Deleon 2005

Schizophrenia Research 76 (2005) 135 – 157
www.elsevier.com/locate/schres
A meta-analysis of worldwide studies demonstrates an association

between schizophrenia and tobacco smoking behaviors
Jose de Leona,T, Francisco J. Diazb
a
Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508, USA
b
Department of Statistics, Universidad Nacional, Medellin, Colombia
Received 11 April 2004; received in revised form 11 February 2005; accepted 16 February 2005
Available online 8 April 2005
Abstract
A meta-analysis of worldwide studies, found by a 10-year literature follow-up and/or by searching PubMed, was performed.
Forty-two studies across 20 nations consistently demonstrated an association between schizophrenia and current smoking
(weighted average odds ratio, OR = 5.9; 95% confidence interval, CI 4.9–5.7). In 32 male studies across 18 nations, the
weighted average OR was 7.2 (CI, 6.1–8.3). In 25 female studies across 15 nations, the weighted average OR was 3.3 (CI, 3.0–
3.6). The association between schizophrenia and current smoking remained after using severe mentally ill controls (18 studies
across 9 countries, weighted average OR was 1.9, CI 1.7–2.1) and controlling for other variables (3 studies, adjusted ORs
ranged 2–3).
Heavy smoking (6 studies across 4 countries, ORs ranged 1.9–6.4) and high nicotine dependence were more frequent in
smokers with schizophrenia versus the general population. There was no consistent evidence that heavy smoking or high
nicotine dependence was more frequent in smokers with schizophrenia versus severe mentally ill controls. Cessation rates were
lower in schizophrenia smokers versus the general population.
Schizophrenia patients had a higher prevalence of ever smoking than the general population (9 studies across 6 countries,
weighted average OR = 3.1, CI 2.4–3.8) and than severe mentally ill patients (5 studies across 5 countries, OR = 2.0, CI 1.6–2.4).
Moreover, in two studies adjusting for confounders schizophrenia patients had an increased risk of starting daily smoking than
controls. Thus, people who are going to develop schizophrenia have risk factors that make them more vulnerable to start
smoking.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia; Tobacco; Nicotine; Smoking; Logistic regression
1. Introduction
T Corresponding author. Tel.: +1 859 246 7487; fax: +1 859 246 Clinicians have observed for a long-time that
7019. schizophrenia patients are markedly prone to smoke
E-mail address: jdeleon@uky.edu (J. de Leon). tobacco (Lohr and Flynn, 1992). Although other
0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2005.02.010
136 J. de Leon, F.J. Diaz / Schizophrenia Research 76 (2005) 135–157
severe psychiatric illnesses such as mood disorders search. In 1995, the first author published his first
are associated with tobacco smoking, the association article on schizophrenia and smoking and started
between schizophrenia and tobacco smoking may be collecting articles providing representative prevalen-
stronger (Hughes et al., 1986; de Leon et al., 1995, ces of smoking in schizophrenia patients from any
2002a,b; Diwan et al., 1998; LLerena et al., 2003). It country. He read the references in any found article,
has been suggested that biological factors may searching for any missing article in his collection. The
underlie the association between schizophrenia and most updated PubMed search, limited to studies with
tobacco smoking (Dalack et al., 1998; Freedman et human subjects, was conducted on 12/9/04. The first
al., 1997). This article explores the hypothesis that the MeSH term search conducted, for bSchizophreniaQ
association between schizophrenia and tobacco smok- [MeSH] and (bSmokingQ[MeSH] or bNicotineQ
ing is relatively independent of sociocultural factors [MeSH]), provided 271 articles. A second search with
and can be demonstrated across countries and the same search words but not defining them as MeSH
cultures. headings, bSchizophrenia and (smoking or nicotine)Q,
provided 477 articles. The first author read all
available abstracts from 447 articles; most did not
2. Methodological issues report unbiased studies or prevalences of smoking. If
an article did not specifically provide prevalences for
A meta-analysis of studies conducted in different schizophrenia patients but provided unbiased preva-
countries was performed to examine the above lences for severe mentally ill patients, data specific to
hypothesis. The rationale behind this review is that schizophrenia patients were requested from article
if an association between schizophrenia and tobacco authors. An effort was made to include all possible
smoking is observed in a variety of different cultures, studies from all over the world; some of the articles
then it is likely that a biological factor may underlie obtained through personal collection were not pub-
such association. Comparisons of schizophrenia lished in English. Please note that PubMed is biased
patients with the general population and with other against articles in other languages. The title of one
severe mentally ill patients were carried out. Schizo- Japanese article found in the PubMed search suggested
affective patients were included in the group of a potentially interesting sample, but no abstract was
schizophrenia patients since the former appear to be provided. Its authors did not reply to e-mail requests
similar to the latter regarding tobacco smoking for information. Ultimately, the two methods yielded a
behaviors (de Leon et al., 2002b). total of 49 articles (31 found by both methods, 6 found
in PubMed search and 12 found by personal collec-
2.1. Article search tion) reporting unbiased prevalences of smoking
behaviors in schizophrenia patients. These prevalences
This meta-analysis included only schizophrenia are described in Tables 1–11.
