Alcohol Use DisorderPhase 2NCT03220776

Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics

A Phase 2 study testing N-Acetylcysteine and Gabapentin in people with Alcohol Use Disorder and Bipolar Disorder, run by Medical University of South Carolina at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Alcohol Use Disorder, Bipolar Disorder
What is being tested?: N-Acetylcysteine and Gabapentin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 54 participants
Where: 1 siteUnited States
Study dates: 7 Aug 2017to 21 Nov 2022
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Meets DSM-V diagnostic criteria for Bipolar Disorder
Using at least one mood stabilizing medication
Meets diagnostic criteria Alcohol Use Disorder, with active drinking in the past month.

Who cannot join

Serious medical or non-inclusionary psychiatric disease
Concomitant use of benzodiazepine medications or any medications hazardous if taken with gabapentin/N-acetylcysteine
History of clinically significant brain injury
Presence of non-MRI safe material, or clinically significant claustrophobia.

Trial locations and contacts

1 site in 1 country.

United States1 site

Medical University of South Carolina
Charleston, South Carolina, 29425

Other trials in United States

About this study

Official title: Imaging Framework for Testing GABAergic/Glutamatergic Drugs in Bipolar Alcoholics

The proposed 3-week, double-blind, crossover, proof of concept study aims to manipulate neurochemical dysfunctions characteristic of individuals with co-occurring BD and AUD (i.e., abnormally low prefrontal GABA and glutamate), using medications that have been shown to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., NAC) levels in past research, and to evaluate medication-related changes in response inhibition and alcohol cue-reactivity fMRI tasks as well as drinking and mood in individuals with AUD+BD.

Read the detailed description

Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with substance use disorder (SUD); diagnostic co-occurrence is particularly high between BD and alcohol use disorder (AUD). Individuals with co-occurring SUD and BD (SUD+BD) have substantially worse clinical outcomes than those with either BD or SUD alone. Nonetheless, little is known about optimal treatment for individuals with SUD+BD; response to lithium appears to be poor, and only one double-blind, randomized, placebo-controlled trial of valproate has demonstrated improved drinking outcomes in this population. Traditionally, treatment trials for SUD+BD have investigated medications that have been FDA approved to treat either BD or SUD in hopes that such medications would prove efficacious in individuals with SUD+BD. A different approach to selecting, and ideally developing, medications for SUD+BD treatment trials would be to target neurochemical dysfunctions characteristic of individuals with both BD and SUD. Recent research by the current investigator has demonstrated unique disturbances in prefrontal gamma-Aminobutyric acid (GABA) and glutamate concentrations in this population using proton magnetic resonance spectroscopy (1H-MRS), with individuals with co-occurring alcohol dependence (AD) and BD having significantly lower levels of GABA and glutamate relative to individuals with BD alone, AD alone, or healthy controls. Lower levels of prefrontal GABA and glutamate were in turn associated with elevated impulsivity and alcohol craving. The proposed 3-week, double-blind, crossover, proof of concept study will evaluate: a) whether medications that have been demonstrated to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., N-Acetylcysteine [NAC]) concentrations in individuals with epilepsy and cocaine dependence, respectively, may similarly act to normalize prefrontal GABA and glutamate levels in individuals with AUD+BD, and b) whether normalization of prefrontal GABA and glutamate levels will be associated with improvements in functional brain activity to tasks that assess core neurobehavioral deficits of AUD and BD (i.e., response inhibition, alcohol cue-reactivity), as well as drinking and mood symptoms. Positive results may support investigation of gabapentin and/or NAC as adjunctive treatments for AUD+BD in large-scale, randomized clinical trials. Most importantly, the proposed study may provide successful demonstration of a neuro-behavioral, multimodal neuroimaging platform for evaluating the potential promise of GABAergic and glutamatergic drugs for AUD and/or BD, as well as other conditions marked by GABAergic/glutamatergic dysfunction.

