Genetic influences on treatment response and relapse
The last decade has seen a marked increase in the number of human molecular genetic studies in medical and behavioral research, due largely to rapid technological advances in genotyping platforms, decreasing cost of molecular analyses, and the advent of genome-wide association studies (GWAS). Not surprisingly, molecular genetic approaches have increasingly been incorporated in treatment outcome studies, allowing novel opportunities to study biological influences on relapse. Given the rapid growth in this area, we allocate a portion of this review to discussing initial evidence for genetic associations with relapse. Specifically, we focus on recent, representative findings from studies evaluating candidate single nucleotide polymorphisms (SNPs) as moderators of response to substance use interventions. It is important to note that these studies were not designed to evaluate specific components of the RP model, nor do these studies explicitly espouse the RP model. Also, many studies have focused solely on pharmacological interventions, and are therefore not directly related to the RP model. However, we review these findings in order to illustrate the scope of initial efforts to include genetic predictors in treatment studies that examine relapse as a clinical outcome. These findings may be informative for researchers who wish to incorporate genetic variables in future studies of relapse and relapse prevention.
Broadly speaking, there are at least three primary contexts in which genetic variation could influence liability for relapse during or following treatment. First, in the context of pharmacotherapy interventions, relevant genetic variations can impact drug pharmacokinetics or pharmacodynamics, thereby moderating treatment response (pharmacogenetics). Second, the likelihood of abstinence following a behavioral or pharmacological intervention can be moderated by genetic influences on metabolic processes, receptor activity/expression, and/or incentive value specific to the addictive substance in question. For instance, SNPs with functional implications for relevant neurotransmitter or metabolic pathways can influence the reward value of marijuana (e.g., FAAH; CNR1); nicotine (e.g., CYP2A6, CHRNB2, CHRNA4); and alcohol (ALDH2, ADH1B), while others show potential for influencing the incentive value of multiple drugs (e.g., ANKK1; DRD4; OPRM1). Third, variants implicated in broad traits relevant for addictive behaviors--for instance, executive cognitive functioning (e.g., COMT) or externalizing traits (e.g., GABRA2, DRD4)--could influence relapse proneness via general neurobehavioral mechanisms, irrespective of drug class or treatment modality. As summarized below, preliminary empirical support exists for each of these possibilities.
Genetic influences on relapse have been studied most extensively in the context of pharmacogenetics, with the bulk of studies focusing on nicotine dependence (for recent reviews see [
83,
84]). Several candidate polymorphisms have been examined in response to smoking cessation treatments, especially nicotine replacement therapy (NRT) and bupropion [
84]. The catechol-O-methyltransferase (COMT) Val158Met polymorphism, established as predicting variability in prefrontal dopamine levels, has been evaluated in relation to smoking cessation in several studies. Independent trials of NRT have found cessation rates to differ based on
COMT genotype [
85‐
87]. A polymorphism in the nicotinic acetylcholine ß2 receptor gene (
CHRNB2) has been associated with length of abstinence and withdrawal symptoms during bupropion treatment [
88] and with relapse rates and ability to quit on the target day during NRT [
89]. One bupropion trial found that
DRD2 variations predicted withdrawal symptoms, medication response and time to relapse [
90]. In a study of the mu-opioid receptor (
OPRM1) Asn40/Asp40 variant during NRT, those with the Asp40 variant had higher rates of abstinence and reduced negative affect compared to Asn40 individuals [
91]. Additionally, post-hoc analyses indicated that Asp40 carriers were more likely to regain abstinence following a lapse, suggesting a possible role of the genotype in predicting prolapse.
The most promising pharmacogenetic evidence in alcohol interventions concerns the
OPRM1 A118G polymorphism as a moderator of clinical response to naltrexone (NTX). An initial retrospective analysis of NTX trials found that
OPRM1 influenced treatment response, such that individuals with the Asp40 variant (G allele) receiving NTX had a longer time until the first heavy drinking day and were half as likely to relapse compared to those homozygous for the Asn40 variant (A allele) [
92]. This finding was later extended in the COMBINE study, such that G carriers showed a greater proportion of days abstinent and a lower proportion of heavy drinking days compared in response to NTX versus placebo, whereas participants homozygous for the A allele did not show a significant medication response [
93]. Moreover, 87.1% of G allele carriers who received NTX were classified as having a good clinical outcome at study endpoint, versus 54.5% of Asn40 homozygotes who received NTX. (Moderating effects of
OPRM1 were specific to participants receiving medication management without the cognitive-behavioral intervention [CBI] and were not evident in participants receiving NTX and CBI). A smaller placebo controlled study has also found evidence for better responses to NTX among Asp40 carriers [
94]. The Asp40 variant has further been linked to intermediate phenotypes that could influence relapse proneness, including hedonic responses to alcohol [
95], increased neural responses to alcohol primes [
96], greater craving in response to alcohol use [
97] and increased dopamine release in the ventral striatum during alcohol challenge [
98]. One study found that the Asp40 allele predicted cue-elicited craving among individuals low in baseline craving but not those high in initial craving, suggesting that tonic craving could interact with genotype to predict phasic responses to drug cues [
97].
Findings concerning possible genetic moderators of response to acamprosate have been reported [
99], but are preliminary. Additionally, other findings suggest the influence of a
DRD4 variable number of tandem repeats (VNTR) polymorphism on response to olanzapine, a dopamine antagonist that has been studied as an experimental treatment for alcohol problems. Olanzapine was found to reduce alcohol-related craving those with the long-repeat VNTR (
DRD4 L), but not individuals with the short-repeat version (
DRD4 S; [
100,
101]). Further, a randomized trial of olanzapine led to significantly improved drinking outcomes in
DRD4 L but not
DRD4 S individuals [
100].
