Larry W. Hawk

Role of Functional Genetic Variation in the Dopamine D2 Receptor ( DRD2 ) in Response to Bupropion and Nicotine Replacement Therapy for Tobacco Dependence: Results of Two Randomized Clinical Trials

Although bupropion and nicotine replacement therapy (NRT) are efficacious tobacco dependence treatments, there is substantial interindividual variability in therapeutic response and most smokers relapse. Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response. We investigated the roles of two functional genetic variants in the dopamine D2 receptor (DRD2) gene in response to pharmacotherapy for tobacco dependence among participants in two randomized clinical trials with a 6-month follow-up period: a double-blind placebo-controlled trial of bupropion (n=414) and an open label trial of transdermal nicotine vs nicotine nasal spray (n=368). At the end of the treatment phase, a statistically significant (p=0.01) interaction between the DRD2 − 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion among smokers homozygous for the Ins C allele compared to those carrying a Del C allele. By contrast, smokers carrying the Del C allele had statistically significantly (p=0.006) higher quit rates on NRT compared to those homozygous for the Ins C allele, independent of NRT type. The C957T variant was also associated (p=0.03) with abstinence following NRT. These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 − 141 Ins C allele, while NRT may be more beneficial for those who carry the Del C allele. Study findings require confirmation in additional larger samples before they are applied in practice.

Pharmacogenetic investigation of smoking cessation treatment.

Despite the efficacy of bupropion for smoking cessation, smokers exhibit variability in treatment outcome. The CYP2B6 gene has been implicated in bupropion kinetics and nicotine metabolism, and is a plausible candidate for pharmacogenetic studies of treatment response. We investigated whether a functional genetic polymorphism in the CYP2B6 gene predicts smoking outcomes in a placebo-controlled randomized trial. Four hundred and twenty-six smokers of European Caucasian ancestry provided blood samples and received bupropion (300 mg/day for 10 weeks) or placebo, plus counseling. Smoking status, abstinence symptoms and side-effects were recorded weekly, and smoking status was verified at the end of treatment and at 6-month follow-up. Smokers with a decreased activity variant of CYP2B6 reported greater increases in cravings for cigarettes following the target quit date and had higher relapse rates. These effects were modified by a significant gender x genotype x treatment interaction, suggesting that bupropion attenuated the effects of genotype among female smokers. We conclude that smokers with the CYP2B6 variant may be more vulnerable to abstinence symptoms and relapse. Bupropion may attenuate these effects, especially among females. Additional trials are warranted to confirm these results, as are studies to explore the neurobiological mechanisms. Such research could ultimately enable practitioners to select the optimal type and dose of medication for individual smokers.

Mediating mechanisms for the impact of bupropion in smoking cessation treatment

Several studies have documented the effectiveness of bupropion for smoking cessation, yet little is known about the mechanisms by which it facilitates abstinence. In this placebo-controlled randomized trial. We examined whether bupropions effects on cessation were mediated by changes in withdrawal and/or negative or positive affect (PA). Two hundred and fifty-one smokers received 10-week treatment with bupropion or placebo, plus behavioral counseling. Changes in affect and withdrawal symptoms from pre-quit to 1 week post quit were examined as mediating variables in structural equation models. Cotinine-verified 7-day point prevalence cessation rates at the end of treatment (8-weeks post quit date) were 48% for bupropion and 29% for placebo (P=0.001). There were significant treatment effects on withdrawal and negative affect (NA); however, only change in NA predicted cessation. In a path model, change in NA was a significant mediator of bupropions effects on cessation. However, the proportion of variance accounted for by this mediator was small, suggesting that other unmeasured factors play an important role. Laboratory-based paradigms may be useful to identify other mediators of bupropions effects, thereby pointing to mechanisms of effect that can be bolstered in future treatment studies.

Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo-controlled Trial of Bupropion

We examined whether a pretreatment phenotypic marker of nicotine metabolism rate (NMR) predicts successful smoking cessation with bupropion. Smokers (N = 414) were tested for pretreatment NMR, based on the ratio of 3′‐hydroxycotinine/cotinine derived during smoking, before entering a placebo‐controlled randomized trial of bupropion plus counseling. At the end of the 10‐week treatment phase, slow metabolizers (1st NMR quartile) had equivalent quit rates with placebo or bupropion (32%). Fast metabolizers (4th NMR quartile) had low quit rates with placebo (10%), and these were enhanced significantly by bupropion (34%). Smokers in the 2nd quartile (placebo: 25%, bupropion: 30%) and the 3rd quartile (placebo: 20%, bupropion: 30%) did not benefit significantly from bupropion. At the 6‐month follow‐up, the relationship between the NMR and quitting remained similar, but was no longer statistically significant. A pretreatment assessment of NMR may identify smokers who are most and least likely to benefit from treatment with bupropion for smoking cessation.

Reaction Time Variability in ADHD: A Review

For the past decade, intra-individual variability in reaction times on computerized tasks has become a central focus of cognitive research on Attention-Deficit/Hyperactivity Disorder (ADHD). Numerous studies document increased reaction time variability among children and adults with ADHD, relative to typically developing controls. However, direct comparisons with other disorders with heightened reaction time variability are virtually nonexistent, despite their potential to inform our understanding of the phenomenon. A growing literature examines the sensitivity of reaction time variability to theoretically and clinically relevant manipulations. There is strong evidence that stimulus treatment reduces reaction time variability during a range of cognitive tasks, but the literature is mixed regarding the impact of motivational incentives and variation in stimulus event rate. Most studies of reaction time variability implicitly assume that heightened reaction time variability reflects occasional lapses in attention, and the dominant neurophysiological interpretation suggests this variability is linked to intrusions of task-negative brain network activity during task performance. Work examining the behavioral and neurophysiological correlates of reaction time variability provides some support for these hypotheses, but considerably more work is needed in this area. Finally, because conclusions from each of domains reviewed are limited by the wide range of measures used to measure reaction time variability, this review highlights the need for increased attention to the cognitive and motivational context in which variability is assessed and recommends that future work always supplement macro-level variability indices with metrics that isolate particular components of reaction time variability.

CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial

BACKGROUND CYP2B6 is the primary enzyme involved in bupropion (Zyban; GlaxoSmithKline, Research Triangle Park, North Carolina) metabolism. Genetic polymorphisms in CYP2B6, such as CYP2B6*6, can alter bupropion metabolism and may affect bupropion treatment outcome. METHODS Subjects participated in a smoking cessation clinical trial of bupropion versus placebo. The main outcome was a 7-day point prevalence abstinence rate measured 10 weeks after the start of treatment (i.e., end of treatment) and at the 6-month follow-up; secondary outcomes were severity of adverse effects, withdrawal, and urge to smoke. Subjects were haplotyped for the CYP2B6*6 variants. RESULTS Among smokers in the CYP2B6*6 group (CYP2B6*1/*6 or CYP2B6*6/*6 genotype, n = 147, 45% of the population), bupropion produced significantly higher abstinence rates than placebo at the end of treatment (32.5% vs. 14.3%, p = .01) and at the 6-month follow-up (31.2% vs. 12.9%, p = .008). In contrast, bupropion was no more effective than placebo for smokers in the CYP2B6*1 group (CYP2B6*1/*1, n = 179) at the end of treatment (31.0% vs. 31.6%, p = .93) or at the 6-month follow-up (22.0% vs. 21.5%, p = .94). There was a significant genotype by treatment interaction at the end of treatment (odds ratio [OR] = 2.97, confidence interval [CI] = 1.05-8.40, p = .04), which was similar at 6-month follow-up (OR = 2.98, CI = .98-9.06, p = .05). CONCLUSIONS These data suggest that smokers with the CYP2B6*6 genotype have a higher liability to relapse on placebo and that they may be good candidates for bupropion treatment for smoking cessation.

Effects of methylphenidate on discounting of delayed rewards in attention deficit/hyperactivity disorder.