Conditions: Alcohol Use Disorder, Bipolar Disorder
Being tested: N-Acetylcysteine, Gabapentin, Placebo Oral Tablet
Medical subject headings: Alcoholism, Bipolar Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

N-AcetylcysteineDrug
5 day trial of N-acetylcysteine with titration to 2,400mg
GabapentinDrug
5 day trial of gabapentin with titration to 1,200mg
Placebo Oral TabletDrug
5 day trial of matched placebo

Study groups in NCT03220776
Study group	Role	What they receive
Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule	Experimental	Three, 1-week conditions. Week 1 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 Week 2 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 3 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 Tablet: 5 day trial of matched placebo Receives: Drug: N-Acetylcysteine; Drug: Gabapentin; Drug: Placebo Oral Tablet
N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin	Experimental	3, 1 week conditions. Week 1 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 2 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 Tablet: 5 day trial of matched placebo Week 3 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 Receives: Drug: N-Acetylcysteine; Drug: Gabapentin; Drug: Placebo Oral Tablet
Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine	Placebo comparator	Three, 1-week conditions. Week 1 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 Tablet: 5 day trial of matched placebo Week 2 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 Week 3 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Receives: Drug: N-Acetylcysteine; Drug: Gabapentin; Drug: Placebo Oral Tablet
Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin	Experimental	Three, 1-week conditions. Week 1 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 Tablet: 5 day trial of matched placebo Week 2 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 3 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 Receives: Drug: N-Acetylcysteine; Drug: Gabapentin; Drug: Placebo Oral Tablet
Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine	Experimental	Three, 1-week conditions. Week 1 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 Week 2 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 Tablet: 5 day trial of matched placebo Week 3 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Receives: Drug: N-Acetylcysteine; Drug: Gabapentin; Drug: Placebo Oral Tablet
N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule	Experimental	Three, 1-week conditions. Week 1 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 2 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 Week 3 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 Tablet: 5 day trial of matched placebo Receives: Drug: N-Acetylcysteine; Drug: Gabapentin; Drug: Placebo Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

Prefrontal GABA+ Concentrations
Concentrations of GABA+, referenced to unsuppressed water and corrected for within-voxel CSF proportion, in dorsal anterior cingulate cortex measured via Proton Magnetic Resonance Spectroscopy (i.e., MEGA-PRESS).
Measured: Day 5 of each experimental condition
Prefrontal Glx Concentrations
Concentrations of Glx (i.e., glutamate + glutamine), referenced to unsuppressed water and corrected for within-voxel CSF proportion, in dorsal anterior cingulate cortex measured via Proton Magnetic Resonance Spectroscopy.
Measured: Day 5 of each experimental condition

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

7 Aug 201721 Nov 2022

First posted18 Jul 2017
Study start7 Aug 2017
Primary completion21 Nov 2022
Study completion21 Nov 2022

