Examining Neurobiological Mechanisms Underlying the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder (BD)
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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 Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- Blood oxygen level-dependent (BOLD) signal at Scan 1 [Baseline Scan 1 (all participants)]
The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity
- Blood oxygen level-dependent (BOLD) signal at Scan 2 [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity
- Blood oxygen level-dependent (BOLD) signal at Scan 3 [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
The blood oxygen level-dependent (BOLD) signal indicates brain activity and connectivity
- Manic symptoms at Scan 1 [Baseline Scan 1 (all participants)]
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)
- Manic symptoms at Scan 2 [Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
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)
- Manic symptoms at Scan 3 [Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
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)
- Fasting Glucose at Baseline [Baseline (all participants)]
Fasting glucose blood levels
- Fasting lipids at Baseline [Baseline (all participants)]
Fasting lipid blood levels
- Fasting hepatic function panel at Baseline: total protein [Baseline (all participants)]
Fasting levels of total protein in the blood
- Fasting hepatic function panel at Baseline: albumin [Baseline (all participants)]
Fasting levels of albumin in the blood
- Fasting hepatic function panel at Baseline: bilirubin [Baseline (all participants)]
Fasting levels of bilirubin in the blood
- Fasting hepatic function panel at Baseline: liver enzyme [Baseline (all participants)]
Fasting levels of liver enzyme in the blood
- Fasting Glucose at halfway point through first dietary phase [Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting glucose blood levels
- Fasting lipids at halfway point through first dietary phase [Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting lipid blood levels
- Fasting hepatic function at halfway point through first dietary phase: total protein [Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of total protein in the blood
- Fasting hepatic function at halfway point through first dietary phase: albumin [Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of albumin in the blood
- Fasting hepatic function at halfway point through first dietary phase: bilirubin [Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of bilirubin in the blood
- Fasting hepatic function at halfway point through first dietary phase: liver enzyme [Halfway point through first dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of liver enzyme in the blood
- Fasting Glucose at end of first dietary phase [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting glucose blood levels
- Fasting lipids at end of first dietary phase [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting lipid blood levels
- Fasting hepatic function at end of first dietary phase: total protein [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of total protein in the blood
- Fasting hepatic function at end of first dietary phase: albumin [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of albumin in the blood
- Fasting hepatic function at end of first dietary phase: bilirubin [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of bilirubin in the blood
- Fasting hepatic function at end of first dietary phase: liver enzyme [End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of liver enzyme in the blood
- Fasting Glucose at halfway point through second dietary phase [Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting glucose blood levels
- Fasting lipids at halfway point through second dietary phase [Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting lipid blood levels
- Fasting hepatic function at halfway point through second dietary phase: total protein [Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of total protein in the blood
- Fasting hepatic function at halfway point through second dietary phase: albumin [Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of albumin in the blood
- Fasting hepatic function at halfway point through second dietary phase: bilirubin [Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of bilirubin in the blood
- Fasting hepatic function at halfway point through second dietary phase: liver enzyme [Halfway point through second dietary phase (4-5 weeks) (participants with Bipolar Disorder)]
Fasting levels of liver enzyme in the blood
- Fasting Glucose at end of second dietary phase [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting glucose blood levels
- Fasting lipids at end of second dietary phase [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting lipids blood levels
- Fasting hepatic function at end of second dietary phase: total protein [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of total protein in the blood
- Fasting hepatic function at end of second dietary phase: albumin [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of albumin in the blood
- Fasting hepatic function at end of second dietary phase: bilirubin [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of bilirubin in the blood
- Fasting hepatic function at end of second dietary phase: liver enzyme [End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Fasting levels of liver enzyme in the blood
- Gamma-aminobutyric acid (GABA) at Baseline [Baseline Scan 1 (all participants)]
Gamma-aminobutyric acid (GABA) concentrations in the brain
- Glutamate at Baseline [Baseline Scan 1 (all participants)]
Glutamate concentrations in the brain
- Lactate at Baseline [Baseline Scan 1 (all participants)]
Lactate concentrations in the brain
- Gamma-aminobutyric acid (GABA) at end of first dietary phase [Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Gamma-aminobutyric acid (GABA) concentrations in the brain
- Glutamate at end of first dietary phase [Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Glutamate concentrations in the brain
- Lactate at end of first dietary phase [Scan 2 at end of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Lactate concentrations in the brain
- Gamma-aminobutyric acid (GABA) at end of second dietary phase [Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Gamma-aminobutyric acid (GABA) concentrations in the brain
- Glutamate at end of second dietary phase [Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Glutamate concentrations in the brain
- Lactate at end of second dietary phase [Scan 3 at end of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Lactate concentrations in the brain
Secondary Outcome Measures
- Average total sleep time during Ketogenic vs Normal diet [Wrist actigraphy will be collected throughout the 8-10wk ketogenic diet and normal diet study intervals]
Total sleep time will be assessed using wrist actigraphy. Wrist actigraphy will be collected continuously, at-home.
- Average rest-activity rhythm interdaily stability during Ketogenic vs Normal diet [Wrist actigraphy will be collected throughout the 8-10 wk ketogenic diet and normal diet study intervals.]
Rest-activity rhythm interdaily stability will be assessed using wrist actigraphy. Wrist actigraphy will be collected continuously, at-home
- Ecological momentary assessments (EMA) during the first dietary phase: Mood monitoring [The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
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
- Ecological momentary assessments (EMA) during the first dietary phase: Energy monitoring [The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
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
- Ecological momentary assessments (EMA) during the first dietary phase: Suicidality monitoring [The first dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Suicidality monitoring in real time in participants with Bipolar Disorder: answer yes or no to having self-harm/suicide thoughts and plans
- Ecological momentary assessments (EMA) during the second dietary phase: Mood monitoring [The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
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
- Ecological momentary assessments (EMA) during the second dietary phase: Energy monitoring [The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
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
- Ecological momentary assessments (EMA) during the second dietary phase: Suicidality monitoring [The second dietary phase (8-10 weeks) (participants with Bipolar Disorder)]
Suicidality monitoring in real time in participants with Bipolar Disorder: answer yes or no to having self-harm/suicide thoughts and plans
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | United States | 15213 |
Sponsors and Collaborators
- University of Pittsburgh
- Baszucki Brain Research Fund
Investigators
- Principal Investigator: Mary Phillips, MD, University of Pittsburgh
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- STUDY23080048