Examining Neurobiological Mechanisms Underlying the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder (BD)

Elucidating Neurobiological Mechanisms Underlying the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder (BD): a Multidisciplinary Mechanistic Study

The investigators aim to examine the effect of the ketogenic diet on brain activity, metabolism, and emotions in adults with Bipolar Disorder (BD).

Study Overview

• Status: Recruiting
• Conditions: Bipolar Disorder
• Intervention / Treatment: Other: Non-ketogenic Diet; Other: Ketogenic Diet; Other: No diet

Detailed Description

The investigators hypothesize that a ketogenic diet will enhance levels of the ketone body β-Hydroxybutyrate (beta OHB), resulting in reduced mania/hypomania severity and predisposition to mania/hypomania in individuals with BD. To test this hypothesis in depth, the investigators will use a novel, multidisciplinary mechanistic study using multimodal neuroimaging, peripheral markers of mitochondrial metabolism, and participant-derived induced pluripotent stem cell (iPSC)-derived organoids.

• Study Type: Interventional
• Enrollment (Estimated): 107
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jill Morris-Tillman; Phone Number: 412-383-8206; Email: morristillmanje@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Jill Morris-Tillman; Phone Number: 412-383-8206; Email: morristillmanje@upmc.edu
      • Principal Investigator: Mary L Phillps, MD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

All participants:

• 18-40 years of age
• Not following a ketogenic diet

BD hypomanic group (n=30):

• Meeting sex proportion: 50% female
• Meeting diagnosis proportion: 50:50% Bipolar I: Bipolar II (BDI:II) (Diagnostic and Statistical Manual of Mental Disorders 5; DSM-5)
• Score greater than 10 on the Young Mania Rating Scale score(YMRS)
• BD medications will be allowed as in our previous studies: any combination of atypical antipsychotics, lithium, antidepressants, anxiolytics (common in BD)

BD euthymic group (n=30):

• Meeting sex proportion: 50% female
• Meeting diagnosis proportion: 50:50% BDI:II (DSM-5)
• Score less than or equal to 10 on YMRS
• BD medications will be allowed as in our previous studies: any combination of atypical antipsychotics, lithium, antidepressants, anxiolytics (common in BD)

Healthy Control (HC) Group (n=30):

• Sex matched with BD groups
• No psychiatric history

Exclusion Criteria:

All participants:

• Not between 18-40 years of age
• History of head injury, neurological, pervasive developmental disorder (e.g. autism), systemic medical disease and treatment (medical records, participant report)
• Mini-Mental State Examination score (cognitive state) <24
• Premorbid National Adult Reading Test Intelligent Quotient (NAART IQ) estimate<85
• Visual disturbance: <20/40 Snellen visual acuity
• History of alcohol/substance use disorder (SUD; all substances, including nicotine), and/or illicit substance use (except cannabis) over the last 6 months (SCID-5). Note: lifetime/present cannabis use (at non-abuse (<3 times in the past month) and non SUD levels) will be allowed, given its common usage in BD and young adults. Cannabis SUD over the last 6 months will not be allowed. Urine tests on scan days will exclude current illicit substance use (except cannabis). Salivary alcohol tests on scan days will exclude intoxicated individuals
• MRI exclusion: metallic objects, e.g., surgical implants; claustrophobia; positive pregnancy test for females or self-report pregnancy
• Unable to understand English
• Conditions related to the pancreas, liver, thyroid or gallbladder.
• Taking anticoagulants and/or those with blood dyscrasias (illnesses) who have coagulation disorders (eg, hemophilia) because of the ketomojo finger stick blood tests
• Scoring 3 or higher on positive symptom factor questions on the Positive and Negative Syndrome Scale (PANSS) questionnaire (indicative of psychotic symptoms)
• Currently following a ketogenic diet
• Head circumference larger than 24 inches (62cm) and/or chest circumference larger than 55 inches (139 cm)

BD hypomanic group:

• Must be meeting sex proportions: not 50% female
• Must be meeting diagnosis proportions: not 50:50% BDI:II (DSM-5)
• Diagnosis of BD in a manic or euthymic episode
• Score 10 or lower on the Young Mania Rating Scale score(YMRS)
• Using psychotropic medications other than those allowed in inclusion criteria
• Does not have a smartphone with a) iOS version 12.0 or above, or b) Android version 8 and later to use with the Keto-Mojo app

BD euthymic group:

• Not meeting sex proportion: not 50% female
• Not meeting diagnosis proportion: not 50:50% BDI:II
• Diagnosis of BD in a depressive, hypomanic, or manic episode
• Score greater than 10 on YMRS
• Using psychotropic medications other than those allowed in inclusion criteria
• Does not have a smartphone with a) iOS version 12.0 or above, or b) Android version 8 and later to use with the Keto-Mojo app

