Examining Neurobiological Mechanisms Underlying the Therapeutic Effect of the Ketogenic Diet in 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.

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