studies reporting prevalences of smoking computed Some articles provided smoking data from
from samples of patients obtained through unbiased schizophrenia patients but did not provide compa-
recruitment. Thus, the analysis did not include rable data from the general population. In this case,
samples obtained from smoking treatment interven- comparable data was obtained from independent
tions, pharmacological trials, small biological studies, (usually government) surveys (Campo-Arias et al.,
or samples including only individuals with very 2004; Centers for Disease Control and Prevention,
specific characteristics such as twins, pregnant 1994a,b, 1998, 2001; Corrao et al., 2000; Giovino
women, substance abusers or conscripts. However, et al., 1994; Physicians for a Smoke-free Canada,
biased studies were described in the discussion if they 2002; Mackay and Eriksen, 2002; Ministerio de
provided additional meaningful points. Sanidad y Consumo de España, 1996, 1999, and
A deliberate attempt to include as many unbiased World Health Organization (WHO), 1997). General
schizophrenia studies as possible was made. The population data from these surveys were considered
articles were collected using two methods: personal comparable with data from a schizophrenia study
collection of the literature and a PubMed computer when the former were gathered in the same city,
J. de Leon, F.J. Diaz / Schizophrenia Research 76 (2005) 135–157 137
Table 1
Odds ratios (OR) comparing prevalences of current smoking in patients with schizophrenia versus people from the general population (males
and females combined)
Author Country Type Current smokers, % OR CI
Schizophrenia General population
Fowler et al., 1998 Australia Outpatients 74 (144 / 194) 29a 7.0 5.2–9.4b
El-Guebaly and Hodgins, 1992 Canada Outpatients 61 (65 / 106) 32 3.3 2.4–5.1b
Challis, 1999 Canada Inpatients 63 (32/51) 29a 4.2 2.4–8.0b
Gerber et al., 2003 Canada Outpatients 71 (73 / 103) 26 6.9 4.5–10.5b
Margolese et al., 2004 Canada Outpatients 66 (137 / 207) 22a 6.9 5.1–9.2b
Carvajal et al., 1989 Chile Inpatients 81 (78 / 96) 41 6.1 3.9–11.1b
Ghisays et al., 1996 Colombia Outpatients 26 (10 / 38) 18 1.6 0.69–3.0b
Suárez et al., 1996 Colombia Outpatients 14 (12 / 85) 18 0.74 0.35–1.3b
Campo et al., 2004 Colombia Outpatients 26 (19 / 74) 18a 1.6 0.83–2.5b
Brown et al., 1999 England Outpatients 62 (63 / 102) 27 4.4 3.0–6.8b
Taiminen et al., 1998 Finland Outpatients 56 (49 / 88) 23a 4.3 2.8–6.5b
Tanskanen et al., 1998 Finland In/outpatients 55 (223 / 403) 27 3.3 2.7–4.0b
Salokangas et al., 2000 Finland Outpatients 61 (460 / 760) 25 4.7 4.0–5.5b
Poirier et al., 2002 France In/outpatients 66 (136 / 207) 34 3.8 2.8–5.1b
Steinert et al., 1996 Germany Inpatients 47 (42 / 90) 31 2.0 1.3–2.9b
Beratis et al., 2001 Greece In/outpatients 58 (237 / 406) 42c 1.9 1.6–2.3b
Masterson and O’Shea, 1984 Ireland Inpatients 87 (87 / 100) 58a 4.8 2.9–9.6b
Itkin et al., 2001 Israel Outpatients 45 (29 / 64) 28 2.1 1.3–3.5b
Mori et al., 2003 Japan Outpatients 34 (47 / 137) 37 0.88 0.58–1.3b
McCreadie, 2002 Scotland In/outpatients 65 (162 / 250) 40d 2.8 2.2–3.6b
Chong and Choo, 1996 Singapore Outpatients 32 (62 / 195) 16 2.5 1.8–3.2b
Arias-Horcajadas et al., 1997 Spain Outpatients 67 (37 / 55) 37a 3.5 2.0–6.1b
Herrán et al., 2000 Spain Outpatients 64 (41 / 64) 51 1.7 1.0–2.9b
LLerena et al., 2003 Spain Inpatients 70 (70 / 100) 37a 4.0 2.7–6.0b
Gurpegui et al., 2005 Spain Outpatients 69 (173 / 250) 35 4.1 3.2–5.6b
Bejerot and Nylander, 2003 Sweden Outpatients 49 (79 / 161) 19 4.1 3.0–5.5b
Etter et al., 2004 Switzerland Outpatients 70 (106 / 151) 28 6.0 4.4–8.8b
Liao et al., 2002 Taiwan Inpatients 41 (105 / 257) 34a 1.3 1.05–1.7b
Uzun et al., 2003 Turkey Outpatients 50 (58 / 116) 43 1.3 0.94–1.9b
Hughes et al., 1986 USA Outpatients 88 (21 / 24) 30 17.1 7–53.7b
Sandyk and Kay, 1991 USA Inpatients 51 (73 / 142) 23a 3.5 2.5–4.8b
Goff et al., 1992 USA Outpatients 74 (58 / 78) 24a 9.0 5.7–15.8b
Chiles et al., 1993 USA Outpatients 88 (70 / 80) 22a 26.0 14.2–67.4b
Ziedonis et al., 1994 USA Outpatients 68 (180 / 265) 22a 7.5 5.9–9.9b
de Leon et al., 1995 USA Inpatients 85 (201 / 237) 24a 17.9 13.0–27.5b
Combs and Advokat, 2000 USA Inpatients 69 (27 / 39) 26a 6.3 3.3–13.0b
Patkar et al., 2002 USA Inpatients 76 (66 / 87) 24a 10.0 6.3–18.0b
de Leon et al., 2002a USA Inpatients 75 (335 / 449) 24a 9.5 7.7–12.0b
de Leon et al., 2002b USA Inpatients 83 (55 / 66) 26 13.9 7.6–28.5b
Vanable et al., 2003 USA Outpatients 64 (591 / 919) 24 5.6 4.9–6.5b
Himelhoch et al., 2004 USA Outpatients 61 (121 / 199) 27 4.2 3.2–5.7b
Adding 42 samples 20 nationse In/outpatients 62 (4686 / 7593) 5.3f 4.9–5.7g
a
A comparable percentage was not reported by author(s) and was obtained from an independent source (see Section 2.1 for a list of references).
