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Effects of dopamine D2 receptor gene polymorphisms on smoking cessation: abstinence and withdrawal symptoms
Marcus R Munafò &
Evaluation of: Robinson JD, Lam CY, Minnix JA et al.: The DRD2 TaqI-B
Elaine C Johnstone
polymorphism and its relationship to smoking abstinence and withdrawal
symptoms. Pharmacogenomics J. (2006) (Epub ahead of print).
1University of Bristol, Department of Experimental
number of studies have investigated the role of genetic factors in smoking cessation, and
in response to smoking cessation pharmacotherapy. Robinson and colleagues report data
on the effects of the dopamine D2 receptor gene Taq1B polymorphism on smoking
Tel.: +44 117 954 6841;Fax: +44 117 928 8588;
cessation and withdrawal. While the results add to the growing literature on smoking
cessation pharmacogenetics, they also illustrate that minor differences in phenotype
definition may influence the results of pharmacogenetic analyses. Existing studies also lack
2University of Oxford, Department of Clinical
direct comparability, which makes it difficult to judge evidence for replication. Several
future directions for smoking cessation pharmacogenetics research are discussed.
Infirmary, Oxford OX2 6HA, UKTel.: +44 186 522 4338;
The pharmacogenetic analysis reported by Rob-
allele responding to the drug with a substantial
inson and colleagues  of clinical trial data from
reduction in negative affect, whereas those carry-
a Phase II placebo-controlled trial of venlafaxine
ing the A1 allele (A1/A1 and A1/A2) showed no
for smoking cessation, given in conjunction with
significant reduction in negative mood .
behavioral support and nicotine replacement
Participants were smokers recruited for a
transdermal patch, adds to the small but rapidly
double-blind, placebo-controlled clinical trial of
growing literature on the pharmacogenetics of
the antidepressant venlafaxine for smoking
smoking cessation. Cigarette smoking is the larg-
cessation  who were subsequently genotyped
est preventable cause of death and morbidity in
for the DRD2
Taq1A and Taq1B polymorphisms
the USA, Europe and the developed world , but
to investigate possible pharmacogenetic effects.
despite decades of research to develop effective
Participants were required to smoke at least ten
smoking cessation treatments, a large proportion
cigarettes per day at baseline, and be aged
of smokers who attempt to quit are doomed to
between 18 and 75 years. Both the Taq1A1 and
fail . Therefore, the public health impact of cig-
Taq1B1 polymorphisms have been reported to
arette smoking remains substantial, which means
be associated with a decrease in D2 dopamine
that any improvement in the currently modest
receptor density in the striatum [8,9] (i.e., reduced
success rates achieved by smokers attempting to
function), although there are conflicting
quit would have the potential to afford a consid-
results . It would be interesting to know
erable improvement in public health. This has
whether these markers are in linkage disequilib-
prompted a growing interest in pharmacogenetics
rium in this study, as has been reported else-
research to determine whether the efficacy of dif-
where , in particular given the different results
ferent pharmacotherapies for the treatment of
for these markers reported by Robinson and
nicotine dependence is influenced by inherited
variation in drug-metabolizing enzymes and drug
Participants recorded their daily cigarette
intake each night in a diary prior to going to bed
The findings reported by Robinson and col-
for 56 consecutive days (14 days prequit and
leagues extend on this work by investigating var-
42 days postquit), recording cigarette use over
iation in a relatively rarely investigated
the past 24 h, counting even a single puff as a
cigarette. Daily abstinence was calculated based
) gene, the Taq1B variant, as well as the
on this smoking diary, with zero cigarettes
more commonly studied Taq1A variant. This
defined as abstinent and all other responses,
follows a previous report by the same group on
including missing, defined as nonabstinent.
the same sample indicating a DRD2
Withdrawal symptoms were measured using two
otype × treatment interaction effect on negative
standardized, validated instruments – the Wis-
affect, with smokers homozygous for the A2
10.2217/146224126.96.36.1993 2007 Future Medicine Ltd ISSN 1462-2416
PRIORITY PAPER EVALUATION – Munafò & Johnstone
which consists of seven subscales (anger, anxiety,
among studies of genetic and pharmacogenetic
concentration, craving, hunger, sadness and
effects on smoking cessation, where very few of
sleep) and the Minnesota Withdrawal Symptom
those studies published to date have been explicitly
Checklist (MWSC), which is a nine-item list of
designed to investigate these effects.
tobacco withdrawal symptoms summed to gen-erate an overall withdrawal scale. Both question-
naires were completed on a daily basis for
The study by Robinson and colleagues adds to the
56 days, along with the smoking diary.
growing but disparate literature on the role of
Although the original trial from which these
genetic effects on smoking cessation. Case–con-
data were drawn randomized participants, strati-
trol studies of smoking status phenotypes (e.g.,
fied by sex and history of depression, to receive
comparing current smokers with ex-smokers)
either venlafaxine or placebo, no DRD2
have generally reported an increased likelihood of
genotype × treatment interactions effects were
being a smoker among those carrying one or more
copies of the reduced function Taq1A or Taq1B
colleagues for either the A1 or A2 variants.
