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

University of Pittsburgh107 enrolled

Overview

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

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

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

107

Conditions

Bipolar Disorder

Interventions

Non-ketogenic DietOTHER

Consuming a non-ketogenic diet

Ketogenic DietOTHER

Consuming a ketogenic diet

No dietOTHER

Participants without Bipolar Disorder will not participate in the diet phases of the study

Eligibility

Sex: ALLMin age: 18 YearsMax age: 40 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

RECRUITING

Outcomes

Primary Outcomes

Blood oxygen level-dependent (BOLD) signal at Scan 1

The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)

Fasting Glucose at Baseline

Fasting glucose blood levels

Central Contacts

Jill Morris-Tillman

CONTACT

412-383-8206 morristillmanje@upmc.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time frame: Baseline (all participants)

Fasting lipids at Baseline

Fasting lipid blood levels

Time frame: Baseline (all participants)

Fasting hepatic function panel at Baseline: total protein

Fasting levels of total protein in the blood

Time frame: Baseline (all participants)

Fasting hepatic function panel at Baseline: albumin

Fasting levels of albumin in the blood

Time frame: Baseline (all participants)

Fasting hepatic function panel at Baseline: bilirubin

Fasting levels of bilirubin in the blood

Time frame: Baseline (all participants)

Fasting hepatic function panel at Baseline: liver enzyme

Fasting levels of liver enzyme in the blood

Time frame: Baseline (all participants)

Fasting Glucose at halfway point through first dietary phase

Fasting glucose blood levels

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)

Fasting lipids at end of first dietary phase

Fasting lipid blood levels

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)

Fasting lipids at end of second dietary phase

Fasting lipids blood levels

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Baseline Scan 1 (all participants)

Glutamate at Baseline

Glutamate concentrations in the brain

Time frame: Baseline Scan 1 (all participants)

Lactate at Baseline

Lactate concentrations in the brain

Time frame: Baseline Scan 1 (all participants)

Gamma-aminobutyric acid (GABA) at end of first dietary phase

Gamma-aminobutyric acid (GABA) concentrations in the brain

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)

Secondary Outcomes

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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)