b
CIs, 95% bootstrap confidence intervals (Simon, 1999).
c
Samples were matched for gender, age, area of residence (rural or urban), occupation and educational level.
d
Samples were matched for gender, age and postcode area of residence.
e
In some other tables the word used is contries. In Tables 1–3 the word nations is used instead of contries. Two nations, Scotland and England
are included in Tables 1–3 and they are part of same country, United Kingdom.
f
Weighted average of all ORs, using schizophrenia sample sizes as weights.
g
CI, 95% confidence interval, computed by using the delta method (Casella and Berger, 2002).
Table 2
Odds ratios (OR) comparing prevalences of current smoking in male patients with schizophrenia versus males from the general population
Author Country Type Current smokers in males, % OR CI
El-Guebaly and Hodgins, 1992 Canada Outpatients 69 (39 / 57) 33a 4.5 2.8–8.5b
Beratis et al., 2001 Greece In/outpatients 70 (171 / 245) 50 2.3 1.8–3.2b
Srinivasan and Thara, 2002 India Outpatients 38 (109 / 286) 43 0.81 0.64–1.0b
Masterson and O’Shea, 1984 Ireland Inpatients 92 (46 / 50) 51 11.0 5.0–47.1b
Itkin et al., 2001 Israel Outpatients 71 (22 / 31) 33a 5.0 2.5–10.6b
Calabresi et al., 1991 Italy Outpatients 80 (57 / 71) 46 4.7 2.8–9.2b
Calabresi et al., 1991 Italy Inpatients 88 (57 / 65) 46 8.6 4.7–24.3b
Al-Habeeb and Qureshi, 2000 Saudi Arabia Outpatients 56 (61 / 108) 22a 4.5 3.2–6.8b
Kelly and McCreadie, 1999 Scotland In/outpatients 71 (52 / 73) 28 6.3 3.9–10.8b
Chong and Choo, 1996 Singapore Outpatients 54 (52 / 96) 32a 2.5 1.7–3.7b
Herrán et al., 2000 Spain Outpatients 79 (26 / 33) 45a 4.6 2.1–12.2b
Liao et al., 2002 Taiwan Inpatients 71 (90 / 127) 62 1.5 1.009–2.3b
O’Farrell et al., 1983 USA Inpatients 88 (180 / 204)c 37 12.5 8.5–20.0b
Glynn and Sussman, 1990 USA In/outpatients 78 (46 / 59)d 31a 7.9 4.7–16.5b
Diwan et al., 1998 USA Outpatients 86 (54 / 63) 28 15.8 8.2–37.9b
Adding 32 samples 18 nations In/outpatients 71 (2576 / 3634) – 7.2e 6.1–8.3f
a
A comparable percentage was not reported by author(s) and was obtained from an independent source (see Section 2.1 for a list of
references).
b
c
Included a small number of females.
d
Includes 4 females.
e
f
state, or country, and at a date that was not earlier frequent way of consuming tobacco over the world
or later than 3 years from the schizophrenia study’s and schizophrenia patients rarely use other forms of
year of publication. tobacco. Therefore, for this review, tobacco smoking
refers to cigarette smoking.
