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Cigarette smoking, nicotine dependence and anxiety disorders: a systematic
review of population-based, epidemiological studies
BMC Medicine 2012, 10:123doi:10.1186/1741-7015-10-123
Steven Moylan (email@example.com)
Felice N Jacka (firstname.lastname@example.org)
Julie A Pasco (juliep@BarwonHealth.org.au)
Michael Berk (email@example.com)
30 April 2012
29 August 2012
19 October 2012
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Cigarette smoking, nicotine dependence and anxiety disorders: a systematic
review of population-based, epidemiological studies
Steven Moylan,1,* Felice N Jacka,1,2 Julie A Pasco1,3 and Michael Berk1,2,4,5
1Deakin University School of Medicine, Barwon Health, Geelong, Victoria, Australia
2Department of Psychiatry, Melbourne University, Parkville, Victoria, Australia
3NorthWest Academic Centre, Department of Medicine, The University of Melbourne,
St Albans, Victoria, Australia
4Orygen Youth Health Research Centre, Centre for Youth Mental Health, Parkville,
5The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria,
Background: Multiple studies have demonstrated that rates of smoking and nicotine
dependence are increased in individuals with anxiety disorders. However, significant
variability exists in the epidemiological literature exploring this relationship, including
study design (cross-sectional versus prospective), the population assessed (random
sample versus clinical population) and diagnostic instrument utilized.
Methods: We undertook a systematic review of population-based observational
studies that utilized recognized structured clinical diagnostic criteria (Diagnostic and
Statistical Manual of Mental Disorders (DSM) or International Classification of
Diseases (ICD)) for anxiety disorder diagnosis to investigate the relationship
between cigarette smoking, nicotine dependence and anxiety disorders.
Results: In total, 47 studies met the predefined inclusion criteria, with 12 studies
providing prospective information and 5 studies providing quasiprospective
information. The available evidence suggests that some baseline anxiety disorders
are a risk factor for initiation of smoking and nicotine dependence, although the
evidence is heterogeneous and many studies did not control for the effect of
comorbid substance use disorders. The identified evidence however appeared to
more consistently support cigarette smoking and nicotine dependence as being a
risk factor for development of some anxiety disorders (for example, panic disorder,
generalized anxiety disorder), although these findings were not replicated in all
studies. A number of inconsistencies in the literature were identified.
Conclusions: Although many studies have demonstrated increased rates of
smoking and nicotine dependence in individuals with anxiety disorders, there is a
limited and heterogeneous literature that has prospectively examined this
relationship in population studies using validated diagnostic criteria. The most
consistent evidence supports smoking and nicotine dependence as increasing the
risk of panic disorder and generalized anxiety disorder. The literature assessing
anxiety disorders increasing smoking and nicotine dependence is inconsistent.
Potential issues with the current literature are discussed and directions for future
research are suggested.
Keywords: agoraphobia, anxiety disorder, cigarette smoking, epidemiology,
generalized anxiety disorder, nicotine dependence, obsessive-compulsive disorder,
panic disorder, post-traumatic stress disorder, specific phobia.
Anxiety disorders (ADs) represent the most common mental illness diagnoses
across many countries [1,2] and are associated with significant impairment to health
and quality of life [3,4]. Multiple population-based epidemiological studies have
identified increased rates of smoking amongst individuals with mental illness, and
increased rates of mental illness amongst smokers . Specifically, ADs have been
reported to be associated with increased rates of smoking, increased consumption of
cigarettes per smoker, and lower rates of smoking cessation than non-anxiety
disordered control groups [6,7]. In addition, increased anxiety symptoms as
measured on symptom scales appear to be correlated with increased rates of
The relationship between ADs, smoking behavior and nicotine dependence (ND)
could be explained by three non-mutually exclusive relationships. Firstly, smoking
behavior and/or ND may increase the chances of developing an AD. Potential
mechanisms underpinning this include adverse effects of smoking on
neurodevelopment and neurotransmitter pathways modulating anxiety that may
predispose individuals to developing enhanced anxiety, or direct effects to the
respiratory and autonomic systems that may alter physical responses to anxiety
provoking situations [9,10]. Secondly, ADs may increase smoking behavior and the
risk for ND. Mechanisms for this could include a propensity for those with increased
anxiety to commence smoking, or use of cigarettes as an anxiolytic self-treatment
[11,12]. Thirdly, the relationship may be underpinned by a shared vulnerability factor
or group of factors that increase the likelihood of smoking, ND and AD development
(for example, low socioeconomic status) [2,13].
However, a number of inconsistencies exist within the current literature examining
the relationships between cigarette smoking, ND and ADs. Firstly, many currently
available population-based epidemiological investigations have utilized clinical
symptom severity scales rather than validated diagnostic instruments to make AD
diagnoses. Secondly, many studies utilizing validated diagnostic instruments have
been cross-sectional, and therefore unable to provide insight into the direction of
causality underpinning the association. Thirdly, many investigations have been
drawn from clinical populations as opposed to whole population samples, potentially
introducing selection biases. An accurate assessment of the association between
cigarette smoking, ND and validated ADs, including direction of causality and
potential variation amongst differing anxiety disorder subgroups or populations, may
help inform targeted interventions in at risk populations.
This paper aims to critically review the available epidemiological studies that have
utilized general population samples and validated diagnostic instruments based upon
recognized Diagnostic and Statistical Manual (DSM)  or International
Classification of Diseases (ICD) systems , exploring the relationship between
cigarette smoking, ND and ADs. Structured diagnostic instruments have advantages,
as they are replicable across studies, and in some cases include an interview (for
example, the Composite International Diagnostic Interview (CIDI)). These interviews
often document date of onset and recent symptom expression, allowing for
assessments of temporality. A particular focus for this review is on studies that have
utilized prospective designs and can therefore provide insight into the direction of the
potential underlying causal relationships.