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (162)Papers the sponsor has linked to this study.
Other trials for Alcohol Use DisorderStudies of the same condition, open and under way.
More trials run by Medical University of South CarolinaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 54 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03220776
Sponsor's protocol ID: 64964
Other IDs: R01AA025365
Status last verified: Dec 2023
First submitted: 14 Jul 2017
Last updated: 13 Dec 2023
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Altshuler LL, Bookheimer SY, Townsend J, Proenza MA, Eisenberger N, Sabb F, Mintz J, Cohen MS. Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study. Biol Psychiatry. 2005 Nov 15;58(10):763-9. doi: 10.1016/j.biopsych.2005.09.012.
PubMed 16310510
Anton RF, Moak DH, Latham P. The Obsessive Compulsive Drinking Scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res. 1995 Feb;19(1):92-9. doi: 10.1111/j.1530-0277.1995.tb01475.x.
PubMed 7771669
Anton RF, Myrick H, Baros AM, Latham PK, Randall PK, Wright TM, Stewart SH, Waid R, Malcolm R. Efficacy of a combination of flumazenil and gabapentin in the treatment of alcohol dependence: relationship to alcohol withdrawal symptoms. J Clin Psychopharmacol. 2009 Aug;29(4):334-42. doi: 10.1097/JCP.0b013e3181aba6a4.
PubMed 19593171
Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, Randall PK. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry. 2011 Jul;168(7):709-17. doi: 10.1176/appi.ajp.2011.10101436. Epub 2011 Mar 31.
PubMed 21454917
Aufhaus E, Weber-Fahr W, Sack M, Tunc-Skarka N, Oberthuer G, Hoerst M, Meyer-Lindenberg A, Boettcher U, Ende G. Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: a MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression. Magn Reson Med. 2013 Feb;69(2):317-20. doi: 10.1002/mrm.24257. Epub 2012 Apr 5.
PubMed 22488982
Bagga D, Khushu S, Modi S, Kaur P, Bhattacharya D, Garg ML, Singh N. Impaired visual information processing in alcohol-dependent subjects: a proton magnetic resonance spectroscopy study of the primary visual cortex. J Stud Alcohol Drugs. 2014 Sep;75(5):817-26. doi: 10.15288/jsad.2014.75.817.
PubMed 25208200
Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006 Aug;98(3):641-53. doi: 10.1111/j.1471-4159.2006.03913.x. Epub 2006 Jun 19.
PubMed 16787421
Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci. 2003 Jul;6(7):743-9. doi: 10.1038/nn1069.
PubMed 12778052
Bauer J, Pedersen A, Scherbaum N, Bening J, Patschke J, Kugel H, Heindel W, Arolt V, Ohrmann P. Craving in alcohol-dependent patients after detoxification is related to glutamatergic dysfunction in the nucleus accumbens and the anterior cingulate cortex. Neuropsychopharmacology. 2013 Jul;38(8):1401-8. doi: 10.1038/npp.2013.45. Epub 2013 Feb 12.
PubMed 23403696
Beck A, Schlagenhauf F, Wustenberg T, Hein J, Kienast T, Kahnt T, Schmack K, Hagele C, Knutson B, Heinz A, Wrase J. Ventral striatal activation during reward anticipation correlates with impulsivity in alcoholics. Biol Psychiatry. 2009 Oct 15;66(8):734-42. doi: 10.1016/j.biopsych.2009.04.035. Epub 2009 Jun 27.
PubMed 19560123
Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996 Dec;67(3):588-97. doi: 10.1207/s15327752jpa6703_13.
PubMed 8991972
Behar KL, Rothman DL, Petersen KF, Hooten M, Delaney R, Petroff OA, Shulman GI, Navarro V, Petrakis IL, Charney DS, Krystal JH. Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients. Am J Psychiatry. 1999 Jun;156(6):952-4. doi: 10.1176/ajp.156.6.952.
PubMed 10360140
Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology. 2001 Jul;25(1):1-27. doi: 10.1016/S0893-133X(01)00225-1.
PubMed 11377916
Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008 Sep 15;64(6):468-75. doi: 10.1016/j.biopsych.2008.04.022. Epub 2008 Jun 5.
PubMed 18534556
Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, Kohlmann K, Jeavons S, Hewitt K, Allwang C, Cobb H, Bush AI, Schapkaitz I, Dodd S, Malhi GS. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011 Dec;135(1-3):389-94. doi: 10.1016/j.jad.2011.06.005. Epub 2011 Jun 29.
PubMed 21719110

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 13 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Imaging Framework for Testing GABAergic/Glutamatergic Drugs in Bipolar Alcoholics
ClinicalTrials.gov ID: NCT03220776
Acronym / sponsor ID: 64964
Conditions: Alcohol Use Disorder, Bipolar Disorder
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 54 participants (actual)
Lead sponsor: Medical University of South CarolinaUniversity, hospital or other
Collaborators: National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Study start: 7 Aug 2017 (actual)
Primary completion: 21 Nov 2022 (actual)
Study completion: 21 Nov 2022 (actual)
First posted: 18 Jul 2017 (actual)
Results: Posted 13 Dec 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 6

Arm	Type	Receives
Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule	Experimental	Drug: N-Acetylcysteine, Drug: Gabapentin, Drug: Placebo Oral TabletThree, 1-week conditions. Week 1 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 Week 2 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 3 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 Tablet: 5 day trial of matched placebo
N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin	Experimental	Drug: N-Acetylcysteine, Drug: Gabapentin, Drug: Placebo Oral Tablet3, 1 week conditions. Week 1 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 2 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 Tablet: 5 day trial of matched placebo Week 3 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
Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine	Placebo comparator	Drug: N-Acetylcysteine, Drug: Gabapentin, Drug: Placebo Oral TabletThree, 1-week conditions. Week 1 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 Tablet: 5 day trial of matched placebo Week 2 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 Week 3 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg
Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin	Experimental	Drug: N-Acetylcysteine, Drug: Gabapentin, Drug: Placebo Oral TabletThree, 1-week conditions. Week 1 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 Tablet: 5 day trial of matched placebo Week 2 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 3 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
Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine	Experimental	Drug: N-Acetylcysteine, Drug: Gabapentin, Drug: Placebo Oral TabletThree, 1-week conditions. Week 1 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 Week 2 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 Tablet: 5 day trial of matched placebo Week 3 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg
N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule	Experimental	Drug: N-Acetylcysteine, Drug: Gabapentin, Drug: Placebo Oral TabletThree, 1-week conditions. Week 1 condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7). N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 2 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 Week 3 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 Tablet: 5 day trial of matched placebo