2.2. Definitions of tobacco smoking behaviors
2.2.1. Current smoking
In most countries, cigarettes are easier to obtain The simplest way of describing cigarette smoking
and cheaper than other tobacco products (pipes, cigars behaviors is by computing the proportion of people
or snuff). Thus, smoking cigarettes is the most who currently smoke. Current smoking is usually
Table 3
Odds ratios (OR) comparing prevalences of current smoking in female patients with schizophrenia versus females from the general population
Author Country Type Current smokers in females, % OR CI
El-Guebaly and Hodgins, 1992 Canada Outpatients 52 (25 / 49) 31a 2.4 1.4–4.6b
Beratis et al., 2001 Greece In/outpatients 41 (66 / 161) 32 1.5 1.07–2.1b
Masterson and O’Shea, 1984 Ireland Inpatients 82 (41 / 50) 64 2.6 1.4–6.5b
Itkin et al., 2001 Israel Outpatients 21 (7 / 33) 25a 0.80 0.30–1.7b
Kelly and McCreadie, 1999 Scotland In/outpatients 42 (26 / 62) 26 2.1 1.3–3.5b
Chong and Choo, 1996 Singapore Outpatients 10 (10 / 99) 3a 3.6 1.4–6.7b
Herrán et al., 2000 Spain Outpatients 48 (15 / 31) 27a 2.5 1.3–5.3b
Liao et al., 2002 Taiwan Inpatients 12 (15 / 130) 5 2.6 1.3–4.1b
Adding 25 samples 15 nations In/outpatients 44 (933 / 2106) – 3.3c 3.0–3.6d
a
A comparable percentage was not reported by author(s) and was obtained from an independent source (see Section 2.1 for a list of
references).
b
c
d
assessed from personal reports, which are relatively severity of smoking in a population. Such smokers
reliable unless people are in situations where smoking are called heavy smokers. Most (but not all)
is not well considered, e.g. smoking cessation epidemiological surveys and schizophrenia studies
programs (SNRT Subcommittee on Biochemical define heavy smoking as smoking z 30 cigarettes
Verification, 2002). In psychiatric epidemiological (or 1.5 packs) per day according to self-report.
surveys, current smoking is usually defined as current Patients who smoke large quantities of cigarettes
daily smoking. Non-daily smokers are very rare exhibit certain signs of tobacco addiction such as
among schizophrenia patients and almost none of tainted or burned fingers. In long-term facilities,
the reviewed articles report them. In general popula- heavy smoking can be assessed by hospital staff and
tion surveys, current smokers usually include both defined as a score of 5 or 6 in the Elgin Repetitive
current daily smokers and non-daily smokers but the Behavior Scale (buses tobacco products constantly,
latter usually comprise less than 5% of the population. burns fingers on stubs, requires supervision or
restriction to avoid overuseQ; Luchins et al., 1992;
2.2.2. Heavy smoking Tracy et al., 1996). In this review, this definition
A high value for the percentage of smokers who will be called heavy smoking according to hospital
smoke a large number of cigarettes indicates a high staff.
Table 4
Odds ratios (ORs) comparing frequencies of current smoking in patients with schizophrenia versus patients with other mental illnesses
Author Country Type Current smokers in samples with both genders, % OR CIa
Schizophrenia No schizophrenia
Gerber et al., 2003 Canada Outpatients 71 (73 / 103) 48 (20 / 42)b 2.7 1.3–5.6
Carvajal et al., 1989 Chile Inpatients 81 (78 / 96) 66 (217 / 331) 2.3 1.3–4.0
Ghisays et al., 1996 Colombia Outpatients 26 (10 / 38) 11 (20 / 181)c 2.9 1.2–6.8
Suárez et al., 1996 Colombia Outpatients 14 (12 / 85) 14 (22 / 158)c 1.0 0.48–2.2
Campo et al., 2004 Colombia Outpatients 26 (19 / 74) 7 (8 / 111) 4.4 1.8–10.8
Tanskanen et al., 1998 Finland In/outpatients 55 (223 / 403) 46 (284 / 617) 1.5 1.1–1.9
Poirier et al., 2002 France In/outpatients 66 (136 / 207) 52 (221 / 422)d 1.7 1.2–2.5
Steinert et al., 1996 Germany Inpatients 47 (42 / 90) 19 (17 / 90)e 3.8 1.9–7.3
Itkin et al., 2001 Israel Outpatients 45 (29 / 64)f 43 (30 / 70) 1.1f 0.54–2.1
Arias-Horcajadas et al., 1997 Spain Outpatients 67 (37 / 55) 55 (31 / 56) 1.7 0.8–3.6
Herrán et al., 2000 Spain Outpatients 64 (41 / 64) 39 (45 / 115) 2.8 1.5–5.2
LLerena et al., 2003 Spain Inpatients 70 (70 / 100)g 53 (53 / 100)g 2.1 1.2–3.7
LLerena et al., 2003 Spain Inpatients 53 (52 / 98)g 36 (72 / 202)g 2.0 1.3–3.3
Hughes et al., 1986 USA Outpatients 88 (21 / 24) 48 (92 / 193) 7.7 2.2–26.6
de Leon et al., 1995 USA Inpatients 85 (201 / 237) 67 (83 / 123) 2.7 1.6–4.5
de Leon et al., 2002a USA Inpatients 75 (335 / 449) 55 (70 / 127) 2.4 1.6–3.6
de Leon et al., 2002b USA Inpatients 83 (55 / 66) 65 (33 / 51) 2.7 1.1–6.5
Vanable et al., 2003 USA Outpatients 64 (591 / 919) 61 (641 / 1048)b 1.1 0.95–1.4
Adding 18 samples 9 countries In/outpatients 64 (2025 / 3172) 49 (1959 / 4037) 1.9 1.7–2.1
a
CIs, 95% confidence intervals, were computed from two-way cross-tabulations (SPSS Inc., 1999).
b
Subjects with diagnoses other than depression or bipolar disorder were excluded from this computation.
c
Only mood and anxiety disorders were used in this computation.
d
Subjects with primary diagnosis of substance abuse were excluded.
e
Only patients with depression were used in this computation.
f
The sample included a small subsample of female schizophrenic patients with an unusual ethnic background and who smoked less than the
Israeli female general population.
g
Second sample of LLerena et al. had subjects of older age than first sample.
