRS) total score. Scores range from 0-102; a higher score indicates more severe symptoms.	12 weeks
Change in Pittsburgh Sleep Quality Index (PSQI) total score	Change from baseline to week 12 in Pittsburgh Sleep Quality Index (PSQI) total score. Scores range from 0-21; a higher score indicates worse sleep quality.	12 weeks

Collaborators and Investigators

• Sponsor: Mclean Hospital
• Collaborators: Baszucki Family Foundation
• Investigators: Principal Investigator: Virginie-Anne Chouinard, MD, McLean Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2024
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: January 11, 2024
• First Submitted That Met QC Criteria: January 23, 2024
• First Posted (Actual): January 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Insulin resistance; Bipolar Disorder; Schizoaffective Disorder; Ketogenic Diet; First episode psychosis; Magnetic resonance spectroscopy (MRS); Brain energy metabolism; Redox; Creatine kinase; Keto
• Additional Relevant MeSH Terms: Mood Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Bipolar and Related Disorders; Psychotic Disorders; Mental Disorders; Bipolar Disorder
• Other Study ID Numbers: 2023P002849

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No