Nearly 60% of individuals with posttraumatic stress disorder (PTSD) have a comorbid alcohol use disorder (AUD). This comorbidity is associated with more severe PTSD symptoms, higher rates of psychosocial and medical problems, higher relapse rates, and poorer treatment outcome. Pre-clinical studies have indicated that PTSD and AUD share common molecular underpinnings that feed in to each other. Particularly, the adaptations in the brain neuro- transmitter systems to chronic excessive drinking that are evident during alcohol withdrawal share similarities with PTSD cluster B and E symptoms (characterized by symptoms of re-experiencing and hyper-arousal), which initiate a cycle of relapse into excessive drinking and worsening of PTSD symptoms. Excessive glutamate and reduced gamma- aminobutyric acid (GABA) neurotransmitter concentrations were found in various brain regions in individuals with co- morbid PTSD/AUD. The anticonvulsant topiramate modulates cortico-mesolimbic dopamine neurons by inhibiting glutamate and facilitating GABA neurotransmission and has shown efficacy in reducing drinking and heavy drinking in AUD. To date, there have been two small published trials showing benefit of topiramate for the treatment of PTSD/AUD. To better evaluate the impact of topiramate on AUD in PTSD, studies must utilize larger samples with sufficient statistical power to determine whether topiramate reduces both heavy drinking and PTSD symptoms. Samples must also be diverse in terms of the types of trauma represented and should include participants from community and VA settings with both combat and non-combat-related traumas. In addition, an important strategy to enhance treatment of AUD uses a personalized medicine approach to optimize treatment effects by selecting individuals who may be a therapeutic match for a specific medication. A recent study showed that a single nucleotide polymorphism (rs2832407, common in individuals of European ancestry) in GRIK1, encoding the GluK1 subunit of the kainate receptor, moderated the treatment effect of topiramate in alcohol-dependent European Americans (Kranzler et al. 2014). Topiramate at 200mg/day reduced heavy drinking only in individuals homozygous for the rs2832407: C allele. We propose to test the efficacy of topiramate in reducing both AUD and PTSD Clusters B or E in a 3 x 2, double- blind, placebo-controlled 16-week clinical trial with a set target quit-date (TQD) for drinking. We will utilize a large and diverse sample of European ancestry individuals that includes both genders and individuals with different types of trauma. We will randomize participants based on the three genotypes of GRIK1 SNP rs2832407 (i.e., CC vs. AC vs. AA) to test the differential efficacy of topiramate within the three groups separately. We will then use an escalating dose of topiramate -50mg/day up to 300mg/day and placebo, from baseline up to week 6; the TQD will be set at week 8. The split design (post-TQD vs. pre-TQD) will allow us to separately examine both whether topiramate's anti-glutaminergic effects reduce drinking and prevent relapse post cessation and whether the cessation of drinking results in improved PTSD cluster B or E symptoms in carriers of specific rs2832407 genotypes. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment and follow-up post treatment and 3 month assessments.
Identifying effective treatments for posttraumatic stress disorder and comorbid alcohol use disorder is a critically important public health priority. We will run a clinical trial in a large ample of participants recruited from both community and VA mental health treatment settings to test the efficacy of mediation treatment for people with posttraumatic stress disorder and comorbid alcohol use disorder. We will study the medication in individuals carrying specific genetic variants that may cause them to experience an especially strong benefit. Using this type of personalized medicine approach will help to determine if there is a genetic subgroup of individuals for whom this medication may be especially effective.
| Johnson, Bankole A (2017) Toward Rational, Evidence-Based, and Clinically Relevant Measures to Determine Improvement Following Treatment for Alcohol Use Disorder. Alcohol Clin Exp Res 41:703-707 |