Cigarettes are very sophisticated tools for deliver- al., 1997; Caraballo et al., 1998). This probably
ing nicotine to the brain and smokers tend to keep the reflects that a subgroup of African–Americans do
number of cigarettes smoked daily relatively constant not eliminate nicotine efficiently. It is believed that
(Benowitz, 1988). Thus, the number of cigarettes some African–Americans cannot perform the glucur-
smoked per day is considered a gross, relatively stable onidation of some nicotine metabolites (Benowitz et
measure of nicotine addiction severity. Heavy smok- al., 1999; de Leon et al., 2003b). These poor-
ing, defined as smoking a high daily number of metabolizers of nicotine could deliver high nicotine
cigarettes, is a gross indicator of nicotine dependence levels to the brain without being heavy smokers.
but its correct interpretation must take pharmacoki- Thus, non-heavy smoking does not always indicate
netic factors into account. In particular, individual non-high nicotine dependence.
differences in nicotine metabolic rates may affect
heavy smoking. Although heavy smoking may 2.2.3. Nicotine dependence
indicate a large nicotine intake, it does not necessarily Recently the nicotine researchers’ focus has shifted
indicate an elevated delivery of nicotine to the brain. from tobacco smoking to nicotine dependence (Bre-
As a matter of fact, some non-heavy smokers may slau et al., 2001; Hughes, 2001). Nicotine is a very
have a large nicotine delivery to the brain. As an addictive substance, as addictive as cocaine (Hen-
example of the influence of pharmacokinetic factors ningfeld et al., 1991). In most cases, daily smoking is
on the daily number of cigarettes smoked, heavy probably caused by an addiction to nicotine that
smoking has been reported to be less frequent in US makes smokers consume nicotine everyday to avoid
African–Americans than Caucasians (Perez-Stable et withdrawal symptoms. There is no a unique definition
Table 5
Odds ratios comparing frequencies of current smoking in patients with schizophrenia versus patients with other mental illnesses, stratifying by
gender
Author Country Type Schizophrenia, % No schizophrenia, % OR CIa
Current smokers in males
Steinert et al., 1996 Germany Inpatients 70 (30 / 43) 37 (16 / 43) 3.9 1.6–9.6
Srinivasan and Thara, 2002 India Outpatients 38 (109 / 286) 23 (52 / 224) 2.0 1.4–3.0
Itkin et al., 2001 Israel Outpatients 71 (22 / 31) 34 (11 / 32) 4.7 1.6–13.5
Calabresi et al., 1991 Italy Outpatients 80 (57 / 71) 66 (19 / 29) 2.1 0.82–5.6
Calabresi et al., 1991 Italy Inpatients 88 (57 / 65) 90 (18 / 20) 0.80 0.15–4.1
Al-Habeeb and Qureshi, 2000 Saudi Arabia Outpatients 56 (61 / 108) 57 (141 / 248) 0.99 0.62–1.6
LLerena et al., 2003 Spain Inpatients 81 (68 / 84) 64 (44 / 69) 2.4b 1.2–5.0
LLerena et al., 2003 Spain Inpatients 73 (48 / 66) 51 (67 / 131) 2.5b 1.3–4.8
O’Farrell et al., 1983 USA Inpatients 88 (180 / 204)b 71 (55 / 77) 3.0 1.6–5.82
Diwan et al., 1998 USA Outpatients 86 (54 / 63) 30 (6 / 20) 14.0 4.3–46.0
Current smokers in females

Steinert et al., 1996 Germany Inpatients 26 (12 / 47) 2 (1 / 47) 15.8 2.0–127.1
Itkin et al., 2001 Israel Outpatients 21 (7 / 33)c 50 (19 / 38) 0.27c 0.09–0.77
LLerena et al., 2003 Spain Inpatients 13 (2 / 16)d 29 (9 / 31)d 0.35 0.07–1.9
LLerena et al., 2003 Spain Inpatients 13 (4 / 32)d 7 (5 / 71)d 1.9 0.47–7.5
a
b
Included a small number of females.
c
d
Second sample of LLerena et al. had subjects of older age than first sample.
