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

Bipolar Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06081426
• Other study ID #: STUDY23080048
• Status: Recruiting
• Phase: N/A
• Start date: January 12, 2024
• Est. completion date: January 2027

Study information

• Verified date: February 2024
• Source: University of Pittsburgh
• Contact: Jill Morris-Tillman
• Phone: 412-383-8206
• Email: morristillmanje[@]upmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 107
• Est. completion date: January 2027
• Est. primary completion date: January 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Bipolar Disorder

Intervention

Other:
• Non-ketogenic Diet
Consuming a non-ketogenic diet
• Ketogenic Diet
Consuming a ketogenic diet
• No diet
Participants without Bipolar Disorder will not participate in the diet phases of the study

Locations

Country	Name	City	State
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	Baszucki Brain Research Fund

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	Fasting Glucose at Baseline	Fasting glucose blood levels	Baseline (all participants)
Primary	Fasting lipids at Baseline	Fasting lipid blood levels	Baseline (all participants)
Primary	Fasting hepatic function panel at Baseline: total protein	Fasting levels of total protein in the blood	Baseline (all participants)
Primary	Fasting hepatic function panel at Baseline: albumin	Fasting levels of albumin in the blood	Baseline (all participants)
Primary	Fasting hepatic function panel at Baseline: bilirubin	Fasting levels of bilirubin in the blood	Baseline (all participants)
Primary	Fasting hepatic function panel at Baseline: liver enzyme	Fasting levels of liver enzyme in the blood	Baseline (all participants)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	Fasting Glucose at end of first dietary phase	Fasting glucose blood levels	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Primary	Fasting lipids at end of first dietary phase	Fasting lipid blood levels	End of first dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	Fasting Glucose at end of second dietary phase	Fasting glucose blood levels	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Primary	Fasting lipids at end of second dietary phase	Fasting lipids blood levels	End of second dietary phase (8-10 weeks) (participants with Bipolar Disorder)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	Gamma-aminobutyric acid (GABA) at Baseline	Gamma-aminobutyric acid (GABA) concentrations in the brain	Baseline Scan 1 (all participants)
Primary	Glutamate at Baseline	Glutamate concentrations in the brain	Baseline Scan 1 (all participants)
Primary	Lactate at Baseline	Lactate concentrations in the brain	Baseline Scan 1 (all participants)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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
Secondary	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.
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)