Systematic review search strategy
A systematic review of the English language literature exploring relationships
between ADs, ND and cigarette smoking was undertaken. The aim was to provide a
descriptive overview of the available literature, with a focus on information that could
inform understanding of direction of causality. A computerized search strategy of
medical databases PubMed and EMBASE utilized the following search strategies,
was limited to English language literature and human studies. No date restrictions
were placed. PubMed: ‘Anxiety Disorders’ (MeSH) AND (Smoking(Title/Abstract) OR
Tobacco(Title/Abstract) OR Nicotine(Title/Abstract) OR Cigarette(Title/Abstract))
AND Anxiety AND (‘humans’ (MeSH terms) AND English); EMBASE: ‘#1 AND #2
AND #3’ where #1 = ‘‘anxiety disorder’/exp AND (humans)/lim AND (english)/lim
AND (embase)/lim’, #2 = ‘smoking:ab OR tobacco:ab OR cigarette:ab OR
nicotine:ab AND (humans)/lim AND (english)/lim AND (embase)/lim’ and #3 =
‘‘anxiety’/exp AND (humans)/lim AND (english)/lim AND (embase)/lim’.
Extraction of references
All extracted references were combined and duplicate references deleted. Titles and
abstracts of all references were initially assessed for relevance to the review topic.
Full texts of references identified as potentially containing relevant information were
assessed against the predetermined inclusion criteria for quality and relevance. For
completeness, bibliographies of extracted references were manually searched for
further relevant references. Where relevant references were discovered, their
bibliographies were manually searched.
The following inclusion criteria were applied to the available references. Included
studies needed to utilize a random sample, drawn from the general population,
investigating the association between ADs, ND and cigarette smoking. The included
population must have been assessed for panic disorder (PD), generalized anxiety
disorder (GAD), obsessive-compulsive disorder (OCD), social phobia (SP), specific
phobia (SPP), post-traumatic-stress disorder (PTSD) and/or agoraphobia (AG),
utilizing a recognized and validated structured diagnostic tool or documented
clinician diagnosis in line with either ICD-9/ICD-10 or DSM-III or DSM-IV criteria. The
criteria establishing cigarette smoking must have been clearly documented, either as
dichotomous (yes/no) or through frequency of cigarette consumption. ND must have
been diagnosed through a recognized diagnostic tool linked to ICD or DSM criteria.
The criteria for ND mirror those of other substance dependence disorders, and
include (amongst others) symptoms of tolerance, withdrawal, increasing use and
difficulty quitting. All data must have represented new information and not replication
of previous study results.
Literature search and application of inclusion criteria
The structured computerized literature search was performed on 18 November 2011
yielded 298 references from PubMed and 138 references from EMBASE. In all, 36
records were duplicated after compilation of search results, leaving 400 unique
records. Initial review of titles and abstracts revealed 91 records with potentially
relevant information for the review. Manual searching of the bibliographies from
these 91 references revealed 16 further potential references. Full text review of
these 107 references revealed 47 studies meeting the inclusion criteria. See Figure 1
for search strategy flowchart and Figure 2 for breakdown of studies.
All data were extracted upon the following variables: (1) study name, (2) study
population, (3) study design (prospective, quasiprospective or cross-sectional), (4)
definition of AD diagnosis, (5) definition of smoking status, (6) statistical parameters
utilized and (7) primary results presented. A focus on measures of association (for
example, odds ratio (OR), hazard ratio (HR)) was taken. Where available, both
unadjusted and adjusted measures were extracted. Data were extracted into a
preprepared structured Microsoft Excel database (Microsoft; Redmond, WA, USA).
There were 47 studies meeting inclusion criteria. The studies were broken down by
type and direction of analysis (prospective, quasiprospective and cross-sectional)
and are represented in Additional files 1-5.
A total of 13 studies were identified that utilized population-based samples to assess
a prospective relationship between ADs, smoking behavior, and ND. These studies
comprised random population samples drawn from the United States, New Zealand,
Germany and The Netherlands, with some samples used in multiple studies.
Discussion of the included studies has been grouped below based on the sample
Influence of anxiety disorders on risk of later smoking or nicotine dependence
(A summary of this section is as follows (see also Additional file 1, Table S1): the
best available evidence is equivocal, but suggests that certain baseline ADs are risk
factors for onset of smoking and nicotine dependence, although results vary across
studies and across different disorders. The best available studies failed to control for
comorbid substance use disorders.)
The first published prospective data were drawn from the Oregon Adolescent Project
Depression project, which randomly recruited adolescents (aged 14 years to 18
years) from high schools in Western Oregon, USA in 1987 to 1989 and followed
them at two time points (1 year later, and on their 24th birthday). Assessment of ADs
was undertaken utilizing the Schedule for Affective Disorders and Schizophrenia for
School-Age Children (K-SADS) for DSM-III revision (DSM-III-R) , and smokers
were defined as those smoking ≥3 times per week. Brown et al.  demonstrated
no difference in the odds for incident smoking at 1-year follow-up in those with
versus without any ADs at baseline, both unadjusted and after controlling for a
variety of demographic and other risk factors. This finding of no association was
replicated in the 24-year-old follow-up  although only PD, and not grouped ADs,
was used as the exposure variable.