of nicotine dependence. DSM-III and more recent The FTND has six items and its total score ranges
reviews of the DSMs define nicotine dependence in a from 0 to 10. High nicotine dependence is defined as a
relatively complex way. These definitions have not total FTND score of 6 or higher (Fagerstrom et al.,
been used in schizophrenia studies. In spite of some 1996; de Leon et al., 2002c). The advantage of this
psychometric problems (Kozlowski et al., 1994; dichotomous definition of nicotine dependence is that
Pomerleau et al., 1994; Payne et al., 1994, Haddock it allows using logistic regression to compare nicotine
et al., 1999), the Fagerstrfm Test for Nicotine dependence in schizophrenia patients versus control
Dependence (FTND) is the most widely used measure subjects, while controlling for potential confounding
of nicotine dependence and has been found to predict variables such as gender or substance abuse. Two
success in stopping smoking (Heatherton et al., 1991). FTND items, which are each scored between 0 and 3,
However, when schizophrenia patients are restricted may reflect nicotine dependence best: Item 1 (the time
from smoking (e.g. in long-term non-smoking units), to the first cigarette of the day) and Item 4 (the
FTND scores may underrepresent nicotine depend- number of cigarettes smoked per day). The sum of the
ence (Steinberg et al., 2005) and artificially decrease scores of these two items is called the heaviness of
the association between schizophrenia and nicotine smoking index (HSI) (Heatherton et al., 1998). High
dependence. HSI scores appear to be a good indication of high
Table 6
Odds ratios (ORs) comparing frequencies of heavy smoking among smokers with schizophrenia versus smokers from the general population
Author Country Type Schizophrenia, % General population, % OR CIa Definition
Heavy smokers in males and females combined
El-Guebaly and Hodgins, 1992 Canada Outpatients 31 (20 / 65) 10 4.0 2.3–6.8 (N25 cig/day)
McCreadie, 2002 Scotland In/outpatients 40 (50 / 125) 10 6.0 4.2–8.6 (z30 cig/day)
Herrán et al., 2000 Spain Outpatients 44 (18 / 41) 29 1.9 1.01–3.5 (N20 cig/day)
Gurpegui et al., 2005 Spain Outpatients 41 (71 / 173) 15 3.9 2.9–5.3 (N30 cig/day)
Ziedonis et al., 1994 USA Outpatients 46 (82 / 180) 22 3.0 2.3–4.1 (N25 cig/day)
de Leon et al., 2002b USA Inpatients 29 (14 / 48) 6 6.4 3.1–11.2 (N30 cig/day)
Heavy smokers in males

Masterson and O’Shea, 1984 Ireland Inpatients 81 (34 / 42) 57 3.2 1.5–9.8 (N20 cig/day)
Heavy smokers in females

Masterson and O’Shea, 1984 Ireland Inpatients 61 (25 / 41) 44 2.0 1.1–3.9 (N20 cig/day)
a
CIs, 95% bootstrap percentile confidence intervals.
Table 7
Odds ratios (ORs) comparing frequencies of heavy smoking among smokers with schizophrenia versus smokers with other mental illnesses
Author Country Type Schizophrenia, % No schizophrenia, % OR CIa Definition
Heavy smokers in males and females combined
LLerena et al., 2003 Spain Inpatients 40 (28 / 70) 43 (23 / 53) 0.87 0.42–1.8 (z30 cig/day)
de Leon et al., 1995 USA Inpatients 45 (90 / 201) 28 (23 / 83) 2.1 1.2–3.7 (z30 cig/day)
de Leon et al., 2002a USA Inpatients 19 (56 / 303) 13 (8 / 63) 1.6 0.7–3.5 (z30 cig/day)
Adding 3 samples 2 countries Inpatients 30 (174 / 574) 27 (54 / 199) 1.2 0.8–1.7 (z30 cig/day)
Other definitions:
de Leon et al., 2002b USA Inpatients 29 (14 / 48) 36 (12 / 33) 0.72 0.28–1.9 (N30 cig/day)
Vanable et al., 2003 USA Outpatients 37 (218 / 591) 27 (173 / 641)b 1.6 1.2–2.01 (N20 cig/day)
Heavy smokers in males

Calabresi et al., 1991 Italy Outpatients 53 (30 / 57) 11 (2 / 19) 9.4 2.0–44.7 (z30 cig/day)
Calabresi et al., 1991 Italy Inpatients 56 (32 / 57) 50 (9 / 18) 1.3 0.44–3.7 (z30 cig/day)
Adding 5 samples 3 countries In/outpatients 38 (202 / 534) 29 (53 / 184) 1.5 1.05–2.2 (z30 cig/day)
Other definitions:
Srinivasan and Thara, 2002 India Outpatients 24 (26 / 109) 13 (7 / 52) 2.0 0.81–5.0 (z20 cig/day)
Heavy smokers in females

Adding 3 samples 2 countries Inpatients 22 (34 / 154) 23 (12 / 52) 0.94 0.45–2.0 (z30 cig/day)
Other definitions:
a
b
Subjects with diagnoses other than depression or bipolar disorder were excluded from these computations.
