Gabapentin Improves Outcome in Alcoholism

Molecular Model of GABA

Improving abstinence rates in alcoholism continues to be a goal of treatment research. Several novel drug treatment strategies in alcoholism have targeted the neurotransmitter gamma-aminobutryic acid or GABA. GABA is the major inhibitor neurotransmitter in the brain.  Alcohol has effects through the GABA receptor.  Alcohol withdrawal is typically treated with the sedative drug class of benzodiazepines known to have effects on GABA receptors.  There are two main types of CNS GABA receptors GABA(A) and GABA(B).

Here is summary of drugs known to have effects through GABA and the GABA receptor:
GABA analogues: gabapentin, pregabalin
GABA(A) agonists (activators): alcohol, benzodiazepines, barbiturates,carisoprodol (SOMA), propofol, kava, valerian
GABA (A) antagonists (inhibitors):  flumazenil
GABA(B) agonists: baclofen
GABA(B) antagonists:phaclofen
GABA reuptake inhibitors (activators): tiagabine

Naltrexone (an opioid receptor antagonist) has an FDA indication for alcohol dependence in the United States.  However, a significant number of patients taking naltrexone for alcohol dependence do relapse, so successful augmentation strategies are necessary. A recent randomized clinical has been published online at the American Journal of Psychiatry looking at augmentation of naltrexone with gabapentin in alcohol dependence.  Here are the key elements of the study design:

Molecular Model of Gabapentin

Inclusion criteria: DSM-IV alcohol dependence, consuming 5 or more drinks per day (4 for women), able to enter study with a minimum of 4 days of abstinence
Exclusion criteria: current suicidal or homicidal ideation, no drug dependence, use of illicit drugs in last 30 days, positive urine drug screen, psychotropic or anticonvulsant drug use, medical problems including elevated liver enzymes
Random drug assignments: placebo, naltrexone 50 mg, naltrexone 50 mg plus gabapentin up to 1200 mg daily

The study found that the combined medication group was less likely to relapse to at least one heavy drinking day through six weeks (33% vs about 50% for both placebo and naltrexone alone).  Biomarkers of drinking also favored the combined group suggesting validity to the self-reported drinking history finding.  Interestingly, the combined gabapentin/naltrexone group reported the fewest complaints about sleep during the study.  Sleep complaints correlated with number of heavy drinking days. Additionally, gabapentin augmentation appeared to also be most beneficial in subjects with a history of alcohol withdrawal.

Gabapentin was withdrawn after six weeks and the drinking outcome improvement in the combined group waned in the ensuing 10 weeks of follow up.   This suggests that longer term treatment with gabapentin may be necessary to sustain the original superior reponse.

Although, this study is not large enough to change practice guidelines the results are encouraging and need replication.  Gabapentin is currently available (and in generic form) and approved for the treatment of seizures. If confirmed effective in alcoholism gabapentin could provide clinicians with another safe medication option.

Molecular Model of GABA From Creative Commons file--source Wikipedia author Ben Mills
Molecular Model of Gabapentin From Creative Commons file--source Wikipedia, author Fvasconellos

Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, & Randall PK (2011). Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence. The American journal of psychiatry PMID: 21454917

GABA Neurons and Rett Syndrome

Rett Syndrome is a rare (1 in every 10,000 to 15,000 live female births) neurodevelopmental disorder that occurs almost exclusively in young girls. This syndrome shares features with autism.  The disorder is caused by a mutation of the MECP2 (methyl-CpG-binding protein 2) gene (MECP2 translation protein diagram noted on the right).  This gene is found on the X chromosome. Infant boys born with the mutation typically die shortly after birth as they have no reserve X chromosome that may compensate to a degree with the mutation.