Breslau et al.  utilized a random population sample of 1,007 young adults (21
years to 30 years), drawn from the Detroit Epidemiologic Study, to examine PD as a
predictor of cigarette smoking. Baseline assessment occurred in 1989 and three
follow-ups (1990, 1992 and 1994) were conducted. Diagnosis of PD was made
through use of the National Institute of Mental Health Diagnostic Interview Schedule
 for DSM-III-R criteria, and ‘daily smoking’ was defined as smoking daily for ≥1
month. Risk of smoking onset was increased in those with PD at baseline (HR = 2.20
(95% CI 1.10 to 4.42)), but this significance was lost when controlled for the
presence of major depressive disorder (MDD). Breslau et al.  extended their
investigation, incorporating two further follow-ups (1999 and 2001) to assess the
interaction between PTSD and ND over 10 years. After adjusting for gender, race
and education, the odds of incident ND at follow-up was 4.03 (95% CI 2.10 to 7.72)
in those with baseline PTSD versus those without a trauma history.
Johnson et al.  followed a random sample of adolescents from New York state,
assessed at baseline in 1983 (mean age 14 years) and at two subsequent follow-ups
in 1985 to 1986 (mean age 16 years) and 1991 to 1993 (mean age 22 years).
Diagnosis of ADs (grouped and individual) at baseline was made using the
Diagnostic Interview Schedule for Children (DIS-C)  to DSM-III criteria. Smoking
assessment was by self-report, and categorized into smoking >1 pack (20+
cigarettes) versus smoking <1 pack (1 to 19 cigarettes) per day (not non-smokers).
After adjusting for a variety of demographic and other risk factors no association was
detected between adolescent anxiety disorder status and onset of smoking in
The Early Developmental Stages of Psychopathology (EDSP) study has been
utilized to assess the association between ADs, ND and smoking behavior. In this
study, a random community cohort of 3,021 adolescents and young adults (age 14
years to 24 years) was sampled from metropolitan Munich. The cohort was assessed
at baseline (1995) and two follow-ups, the first between 1996 and 1997 and the
second between 1998 and 1999 (a third follow-up was subsequently conducted in
2005 to 2006) . AD and ND diagnoses were made utilizing an updated version
 of the Composite International Diagnostic Interview  for DSM-IV criteria and
smoking was assessed by self-report. Isensee et al.  categorized participants
from the EDSP into non-smokers, occasional smokers, non-dependent regular
smokers and dependent regular smokers (see Additional file 1, Table S1 for
definitions) and calculated odds ratios for incident smoking by baseline AD status.
No associations were found between baseline AD status and odds of incident
smoking. Sonntag et al.  extended this study in SP but once again found no
association, although a positive association was found between those with social
fears symptoms and later development of ND.
Woodward et al.  utilized a New Zealand birth cohort to compare the risk of DSM-
IV ND between the ages of 18 and 21, dependent upon diagnosis of ADs between
the ages of 14 to 16. A linear association was found between increasing number of
ADs at age 14 to 16 (0 to 3+) and subsequent ND diagnosis, although this was not
significant after controlling for childhood sexual abuse, alcohol abuse, parental
changes and deviant peer affiliations.
Chou et al.  utilized the National Epidemiologic Survey on Alcohol and Related
Conditions (NESARC) to investigate the association between ADs and ND in adults
age 60 years and older (n = 8,012). Diagnoses were made utilizing the Alcohol Use
Disorders and Associated Disabilities Interview Schedule for DSM-IV criteria
(AUDADIS-IV)  and the risk of incident ND was assessed between baseline
(2000 to 2001) and follow-up (2004 to 2005). No associations were found between
baseline AD status and subsequent ND.
Cuijpers et al.  utilized data from the Netherlands Mental Health Survey and
Incident Study (NEMESIS) to investigate the relationship between incident ADs
(expressed as incident rate ratios) and previous smoking status. The NEMESIS
study randomly recruited adults (18 years to 64 years) from 90 municipalities in The
Netherlands, undertaking baseline assessments and 2 follow-ups at 1 year and 3
years (n = 4,796). The CIDI  was used for DSM-III-R diagnoses, and smoking
was assessed by self-report, with participants placed into 4 categories (non-
smokers, 1 to 9 cigarettes daily, 10 to 19 cigarettes daily and 20+ cigarettes daily). In
a follow-up analysis, having 12-month (incidence rate ratio (IRR) 4.46 (P <0.05)) and
lifetime GAD (IRR 4.46 (P <0.05)) was associated with increased risk of smoking
onset at follow-up.
Johnson et al.  utilized the prospective follow-up of the full NESARC database (n
= 34,653) to assess the impact of AD on smoking onset and persistence. Grouped
ADs were associated with reduced daily smoking onset (OR 0.62 (95% CI 0.39 to
0.99)) when adjusting for demographics and socioeconomic status, but not with
smoking persistence. Interestingly, comorbid substance use was an effect modifier;
respondents with a comorbid substance use disorder (for example, alcohol,
marijuana, amphetamines, opioids, sedatives, tranquilizers, cocaine, inhalants,
hallucinogens, heroin, and other drugs) and AD demonstrated an increased risk of
daily smoking onset (OR 2.22 (1.01 to 4.91)), whereas those without comorbid
substance use disorder had a decreased risk of smoking onset (OR 0.43 (0.23 to
Most recently, Swendsen et al.  utilized a 10-year follow-up of 5,001 participants
drawn from the National Co-morbidity Survey (NCS) to investigate mental disorders
as a risk factor for onset of daily smoking or ND. The NCS, conducted in the US
between 1990 and 1992, was a stratified multistage probability sample of 8,098 non-
institutionalized residents (age 15 years to 54 years), utilizing the CIDI (V1.1), that
assessed the interaction between smoking, ND and DSM-III-R mental disorders. The
NCS2, performed in 2001 to 2002, was a 10-year re-interview of 5,001 participants
from the NCS, but which utilized an updated version CIDI (V3.0) for DSM-IV criteria.