Healthy Control (HC) Group

• Not sex-matched with BD groups
• Has psychiatric history

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1st phase Non-ketogenic Diet / 2nd phase Ketogenic Diet; Participants with Bipolar Disorder will consume a non-ketogenic diet for the first phase of the study and then a ketogenic diet for the second phase of the study	Other: Non-ketogenic Diet; Consuming a non-ketogenic diet; Other: Ketogenic Diet; Consuming a ketogenic diet
Experimental: 1st phase Ketogenic Diet / 2nd phase Non-ketogenic Diet; Participants with Bipolar Disorder will consume a ketogenic diet for the first phase of the study and then a non-ketogenic diet for the second phase of the study	Other: Non-ketogenic Diet; Consuming a non-ketogenic diet; Other: Ketogenic Diet; Consuming a ketogenic diet
Other: No diet; Participants without Bipolar Disorder will not participate in the diet phases of the study	Other: No diet; Participants without Bipolar Disorder will not participate in the diet phases of the study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood oxygen level-dependent (BOLD) signal at Scan 1	The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity	Baseline Scan 1 (all participants)
Blood oxygen level-dependent (BOLD) signal at Scan 2	The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Blood oxygen level-dependent (BOLD) signal at Scan 3	The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Manic symptoms at Scan 1	The Young Mania Rating Scale (YMRS) indicates the level of manic symptoms with a total score that varies between zero (better outcome) and 60 (worse outcome)	Baseline Scan 1 (all participants)
Manic symptoms at Scan 2	The Young Mania Rating Scale (YMRS) indicates the level of manic symptoms with a total score that varies between zero (better outcome) and 60 (worse outcome)	Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Manic symptoms at Scan 3	The Young Mania Rating Scale (YMRS) indicates the level of manic symptoms with a total score that varies between zero (better outcome) and 60 (worse outcome)	Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting Glucose at Baseline	Fasting glucose blood levels	Baseline (all participants)
Fasting lipids at Baseline	Fasting lipid blood levels	Baseline (all participants)
Fasting hepatic function panel at Baseline: total protein	Fasting levels of total protein in the blood	Baseline (all participants)
Fasting hepatic function panel at Baseline: albumin	Fasting levels of albumin in the blood	Baseline (all participants)
Fasting hepatic function panel at Baseline: bilirubin	Fasting levels of bilirubin in the blood	Baseline (all participants)
Fasting hepatic function panel at Baseline: liver enzyme	Fasting levels of liver enzyme in the blood	Baseline (all participants)
Fasting Glucose at halfway point through first dietary phase	Fasting glucose blood levels	Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting lipids at halfway point through first dietary phase	Fasting lipid blood levels	Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through first dietary phase: total protein	Fasting levels of total protein in the blood	Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through first dietary phase: albumin	Fasting levels of albumin in the blood	Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through first dietary phase: bilirubin	Fasting levels of bilirubin in the blood	Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through first dietary phase: liver enzyme	Fasting levels of liver enzyme in the blood	Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting Glucose at end of first dietary phase	Fasting glucose blood levels	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting lipids at end of first dietary phase	Fasting lipid blood levels	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of first dietary phase: total protein	Fasting levels of total protein in the blood	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of first dietary phase: albumin	Fasting levels of albumin in the blood	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of first dietary phase: bilirubin	Fasting levels of bilirubin in the blood	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of first dietary phase: liver enzyme	Fasting levels of liver enzyme in the blood	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting Glucose at halfway point through second dietary phase	Fasting glucose blood levels	Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting lipids at halfway point through second dietary phase	Fasting lipid blood levels	Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through second dietary phase: total protein	Fasting levels of total protein in the blood	Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through second dietary phase: albumin	Fasting levels of albumin in the blood	Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through second dietary phase: bilirubin	Fasting levels of bilirubin in the blood	Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at halfway point through second dietary phase: liver enzyme	Fasting levels of liver enzyme in the blood	Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
Fasting Glucose at end of second dietary phase	Fasting glucose blood levels	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting lipids at end of second dietary phase	Fasting lipids blood levels	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of second dietary phase: total protein	Fasting levels of total protein in the blood	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of second dietary phase: albumin	Fasting levels of albumin in the blood	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of second dietary phase: bilirubin	Fasting levels of bilirubin in the blood	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Fasting hepatic function at end of second dietary phase: liver enzyme	Fasting levels of liver enzyme in the blood	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Gamma-aminobutyric acid (GABA) at Baseline	Gamma-aminobutyric acid (GABA) concentrations in the brain	Baseline Scan 1 (all participants)
Glutamate at Baseline	Glutamate concentrations in the brain	Baseline Scan 1 (all participants)
Lactate at Baseline	Lactate concentrations in the brain	Baseline Scan 1 (all participants)
Gamma-aminobutyric acid (GABA) at end of first dietary phase	Gamma-aminobutyric acid (GABA) concentrations in the brain	Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Glutamate at end of first dietary phase	Glutamate concentrations in the brain	Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Lactate at end of first dietary phase	Lactate concentrations in the brain	Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Gamma-aminobutyric acid (GABA) at end of second dietary phase	Gamma-aminobutyric acid (GABA) concentrations in the brain	Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Glutamate at end of second dietary phase	Glutamate concentrations in the brain	Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Lactate at end of second dietary phase	Lactate concentrations in the brain	Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average total sleep time during Ketogenic vs Normal diet	Total sleep time will be assessed using wrist actigraphy. Wrist actigraphy will be collected continuously, at-home.	Wrist actigraphy will be collected throughout the 8-10wk ketogenic diet and normal diet study intervals
Average rest-activity rhythm interdaily stability during Ketogenic vs Normal diet	Rest-activity rhythm interdaily stability will be assessed using wrist actigraphy. Wrist actigraphy will be collected continuously, at-home	Wrist actigraphy will be collected throughout the 8-10 wk ketogenic diet and normal diet study intervals.
Ecological momentary assessments (EMA) during the first dietary phase: Mood monitoring	Mood monitoring in real time in participants with Bipolar Disorder: rate mood on a scale of 1-7 with 1 being very low mood and 7 being very high mood	The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Ecological momentary assessments (EMA) during the first dietary phase: Energy monitoring	Energy monitoring in real time in participants with Bipolar Disorder: rate energy on a scale of 1-7 with 1 being very low energy and 7 being very high energy	The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Ecological momentary assessments (EMA) during the first dietary phase: Suicidality monitoring	Suicidality monitoring in real time in participants with Bipolar Disorder: answer yes or no to having self-harm/suicide thoughts and plans	The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Ecological momentary assessments (EMA) during the second dietary phase: Mood monitoring	Mood monitoring in real time in participants with Bipolar Disorder: rate mood on a scale of 1-7 with 1 being very low mood and 7 being very high mood	The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Ecological momentary assessments (EMA) during the second dietary phase: Energy monitoring	Energy monitoring in real time in participants with Bipolar Disorder: rate energy on a scale of 1-7 with 1 being very low energy and 7 being very high energy	The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Ecological momentary assessments (EMA) during the second dietary phase: Suicidality monitoring	Suicidality monitoring in real time in participants with Bipolar Disorder: answer yes or no to having self-harm/suicide thoughts and plans	The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Baszucki Brain Research Fund
• Investigators: Principal Investigator: Mary Phillips, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: September 22, 2023
• First Submitted That Met QC Criteria: October 5, 2023
• First Posted (Actual): October 13, 2023