Table 8
Odds ratios (ORs) comparing frequencies of smoking cessation in patients with schizophrenia versus the general population
Author Country Schizophrenia, % General population, % OR CI
Cessation rates a in males and females combined
Beratis et al., 2001 Greece 4 (11 / 248) 14 0.26 0.10–0.45b
McCreadie, 2002c Scotland 17 (34 / 196) 39 0.32 0.21–0.45b
Gurpegui et al., 2005 Spain 4 (7 / 180) 38 0.07 0.03–0.12b
Etter et al., 2004 Switzerland 15 (19 / 125) 47 0.20 0.11–0.30b
Ziedonis et al., 1994 USA 9 (19 / 201) 49d 0.10 0.06–0.16b
de Leon et al., 2002b USA 10 (6 / 61) 44 0.14 0.04–0.28b
Adding 6 samples 5 countries 9 (96 / 1011) – 0.19e 0.14–0.24f
Cessation rates in males

Kelly and McCreadie, 1999 Scotland 10 (6 / 58) 53 0.10 0.03–0.21b
Gurpegui et al., 2005 Spain 3 (4 / 150) 44 0.04 0.01–0.081b
Glynn and Sussman, 1990 USA 19 (11 / 57) 48d 0.25 0.10–0.46b
de Leon et al., 2002b USA 5 (2 / 41) 38 0.10 0.00–0.23b
Cessation rates in females

Kelly and McCreadie, 1999 Scotland 37 (15 / 41) 45 0.72 0.34–1.3b
Gurpegui et al., 2005 Spain 10 (3 / 30) 33 0.23 0–0.62b
de Leon et al., 2002b USA 20 (4/20) 46 0.29 0.06–0.78b
a
A cessation rate is the percentage of ever smokers who are not current smokers.
b
c
Includes samples in Kelly and McCreadie (1999).
d
A comparable percentage was not reported by authors and was obtained from an independent source (see Section 2.1 for a list of references).
e
Weighted average ORs using schizophrenia sample sizes as weights.
f
nicotine dependence (de Leon et al., 2003a; Diaz et heavy smoking (Covey et al., 1994; Lasser et al.,
al., 2005). 2000). Such surveys are ideal for studying the
association between psychiatric diagnoses and current
2.2.4. Ever smoking and smoking cessation and heavy smoking after taking into account the
Ever smokers include current smokers and quitters. effects of confounding variables. Unfortunately, these
Therefore, in a cross-sectional study, current smoking surveys have included very few schizophrenia
reflects ever smoking (initiation of smoking) and lack patients. Although their authors did not provide an
of smoking cessation. Many smokers try several times explanation for this (Covey et al., 1994; Lasser et al.,
to quit smoking before being able to stop completely, 2000), a possible explanation is that schizophrenia
which suggests that smoking cessation is a complex patients do not live in standard housing arrangements
behavior. For this meta-analysis, any data describing and are not cooperative with complex surveys. As a
smoking cessation were included, even if the duration result, general population surveys do not usually
of smoking cessation was not reported. provide sufficient information on the association
between schizophrenia and smoking. For this reason,
2.3. Selection of a control group (general population case-control designs are the usual way to study such
versus non-schizophrenia patients) association.
Case-control studies can recruit two types of
Some large epidemiological surveys of the general controls: people from the general population or
population have suggested that some severe mental patients with other severe mental illnesses. Using
illnesses other than schizophrenia, such as mood general population controls may not be the ideal
disorders, are associated with current smoking and methodological approach. The reason is that people
Table 9
Odds ratios (ORs) comparing frequencies of smoking cessation in patients with schizophrenia versus patients with other mental illnesses
Author Country Schizophrenia, % No schizophrenia, % OR CI
Cessation rates in males and females combined
Poirier et al., 2002 France 6 (9 / 145) 13 (34 / 255) 0.43 0.20–0.93a
Itkin et al., 2001 Israel 17 (6 / 35) 29 (12 / 42) 0.52 0.17–1.6a
Arias-Horcajadas et al., 1997 Spain 10 (4 / 41) 9 (3 / 34) 1.1 0.23–5.4a
de Leon et al., 2002b USA 10 (6 / 61) 18 (7 / 40) 0.51 0.16–1.7a
Combination of 4 samples 4 countries 9 (25 / 282) 15 (56 / 371) 0.55 0.33–0.90a
Cessation rates in males

Srinivasan and Thara, 2002 India 27 (40 / 149) 40 (34 / 86) 0.56 0.32–0.99a
Itkin et al., 2001 Israel 0 (0 / 22) 45 (9 / 20) 0.05 0.00–0.32b
Diwan et al., 1998 USA 10 (6 / 60) 57 (8 / 14) 0.08 0.02–0.32a
Cessation rates in females

Itkin et al., 2001 Israel 46 (6 / 13)c 14 (3 / 22) 5.4c 1.06–27.8a
a
b
CI, 95% exact confidence interval (Cytel Sotware Co., 2000).
c
from the general population differ considerably from are usually treated in the same settings as schizo-
schizophrenia patients in some factors that strongly phrenia patients, which contribute to the similarity of
affect smoking behaviors. Smoking behaviors, partic- the two populations. However, even when non-
ularly ever and current smoking, are influenced by schizophrenia patients are used as control subjects,
gender, sociocultural and economical factors. For gender-stratification is still important because gender
instance, currently in the US, current smoking is is a major determinant of current smoking in all
associated with low levels of education in males and countries (de Leon and Diaz, 2002).
females. In contrast, in some European countries (e.g.