After adjusting for sociodemographic characteristics, the odds of commencing daily
smoking was increased for respondents with baseline PD, SP, GAD and specific
phobia, but not for those with baseline PTSD or agoraphobia. In contrast, in those
respondents with baseline daily smoking the odds of ND onset were raised in PTSD,
agoraphobia and specific phobia, but not PD, SP or GAD. When considering the
whole population odds of ND onset, having baseline PTSD, SP and specific phobia
conferred an increased risk (see Additional file 1, Table S1).
Smoking and nicotine dependence as risk factors for later anxiety disorders
(A summary of this section is as follows (see also Additional file 2, Table S2): the
available prospective evidence associating smoking and nicotine dependence as risk
factors for incident anxiety disorders is limited and heterogeneous. However,
smoking has been demonstrated as a risk factor for grouped anxiety disorders, panic
disorder and generalized anxiety disorder in a number of studies, although these
findings are not replicated in all studies.)
Data from the Oregon Adolescent Depression Project were utilized to assess the
relationship between baseline smoking status and incident ADs. Goodwin et al. 
demonstrated an association between increased odds of PD diagnosis at age 24 in
those with daily smoking at baseline versus those not smoking daily (OR 5.1 (2.4 to
10.5)), which remained significant after controlling for other ADs and parental risk
factors. No other associations were found.
Utilizing data from the Detroit Epidemiologic Study, Breslau et al.  found
increased risk of subsequent PD onset in individuals with prior daily smoking even
when controlling for gender and MDD (HR 13.13 (4.41 to 39.10)). In addition, prior
daily smokers who continued to smoke were more likely to experience incident PD
(HR 14.46 (4.81 to 43.5)) when controlled for gender and MDD.
In the New York Adolescent Cohort, relationships were discovered between odds of
adult ADs when grouped (OR 10.78 (1.48 to 78.55)), GAD (OR 5.53 (1.84 to 16.66)
and PD (OR 15.58 (2.31 to 105.14) when comparing baseline >1 pack per day
smokers versus <1 pack per day smokers . Data from the EDSP studies 
demonstrated relationships between increased incident PD, agoraphobia, SP and
PTSD when comparing baseline ND smokers versus non-users, however all
associations became non-significant when controlled for comorbid conditions at
baseline (depressive disorders, panic attacks, other ADs, alcohol and drug disorders,
and eating disorders). In the NESARC study, Chou et al.  assessed the
relationship between ND at baseline and subsequent ADs, finding no associations.
Cuijpers et al.  utilized data from the NEMESIS to investigate the relationship
between incident ADs (expressed as incident rate ratios) and past smoking status.
Smoking at 1-year follow-up was associated with increased incidence of grouped
ADs (IRR 1.77 (1.10 to 2.86)) and GAD (IRR 3.80 (1.09 to 13.21)) after controlling
for demographics and other risk factors. No other relationships were found (see
Additional file 2, Table S2).
(A summary of this section is as follows: a small number of studies have utilized a
single time point analysis and retrospective self-report patient data to draw
quasiprospective associations between smoking, ND and ADs. These studies
generally indicate increased smoking behaviors or nicotine dependence in
individuals with pre-existing anxiety disorders, and vice versa, although studies are
limited by the retrospective nature of data.)
Baseline anxiety disorders and risk of smoking or nicotine dependence
See also Additional file 3, Table S3. Breslau et al.  examined the 4,411
participants who completed the tobacco supplement of the NCS to assess the
interaction between smoking, ND and DSM-III-R ADs, utilizing discrete time survival
models with ADs as time dependent variables and controlling for race, gender,
education and age. The onset of daily smoking was the age at which respondents
first smoked daily for ≥1 month. Increased odds for daily smoking were found in
patients with pre-existing (OR 1.9 (1.05 to 3.7)) or currently active GAD (OR 2.1 (1.1
to 3.9)), pre-existing (OR 1.6 (1.3 to 1.8)) or currently active specific phobia (OR 1.5
(1.3 to 1.8)), pre-existing (OR 1.5 (1.2 to 1.7)) or currently active SP (OR 1.3 (1.1 to
1.6)), and pre-existing (OR 2.1 (1.6 to 2.9)) or currently active PTSD (OR 2.0 (1.4 to
Breslau et al.  further investigated the odds of smoking persistence and the
transitioning from daily smoking to ND based upon pre-existing and currently active
ADs. Increased odds of transitioning from daily smoking to ND were found in
individuals with pre-existing and currently active agoraphobia, specific phobia, SP
and PTSD. Interestingly, having pre-existing, but not currently active, PD was also
strongly associated with increased odds of daily smoking to ND transition (OR 5.8
(3.0 to 11.6)). No associations existed between odds of smoking persistence and
any pre-existing AD.
Koenen et al.  utilized data from the national Vietnam Era Twin (VET) registry
and retrospective self-report of age of onset to test prospective onset associations
between DSM-III-R ADs and ND. Associations were controlled for various
demographic and other risk factors and time-dependent covariates (conduct
disorder, MDD, alcohol and drug abuse or dependence) were entered into models.
The results demonstrated that pre-existing PTSD was associated with increased
odds of subsequent ND (OR 1.73 (1.38 to 2.17)). Utilizing the Greater Smoky
Mountain Study (GSMS), a longitudinal representative study of 4,500 children (aged
9 years, 11 years and 13 years) from western North Carolina, USA, Costello et al.
 found children, both boys and girls, with any AD were more likely to commence
smoking than those without an AD (see Additional file 3, Table S3).
