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Editorial
Searching for More Effective Smoking

Cessation Treatment
The study by Rose and Behm in this issue (1) is a remarkable rst attempt to
improve smoking cessation by selecting treatment for individual patients based
on an initial test period. Smoking cessation treatments specify a quit date, usually
2 weeks after the initiation of treatment. Rose and Behm used this 2-week period to
identify those patients who would likely respond to nicotine replacement therapy,
the simplest and safest treatment. The test was to identify those patients who de-
creased their smoking by 50% during open-label treatment with a nicotine
transdermal patch. Most patients receivedone 21-mg patchdaily, but heavier smokers
received two patches. The one-third of patients who decreased their cigarette
consumption by 50% or more then continued on the patch for 12 weeks. Half these
patients remained abstinent at 12 weeks, and 22%remained abstinent at 6 months.
The favorable prognosis for patients who immediately decreased smoking with
nicotine patch treatment replicates earlier ndings from Rose and colleagues (2).
The unique feature of this study is the double-blind comparison of three
interventions for patients who did not decrease their smoking by 50% during the
prequit phase. One-third were continued on nicotine patch, one-third received the
nicotine patch plus bupropion, and one-third were switched to varenicline.
Bupropion was titrated to 150 mg twice daily and varenicline to 1 mg twice daily.
The treatment period lasted 12 weeks, and approximately 100 patients were in each
group. At 12 weeks, the abstinence rate for treatment with nicotine patch alone was
less than 7%for patients who had not decreased their smoking before the quit date,
compared with 50% for those patients who had decreased smoking before the quit
date. Patients who had bupropion added to the nicotine patch achieved a response
rate of 19%, and patients who were switched to varenicline achieved a response rate
of 12%, the latter effect not signicantly different fromthe nicotine patchcondition.
At 6 months, among the patients who had not responded during the prequit
phase, 7% of those on nicotine patch alone, 17% of those who received bupropion
in addition, and 16% of those on varenicline were abstinent. Thus, the addition of
bupropion to the nicotine patch for patients who did not respond quickly to
patch alone signicantly increased the response rate. Varenicline had longer-term
effects that were also signicantly better than the patch alone for nonresponding
patients.
In a second phase of the study, a second intervention was made to try to rescue
patients who relapsed during the rst postquit week despite a favorable prequit
response. This intervention was not as successful, unfortunately. However, the
small number of participants in each group, approximately 30, may have con-
tributed to the inconclusive ndings.
Clinical lessons from the study include the nding that patients self-report of
cigarette consumption closely correlated with the results of carbon monoxide
monitoring and that percent decrease in smoking predicted the clinical course
better than absolute levels of cigarette consumption. The study design is complicated
This article is featured in this months AJP Audio
818 ajp.psychiatryonline.org Am J Psychiatry 170:8, August 2013
because of the multiple interventions, but it effectively used the 600 patients enrolled
to answer questions as clinicians would address them: Does the simplest, safest
treatment, nicotine patch, work for a givenpatient? If not, what additions (bupropion)
or changes (varenicline) are likely to help? The answer is that nicotine patch alone
works for half the patients, andthe additionof bupropionwill rescue about 20%of the
remaining half. Over 6 months, only about 15%220% of patients stop smoking with
any of the three treatments. The nicotine patch challenge is a useful way to direct
more effective treatment to those patients who show early on that they need it.
Althoughmany patients inthis study were helped, most hadreturnedtosmoking at
6 months, which points out the recalcitrance of this addiction to remediation. Public
policy to discourage or prohibit smoking has been helpful, but the mass marketing of
cigarettes and their continued adoption by young smokers, who are those most
vulnerable to longer-term addiction, is problematic (3). Patients with psychiatric
disorders other than obsessive-compulsive disorder, ADHD, and anxiety disorders
were excluded, despite the fact that psychotic, depressed, and alcohol-abusing
patients have much higher smoking
rates and cigarette consumption than
any other group (4). Rose and Behm
speculate on whether the overall rate
of response at 6 months suggests that
longer-term treatments with multiple
agents might be more effective for all
patients, but studies have not yet
addressed this question. More effective treatment is needed for the many patients
who relapse in the course of the rst 3 months of treatment.
In the search for new treatments, it is also worthwhile to consider what brain
mechanisms might underlie the difference inresponse betweenpatients. Nicotine, like
most drugs of abuse, hijacks neuronal receptors inthe brain. Afamily of nearly a dozen
nicotinic acetylcholine receptors, which normally respond to acetylcholine, are the
mechanism used by nicotine to maintain addiction. Genetic variation in the
expression and function of these nicotinic receptors is known to be a signicant
determinant of the liability to nicotine addiction and the response to nicotine
replacement therapy (4, 5). It is possible that the Rose andBehmtest, simple enoughto
be applied in any clinical treatment setting, identies some of this genetic variation. If
that is the case, thenthis clinical insight might also helpidentify whichgenetic variants
are the most treatment resistant and might be the targets of additional treatment
development.
References
1. Rose JE, Behm FM: Adapting smoking cessation treatment according to initial response to precessation nic-
otine patch. Am J Psychiatry 2013; 170:860867
2. Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR: Personalized smoking cessation: interactions between nicotine
dose, dependence, and quit-success genotype score. Mol Med 2010; 16:247253
3. Kendler KS, Myers J, Damaj MI, Chen X: Early smoking onset and risk for subsequent nicotine dependence:
a monozygotic co-twin control study. Am J Psychiatry 2013; 170:408413
4. Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, Horton
WJ, Breslau N, Budde J, Cloninger CR, Dick DM, Foroud T, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J,
Kuperman S, Madden PA, Mayo K, Nurnberger J Jr, Pomerleau O, Porjesz B, Reyes O, Schuckit M, Swan G,
Tischeld JA, Edenberg HJ, Rice JP, Goate AM: Variants in nicotinic receptors and risk for nicotine dependence.
Am J Psychiatry 2008; 165:11631171
5. Chen LS, Baker TB, Piper ME, Breslau N, Cannon DS, Doheny KF, Gogarten SM, Johnson EO, Saccone NL, Wang
JC, Weiss RB, Goate AM, Bierut LJ: Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation
treatments in smoking cessation success. Am J Psychiatry 2012; 169:735742
In the search for new treatments, it
is also worthwhile to consider what
brain mechanisms might underlie the
difference in response between patients.
Am J Psychiatry 170:8, August 2013 ajp.psychiatryonline.org 819
EDITORIAL
ROBERT FREEDMAN, M.D.
From the Department of Psychiatry, University of Colorado Denver Health Sciences Center, Aurora. Address
correspondence to Dr. Freedman ([email protected]). Editorial accepted for publication June
2013 (doi: 10.1176/appi.ajp.2013.13060758).
Disclosures of Editors of the American Journal of Psychiatry are published each year in the January issue.
820 ajp.psychiatryonline.org Am J Psychiatry 170:8, August 2013
EDITORIAL

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Searching for More Effective Smoking

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