5-HTTLPR moderates naltrexone and psychosocial treatment responses in heavy drinking men who have sex with men

Risk of psychiatric illness and response to its treatment are genetically influenced. Although a number of genetic moderators of pharmacotherapies for psychiatric disorders have been identified (e.g., review by Malhotra et al., 2012), much less is known about genetic moderators of the response to psychotherapy and combined pharmacotherapy and psychotherapy, particularly in the treatment of substance use disorders (Bauer et al., 2007). One widely studied polymorphism that has been shown to moderate alcohol dependence risk and treatment response in some studies is a functional insertion/deletion polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene SLC6A4 (Feinn et al., 2005, Olsson et al., 2005, Florez et al., 2008). 5-HTTLPR has been reported to modulate the transcriptional activity of SLC6A4 and levels of 5-HTT messenger RNA (mRNA) (Heils et al., 1996, Lesch et al., 1996, Hranilovic et al., 2004). Homozygotes for the low-expression short 5-HTTLPR (S) allele had greater anxiety symptoms in response to stress than long (L) allele carriers (Caspi et al., 2010), which may reflect greater reactivity to environmental stimuli and diminished ability to self-regulate anxiety, although mixed results have been reported regarding the relationship between 5-HTTLPR genotype and anxiety-related traits (e.g., Schinka et al., 2004). Studies generally have found greater alcohol use and dependence among individuals with the S allele, which may be related to individuals′ anxiety or depression (Feinn et al., 2005). It has also been reported that the S allele is associated with more frequent heavy episodic drinking and drinking to “get drunk” among college students (Herman et al., 2003). However, young adults with the LL genotype have also been reported to exhibit more hazardous drinking when exposed to high psychosocial adversity (Laucht et al., 2009). One possible explanation for the discrepant results is heterogeneity in the alcohol use disorder phenotype. 5-HTTLPR is functionally tri-allelic, in contrast to the bi-allelic categorization often reported (Hu et al., 2006, Zalsman et al., 2006). In addition to the insertion-deletion polymorphism, a single nucleotide polymorphism (SNP; rs25531) was found to be tightly linked with the L-specific insertion. The SNP encodes an A→G exchange that renders the L allele functionally equivalent to the lower activity S allele in terms of promoter activity and RNA levels produced in cell culture systems (Hu et al., 2006, Perroud et al., 2010). Therefore, the L allele is differentiated into two variants: LA or LG. The lower expression LG variant is more appropriately grouped with the S than the LA variant. Using the tri-allelic approach, studies have been reported associations between 5-HTTLPR and the severity of depression (Zalsman et al., 2006) and the response to treatment with a selective serotonin reuptake inhibitor in patients with social anxiety (Stein et al., 2006) In the present study, we examined the moderating effect of 5-HTTLPR on both pharmacotherapeutic and psychotherapeutic outcomes in high-functioning male heavy drinkers recruited for a randomized controlled trial in which the goal of treatment was to reduce drinking, rather than abstinence from alcohol. We hypothesized that the lowest expression (S′S′) genotype, which may reflect a greater reactivity to changes in environment, would be associated with a greater reduction in heavy drinking following the intervention with cognitive behavioral therapy (CBT) or the opioid antagonist naltrexone.