Smoking and nicotine dependence and risk of incident anxiety disorders
See also Additional file 4, Table S4. Breslau et al.  utilized the NCS, including
respondent recall about their age of smoking and ND onset, to assess the effect of
these parameters on developing ADs. Adjusting for demographic characteristics,
pre-existing daily smoking (defined as onset >1 year prior to disorder onset) was
associated with increased odds of PD (OR 2.6 (1.2 to 5.4)) and agoraphobia (OR 4.4
(2.3 to 8.2)). The role of ND was assessed across all ADs. In this analysis, ND
smokers and non-ND smokers maintained increased odds of PD and agoraphobia,
but no other ADs. The only other associations were found in relation to past smokers
(without ND) who exhibited decreased odds of PTSD (OR 0.2 (0.1 to 0.5)) when
controlled for demographics and other pre-existing psychiatric disorders. Breslau et
al.  extended their study by comparing the age of smoking onset (early vs not
early; see Additional file 4, Table S4 for definitions), standardized pack years of
smoking and time since quitting against odds of AD diagnosis. No association was
found between early onset smoking and ADs, but increased years since quitting was
associated with decreased odds of subsequent PD (OR 0.5 (0.4 to 0.7)),
agoraphobia (OR 0.5 (0.5 to 0.8)) and SP (OR 0.6 (0.4 to 0.8)). The associations
between standardized pack years of smoking were not significant in all ADs except
PD, where increased pack years of smoking appeared protective in current smokers
but a risk factor in past smokers, and GAD where increased pack years was
associated with increased odds of GAD in both current and past smokers.
In a separate analysis utilizing a subsample of NCS data, Breslau et al. 
investigated the interaction between smoking characteristics and subsequent onset
of PD. Significant relationships were discovered between prior daily smoking (HR
2.93 (1.84 to 4.66)) and smoking persistence in prior daily smokers (HR 3.18 (1.99 to
5.10)) and subsequent onset of PD. In addition, pre-existing ND was associated with
increased odds of subsequent PTSD onset (OR 2.24 (1.78 to 2.83)) in the
aforementioned study drawn from the VET registry .
(A summary of this section is as follows (see also Additional file 5, Table S5): a large
number of studies have reported cross-sectional relationships between cigarette
smoking, nicotine dependence and anxiety disorders. Many demonstrate higher
rates of smoking and nicotine dependence in those with anxiety disorders, and vice
versa. However, their utility is limited due to their inherent inability to provide insight
into direction of causality.)
Almost all studies included in this review reported cross-sectional associations
between smoking and/or ND and ADs. Studies providing cross-sectional information
[6,7,17,19,23,27,28,32,39-67] are listed in Additional file 5, Table S5. Descriptions of
some selected larger studies utilizing population-based data are detailed below.
Smoking or nicotine dependence by anxiety disorder status
Lasser et al.  utilized the NCS to demonstrate increased rates of current and
lifetime smoking in respondents with current and lifetime SP (39.5% and 54%),
agoraphobia (38.4% and 58.9%), PD (35.9% and 61.3%), specific phobia (40.3%
and 57.8%), PTSD (45.3% and 63.3%) and GAD (46% and 68.4%) when controlling
for gender, age and geographical region. Utilizing the NCS-R data, Cougle et al. 
explored the role of comorbidity in the association between ADs and smoking
behavior. After controlling for demographics, depression and drug
abuse/dependence, associations between increased odds of lifetime and 12-month
daily smoking were observed with PTSD (Lifetime: OR 1.58 (1.21 to 2.06); 12-month:
OR 1.46 (1.08 to 1.97)), 12-month daily smoking with PD (OR 1.42 (1.04 to 1.94)),
and Lifetime daily smoking with GAD (OR 1.23 (1.05 to 1.61)).
In a nationally representative sample of the New Zealand population, individuals with
ADs (grouped) had a smoking prevalence of 30.4% (27.7 to 33.0), and consumed
approximately 16% of all cigarettes in New Zealand . In Australia, data from the
nationally representative National Survey of Mental Health and Wellbeing 2007
reported rates of current and daily smoking in those with individual ADs (range for
current smoker: 33% to 45%; range for daily smoker: 27% to 42%) well above the
rates in respondents not reporting a mental disorder (current: 13.6%; daily: 10.8%)
Cougle et al.  demonstrated increased odds of ND in patients with SP (OR 1.31
(1.01 to 1.71)), GAD (OR 1.59 (1.21 to 1.98)) and PTSD (OR 1.47 (1.01 to 2.16))
when adjusting for demographics, depression and drug abuse/dependence. Utilizing
the NESARC for adults aged 18 to 25 years , the odds of 12-month ND were
significantly increased for respondents with lifetime specific phobia (OR 1.8 (1.16 to
2.88)) after controlling for other psychiatric disorders, smoking and demographic
Anxiety disorder by smoking or nicotine dependence status
Utilizing the German Transitions in Alcohol Consumption and Smoking study,
Schumann et al.  calculated unadjusted odds ratios for individual ADs based on
smoking and ND status. When comparing ND ever smokers (respondents with ND
who had smoked at least one cigarette daily for ≥4 weeks at some point in their life)
to non-ND ever smokers, increased odds were found for PD (OR 2.92 (1.78 to
2.73)), SP (OR 3.07 (1.70 to 5.57)), specific phobia (OR 2.09 (1.63 to 2.68)), GAD
(OR 4.26 (1.85 to 9.84)) and PTSD (OR 2.08 (1.13 to 3.83)). Grant et al.  used
data from NESARC to compare the odds of ADs on ND status. Unadjusted odds
ratios with individual ADs as dependent variables were greater across all assessed
ADs. Point estimates for odds ratios ranged from 2.6 for SP to 4.6 for PD with
agoraphobia for respondents with versus without ND. Data from the UK National
Households Survey  demonstrated increased rates of GAD (4.1% vs 2.4%),
specific phobia (1.5% vs 0.8%) and PD (1.5% vs 0.5%) in respondents with ND
versus those without ND. Degenhardt et al.  utilized the 1997 National Survey of
Mental Health and Wellbeing in Australia to demonstrate increased odds of ADs
(grouped) in current smokers versus never smokers (OR 1.50 (1.21 to 1.87)) when
adjusted for demographic status, other drug use and neuroticism.
