Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD

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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 h...

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. 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-amino butyric acid (GABA) neurotransmitter concentrations were found in various brain regions in individuals with co-morbid PTSD/AUD. The anticonvulsant pregabalin (with high affinity for the alpha-2-delta auxiliary site of voltage gated calcium channels) that modulates the effects of the GABA transporter (GAT-1) and increases its density of GABA, has shown preliminary efficacy in reducing drinking in AUD with comorbid generalized anxiety disorder, and improves outcomes from PTSD. Large scale studies with ample statistical power in VA settings and community populations, with diverse combat and non-combat related trauma, are now warranted to evaluate the promising preliminary evidence that pregabalin can improve outcomes for those with AUD and PTSD. An important personalized medicine approach to optimize pregabalin efficacy would be to select individuals with AUD and PTSD with genetic variation at the GAT-1 transporter so as to match its potential therapeutic effects with specific types of individual. In African-Americans, variants at the SLC6A1 gene promoter region insertion (i.e., non-insertion/insertion or insertion/insertion (NI/I or I/I) compared with those of Non-insertion/Non-insertion (NI/NI) type have significantly higher levels of GAT-1promoter activity. The investigators will, therefore, segregate our target sample by genetic variation at the GAT-1 transporter. Because of the low allelic frequency of individuals with the double copy insertion, the investigators will combine these into one group with those with the single copy (i.e., NI/I/II). This study will test pregabalin efficacy in reducing both AUD and PTSD Clusters B or E in 2 treatment groups of medication (pregabalin, placebo) x 2 genetic variants (NI/I/II vs. NI/NI) in a double- blind, placebo-controlled 12-week clinical trial with a set target quit-date (TQD) for drinking. The investigators will utilize a large and diverse sample of African-Americans that includes both genders and individuals with different types of trauma. Pregabalin dose and placebo will be titrated to the maximum dose from baseline to week 6 using a double-dummy procedure to ensure equivalence of capsules received. The TQD will be set at week 6. The split design (post-TQD vs. pre-TQD) will allow the study to separately examine both whether pregabalin's therapeutic 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 GAT-1 transporter genotypes. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment (BBCET) and follow-up post treatment and 3 month assessments. The specific aims are as follows: Specific Aim 1: To test the hypothesis that AUD patients treated with pregabalin and having the non-insertion/insertion or insertion/insertion (NI/I or I/I) variant of the SLC6A1 gene for GABA transporter (GAT-1) will be more predictive of the ability not drink heavily than pregabalin-treated patients with the NI/NI genetic variant and placebo-treated patients. Specific Aim 2: To test the hypothesis that AUD patients treated with pregabalin and having the non-insertion/insertion or insertion/insertion (NI/I or I/I) variant of the SLC6A1 gene for GABA transporter (GAT-1) will be more efficacious in reducing PTSD cluster B or E symptoms (or both) than pregabalin-treated patients with the NI/NI genetic variant and placebo-treated patients.

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