Study Record Updates

• Last Update Posted (Actual): December 10, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Ketogenic Diet
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Mental Disorders; Mood Disorders; Bipolar Disorder; Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; Diet, Carbohydrate-Restricted; Diet, Ketogenic
• Other Study ID Numbers: STUDY23080048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Informed consent will be collected from study participants that allows for broad sharing of participants' de-identified data. Data transfer procedures will be in accordance with all Institutional Review Board guidelines and federal regulations including HIPAA (Health Insurance Portability and Accountability Act of 1996).
• IPD Sharing Time Frame: The principal investigators (PIs) reserve the right to publish on the stated aims in a timely manner. Data will be available for addressing other research questions (i.e. which are not described in funded/pending grants) as soon as the data have been checked for accuracy (a period which will be no later than one year after the completion of each assessment). After the study has ended, the study investigators will continue to test the stated aims, but will also continue to solicit collaborations with outside researchers and to consider data requests in a timely manner.
• IPD Sharing Access Criteria: Outside investigators must submit a 1)proposal of the study aims, hypotheses, variables/constructs, analytic approach, and estimated duration of the proposed research; 2)resume, qualifications, source of financial support, and conflict of interest statement; 3)sign a data-sharing agreement and confidentiality statement that stipulates using the data for the stated research purposes only, securing the data using appropriate computer technology, not manipulating the data in order to identify participants, acknowledging the grant that supported data collection and management in publications/presentations, and destroying or returning the data after analyses are complete; 4)obtain approval from their Institutional Review Board, and along with other staff members who have access to the data, submit certificates of the University of Pittsburgh Education and Certification Program in Research Practice Fundamentals or provide written documentation of similar human subjects protection training.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No