Our systematic review of the literature revealed a total of 17 studies that provided
prospective or quasiprospective information regarding the relationship between ADs,
ND and cigarette smoking. Of these studies 14 provided prospective or
quasiprospective information on the role of ADs on the risk of smoking or ND, and 7
studies provided the role of daily smoking or ND on onset of ADs. A further 31
studies reported only cross-sectional relationships between smoking, ND and ADs.
The association between smoking, ND and ADs could be explained by three non-
mutually exclusive relationships; smoking and ND leads to increased ADs, the
reverse association, or a shared vulnerability model where a factor or group of
factors increase smoking, ND and AD expression.
Are anxiety disorders a risk factor for smoking onset?
A relatively common hypothesis links increased anxiety with smoking onset and
increased smoking behaviors. Multiple studies conducted in both general and clinical
populations have demonstrated increased rates of smoking amongst individuals with
all AD subtypes [68-70], although exceptions exist . The results of these
prospective, quasiprospective and cross-sectional studies are inconsistent, and
importantly, many of these studies have failed to take into account the important role
of comorbid substance use disorders. In a study of patients with ADs where those
with alcohol and substance use disorders were excluded, rates of smoking were
lower than the control population , indicating comorbid illness is important in
understanding this association.
This review found a limited and heterogeneous literature evaluating the prospective
effect of ADs on smoking onset in random population samples. The available data
varied significantly on population characteristics (whole population vs specific age
range), length of prospective follow-up (1 year to 10 years), diagnostic tool utilized
and smoking definition. On balance, the 10-year follow-up of the National
Comorbidity Survey  represents the likely best evidence available to date. From
this analysis, baseline PD, SP, GAD and specific phobia, but not PTSD or
agoraphobia, were associated with increased odds of commencing daily smoking.
There are however important considerations in interpreting this study. First, the
diagnostic classification system utilized in the first NCS (DSM-III-R) was updated in
the NCS2 (DSM-IV). Although there is a large concordance between these
diagnostic classifications across most ADs, some significant differences exist,
particularly in the criteria of PTSD, which may have altered relative prevalence rates
. Second, and most importantly, the presented analyses did not control for the
presence of other psychiatric disorders or for alcohol or drug abuse/dependence. As
noted by Cougle et al. , ADs are often comorbid disorders, particularly with MDD
and substance abuse disorders. In other presented prospective studies, univariate
relationships between PD and smoking onset failed to sustain significance when
comorbid MDD was included in the analytic models , and the presence of a
comorbid substance use disorder reversed the direction of effect of baseline AD from
protective to causative in the NESARC cohort . The NCS follow-up revealed
larger increased odds of daily smoking onset in respondents with alcohol or other
substance abuse/dependence (OR point estimates between 2.6 and 4.2). As such, it
is probable that some of the association between ADs and smoking is due to effects
of comorbid substance abuse disorders.
Considering that most of the other available prospective studies failed to find
significant associations between ADs and subsequent onset of smoking, it is
currently difficult to draw definitive conclusions regarding AD as a risk factor for
smoking. One potential factor that should be taken into account is the populations
considered in the available literature. Population-based studies suggest that the
average age individuals first use cigarettes has been declining, and now ranges
between 12 years and 16 years . In addition, smokers who commence earlier are
more likely to persist than those that commence at a later age . Given that most
of the included studies assessed adult populations, it is possible many participants
with ADs were already smoking and hence new onset smoking was relatively rare in
assessed populations. In contrast to cross-sectional analyses, very limited
prospective information is available on varying characteristics of smoking behavior
(for example, persistence) and ADs in the available prospective studies.
Some studies have used a quasiprospective design, pairing cross-sectional data with
retrospective self-report data, to assess the impact of ADs on smoking status. Such
strategies are limited by recall bias, and any conclusions drawn must consider this.
Analysis of the NCS by Breslau et al.  found increased odds of daily smoking in
those with a variety of pre-existing or current ADs. However, these analyses did not
control for the effects of comorbid substance use disorders or other psychiatric
disorders and, additionally, were limited to onset of daily smoking as opposed to
smoking more generally. When considering the effects of pre-existing ADs on
smoking persistence, no significant associations were found.
A number of theories are proposed to explain why ADs may lead to increased rates
of smoking. Theoretical explanations are informed by both psychological (for
example, conditioning theory, cognitive theory, anxiety sensitivity ) and biological
(for example, nicotine effects and withdrawal) factors. One explanatory model relates
to the use of cigarettes as an anxiolytic agent (that is, self-treatment). Evidence
supports that nicotine exposure does produce a subjective calming effect, although
this is coupled with an increase in objective measures of physiological arousal .
Tachyphylaxis and homeostatic adjustment however implies that acute and chronic
effects of cigarettes, as with any agents that induce tolerance and dependence, may
differ substantially. Treatment of this extensive literature is beyond this review,
although we refer readers to a number of excellent comprehensive reviews on this
subject [78-81], which include identification of the methodological challenges in
exploring the effect of anxiety traits and states on smoking behaviors.
Are anxiety disorders a risk factor for later nicotine dependence?