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Meets DSM-V diagnostic criteria for Bipolar Disorder
Using at least one mood stabilizing medication
Meets diagnostic criteria Alcohol Use Disorder, with active drinking in the past month.

Key exclusion criteria (4 listed)

Serious medical or non-inclusionary psychiatric disease
Concomitant use of benzodiazepine medications or any medications hazardous if taken with gabapentin/N-acetylcysteine
History of clinically significant brain injury
Presence of non-MRI safe material, or clinically significant claustrophobia.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
N-Acetylcysteine5 day trial of N-acetylcysteine with titration to 2,400mg	Drug	Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule, Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine, N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule, N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin, Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin, Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine
Gabapentin5 day trial of gabapentin with titration to 1,200mg	Drug	Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule, Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine, N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule, N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin, Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin, Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine
Placebo Oral Tablet5 day trial of matched placebo	Drug	Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule, Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine, N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule, N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin, Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin, Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine

Primary outcome

Prefrontal GABA+ Concentrations
Time frame: Day 5 of each experimental condition
Concentrations of GABA+, referenced to unsuppressed water and corrected for within-voxel CSF proportion, in dorsal anterior cingulate cortex measured via Proton Magnetic Resonance Spectroscopy (i.e., MEGA-PRESS).
Prefrontal Glx Concentrations
Time frame: Day 5 of each experimental condition
Concentrations of Glx (i.e., glutamate + glutamine), referenced to unsuppressed water and corrected for within-voxel CSF proportion, in dorsal anterior cingulate cortex measured via Proton Magnetic Resonance Spectroscopy.

Results and safety

Results posted to the registry on 13 Dec 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Gabapentin, Washout, Then N-Acetylcysteine, Washout, Then Placebo Oral Capsule, Washout	9	7
N-Acetylcysteine, Washout, Then Placebo Oral Capsule, Washout, Then Gabapentin, Washout	9	8
Placebo Oral Tablet, Washout, Then Gabapentin, Washout, Then N-Acetylcysteine, Washout	9	8
Placebo Oral Capsule, Washout, Then N-Acetylcysteine, Washout, Then Gabapentin, Washout	9	5
Gabapentin, Washout, Then Placebo Oral Capsule, Washout, Then N-Acetylcysteine, Washout	9	8
N-Acetylcysteine, Washout, Then Gabapentin, Washout, Then Placebo Oral Capsule, Washout	9	7

Primary outcome: Prefrontal GABA+ Concentrations

Time frame: Day 5 of each experimental condition. Mean (Standard Deviation). Unit: mmol/kg

Measure	N-Acetylcysteine n = 43	Gabapentin n = 41	Placebo Oral Tablet n = 46
Value	3.90 (0.543)	3.93 (0.646)	3.73 (0.705)

Population analysed: Overall number of participants analyzed includes participants who completed the entire medication condition (i.e. participants who started N-Acetylcysteine, Gabapentin, or Placebo Oral Tablet but who did not complete the MRI portion of the condition have been removed from outcome measure data analysis, but are included in other portions of this study record \[Adverse Events, Demographics, etc.\]).

