Gabapentin for Bipolar & Cannabis Use Disorders

• Sponsor: Medical University of South Carolina (Other)
• Overall Status: Completed
• CT.gov ID: NCT03334721
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 23
• Location: 1
• Arms: 2
• Actual Duration (Months): 21
• Patients Per Site Per Month: 1.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar I Disorder; Bipolar II Disorder; Cannabis Use Disorder; Substance Use Disorders	Drug: Gabapentin; Drug: Placebo Oral Capsule	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Gabapentin for Bipolar & Cannabis Use Disorders
• Actual Study Start Date: Oct 1, 2017
• Actual Primary Completion Date: Jul 1, 2019
• Actual Study Completion Date: Jul 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gabapentin, Then Placebo Oral Capsule Week 1: 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: 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).	Drug: Gabapentin; 5 day trial of gabapentin with titration to 1,200mg; Drug: Placebo Oral Capsule; 5 day trial of matched placebo
Experimental: Placebo Oral Capsule, Then Gabapentin Week 1: 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: 1-week condition will consist of an in-person study visit for assessment and dispensing of Gabapentin medication (Day 1), titration to maximum dose (i.e., 1,200mg gabapentin) (days 1-5), MRI (Day 5), and medication washout (Days 5-7).	Drug: Gabapentin; 5 day trial of gabapentin with titration to 1,200mg; Drug: Placebo Oral Capsule; 5 day trial of matched placebo

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of South Carolina	Charleston	South Carolina	United States	29425

Sponsors and Collaborators

• Medical University of South Carolina
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: James J Prisciandaro, PhD, Medical University of South Carolina

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 25, 2017

More Information

Publications

None provided.

• Responsible Party: James J. Prisciandaro, Assistant Professor, Medical University of South Carolina
• ClinicalTrials.gov Identifier: NCT03334721
• Other Study ID Numbers: 69905; R21DA04391701A1
• First Posted: Nov 7, 2017
• Last Update Posted: Nov 13, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Disease; Substance-Related Disorders; Marijuana Abuse; Gabapentin

Study Results

Participant Flow

Arm/Group Title	Gabapentin, Then Placebo Oral Capsule	Placebo Oral Capsule, Then Gabapentin
Arm/Group Description	Week 1: 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: 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). Gabapentin: 5 day trial of gabapentin with titration to 1,200mg Placebo Oral Capsule: 5 day trial of matched placebo	Week 1: 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: 1-week condition will consist of an in-person study visit for assessment and dispensing of Gabapentin medication (Day 1), titration to maximum dose (i.e., 1,200mg gabapentin) (days 1-5), MRI (Day 5), and medication washout (Days 5-7). Gabapentin: 5 day trial of gabapentin with titration to 1,200mg Placebo Oral Capsule: 5 day trial of matched placebo
Period Title: Overall Study
STARTED	12	11
COMPLETED	10	11
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Gabapentin, Then Placebo Oral Capsule	Placebo Oral Capsule, Then Gabapentin	Total
Arm/Group Description	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).	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).	Total of all reporting groups
Overall Participants	12	11	23
Age (Count of Participants)
<=18 years	0 0%	1 9.1%	1 4.3%
Between 18 and 65 years	12 100%	10 90.9%	22 95.7%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	38.58	35.45	37.09
Sex: Female, Male (Count of Participants)
Female	6 50%	5 45.5%	11 47.8%
Male	6 50%	6 54.5%	12 52.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	12 100%	11 100%	23 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 8.3%	0 0%	1 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 16.7%	4 36.4%	6 26.1%
White	9 75%	7 63.6%	16 69.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%	11 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Prefrontal GABA Concentrations Through Proton Magnetic Resonance Spectroscopy
Description	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

Outcome Measure Data

Analysis Population Description

Individuals with Bipolar Disorder and Cannabis Use Disorder

Arm/Group Title	Gabapentin	Placebo Oral Capsule
Arm/Group Description	Each 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). Gabapentin: 5 day trial of gabapentin with titration to 1,200mg	Each 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). Placebo Oral Capsule: 5 day trial of matched placebo
Measure Participants	22	21
GABA (randomization order 1, gabapentin 1st)	2.625 (0.324)	2.696 (0.313)
GABA (randomization order 2, placebo 1st)	2.609 (0.290)	2.720 (0.248)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gabapentin, Placebo Oral Capsule
	Comments
	Type of Statistical Test	Superiority
	Comments	Given the crossover design through which the data were collected, the statistical model also included a "Visit" (1 vs. 2) factor and a Visit by Treatment Condition interaction term. Analysis used Linear Mixed Modeling with Fixed Factors.
Statistical Test of Hypothesis	p-Value	0.711
	Comments	Treatment Condition Factor (0 = Placebo, 1 = Gabapentin)
	Method	Mixed Models Analysis
	Comments	df = 1, 20.183
Method of Estimation	Estimation Parameter	Test III Tests of Fixed Effects (F)
	Estimated Value	0.141
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Given the crossover design through which the data were collected, the statistical model also included a "Visit" (1 vs. 2) factor and a Visit by Treatment Condition interaction term.

Adverse Events

Time Frame	Adverse events were collected over a total of 4 visits (Med 1, MRI 1, Med 2, MRI 2) for each participant; 2-weeks.
Adverse Event Reporting Description	Please note -23 participants took gabapentin but only 22 took placebo because one participant dropped out of the study prior to receiving the placebo oral capsule (this was a crossover study).
Arm/Group Title	Gabapentin		Placebo Oral Capsule
Arm/Group Description	Each 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). Gabapentin: 5 day trial of gabapentin with titration to 1,200mg		Each 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). Placebo Oral Capsule: 5 day trial of matched placebo
All Cause Mortality
	Gabapentin		Placebo Oral Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/22 (0%)
Serious Adverse Events
	Gabapentin		Placebo Oral Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Gabapentin		Placebo Oral Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/23 (34.8%)		6/22 (27.3%)
Eye disorders
Blepharospasm	1/23 (4.3%)	1	0/22 (0%)	0
Gastrointestinal disorders
Nausea	1/23 (4.3%)	1	1/22 (4.5%)	1
Vomiting	1/23 (4.3%)	1	0/22 (0%)	0
Diarrhea	0/23 (0%)	0	1/22 (4.5%)	1
General disorders
Fatigue	4/23 (17.4%)	4	0/22 (0%)	0
Metabolism and nutrition disorders
Increased Appetite	1/23 (4.3%)	1	1/22 (4.5%)	1
Musculoskeletal and connective tissue disorders
Abdominal Pain	0/23 (0%)	0	1/22 (4.5%)	1
Nervous system disorders
Dizziness	2/23 (8.7%)	2	0/22 (0%)	0
Headache	1/23 (4.3%)	1	2/22 (9.1%)	2
Somnolence	1/23 (4.3%)	1	0/22 (0%)	0
Memory Impairment	1/23 (4.3%)	1	1/22 (4.5%)	1
Psychiatric disorders
Insomnia	1/23 (4.3%)	1	0/22 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.