Bipolar I Disorder, Bipolar II Disorder, Cannabis Use Disorder, Substance Use Disorders
Conditions
Brief summary
The proposed 2-week, double-blind, crossover, proof of concept study aims to measure and manipulate core neurochemical (i.e., dysregulated brain GABA/glutamate homeostasis) and neurobehavioral (i.e., elevated impulsivity) dysfunctions characteristic of individuals with cannabis use disorder (CUD) and Bipolar Disorder (BD), using a medication that has been shown to increase cortical GABA (i.e., gabapentin) levels in past research, and to evaluate medication-related changes in response inhibition (go no-go) and cannabis cue reactivity functional Magnetic Resonance Imaging tasks, as well as cannabis use, mood symptoms (including anxiety and sleep), and impulsivity in individuals with CUD+BD.
Detailed description
Bipolar disorder (BD) is the Axis I condition most strongly associated with cannabis use disorder (CUD); there is a six-fold increase in the prevalence of CUD in individuals with BD relative to the general population. Individuals with co-occurring CUD and BD (CUD+BD) have substantially worse clinical outcomes than those with either BD or CUD alone. Response to mood stabilizing medications appears to be poor, yet little is known about optimal treatment for CUD+BD, as there have been no randomized medication trials for CUD+BD to date. Convergent evidence supports dysregulated brain γ-Aminobutyric acid (GABA)/glutamate homeostasis as a candidate target for pharmacological intervention in CUD+BD. Preclinical and clinical studies have demonstrated that CUD and BD are each associated with prefrontal GABA and glutamate disturbances and that impulsivity, a core neurobehavioral feature of both CUD and BD and a key Research Domain Criteria (RDoC) construct, is causally related to GABAergic/glutamatergic functioning. Gabapentin has been consistently shown in preclinical research to modulate GABA and glutamate transmission. In human Proton Magnetic Resonance Spectroscopy (1H-MRS) studies, both acute and chronic gabapentin dosing have been shown to increase brain GABA levels, however, few studies have investigated gabapentin effects on glutamate levels. Researchers propose that gabapentin may impact clinical outcomes in CUD+BD individuals both directly and indirectly through their impact on impulsivity.
Interventions
DRUGGabapentin
5 day trial of gabapentin with titration to 1,200mg
DRUGPlacebo Oral Capsule
5 day trial of matched placebo
Sponsors
National Institute on Drug Abuse (NIDA)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Meets DSM-V criteria for Bipolar Disorder * Meets DSM-V criteria for Cannabis Use Disorder * Using at least one mood stabilizing medication
Exclusion criteria
* Serious medical or non-inclusionary psychiatric disease * Concomitant use of benzodiazepine medications or any medications hazardous if taken with gabapentin * History of clinically significant brain injury * Presence of non-MRI safe material, or clinically significant claustrophobia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy | Day 5 of each experimental condition | Concentrations of GABA, normalized to water and corrected for CSF%, in dorsal anterior cingulate measured via Proton Magnetic Resonance Spectroscopy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gabapentin, Then Placebo Oral Capsule Week 1: Gabapentin: 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 1,200mg gabapentin) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7).
Week 2: Placebo: 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). | 12 |
| Placebo Oral Capsule, Then Gabapentin Week 1: Placebo: 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (Days 1-5), MRI (Day 5), and medication washout (Days 5-7).
Week 2: Gabapentin: 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 1,200mg gabapentin) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). | 11 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No longer met inclusion/exclusion criter | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Gabapentin, Then Placebo Oral Capsule | Placebo Oral Capsule, Then Gabapentin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 10 Participants | 22 Participants |
| Age, Continuous | 38.58 years | 35.45 years | 37.09 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 11 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 7 Participants | 16 Participants |
| Region of Enrollment United States | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 22 |
| other Total, other adverse events | 8 / 23 | 6 / 22 |
| serious Total, serious adverse events | 0 / 23 | 0 / 22 |
Outcome results
Primary
Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy
Concentrations of GABA, normalized to water and corrected for CSF%, in dorsal anterior cingulate measured via Proton Magnetic Resonance Spectroscopy.
Time frame: Day 5 of each experimental condition
Population: Individuals with Bipolar Disorder and Cannabis Use Disorder
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gabapentin | Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy | GABA (randomization order 1, gabapentin 1st) | 2.625 Institutional Units | Standard Deviation 0.324 |
| Gabapentin | Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy | GABA (randomization order 2, placebo 1st) | 2.609 Institutional Units | Standard Deviation 0.29 |
| Placebo Oral Capsule | Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy | GABA (randomization order 1, gabapentin 1st) | 2.696 Institutional Units | Standard Deviation 0.313 |
| Placebo Oral Capsule | Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy | GABA (randomization order 2, placebo 1st) | 2.720 Institutional Units | Standard Deviation 0.248 |
p-value: 0.711Mixed Models Analysis