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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Other: Non-ketogenic Diet
* Other: Ketogenic Diet
* Other: No diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants: *18-30 years of age 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) Young Mania Rating Scale score(YMRS)>10 Score <8 Hamilton Rating Scale for Depression(HRSD) 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 <8 on YMRS Score <8 on Hamilton Depression Rating Scale (HRSD) 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 18-30 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 Left/mixed handedness (Annett criteria) 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. Does not have a smartphone with a) iPhone operating system (iOS) version 12.0 or above, or b) Android version 8 and later to use with the Keto-Mojo app 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 depressive, manic, or euthymic episode Young Mania Rating Scale score(YMRS)10 or lower Score 8 or higher on Hamilton Rating Scale for Depression(HRSD) Using psychotropic medications other than those allowed in inclusion criteria Head circumference larger than about 58 cm (size restriction of 7Tesla (7T) scanner) 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 8 or higher on YMRS Score 8 or higher on HRSD Using psychotropic medications other than those allowed in inclusion criteria Healthy Control (HC) Group Not sex-matched with BD groups Has psychiatric history

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1st phase Non-ketogenic Diet / 2nd phase Ketogenic Diet<br>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<br>* Consuming a non-ketogenic diet<br>Other: Ketogenic Diet<br>* Consuming a ketogenic diet<br>|
| Experimental: 1st phase Ketogenic Diet / 2nd phase Non-ketogenic Diet<br>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<br>* Consuming a non-ketogenic diet<br>Other: Ketogenic Diet<br>* Consuming a ketogenic diet<br>|
| Other: No diet<br>Participants without Bipolar Disorder will not participate in the diet phases of the study | Other: No diet<br>* Participants without Bipolar Disorder will not participate in the diet phases of the study<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketogenic Diet, Magnetic Resonance Imaging