Rett Syndrome is typically diagnosed in early childhood when the following essential diagnostic criteria are met:

• Normal development until 6 to 18 months of age
• Normal head circumference at birth followed by a slowing of the rate of head growth between 3 months and 4 years of age
• Severe impairment in expressive language
• Repetitive and stereotypic hand movements
• Gait abnormalities--toe walking or wide-based, stiff-legged walk

A recent study published in Nature examined a potential mechanism to explain some of the stereotypical behaviors found in Rett Syndrome.  Using a mouse model, mice were produced that lacked MeCP2 in the brain gamma amino butryic acid (GABA) neurons.  These mice demonstrated a series of neurobehavioral abnormalities similar to Rett syndrome including: repetitive behavior, impaired motor coordination, social interaction abnormalites and reduced startle response.  These mice showed evidence of significant reduction in  GABA content in the brain cortex and striatum regions.


The authors note their study "demonstrate(s) that GABAergic dysfunction is a critical mediator of Rett syndrome phenotypes".  They note that MeCP2 mutations are found in a relatively rare number of humans with bipolar disorder, schizophrenia and autism.  They note that GABAergic dysregulation through a variety of mechanisms may be central to these neuropsychiatric disorders.


If you are interested in learning more about the features of Rett Sydrome, I embedded theYouTube video below that documents the developmental history of Chelsea--an 11 year old girl with Rett Syndrome.





Further information on Rett Syndrome at the International Rett Syndrome Association website as well as from a Fact Sheet on Rett Syndrome from the National Institute of Neurological Disorders and Stroke.


Diagram of MECP2 protein is licensed under the Creative Commons Attribution Share Alike 3.0 unported license with author Emw.


Chao, H., Chen, H., Samaco, R., Xue, M., Chahrour, M., Yoo, J., Neul, J., Gong, S., Lu, H., Heintz, N., Ekker, M., Rubenstein, J., Noebels, J., Rosenmund, C., & Zoghbi, H. (2010). Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes Nature, 468 (7321), 263-269 DOI: 10.1038/nature09582

REM Sleep Deficiency in Autism

Pediatric Patient Prepared for Sleep Study

Parents with children who have autism commonly report significant sleep problems.  Clinicians commonly encounter complaints by parents about the child’s sleep problem and consider behavioral or pharmacologic interventions.  Now a study informs parents and clinicians about the type of sleep abnormalities found in children with autism.

Buckley et al conducted sleep studies using polysomnography in a series of children with the diagnosis of autism between the ages of 2 and 13.   Sleep architecture variables were examined compared to controls as well as a group of children with developmental delay without autism.  This second control group is quite helpful as it helps identify whether sleep abnormalities in autism might be due to generally to a developmental delay.

The autism group had significant cognitive impairment with a mean IQ of 57.    Here are the key statistically significant findings with results presented for autism, typical controls and developmentally delayed controls:

• Total sleep time: 7.7 hours, 8.8 hours, 9.2 hours
• Slow wave sleep %:  21.5%, 18.6%, 13.7%
• REM sleep %: 14.5%, 22.6%, 25.0%
• REM sleep latency: 109 min, 64 min, 69 min

 So autism sleep architecture is characterized by less total sleep with more time spent in stage 3 sleep (slow wave sleep) and less time in REM (dream-related) sleep.  The investigators note this pattern might inform us on some of the neurotransmitter abnormalities in autism.  REM sleep control is a complex system that involves:

• GABA
• Glutamate
• Serotonin from the cells in the brain dorsal raphe
• Epinephrine in the locus ceruleus
• Acetylcholine

 The authors note that acetylcholine is a particular driver of slow wave sleep as well as REM sleep.  They note “A more global (not just in the pontine brainstem where REM is orchestrated) cholinergic deficiency would predict a more permissive environment for slow-wave generation and could conceivably be represented by a higher percentage of this state”.

The authors note their study provides some insight into potential drug strategies in treating children with autism and sleep problems.  Additionally, this pattern deserves additional research and an “objective biomarker for identification of infants at risk for autism”.

Photo of pediatric patient being prepared for a polysomnogram sleep study is licensed under the Creative Commons Attribution-Share Alike 2.5 Generic license.  The author is Robert Lawton.

Buckley AW, Rodriguez AJ, Jennison K, Buckley J, Thurm A, Sato S, & Swedo S (2010). Rapid eye movement sleep percentage in children with autism compared with children with developmental delay and typical development. Archives of pediatrics & adolescent medicine, 164 (11), 1032-7 PMID: 21041596