There is also preliminary evidence for the possibility of genetic influences on response to psychosocial interventions, including those incorporating RP strategies. In a secondary analysis of the Project MATCH data, researchers evaluated posttreatment drinking outcomes in relation to a
GABRA2 variant previously implicated in the risk for alcohol dependence [
102]. Analyses included MATCH participants of European descent who provided a genetic sample (n = 812). Those carrying the high-risk
GABRA2 allele showed a significantly increased likelihood of relapse following treatment, including a twofold increase in the likelihood of heavy drinking. Furthermore,
GABRA2 interacted with treatment condition to influence drinking outcomes. Among those with the high-risk genotype, drinking behavior did not appear to be modified by treatment, with outcomes being similar regardless of treatment condition. However, treatment differences emerged in the low-risk genotype group, such that TSF produced the best outcomes, followed by MET [
102]. In another psychosocial treatment study, researchers in Poland examined genetic moderators of relapse following inpatient alcohol treatment [
103]. Results showed that polymorphisms in
BDNF (Val66Met) and
COMT (Val158Met) significantly predicted relapse probability. Overall, evidence for genetic moderation effects in psychosocial trials are consistent with the notion that variants with broad implications for neurotransmitter function, cognitive function, and/or externalizing traits can potentially influence relapse proneness. In the absence of a plausible biological mechanism for differential response to specific psychosocial treatments (e.g., MET vs. CBT) as a function of genotype, the most parsimonious interpretation of these findings is that some variants will impose greater risk for relapse following any quit attempt, regardless of treatment availability or modality.
Findings from numerous non-treatment studies are also relevant to the possibility of genetic influences on relapse processes. For instance, genetic factors could influence relapse in part via drug-specific cognitive processes. Recent studies have reported genetic associations with alcohol-related cognitions, including alcohol expectancies, drinking refusal self-efficacy, drinking motives, and implicit measures of alcohol-related motivation [
51,
52,
104‐
108]. Overall, the body of research on genetic influences on relapse and related processes is nascent and virtually all findings require replication. Consistent with the broader literature, it can be anticipated that most genetic associations with relapse outcomes will be small in magnitude and potentially difficult to replicate. Nonetheless, initial studies have yielded intriguing results. It is inevitable that the next decade will see exponential growth in this area, including greater use of genome-wide analyses of treatment response [
109] and efforts to evaluate the clinical utility and cost effectiveness of tailoring treatments based on pharmacogenetics. Finally, an intriguing direction is to evaluate whether providing clients with personalized genetic information can facilitate reductions in substance use or improve treatment adherence [
110,
111].
Mindfulness-based relapse prevention
In terms of clinical applications of RP, the most notable development in the last decade has been the emergence and increasing application of Mindfulness-Based Relapse Prevention (MBRP) for addictive behaviors [
112,
113]. Given supportive data for the efficacy of mindfulness-based interventions in other behavioral domains, especially in prevention of relapse of major depression [
114], there is increasing interest in MBRP for addictive behaviors. The merger of mindfulness and cognitive-behavioral approaches is appealing from both theoretical and practical standpoints [
115] and MBRP is a potentially effective and cost-efficient adjunct to CBT-based treatments. In contrast to the cognitive restructuring strategies typical of traditional CBT, MBRP stresses nonjudgmental attention to thoughts or urges. From this standpoint, urges/cravings are labeled as transient events that need not be acted upon reflexively. This approach is exemplified by the "urge surfing" technique [
115], whereby clients are taught to view urges as analogous to an ocean wave that rises, crests, and diminishes. Rather than being overwhelmed by the wave, the goal is to "surf" its crest, attending to thoughts and sensations as the urge peaks and subsides.
Results of a preliminary nonrandomized trial supported the potential utility of MBRP for reducing substance use. In this study incarcerated individuals were offered the chance to participate in an intensive 10-day course in Vipassana meditation (VM). Those participating in VM were compared to a treatment as usual (TAU) group on measures of post-incarceration substance use and psychosocial functioning. Relative to the TAU group, the VM group reported significantly lower levels of substance use and alcohol-related consequences and improved psychosocial functioning at follow-up [
116].
More recently, a randomized controlled trial compared an eight-week MBRP course to treatment as usual (TAU), which consisted of 12-step-based process-oriented discussion and psychoeducation groups [
117]. The majority of MBRP participants (86%) engaged in meditation practices immediately posttreatment and 54% continued practice for at least 4 months posttreatment (M = 4.74 days/week, up to 30 min/day). Compared to TAU, MBRP participants reported significantly reduced craving, and increased acceptance and mindful awareness over the 4-month follow-up period, consistent with the core goals of MBRP. Over the course of treatment, MBRP evinced fewer days of use compared to TAU (MBRP: M = .06 days, TAU: M = 2.57 days). These differences persisted at 2-month follow-up (2.08 days for MBRP vs. 5.43 days for TAU). Secondary analyses [
118] showed that compared to TAU, MBRP participants evinced a decreased relation between depressive symptoms and craving following treatment. This attenuation was related to subsequent decreases in alcohol and other drug use, suggesting MBRP led to decreased craving in response to negative affect, thereby lessening the need to alleviate affective discomfort with alcohol and other drug use. Furthermore, individuals with moderate depression in the MBRP group had a significantly lower probability of substance use, fewer drinks per drinking day, and fewer drinks per day than individuals with moderate depression in TAU. A larger, randomized trial comparing MBRP to TAU and RP is currently underway at the University of Washington to evaluate whether the addition of mindfulness to the standard RP treatment leads to better substance use outcomes following treatment. As is the case in other clinical domains [
114], interest in MBRP for substance use disorders is increasing rapidly. Results of additional randomized controlled trials will be important for informing its broader application for various addictive behaviors.