Inconsistent although clearer associations between baseline ADs and subsequent
ND were found in the literature. In the 10-year follow-up of the NCS , having
baseline PTSD, agoraphobia and specific phobia were associated with increased
odds of onset of ND amongst already smokers, and PTSD, SP and specific phobia
were associated with increased odds for ND amongst the whole population. The
clear association between baseline PTSD and ND was replicated by Breslau et al.
 in the Detroit Epidemiologic Study, while Isensee et al.  found baseline PD to
be associated with increased risk for subsequent ND. Given anxiety disorders are
associated with negative affect , and negative affect is linked to increased
smoking motivation , it is possible that negative affect may underpin an increased
likelihood to developing ND in those with ADs. Further evidence demonstrating an
effect of duration of anxiety disorder diagnosis and later ND severity would be useful.
Is smoking or nicotine dependence a risk factor for onset of anxiety
A limited number of prospective studies are available assessing smoking or ND as
risk factors for incident ADs in population-based epidemiological studies. The
available literature supports ND as increasing the odds of later PTSD, and smoking
as increasing the odds for some (PD and GAD), but not all, ADs and interpretation of
some analyses are complicated by non-inclusion of potential confounders. For
example, the prospective odds of PD onset were increased in the Oregon
Adolescent Depression Project, the New York Adolescent Cohort and the EDSP in
individuals with a history of prior smoking versus non-smokers. This result remained
significant when controlling for other ADs in the Oregon Adolescent Depression
Study, but failed to maintain significance when comorbid psychiatric disorders were
controlled for in the EDSP study. However, smoking as a risk factor for PD is
supported by the Detroit Epidemiologic Study, which found increased risk of PD
onset in prior daily smokers, with a stronger association in prior daily smokers who
continued to smoke. These analyses controlled for MDD, but not other psychiatric or
substance use disorders. The use of quasiprospective methodology on data from the
NCS allowed further exploration of this relationship. These data suggested that daily
smoking was a risk factor for increased odds of PD and agoraphobia, with analyses
controlling for other psychiatric disorders including substance use disorders . A
demonstrated dose-dependent relationship would support a causal association
between cigarette smoking and subsequent onset of ADs. Breslau demonstrated that
increased standardized pack years of smoking were associated with increased odds
of GAD, but decreased odds of PD  in dose dependent fashion.
The interaction between panic, PD and cigarette smoking has received more
investigation in epidemiological and laboratory-based studies than other ADs, and
the evidence was recently reviewed . The literature has demonstrated that earlier
age of smoking initiation is associated with increased risk of PD , and smokers
demonstrated earlier PD onset in comparison to non-smokers . Given the
somatic nature of panic attack symptomatology, it is possible that smoking may be
more likely to produce panic-type AD symptoms secondary to the physical effects of
smoking (for example, respiratory and autonomic disturbance). Panic is influenced
by respiratory sensitivity, and nicotine alters the sensitivity set point of cholinergic
respiratory neurons . From their review of the literature, Cosci et al. 
nominated three potential hypotheses underpinning the association between
cigarette smoking and panic. The first is a ‘moderational model’, whereby
neuroticism moderates the panic/smoking association. The second is a ‘pathoplastic
model’, where smoking influences PD expression by ‘exacerbating affective
disturbances and negative health process’ , including a combination of direct
negative health effects (for example, induction of chronic obstructive pulmonary
disease (COPD)), acute physiological effects (for example, increased noradrenaline
and autonomic sensations) and negative self-perception of health status . The
third is the ‘false suffocation alarm’ theory, proposed by Klein , who suggested
that smoking may induce hypersensitivity to suffocation signals and increase the risk
of experiencing panic. The suffocation false alarm may potentially be mediated by
episodic dysfunction in regulation of endogenous opioid function .
A number of studies have assessed the interaction of smoking and PTSD. A
population-based follow-up investigation of individuals affected by a fireworks factory
explosion in The Netherlands found that those who were smokers at time of
traumatic incident had an increased chance of experiencing severe anxiety
symptoms (OR 2.32 (1.19 to 4.53)) and disaster related PTSD (OR 2.64 (1.05 to
6.62)) at 4-year follow-up, controlling for baseline symptoms, demographic
characteristics and life events . This supports the results of Koenen et al. ,
who demonstrated that the presence of ND increased the risk of developing PTSD in
trauma exposed men (HR 1.98 (1.61 to 2.42)) and that shared genetic effects
explained 63% of the ND-PTSD association. A number of neurobiological (for
example, alterations to the hypothalamic-pituitary-adrenal axis, sympathetic nervous
system hyperactivity alteration to neurotransmitter system functioning) and
psychological factors may contribute to a PTSD, ND and cigarette smoking
association (see Fu et al.  for review). ND may increase ADs by exacerbating
anxiety responses , or by facilitating other psychiatric states (for example,
depression) that may predispose individuals to develop anxiety. In addition, the
number of ND symptoms and nicotine withdrawal symptoms has been robustly
correlated in a dose-dependent fashion with increasing anxiety disorder diagnosis
. In reference to other ADs, supportive evidence was found for smoking
increasing the odds of developing GAD, while no evidence was found to support
smoking as a risk factor for onset of SP, although some evidence supports the
reverse association in female ND smokers .
In assessing smoking or ND as a risk factor for ADs, one factor that must be
considered is that ADs have been estimated to exhibit a median age of onset of only
6 years . Given the early age of AD development, from early childhood through
adolescence, exposure to environmental cigarette smoke may influence AD
development. Exposure to second-hand smoke has been demonstrated to be
positively associated with symptoms of GAD, but not PD in children and adolescents
age 8 years to 15 years . Additionally, early onset smoking (10 to 15 years) has
been associated with an earlier onset of ADs when compared to late onset smoking
(>15 years) . It is possible that exposure to cigarette smoke in critical periods of
brain development may be one factor that predisposes individuals to subsequent
develop ADs. A number of biological pathways may underpin this effect, including
alteration in neurotransmitter function, and induction of oxidative and nitrosative
stress that may overwhelm intrinsic defenses inhibiting normal neuronal cell
functions, including neuroplasticity and neurogenesis.
