Commentary on Hartwell et al. (2020): Alcohol use disorder treatment response—where is the variability?
Year: 2020
Type: editorial
Abstract: Naltrexone, a mu opioid receptor antagonist, is a popular treatment for alcohol use disorders (AUD). The OPRM1 gene that encodes the mu subunit includes a missense variant, rs1799971—a substitution of adenine (A) to guanine (G) at position 118 (A118G)—which results in a coding amino acid change from Asparagine to Aspartate, which alters the encoded receptor. Hartwell and colleagues [1] systematically synthesized published data from seven eligible studies on the pharmacogenetic effects of rs1799971 on naltrexone treatment response, and concluded that variability in rs1799971 genotype was not associated with relapse to heavy drinking, complete abstinence, percentage of heavy drinking or abstinent days and after correction for multiple testing with drinks per day. That treatment response, pharmacological or behavioral, is partially attributable to genetic variability has been well demonstrated [2]. Our own studies have shown that remission status is correlated within family members [3]. We speculate that there are several reasons as to why rs1799971, despite its biological plausibility as a pharmacogenetic variant, fails to deliver across these meta-analyzed studies. First, as the authors outline, the aggregated sample size across the seven meta-analyzed studies was small (naltrexone-treated < 700, placebo-treated < 600) by current expectations for the very modest effect sizes that are to be expected from single genetic variants, even when accommodating a purported boost when studying treatment-relevant variants [4, 5]. Secondly, there was marked heterogeneity among studies that could have diluted actual effects and, as the authors note, control for relevant covariates and important second-order interactions [4] was inconsistent. Therefore, the possibility that the results of this meta-analysis constitute a false negative cannot be excluded. However, the clinical implication of the finding, regardless of whether the lack of association is real or merely statistically underpowered, is clear—health-care professionals should be cautious when utilizing information on patient genotype at rs1799971 in their prescribing practices. While researchers are exploring the utility of polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) of AUD and other psychiatrically relevant traits, they remain of limited clinical utility for AUD treatment. Such disorder-based PRS may eventually relate to treatment response but may not be treatment-specific; indeed, as more severe AUD and psychiatric comorbidities can modify treatment outcomes, such PRS may simply reflect disease liability rather than pharmacological specificity. Therefore, there is considerable optimism that as more powerful data sets become available for GWAS of AUD treatment response, novel polygenic pharmacogenetic signals that can reliably provide clinical insights will become available. There is, however, more to treatment response than genetic variation alone. The psychosocial interventions accompanying some of the treatment protocols, unaccounted for in the meta-analysis [1], included cognitive behavioral therapy, motivational interviewing, 12-Step facilitation and encouragement to attend mutual support groups such as Alcoholics Anonymous, all of which have proved to be effective in improving treatment outcomes [6, 7]. The social connection and support provided by each of these treatment modalities is hypothesized to be one source of their effectiveness for individuals who have alcohol-related cognitive impairments that alter their response to treatment, with more impaired individuals benefiting more from the social support of mutual help groups such as Alcoholics Anonymous and less from individualized therapies [8, 9]. Individuals with AUDs also display deficits in social cognition [10, 11], which might similarly benefit from treatments with a focus on interpersonal connections [12, 13]. Given some passing support for an association of OPRM1 variants with sensitivity to social situations in animal [14, 15] and human studies [16, 17], it is possible that the genotype × naltrexone effect on treatment outcome might be masked by the effects of psychosocial treatment which, in and of itself, may reflect genetically influenced predispositions. In conclusion, a future clinical barometer for AUD treatment response is likely to encompass, not a single variant, but the cumulative effects of many loci, some of which may be specific to the pharmacological agent and others that will reflect inherent traits related to treatment seeking, adherence and disease severity, as well as environmental characteristics, some of which will also correlate with genotype. This level of complexity is unavoidable but, as other domains of pharmacogenetic research have shown, ultimately surmountable. Until then, however, as Hartwell et al. [1] carefully note, this single variant should not be used to gauge naltrexone outcomes in studies of individuals with AUD. None.
Source: Addiction
DOI: 10.1111/add.15085
Authors: Arpana Agrawal, Vivia V. McCutcheon
Institution: Washington University in St. Louis
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3020784688