variants. Nevertheless, these findings have by no
Instead, the results of interest relate to main
means been consistent, and findings across studies
effects of genotype on short-term daily absti-
remain highly heterogeneous, with the overall evi-
nence and withdrawal symptoms. Despite the
dence for association remaining modest .
authors predicting that the reduced function
Pharmacogenetic phenotypes have been argued to
offer advantages in the study of smoking cessation
decreased daily abstinence rates and increased
treatment compared with traditional case–control
withdrawal symptoms, no effects of this poly-
phenotypes, such as greater refinement (e.g., pro-
morphism were observed on either short-term
spectively assessed abstinence symptoms, side-
effects and smoking cessation under different
However, the reduced function Taq1B1 vari-
treatment conditions) and the use of experimental
ant was observed to be associated with signifi-
designs that control the dosing and timing of ther-
cantly reduced daily abstinence as the study
apy [4,5]. The use of daily diary data by Robinson
and colleagues illustrates well the potential
genotype × time interaction effect (p < 0.05).
strength of using rich time-course data to specify
homozygous for the Taq1B2 allele were absti-
nent, compared with 60% of those carrying one
findings to date. For example, reduced function
or more copies of the Taq1B1 allele. By 25 days
alleles (i.e., those associated with, for example,
post quit this difference had increased, with
reduced mRNA expression) for polymorphisms
approximately 40% of smokers homozygous for
in the DRD2
gene (e.g., Taq1A1) have generally
the Taq1B2 allele remaining abstinent, com-
been shown to predict better response to nico-
pared with less than 20% of those carrying one
tine replacement therapy (NRT) [13–15], while
or more copies of the Taq1B1 allele.
increased function alleles (e.g., Taq1A2) have
In addition, significant DRD2
Taq1B × time
been reported to predict better response to
interaction effects were observed for several
bupropion [14,16,17]. However, this overall picture
WSWS scales, including anger (p < 0.02), anxi-
is complicated by evidence that the widely inves-
ety (p < 0.004), concentration (p < 0.05), sadness
Taq1A polymorphism alters an
(p < 0.05) and sleep (p < 0.02). A similar interac-
amino acid in a previously undescribed protein
tion effect was observed for the MWSC summary
kinase gene (ANKK1
) near the DRD2
score (p < 0.003). In all cases, participants with
Nevertheless, this does not rule out an associa-
the B2B2 genotype reported fewer withdrawal
tion with the DRD2
gene, since data from the
symptoms over time compared with participants
HapMap project reveal that the Taq1A variant is
with one or more copies of the B1 allele.
in linkage disequilibrium with other variants in
These findings suggest, albeit tentatively given
gene, but not with variants in the
the marginal statistical significance of some of the
gene . Nevertheless, there have also
findings and the large number of statistical tests,
been failures to demonstrate an effect of DRD2
that smokers may exhibit distinct withdrawal tra-
jectories on the basis of DRD2
Another difficulty is that differences in study
Although the results are based on a subgroup anal-
design, and in the specific variants examined, limit
ysis of genetic effects, this is not uncommon
the comparability of the existing trials. With the
Effects of DRD2
polymorphisms on smoking cessation – PRIORITY PAPER EVALUATION
exception of the two randomized controlled trials
necessary, implementing genome-wide analyses
of bupropion versus placebo [14,16,20,21], these stud-
rather than focusing on single or a small number
ies are not directly comparable, comprising both
of variants . Those studies that focus on a sin-
randomized controlled trials and open-label effec-
gle gene should investigate multiple functional
tiveness trials. In particular, it is difficult to com-
variants to maximally capture variation across
pare genotype × treatment interaction effects
the gene, and, ideally, single-gene studies should
observed in placebo-controlled trials of single med-
be supplanted by large-scale studies of multiple
ications (e.g., NRT only), with main effects of
genes operating within a single pathway (e.g.,
genotype observed in trials where participants are
multiple dopamine receptor subtype genes, as
offered combination pharmacotherapy (e.g., venla-
well as genes coding for the dopamine trans-
faxine plus NRT). Moreover, as mentioned previ-
porter and those coding for dopamine metabo-
ously, most of these studies were not explicitly
lizing enzymes such as dopamine β-hydroxylase
designed to address pharmacogenetic questions.
-methyl transferase, in the case of
The results of the study by Robinson and col-
the dopamine pathway). Clearly this will require
leagues, while interesting, add yet another study
studies at least an order of magnitude larger than
design to those already employed in pharmaco-
those currently available to achieve sufficient
genetic studies of smoking cessation. It is notable
that in a previous analysis of the same data by the
same group, a significant effect of DRD2
medications approved for other indications (e.g.,
genotype on smoking cessation was observed
rimonabant), as well as current second-line medi-
when assessing abstinence at regular intervals up
cations for smoking cessation (e.g., nortriptyl-
to 52 weeks post quit , as opposed to daily diary
ine), will also require investigation, both in the
assessment as in the current study. This highlights
context of placebo-controlled trials and effective-
that relatively subtle differences in study design,
ness trials comparing multiple active medica-
such as the operational definition of abstinence
tions. It is possible, for example, that the
employed, may afford quite different results.
apparent lack of efficacy of certain medicationsmay mask the existence of subgroups of individu-
als for whom these medications may be effective,
The study of genetic and phamacogenetic effects
and who may be identifiable on the basis of geno-
on smoking cessation remains in its infancy, but
type. In the case of the current study, as the
the number of studies in this field is increasing
authors themselves note, candidate genes related
rapidly. As in all genetic association studies, robust
to serotonin neurotransmission may have been
replication is the ultimate goal of these studies.
Therefore, future studies should strive for compa-
genotype × treatment interaction effects, given
rability with existing studies in order for the
the mechanism of action of venlafaxine on serot-
extent to which early findings are replicated to be
onin reuptake. Retrospective genotyping of clini-
adequately assessed. The cost and complexity of
cal trial data will allow this possibility to be
trials of smoking cessation pharmacotherapies,
investigated, although any promising findings
which typically offer treatment in combination
will require confirmation in larger, explicitly
with behavioral support and, as in the case of the
study by Robinson and colleagues, in combina-
Genetic associations with tolerability and side-
tion with other pharmacotherapies, presents an
effects should also be examined, as well as with
obstacle to this. While meta-analysis has afforded
withdrawal symptoms, as Robinson and col-
an (imperfect) solution to the perennial problem
leagues have done, given that there may exist fur-
of lack of statistical power in case–control genetic
ther subgroups of individuals who respond well
association studies , where comparability across
to certain medications that are typically not well
studies tends to be greater than in pharmaco-
tolerated, without the frequently concomitant
genetic studies, it is not clear that this will offer a
side-effect profiles associated with these medica-
viable solution when the heterogeneity between
tions. For example, an association between varia-
tion in the DRD2
gene and poor adherence to
As well as improving comparability across
bupropion medication due to side-effects has
studies, if we are to accurately and reliably iden-
been reported , which illustrates the potential
tify genetic variants associated with treatment
to predict likely tolerance on the basis of geno-
response, very large studies explicitly designed to
type, even in the case of pharmacotherapies that
PRIORITY PAPER EVALUATION – Munafò & Johnstone
well as offer the potential to translate these find-
emerge, our knowledge regarding the role of
ings into practice and offer individualized treat-
genetic variation in smoking cessation and
ment tailored on the basis of genotype. Only
response to smoking cessation pharmacotherapy
then will we know whether studies such as that
will increase substantially. This will provide
by Robinson and colleagues will fulfil their
important insights into the mechanisms of
promise of allowing genotype-specific treatment
nicotine addiction and smoking cessation, as
• A pharmacogenetic analysis of a Phase II randomized, double-blind, placebo-controlled clinical trial of the antidepressant
venlafaxine, given in conjunction with behavioral support and nicotine replacement therapy for smoking cessation, was performed. A total of 166 smokers were recruited, of which 147 were randomized and 128 followed-up to 12 months post cessation.
• All participants were genotyped for the dopamine D2 receptor (DRD2
) Taq1A and Taq1B polymorphisms, with one or more copies
of the reduced activity (‘at risk’) allele (A1A1 or A1A2, and B1B1 or B1B2, respectively) compared with those homozygous for the wild-type allele (A2A2 and B2B2, respectively).
• Participants were required to smoke at least ten cigarettes per day at baseline, and be aged between 18 and 75 years old.
Individuals were excluded if they were participating in other smoking cessation treatments or taking psychoactive medication, or had uncontrolled systemic illness, contraindications for venlafaxine or nicotine patches, current substance abuse or other psychiatric disorders.
• The end points for the study were daily abstinence up to 42 days post quit, based on smoking diaries completed by participants
and verified by expired air carbon monoxide (≤10 ppm) at 1, 3 and 6 weeks post quit. Withdrawal symptoms were measured by the Wisconsin Smoking Withdrawal Scale and the Minnesota Withdrawal Symptom Checklist questionnaires.
• Smokers with an ‘at-risk’ B1 (B1B1 or B1B2) genotype were found to be less likely to report abstinence over the course of the
6-week post quit period as time progressed.
• Smokers with an ‘at-risk’ B1 (B1B1 or B1B2) genotype were found to be likely to report more withdrawal symptoms as
• No significant DRD2
Taq1B genotype × treatment (venlafaxfine vs placebo) interactions, and no effects of DRD2
• Smokers carrying the DRD2
Taq1-B1 allele were less likely to abstain from smoking, and reported significantly more symptoms of
daily smoking withdrawal over time compared with smokers homozygous for the B2 allele. These findings may have implications for the development of genotype-specific treatment strategies.
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