Shared vulnerability between smoking, ND and ADs
A number of shared vulnerability factors contribute to cigarette smoking behavior and
ADs, including early childhood experiences and environment [83,98,99], problems
with impulsivity  and distress tolerance and neurotic personality traits [101,102].
Indeed, it is possible that these shared vulnerability factors are further underpinned
by other factors (for example, genetics, fetal insults), and ADs and cigarette smoke
could alter their expression (for example, cigarette smoking may reinforce poor
distress tolerance). For a more detailed discussion of the role and interaction of
shared vulnerability factors see the review by Morissette et al. .
Limitations and directions for future research
It is important to consider the limitations of this study design in interpreting the
results. This review was designed deliberately to only consider random, large
general population samples where validated structured diagnostic tools were utilized
to make diagnoses. Effort was made to identify all studies meeting inclusion criteria,
although it is possible some important sources of information were not identified,
particularly from non-English language journals. The inclusion criteria were designed
to allow for selection of only the best quality evidence not restricted by certain biases
(for example, selection bias, recall bias) although as consequence of this a number
of identified studies involving samples drawn from clinic populations [72,103-105]
and studies which utilized anxiety symptom scores  or non-validated diagnostic
tools (for example, self-report) as end points were excluded from final analysis. The
heterogeneous nature of included studies, particularly in regards to population
demographics; smoking definition; diagnostic criteria utilized; diagnostic group
included; and comorbid factors included in analysis also complicates interpretation. A
number of future studies would assist in clarifying issues from this review. First, the
continuation of current prospective cohorts over longer periods and the recruitment
of new cohorts, incorporating and measuring changes to smoking behavior over
time, would assist in clarifying the relationship between smoking and ADs. Similarly,
given the early onset nature of many ADs, maternal and birth cohorts assessing
these issues would assist greatly in deepening our understanding. Exploration of the
effects of quitting on anxiety and depression would also clarify associations. In
addition, further exploration of potential biological mechanisms underpinning
associated effects of smoking and ADs would help to elucidate shared vulnerabilities
underpinning both ADs and smoking.
A large literature has demonstrated that individuals with ADs have higher rates of
smoking and ND than those without ADs, although most extant information is drawn
from cross-sectional studies. In terms of prospective studies, there exists a limited
heterogeneous literature examining the relationship between cigarette smoking, ND
and ADs in population-based epidemiological studies utilizing structured diagnostic
tools linked to ICD or DSM criteria. The available prospective evidence provides
support for smoking and ND as being risk factors for the onset of PD and GAD,
although varied results are found across studies. In addition, some ADs have been
associated with subsequent onset of smoking and ND, although many studies failed
to include comorbid substance use disorders and other psychiatric disorders in
SM declares no conflicts of interest in relation to this article. FNJ has received
grant/research support from the Brain and Behaviour Research Institute, the National
Health and Medical Research Council, Australian Rotary Health, the Geelong
Medical Research Foundation, the Ian Potter Foundation, Eli Lilly and The University
of Melbourne and has been a paid speaker for Sanofi-Synthelabo, Janssen Cilag
and Eli Lilly. She is supported by an NHMRC Training Fellowship (#628912). JAP
has received speaker fees from Amgen, Eli Lilly and Sanofi-Aventis and funding from
the Geelong Region Medical Research Foundation, Barwon Health, Perpetual
Trustees, the Dairy Research and Development Corporation, The University of
Melbourne, the Ronald Geoffrey Arnott Foundation, ANZ Charitable Trust, the
American Society for Bone and Mineral Research, Amgen (Europe) GmBH and the
NHMRC. MB has received Grant/Research Support from the NIH, Cooperative
Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley
Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical
Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon,
Novartis, Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol
Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer,
Sanofi Synthelabo, Servier, Solvayand Wyeth, and served as a consultant to Astra
Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck
SM conceived of the study, developed the methods, conducted the literature search
and led the development of the final manuscript. FNJ, JAP and MB contributed to the
study design and data analysis, and provided intellectual content to the final
manuscript. All authors read and approved the final manuscript.
The authors wish to thank Professor Dan Stein and Professor Simon Øverland for
their insightful comments and suggestions, which greatly improved this manuscript.
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Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) search strategy flow diagram.
Figure 2. Included studies: prospective, quasiprospective and cross-sectional
association information obtained from each study.
Additional file 1
Title: Table S1.
Description: Prospective longitudinal studies investigating influence of anxiety
disorders on subsequent risk of smoking and nicotine dependence (ND).
Additional file 2
Title: Table S2.
Description: Prospective longitudinal studies investigating influence of smoking and
nicotine dependence (ND) on subsequent risk of anxiety disorders.
Additional file 3
Title: Table S3.
Description: Quasiprospective studies investigating influence of anxiety disorders on
subsequent risk of smoking and nicotine dependence (ND).
Additional file 4
Title: Table S4.
Description: Quasiprospective studies investigating influence of smoking and
nicotine dependence (ND) on subsequent risk of anxiety disorders.
Additional file 5
Title: Table S5.
Description: Cross-sectional studies investigating associations between anxiety
disorders, nicotine dependence (ND) and smoking.
Additional files provided with this submission: Download full-text
Additional file 1: Table 1.xlsx, 43K
Additional file 2: Table 2.xlsx, 40K
Additional file 3: Table 3.xlsx, 49K
Additional file 4: Table 4.xlsx, 26K
Additional file 5: Table 5.xlsx, 49K