Clinical trial NCT06081426: Examining Neurobiological Mechanisms Underlying the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder (BD)
Official title: Elucidating Neurobiological Mechanisms Underlying the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder (BD): a Multidisciplinary Mechanistic Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Bipolar Disorder
Keywords: Ketogenic Diet
Magnetic Resonance Imaging
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Baszucki Brain Research Fund
First posted: 2023-10-13
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Blood oxygen level-dependent (BOLD) signal at Scan 1
timeFrame: Baseline Scan 1 (all participants)
measure: Blood oxygen level-dependent (BOLD) signal at Scan 2
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Blood oxygen level-dependent (BOLD) signal at Scan 3
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Manic symptoms at Scan 1
timeFrame: Baseline Scan 1 (all participants)
measure: Manic symptoms at Scan 2
timeFrame: Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Manic symptoms at Scan 3
timeFrame: Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting Glucose at Baseline
timeFrame: Baseline (all participants)
measure: Fasting lipids at Baseline
timeFrame: Baseline (all participants)
measure: Fasting hepatic function panel at Baseline: total protein
timeFrame: Baseline (all participants)
measure: Fasting hepatic function panel at Baseline: albumin
timeFrame: Baseline (all participants)
measure: Fasting hepatic function panel at Baseline: bilirubin
timeFrame: Baseline (all participants)
measure: Fasting hepatic function panel at Baseline: liver enzyme
timeFrame: Baseline (all participants)
measure: Fasting Glucose at halfway point through first dietary phase
timeFrame: Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting lipids at halfway point through first dietary phase
timeFrame: Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through first dietary phase: total protein
timeFrame: Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through first dietary phase: albumin
timeFrame: Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through first dietary phase: bilirubin
timeFrame: Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through first dietary phase: liver enzyme
timeFrame: Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting Glucose at end of first dietary phase
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting lipids at end of first dietary phase
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of first dietary phase: total protein
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of first dietary phase: albumin
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of first dietary phase: bilirubin
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of first dietary phase: liver enzyme
timeFrame: End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting Glucose at halfway point through second dietary phase
timeFrame: Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting lipids at halfway point through second dietary phase
timeFrame: Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through second dietary phase: total protein
timeFrame: Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through second dietary phase: albumin
timeFrame: Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through second dietary phase: bilirubin
timeFrame: Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at halfway point through second dietary phase: liver enzyme
timeFrame: Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)
measure: Fasting Glucose at end of second dietary phase
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting lipids at end of second dietary phase
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of second dietary phase: total protein
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of second dietary phase: albumin
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of second dietary phase: bilirubin
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Fasting hepatic function at end of second dietary phase: liver enzyme
timeFrame: End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Gamma-aminobutyric acid (GABA) at Baseline
timeFrame: Baseline Scan 1 (all participants)
measure: Glutamate at Baseline
timeFrame: Baseline Scan 1 (all participants)
measure: Lactate at Baseline
timeFrame: Baseline Scan 1 (all participants)
measure: Gamma-aminobutyric acid (GABA) at end of first dietary phase
timeFrame: Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Glutamate at end of first dietary phase
timeFrame: Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Lactate at end of first dietary phase
timeFrame: Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Gamma-aminobutyric acid (GABA) at end of second dietary phase
timeFrame: Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Glutamate at end of second dietary phase
timeFrame: Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Lactate at end of second dietary phase
timeFrame: Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Secondary outcomes:
measure: Average total sleep time during Ketogenic vs Normal diet
timeFrame: Wrist actigraphy will be collected throughout the 8-10wk ketogenic diet and normal diet study intervals
measure: Average rest-activity rhythm interdaily stability during Ketogenic vs Normal diet
timeFrame: Wrist actigraphy will be collected throughout the 8-10 wk ketogenic diet and normal diet study intervals.
measure: Ecological momentary assessments (EMA) during the first dietary phase: Mood monitoring
timeFrame: The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Ecological momentary assessments (EMA) during the first dietary phase: Energy monitoring
timeFrame: The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Ecological momentary assessments (EMA) during the first dietary phase: Suicidality monitoring
timeFrame: The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Ecological momentary assessments (EMA) during the second dietary phase: Mood monitoring
timeFrame: The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Ecological momentary assessments (EMA) during the second dietary phase: Energy monitoring
timeFrame: The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
measure: Ecological momentary assessments (EMA) during the second dietary phase: Suicidality monitoring
timeFrame: The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Mary Phillips, MD
role: PRINCIPAL_INVESTIGATOR
References: