Suicidal Behavior and Depression in Smoking Cessation
Thomas J. Moore1*, Curt D. Furberg2, Joseph Glenmullen3, John T. Maltsberger4, Sonal Singh5
1Institute for Safe Medication Practices, Alexandria, Virginia, United States of America, 2Division of Public Health Sciences, Wake Forest University School of Medicine,
Winston-Salem, North Carolina, United States of America, 3Department of Psychiatry-Cambridge Hospital, Harvard Medical School, Cambridge, Massachusetts, United
States of America, 4Department of Psychiatry-McLean Hospital, Harvard Medical School, Belmont, Massachusetts, United States of America, 5Department of Medicine,
Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Background: Two treatments for smoking cessation—varenicline and bupropion—carry Boxed Warnings from the U.S.
Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. However, some epidemiological
studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs
Methodology: From the FDA’s Adverse Event Reporting System (AERS) database from 1998 through September 2010 we
selected domestic, serious case reports for varenicline (n=9,575), bupropion for smoking cessation (n=1,751), and nicotine
replacement products (n=1,917). A composite endpoint of suicidal/self-injurious behavior or depression was defined as a
case with one or more Preferred Terms in Standardized MedDRA Query (SMQ) for those adverse effects. The main outcome
measure was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events
for that drug.
Results: Overall we identified 3,249 reported cases of suicidal/self-injurious behavior or depression, 2,925 (90%) for
varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. Compared to nicotine replacement, the
disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8–10.4), and bupropion 2.9 (2.3–3.7). The disproportionality
persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or
precautions in the prescribing information. An additional antibiotic comparison group showed that adverse event reports of
suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug
Conclusions: Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-
injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with
other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.
Citation: Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S (2011) Suicidal Behavior and Depression in Smoking Cessation Treatments. PLoS ONE 6(11):
Editor: James M. Wright, University of British Columbia, Canada
Received September 5, 2011; Accepted October 7, 2011; Published November 2, 2011
Copyright: ? 2011 Moore et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: These authors have no support or funding to report.
Competing Interests: TJM and JG have served as expert witnesses in a United States Army General Court Martial for a criminal matter in which varenicline had
been taken; they also have been retained as plaintiffs’ consulting experts in the multi-district U.S. District Court civil litigation relating to varenicline. This does not
alter the authors’ adherence to all the PLoS One policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
Treatments for smoking cessation include counseling without
(a partial agonist of a4b2 nicotinic acetylcholine receptors). The U.S.
Food and Drug Administration (FDA) has required Boxed Warnings
(a.k.a. ‘‘Black Box Warnings’’) for physicians, and a mandatory
Medication Guide for patients regarding serious psychiatric side
effects for two pharmacological treatments, varenicline and bupro-
pion . The warnings refer to suicidal behaviors prominently, but
also mention depression while noting ‘‘Depressed mood may be a
symptom of nicotine withdrawal’’ .
Some epidemiological studies report a higher incidence of suicidal
thoughts and behaviors among current but not former smokers
[3–6]. However, much of the elevated risk may be explained by
differences in the populations being compared rather than as a
possible effect of the nicotine exposure itself. While ‘‘dysphoria and
depressed mood’’ is listed among eight possible nicotine withdrawal
symptoms in the current Diagnostic and Statistical Manual of
be found in clinical studies and reviews. These reports provided
stronger evidence for other withdrawal symptoms such as irritability,
insomnia, and weight gain, [8–10] which suggests that depression is
not common in nicotine withdrawal.
While suicidal behaviors are not associated with smoking
cessation itself, [11,12] they are linked to at least 58 different
approved prescription drugs that have Boxed Warnings, Warnings
or Precautions in the package inserts. The list includes varenicline,
23 antidepressant drugs including bupropion, 17 anti-epileptic
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drugs, and treatments for asthma, viral illness, malaria prevention
and acne. Inspection of the warnings for the various compounds
reveals that suicidal events were rare in clinical trials. Class
warnings for anti-epileptic and antidepressant drugs were based on
FDA meta-analyses of numerous clinical trials and were extended
to drugs with similar indications or mechanisms of action [13,14].
Most other warnings were based on adverse event reports.
Tobacco use is responsible for 1 in 5 deaths in the United States
each year  and adds $193 billion to health care costs. It is
among the most treatment-resistant forms of drug dependency,
with 36% of the nation’s smokers attempting to quit each year but
only 3% succeeding for six months or more .
In this study we examine the comparative neuropsychiatric
safety profiles of varenicline, bupropion and nicotine replacement
products with regard to suicidal/self-injurious behavior and
depression as reflected in adverse drug event data.
Case reports for this study were extracted from a database of all
adverse drug event reports received by the FDA since 1998 into its
Adverse Event Reporting System (AERS), and released for
research use . The case reports are familiar to medical
professionals as ‘‘MedWatch’’ reports, the name that appears on
the FDA direct reporting form. The reports are either submitted
by drug manufacturers, who must forward information about any
serious adverse event of which they are informed, or sent directly
to the FDA by health professionals or consumers.
As in clinical studies, the event narratives are represented by one
or more Preferred Terms drawn from the Medical Dictionary for
Regulatory Affairs (MedDRA) . We selected United States case
reports coded with a serious health outcome, defined by FDA
regulation as death, disability, congenital defect, initial or prolonged
hospitalization, a life-threatening event, an event requiring inter-
Expedited reports from manufacturers but excluded Periodic reports
with ambiguous coding of the health outcome ‘‘other,’’ which could
mean either ‘‘other serious’’ or ‘‘other than serious.’’ We excluded
cases arising from clinical studies and foreign reports, and we also
excluded reports explicitly associated with legal claimsbecause of the
likelihood that they duplicated cases submitted by others. When one
or more follow up reports existed for the same case, the most recent
revision was selected.Whena report listed multiplehealth outcomes,
the most severe outcome was listed in this priority: death, disability,
and other serious events. Report sources were recoded into two
categories, health professionals and consumers. The health profes-
sional category included physicians, pharmacists, the medical
literature, and unspecified ‘‘other’’ health professionals. If both
health professionals and consumers were listed as identifiable report
sources, the cases were coded as health professionals. Drug names
were standardized based on the National Library of Medicine
RxNorm  ingredient names, and do not distinguish between
salts, esters, dosage forms or routes of administration.
We selected case reports from 1998 through September 2010
for varenicline (Chantix, Champix), bupropion for smoking
cessation (Zyban, or bupropion explicitly indicated for smoking
cessation in the adverse event reports). As comparison groups we
selected case reports for all nicotine replacement products
regardless of route of administration, and the combined case
reports for three frequently dispensed antibiotics, amoxicillin,
amoxicillin-clavulanate, and azithromycin. Nicotine replacement,
typically available without prescription, was selected as a
representative comparison group for the patient population trying
to stop smoking using drug therapy. To assess the underlying risks
that might be attributed to the smoking cessation population
independent of study drugs, the antibiotic comparison group was
selected to capture reported event rates in a generally healthy
population not seeking to stop smoking, in short-term drug
treatment, and without a uniformly confounding chronic disease.
To identify cases of suicidal/self-injurious behavior we utilized
the Standardized MedDRA Query (SMQ), narrow scope, for
Suicide/self-injury to select cases that included any of 11 specified
medical terms. To identify depression cases we matched any of the
22 terms in the narrow scope SMQ for Depression (excluding suicide and
self-injury). SMQs were developed and tested by the pharmaceutical
industry to identify possible cases of various types of adverse
reactions. Both MedDRA itself and the SMQs are revised twice a
year. This study relies on MedDRA version 13.1 . We also
selected the MedDRA Preferred Terms Headache, Pain or both as an
outcome because these are widespread general ailments not
associated with any of the study drugs. These terms provided an
additional comparison across drugs because we assumed, a priori,
that these effects should be similar in a similar patient population.
Because the case reports frequently indicated that more than
one drug was being taken at the time of the reported event, we
sought to analyze the influence of concomitant therapy. From
product labeling we identified 58 drugs with a Boxed Warning,
Warning or Precaution about suicidal behaviors, including
varenicline and bupropion (Appendix S1). The texts of the
warnings varied widely. The concomitant therapy variable
permitted us to identify and exclude case reports indicating the
patient had taken other drugs with some form of precaution or
warning about suicidal/self-injurious behavior.
The primary endpoint for this study was every case indicating
either suicidal/self-injurious behavior or depression. Because one
case report might contain MedDRA terms for both SMQs, a
composite endpoint was calculated to eliminate double counting.
To compare event rates we created 262 tables for each drug and
comparator with the endpoint events and all other events for that
drug in each column. We used Fisher’s exact test to calculate the
odds ratio (OR), 95% confidence interval, and test the null
hypothesis that the rates did not differ between drugs. To test for
the independence of the three smoking cessation drugs and reports
of headache/pain we utilized the Yates x2test.
Results for depression and suicidal/self-injurious behavior were
also analyzed separately. The results were also analyzed after
excluding cases indicating concomitant use of any of the 58 drugs
with warnings or precautions about suicidal or self-injurious
The master database of all adverse event reports submitted to
the FDA was maintained on a MySQL open source database
(http://www.mysql.com/) and analyzed with the R Package for
Statistical Computing (http://www.r-project.org/).
Patient and Event Characteristics
We identified 17,290 case reports meeting the study criteria for
all types of serious adverse events, including 13,243 cases in the
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smoking cessation population and 4,047 in the antibiotic
comparison group. In the smoking cessation treatment population,
3,249/13,243 (25%) of the cases reflected either depression,
suicidal/self-injurious behavior or both, compared to 48/4,047
(1%) of the cases in the antibiotic group. Table 1 shows the patient
and case report characteristics overall for the three smoking
cessation drugs and the antibiotic comparison group. While
patient and case report characteristics overall were similar among
all four groups, a few differences could be observed. As might be
expected, antibiotics were used in a wider range of patient age
than were the smoking cessation products, as indicated by a
greater standard deviation in the mean age. Reporting sources
were evenly divided between consumers and health professionals
except for nicotine replacement products, for which 83% of case
reports came from consumers.
The specific medical terms (MedDRA Preferred Terms) that
resulted in the classification of a case in either of the two primary
SMQs are shown in Table 2. For the suicidal/self-injurious
behavior SMQ, suicidal ideation was the most frequent term,
appearing in 1,255/2,045 (61%) of cases. However, completed
suicide appeared in 298 cases (15%) and suicide attempt in
another 388 cases (19%). For the depression SMQ the simple
Preferred Term Depression appeared in 1,913/2,210 (87%) of
selected cases. Among the smoking cessation drugs, the only
marked difference in term frequency was that the varenicline cases
were coded to a greater variety of different terms than were the
bupropion and nicotine products.
The odds ratio and 95% confidence intervals for the endpoints
in this study are shown in Figures 1 and 2. Figure 1 shows the
results compared to nicotine replacement. Varenicline showed
disproportional risks, OR 8.4 (CI 6.8–10.4). The odds ratio for
bupropion was smaller than for varenicline, but also elevated, OR
2.9 (CI 2.3–3.7). For varenicline compared to bupropion, the odds
ratio was 2.9 (CI 2.5–3.4). The results were similar when
depression and suicidal/self-injurious behavior were examined
separately. Also, 954/3,249 (29%) of the composite endpoint cases
fell into both the depression and suicidal/self injurious behavior
SMQs. As seen in Figure 2, the data show that compared to the
antibiotic comparison group, the OR was elevated for all three
smoking cessation treatments, although to different degrees:
varenicline OR 36.6 (CI 27.5–48.9), bupropion OR 12.5 (CI
9.1–17.2); nicotine replacement products OR 4.3 (CI 3.1–6.2).
Concomitant Therapy Drugs
We identified 58 drugs (including bupropion and varenicline)
which currently have a Boxed Warning, Warning or Precaution
about suicidal behaviors in the prescribing information. Overall,
3,068/17,290 (18%) of all cases included concomitant therapy
with another drug with a suicide warning or precaution. The
results when these cases were excluded are also shown in Figures 1
and 2. The statistics were similar to the primary endpoint, which
did not exclude these cases.
Headache and Pain
The headache and pain adverse event terms were selected
because they are among the most frequent and widely reported,
non-specific symptoms both with and without drug therapy, and
not clearly associated with any of the study drugs. Headache or
pain occurred in 1,032/13,243 (8%) of the smoking cessation
cases, but the differences among the three drugs were not
statistically significant (x2=2.5; df=2; p=0.28). However,
headache and pain were reported more frequently for the smoking
cessation treatment patients than for the antibiotic comparison
group OR 1.95 (CI 1.7–2.3). While the difference is small, the
result is plausible since nicotine withdrawal could cause these
Unadjusted Event Totals
Even though varenicline was marketed for approximately 4
years of the nearly 13-year study period, it accounted for a
disproportionate share of the overall total serious adverse drug
events reported in the smoking cessation population, 9,575/13,243
(72%). For the main outcome measure we identified 3,249
reported events of suicidal/self-injurious behavior or depression,
2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%)
for nicotine replacement. For completed suicides, varenicline was
associated with 272/295 (92%) of smoking treatment cases,
bupropion for 19 cases (6%) and nicotine products for 4 cases
(1%). The results were similar for suicide attempts, with 323/381
(85%) of all reported suicide attempts for varenicline, 56 cases
(15%) for bupropion, and 2 cases (,1%) for nicotine replacement
These data support three conclusions about suicidal/self-
injurious behavior and depression in smoking cessation treatment.
First, the risks of these reported serious events were higher among
nicotine replacement patients compared to a broader population
prescribed commonly used antibiotics, suggesting higher risks in
the smoking cessation treatment population employing pharma-
cological assistance. Second, bupropion has some additional excess
reported risk when used for smoking cessation compared to the
nicotine products. Finally, varenicline has markedly higher
reported risk than any of the comparators, a risk that was not
reduced regardless of the form of adjustment used. In addition,
these findings were consistent with a simpler study using United
Kingdom adverse event data  and a prospective cohort study
in New Zealand . Disproportionality analysis is a proven
technique and is increasingly being used to detect associations in
Table 1. Characteristics of Adverse Drug Event Reports.
VareniclineBupropion Nicotine Antibiotics
(N=9575) (N=1751)(N=1917) (N=4047)
N (%) N (%)N (%)N (%)
Female5733 (62.5) 874 (51.5) 1123 (60.9) 2064 (51.0)
Age mean (SD),y49 (12.6) 44(13.4) 50 (14.3) 50(25.3)
Direct to FDA2206 (23.0) 199(11.4) 115(6.0) 1064 (26.3)
Mfr-Expedited6717 (70.2) 1313(75.0) 1757 (91.7) 2813 (69.5)
Mfr-Periodic 652 (6.8)239(13.6) 45(2.3)170 (4.2)
Health professional 3153 (40.0) 741(49.3) 313 (17.1) 1734 (55.3)
Consumer4726 (60.0) 763 (50.7) 1516 (82.9) 1403 (44.7)
Death, any cause470 (4.9)140 (8.0)111 (5.8)318 (7.9)
Disability244 (2.5)165(9.4) 41(2.1) 194(4.8)
Other serious 8861(92.5) 1446(82.6) 1765 (92.1) 3535 (87.3)
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adverse event data that escape detection in clinical trials because of
their rarity or uncertain event ascertainment [24–27]. While the
full text narratives of individual case reports were not available for
this study, the FDA safety analysis that led to the varenicline and
bupropion Boxed Warnings summarized numerous credible
individual case narratives of suicidal behavior occurring for the
first time in persons with no previous psychiatric history .
Adjusting for Possible Confounding Factors
This analysis seeks to adjust for the following confounding
factors: 1) Since adverse event reporting rates might vary over time
because of publicity or other factors, we included the entire time
interval during which the study drugs had been available since
1998. 2) Because patient exposure varied and reporting rates
might theoretically be different, we set the endpoint as the
proportion of cases for each specific drug compared to all other
serious reports for that same drug. 3) To consider the possibility
that the endpoint events might actually be a risk of the underlying
patient population we used nicotine replacement as a proxy for the
smoking cessation population and compared it to a broader
general population exposed to short-term treatment with antibi-
otics. 4) The evidence that this method identifies true differences
between drugs for the primary endpoints is strengthened because
the non-specific headache and pain endpoint showed, as expected,
no differences among smoking cessation drugs. 5) To reduce
possible bias in selection of specific endpoint terms for depression
and suicide/self-injury, we utilized without change SMQs created
by industry to identify possible cases. 6) We evaluated a possible
effect of concomitant therapy by calculating the odds ratios with
and without other drugs with existing suicidal behavior warnings
and precautions. 7) The antibiotic treatment group, which is not
associated with the endpoint, served as an additional check to
Table 2. MedDRA terms in suicidal/self-Injurious behavior and depression SMQs.
SUICIDAL/SELF-INJURIOUS BEHAVIOR SMQ
VARENICLINE BUPROPIONNICOTINE ANTIBIOTIC
n (%) n (%) n (%)n (%)
Completed suicide272 (15.0)19 (12.3)4 (8.0)3 (14.3)
Depression suicidal 10(0.5)3 (1.9)0 (0.0)1 (4.8)
Intentional overdose31 (1.7)32 (20.6)4 (8.0)8 (38.1)
Intentional self-injury49 (2.7)7 (4.5)1 (2.0)1 (4.8)
Multiple drug overdose intentional1 (0.1)0 (0.0)0 (0.0)0 (0.0)
Poisoning deliberate2 (0.1)1 (0.6)0 (0.0)0 (0.0)
Self-injurious ideation65 (3.6)3 (1.9)0 (0.0)0 (0.0)
Self injurious behavior 45 (2.5)0 (0.0)0 (0.0)0 (0.0)
Suicidal behavior63 (3.5)1 (0.6)1 (2.0)0 (0.0)
Suicidal ideation1135(62.4) 73 (47.1) 40(80.0)7 (33.3)
Suicide attempt 323 (17.8)56 (36.1)2 (4.0)7 (33.3)
Total any term*1819 155 50 21
MedDRA TermVARENICLINE BUPROPIONNICOTINE ANTIBIOTIC
Adjustment disorder with depressed mood1(0.1)0 (0.0)0(0.0)0(0.0)
Adjustment disorder with mixed anxiety and
1(0.1)0 (0.0)0 (0.0)0(0.0)
Anhedonia38 (1.9)4(3.3)0 (0.0)0(0.0)
Decreased interest 33(1.7)3 (2.5)1(1.7)0 (0.0)
Depressed mood 180(9.0) 15(12.4)8 (13.8)2(6.5)
Depression1735(86.8) 102(84.3)47(81.0) 29(93.5)
Depressive symptom5 (0.3)1 (0.8)0(0.0)0 (0.0)
Dysthymic disorder1(0.1)1 (0.8)1(1.7)0 (0.0)
Electroconvulsive therapy2(0.1)0 (0.0)0 (0.0)0 (0.0)
Feeling guilty6 (0.3)0(0.0)0 (0.0)0 (0.0)
Feeling of despair 43 (2.2)6 (5.0)3 (5.2)0 (0.0)
Feelings of worthlessness22(1.1)1(0.8)0 (0.0)0(0.0)
Postpartum depression1(0.1)0(0.0)0 (0.0)0(0.0)
Total any term*20001215831
*Totals do not add because more than 1 term could appear in a single case report.
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account for the possibility that any available drug might be taken
randomly in overdose in some suicide attempts. While these
adjustments substantially improve the precision of the estimates,
the character of adverse event data does not permit comparison
groups that are similar to the treatment groups in most identifiable
characteristics, as can be achieved in some epidemiological studies
and randomized controlled trials.
Clinical and Epidemiological Studies
Increased risk of suicidal/self-injurious behavior was generally
not established in clinical trials of varenicline, according to FDA
reviews [11,28] and the sponsor’s meta-analysis . However,
the meta-analysis reported an increased rate of overall psychiatric
side effects when sleep disorders were included, and higher but not
statistically significant incidence of depressed mood disorders.
Several reasons may explain why suicidal/self-injurious behavior
was not apparent in clinical trials prior to approval. The trials were
powered to measure efficacy, not less frequent adverse events.
Suicidal/self-injurious behaviors are a relatively rare event, with
statistically significant excesses of events rarely reported in
individual clinical trials for any approved drug. Patient exposure
in Phase II/III trials for varenicline was relatively small
(n=1,070). The FDA suicidal behavior warnings for antidepres-
sant and anti-epileptic drugs were derived from systematic pooled
analyses combining the results of large numbers of clinical trials.
Even these large pooled trials had few documented events, and in
addition may have underestimated actual risks because few clinical
at the recommended dose
Figure 1. Varenicline, bupriopion versus nicotine replacement.
Figure 2. Varenicline, bupropion versus 3 antibiotics.
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trials used a systematic side effects checklist, relying instead on
spontaneously volunteered patient reports at study clinic visits.
The FDA concluded in 2008 that the pre-approval varenicline
clinical trial data alone were not capable of adequately addressing
the issue of suicidal/self-injurious behavior . A medical records
database study in the United Kingdom also reported finding no
association . However, it was limited by weak event
ascertainment, and contradicted by the strong signal observed in
that country’s adverse event reporting system  and by a cohort
study in New Zealand .
Limitations of the Study
Submission of a case report does not in itself prove that the
suspect drug caused the event observed. In addition, it was not
possible to evaluate each individual case report according to any of
the commonly employed tools to assess issues such as time of onset,
possible alternative causes, effects of discontinuation, rechallenge,
and report quality. On the other hand, the total number of cases
was large, sustained over substantial periods of time, and found in
both direct-to-FDA and manufacturer reports. While these data
provide statistically significant evidence of an association between
varenicline and the study endpoints, it would take a different study
design with an appropriate denominator of users to estimate the
incidence of these adverse effects. In this study we used nicotine
replacement patients as representative of the population seeking to
quit smoking with pharmacological assistance. However, we
cannot exclude the possibility that nicotine replacement might
slightly increase or decrease the risk of reported suicidal/self-
injurious behavior or depression. Previous nicotine studies 
and the relatively small number of reported events compared to
the nearly universal availability of these OTC nicotine products
suggest that the drug effects, if any, are small. The number of
adverse event cases for bupropion was likely undercounted
because information about the indication for treatment was
missing for many adverse event reports and this study selected only
cases with specific information that bupropion was prescribed for
smoking cessation. The risks for varenicline were understated in
these data because the drug was only marketed for approximately
4 years of the nearly 13-year study period, and because of the
possibility that manufacturer coding problems may have led to an
undercount . In addition, while reporting rates for these side
effects are not known, only a small fraction of adverse events that
occur are reported in a voluntary system.
The efficacy of the three major pharmacological interventions for
smoking cessation has been studied in numerous randomized
clinical trials [33,34]. One analysis focusing on longer-term
outcomes reported odds ratios compared to placebo ranging from
1.7 for nicotine gum to 2.4 for varenicline . Retrospective
studies of successful quitters often favor self quitters or cold turkey
approaches . The FDA evaluation of the varenicline trials
showed that the drug had superior quit rates at 12 weeks; but by 52
weeks a large majority in all groups had resumed smoking—only
approximately 25–27% of varenicline patients had remained largely
abstinent compared to 17–19% of bupropion patients and 9–12%
of the placebo group . The only published trial comparing
varenicline to nicotine patches found no statistically significant
difference in reported 7-day abstinence at 52 weeks .
Other Safety Concerns
While suicidal/self-injurious behavior and depression appear to
be prominent side effects of varenicline, they are by no means the
only safety issues. Varenicline has been associated with aggression
and violence in three studies [25,27,38] and carries a warning
about this behavior. Its effect on vision, cognition, and motor
control and other risks have led to its being banned for airline
pilots, air controllers, military pilots and missile crews, and
restricted for truck drivers . Varenicline is also associated with
an increase in the risk of serious cardiovascular events . In
addition, it is associated with hypersensitivity, angioedema and
potentially life-threatening severe cutaneous adverse events .
While a growing body of research from multiple sources
establishes that varenicline substantially increases the risk of
psychiatric side effects, it remains uncertain how frequently these
events occur. Estimating incidence rates would require a large
cohort, a validated psychiatric symptoms checklist, and sufficient
power over one year to detect event rates that may be as low as 1
or 2 per 1,000 but could be more than 1 in 100. The same study
could also assess cardiovascular, accident, and other known risks.
Even better incidence estimates will not address the value
judgment of how to weigh the possible benefits of 52 weeks of
smoking abstinence for 1 or 2 out of every 10 patients treated
against the risk of less frequent adverse events such as violent and
suicidal behavior that can have immediate, catastrophic and
irreversible effects on self, family, and career. In the meantime,
safer alternatives now exist and should be preferred.
Clinical and Regulatory Implications
The overall safety profile of varenicline makes it unsuitable for
first-line use in smoking cessation. We agree with the recommen-
dation of the U.S. Veterans Administration (VA)  that
varenicline should be prescribed only after failure of nicotine
replacement, bupropion, or a combination. The VA also
recommends a mental status examination to assess risk of suicidal
or violent behavior prior to prescribing varenicline. In addition,
varenicline should not be prescribed for sensitive occupations such
as airline pilots, air controllers, active duty military, police officers,
truck and bus drivers, and emergency medical workers. Also, the
FDA should consider revising the suicidal behavior and depression
language in the Boxed Warning and Highlights of Prescribing
Information to state clearly that the risks of suicidal behavior and
depression are higher with varenicline than with other smoking
In conclusion, varenicline shows a substantial, statistically
significant increased risk of reported depression and suicidal/self-
injurious behavior. The excess risk persisted even after adjusting
for numbers of patients exposed, for the possibility of different
reporting rates, and for concomitant therapy. Bupropion for
smoking cessation had increased risks but less so than for
varenicline. The findings for varenicline, combined with other
problems with its safety profile, render it unsuitable for first-line
use in smoking cessation.
Drugs with Suicidal Behavior Warnings.
Conceived and designed the experiments: TJM CDF JG JTM SS.
Performed the experiments: TJM. Analyzed the data: TJM SS JG CDF
JTM. Wrote the paper: TJM. Significant critical input: JTM JG SS CDF.
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PLoS ONE | www.plosone.org7 November 2011 | Volume 6 | Issue 11 | e27016