Impulsivity is a central component of attention deficit/hyperactivity disorder (ADHD). Delay discounting, or a preference for smaller, immediate rewards over larger, delayed rewards, is considered an important aspect of impulsivity, and delay-related impulsivity has been emphasized in etiological models of ADHD. In this study, we examined whether stimulant medication, an effective treatment for ADHD, reduced discounting of delayed experiential and hypothetical rewards among 49 children (ages 9-12 years) with ADHD. After a practice day, participants completed a 3-day double-blind placebo-controlled acute medication assessment. Active doses were long-acting methylphenidate (Concerta), with the nearest equivalents of 0.3 and 0.6 mg/kg TID immediate-release methylphenidate. On each testing day, participants completed experiential (real-world money in real time) and hypothetical discounting tasks. Relative to placebo, methylphenidate reduced discounting of delayed experiential rewards but not hypothetical rewards. Broadly consistent with etiological models that emphasize delay-related impulsivity among children with ADHD, these findings provide initial evidence that stimulant medication reduces delay discounting among those with the disorder. The results also draw attention to task parameters that may influence the sensitivity of various delay discounting measures to medication effects.

Catechol-O-Methyltransferase (COMT) Gene Variants Predict Response to Bupropion Therapy for Tobacco Dependence

BACKGROUND Although bupropion is efficacious for smoking cessation, only a minority of smokers are able to quit. Pharmacogenetic research may improve treatment outcomes through discovery of DNA sequences predictive of successful pharmacotherapy for subgroups of smokers. We investigated variants in the catechol-O-methyltransferase (COMT) gene in a smoking cessation trial of bupropion. METHODS A double-blind, placebo-controlled, 10-week trial of bupropion and counseling (with a 6-month follow-up period) was conducted at two university-based smoking cessation research programs. Abstinence was biochemically verified at the end of treatment and at 6 months after the target quit date. RESULTS At the end of the treatment phase, statistically significant interaction effects indicated that COMT haplotypes of two SNPs (rs737865 and rs165599) predicted the efficacy of bupropion compared with placebo. This interaction effect was attenuated at 6-month follow-up. CONCLUSIONS COMT haplotypes at rs737865 and rs165599 may predict a favorable outcome for bupropion treatment for smoking cessation. European-American smokers with a G allele at both SNPs may not benefit from bupropion treatment. Small numbers of some COMT haplotypes limit interpretation of response. If study findings are confirmed in additional large studies, COMT genotyping could be applied to identify likely responders to bupropion treatment for smoking cessation.

Affective modulation and prepulse inhibition of startle among undergraduates high and low in behavioral inhibition and approach

Valence modulation and prepulse inhibition of startle were examined among 80 undergraduates scoring in the upper and lower quartiles of self-report measures of behavioral inhibition (BIS) and behavioral approach (BAS). Participants viewed a series of pleasant, neutral, and unpleasant pictures. Acoustic startle probes (102 dB) were presented during most pictures and during intertrial intervals, and a prepulse (120-ms SOA) preceded half of the probes. Valence modulation on no-prepulse trials was greater among high-BAS than low-BAS participants. Consistent with theory regarding behavioral approach, post hoc tests demonstrated robust inhibition during pleasant versus neutral pictures among high-BAS participants, but not low-BAS participants. Valence modulation was reliable among high-BIS but not low-BIS participants, but the group difference was not significant. Contrary to our prediction, prepulse inhibition tended to be greater among high-BAS than low-BAS participants. The present data call attention to the role of individual differences in pleasant affective experience in startle modification.

Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling

Among smokers, women may be at greater risk than men for developing smoking-related diseases, perhaps because they have greater difficulty quitting smoking, as suggested by numerous studies. In the present study, we hypothesized that bupropion would reduce this gender disparity among 314 women and 241 men enrolled in a placebo-controlled, randomized trial using behavioral counseling plus 10 weeks of bupropion (300 mg). Prolonged abstinence and biochemically verified point prevalence outcomes were measured at end of treatment (8 weeks after the quit date) and at 6-month follow-up. A logistic regression model of 6-month prolonged abstinence and a Cox regression (survival analysis) model revealed a significant gender by smoking rate by drug interaction and a main effect for marital status. This three-way interaction suggests that bupropion particularly benefited men who smoked more than one pack of cigarettes per day at baseline and, conversely, women who smoked a pack or less. The point prevalence logistic regression model showed no evidence that either gender or smoking rate modified the effect of treatment. These results suggest that bupropion treatment may reduce the gender disparity in prolonged abstinence rates among lighter smokers.