Primary outcome: Prefrontal Glx Concentrations

Time frame: Day 5 of each experimental condition. Mean (Standard Deviation). Unit: mmol/kg

Measure	N-Acetylcysteine n = 43	Gabapentin n = 41	Placebo Oral Tablet n = 46
Value	21.59 (2.518)	21.69 (2.499)	22.25 (2.746)

Adverse events

Time frame: Adverse Event data were collected over each participant's total study duration. This duration was a 3-week period for each participant (i.e. 3, 1-week condition periods). Adverse event data collection took place for the entirety of the study which was 6 years.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
N-Acetylcysteine	0 of 48 (0%)	10 of 48 (20.8%)	0 of 48
Gabapentin	0 of 48 (0%)	9 of 48 (18.8%)	0 of 48
Placebo Oral Tablet	0 of 51 (0%)	6 of 51 (11.8%)	0 of 51

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 Dec 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 16310510Altshuler LL, Bookheimer SY, Townsend J, Proenza MA, Eisenberger N, Sabb F, Mintz J, Cohen MS. Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study. Biol Psychiatry. 2005 Nov 15;58(10):763-9. doi: 10.1016/j.biopsych.2005.09.012.
Background: PubMed 7771669Anton RF, Moak DH, Latham P. The Obsessive Compulsive Drinking Scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res. 1995 Feb;19(1):92-9. doi: 10.1111/j.1530-0277.1995.tb01475.x.
Background: PubMed 19593171Anton RF, Myrick H, Baros AM, Latham PK, Randall PK, Wright TM, Stewart SH, Waid R, Malcolm R. Efficacy of a combination of flumazenil and gabapentin in the treatment of alcohol dependence: relationship to alcohol withdrawal symptoms. J Clin Psychopharmacol. 2009 Aug;29(4):334-42. doi: 10.1097/JCP.0b013e3181aba6a4.
Background: PubMed 21454917Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, Randall PK. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry. 2011 Jul;168(7):709-17. doi: 10.1176/appi.ajp.2011.10101436. Epub 2011 Mar 31.
Background: PubMed 22488982Aufhaus E, Weber-Fahr W, Sack M, Tunc-Skarka N, Oberthuer G, Hoerst M, Meyer-Lindenberg A, Boettcher U, Ende G. Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: a MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression. Magn Reson Med. 2013 Feb;69(2):317-20. doi: 10.1002/mrm.24257. Epub 2012 Apr 5.
Background: PubMed 25208200Bagga D, Khushu S, Modi S, Kaur P, Bhattacharya D, Garg ML, Singh N. Impaired visual information processing in alcohol-dependent subjects: a proton magnetic resonance spectroscopy study of the primary visual cortex. J Stud Alcohol Drugs. 2014 Sep;75(5):817-26. doi: 10.15288/jsad.2014.75.817.
Background: PubMed 16787421Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006 Aug;98(3):641-53. doi: 10.1111/j.1471-4159.2006.03913.x. Epub 2006 Jun 19.
Background: PubMed 12778052Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci. 2003 Jul;6(7):743-9. doi: 10.1038/nn1069.
Background: PubMed 23403696Bauer J, Pedersen A, Scherbaum N, Bening J, Patschke J, Kugel H, Heindel W, Arolt V, Ohrmann P. Craving in alcohol-dependent patients after detoxification is related to glutamatergic dysfunction in the nucleus accumbens and the anterior cingulate cortex. Neuropsychopharmacology. 2013 Jul;38(8):1401-8. doi: 10.1038/npp.2013.45. Epub 2013 Feb 12.
Background: PubMed 19560123Beck A, Schlagenhauf F, Wustenberg T, Hein J, Kienast T, Kahnt T, Schmack K, Hagele C, Knutson B, Heinz A, Wrase J. Ventral striatal activation during reward anticipation correlates with impulsivity in alcoholics. Biol Psychiatry. 2009 Oct 15;66(8):734-42. doi: 10.1016/j.biopsych.2009.04.035. Epub 2009 Jun 27.
Background: PubMed 8991972Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996 Dec;67(3):588-97. doi: 10.1207/s15327752jpa6703_13.
Background: PubMed 10360140Behar KL, Rothman DL, Petersen KF, Hooten M, Delaney R, Petroff OA, Shulman GI, Navarro V, Petrakis IL, Charney DS, Krystal JH. Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients. Am J Psychiatry. 1999 Jun;156(6):952-4. doi: 10.1176/ajp.156.6.952.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

James J Prisciandarao, Ph. D principal investigator

Medical University of South Carolina

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing N-Acetylcysteine and Gabapentin in people with Alcohol Use Disorder and Bipolar Disorder, run by Medical University of South Carolina at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Prefrontal GABA+ Concentrations (time frame: Day 5 of each experimental condition). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03220776, which also lists 162 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Dec 2023.