Spain and France), current smoking is associated with 2.4. The effect of access to the drug
low levels of education in males but with high levels
of education in females (Poirier et al., 2002). When Schizophrenia researchers, unlike drug abuse
compared with the general population schizophrenia researchers, may not be aware that the degree of drug
patients have higher percentages of low socioeco- accessibility determines drug abuse prevalence. Even
nomic and educational levels, so that any comparison if the association between schizophrenia and smoking
of current smoking in people from the general is biological, one should be aware that restricted
population and schizophrenia patients may produce access to tobacco might preclude the manifestation of
biased conclusions if a careful control of educational this association in some countries and societies.
levels and gender is not imposed. Becoming a current smoker requires exposure to
On the other hand, patients with other severe nicotine (so you can become addicted) and sufficient
mental illnesses may be a better control group since money to pay for your tobacco addiction.
they have socioeconomic and educational back- The detection of the association between schizo-
grounds, and levels of alcohol and illegal drugs use, phrenia and smoking is more difficult in societies
that are similar to those of schizophrenia patients. In with very low or very high smoking prevalences in
addition, patients with other severe mental illnesses the general population. Very low prevalences may be
Table 10
Odds ratios (ORs) comparing frequencies of ever smoking in patients with schizophrenia versus the general population
Author Country Schizophrenia, % General population, % OR (CI)
Ever smokers in males and females combined
Beratis et al., 2001 Greece 61 (248 / 406) 49 1.6 (1.3–2.0)a
McCreadie, 2002 Scotland 79 (196 / 250) 65 2.0 (1.5–2.7)a
Gurpegui et al., 2005 Spain 72 (180 / 250) 56 2.1 (1.6–2.8)a
Etter et al., 2004 Switzerland 83 (125 / 151) 53 4.3 (2.8–7.0)a
Chiles et al., 1993 USA 93 (74 / 80) 50b 13.3 (7.0–39.0)a
Ziedonis et al., 1994 USA 76 (201 / 265) 50b 3.2 (2.4–4.3)a
Cohen et al., 2002 USA 73 (82 / 113) 60 1.8 (1.2–2.9)a
de Leon et al., 2002b USA 92 (61 / 66) 47 13.0 (6.3–73.3)a
Campo-Arias et al., 1999 Colombia 20 (30 / 151) 26 0.71 (0.46–1.0)a
Adding 9 samples 6 countries 69 (1197 / 1732) – 3.1c (2.4–3.8)d
Ever smokers in males

Kelly and McCreadie, 1999 Scotland 79 (58 / 73) 59 2.6 (1.6–4.9)a
Glynn and Sussman, 1990 USA 97 (57 / 59)e 60b 21.6 (7.2–38.7)a
Adding 4 samples 3 countries 83 (306 / 370) – 7.3c (1.04–13.6)d,e
Ever smokers in females

Kelly and McCreadie, 1999 Scotland 66 (41 / 62) 47 2.2 (1.4–3.9)a
Adding 3 samples 3 countries 65 (91 / 140) – 2.8c (1.2–4.4)d
a
b
A comparable percentage was not reported by authors and was obtained from an independent source (see Section 2.1 for a list of references).
c
Weighted average ORs using schizophrenia sample sizes as weights.
d
e
Includes 4 females.
mainly explained by economical or social reasons. In use initiation and consequent addiction. If cigarettes
some non-Western countries, economical issues are are unavailable in a society, one is not able to
crucial; many people cannot afford to buy cigarettes. demonstrate the association.
In many non-Western countries, female smoking is Similarly, in a subpopulation with very high
extraordinarily rare. It must be remembered that smoking prevalences (N60%) it may be hard to
some decades ago, female smoking was also rare in detect schizophrenia effects on smoking. The reason
the US and European societies. US and European is that the difference between schizophrenia and
females born in the early years of the twentieth general population prevalences became smaller as
century rarely smoked. Logically, if you never try to they approach to 100% (ceiling effect), making
smoke, you cannot become a smoker. Therefore, it statistical significance difficult to attain. Detection
may be difficult to establish an association between of the association between schizophrenia and smok-
schizophrenia and tobacco smoking in poor coun- ing may become possible in that country, however,
tries, among females from some non-Western coun- once social pressure to quit smoking decreases
tries, and in geriatric females from developing smoking prevalence in the general population.
countries since they were not prone to start smoking.
The lack of smoking in these three situations does 2.5. Statistics
not refute the association between schizophrenia and
tobacco smoking; it only proves economical and Odds ratios (ORs) that compared current smoking
social factors may be a major deterrent in nicotine prevalences in schizophrenia patients versus control
Table 11
Odds ratios (ORs) comparing frequencies of ever smoking in patients with schizophrenia versus other mental illnesses
Author Country Schizophrenia, % No schizophrenia, % OR (CI)
Ever smokers in males and females combined
de Leon et al., 2002b USA 92 (61 / 66) 78 (40 / 51) 3.4 (1.1–10.4)a
Campo-Arias et al., 1999 Colombia 20 (30 / 151) 12 (54 / 445) 1.8 (1.1–2.9)a
Poirier et al., 2002 France 70 (145 / 207) 60 (255 / 422) 1.5 (1.1–2.2)a
Itkin et al., 2001b Israel 55 (35 / 64) 60 (42 / 70) 0.81(0.41–1.6)a
Arias-Horcajadas et al., 1997 Spain 73 (41 / 56) 61 (34 / 56) 1.8 (0.8–3.9)a
Adding 5 samples 5 countries 57 (312 / 544) 41 (425 / 1044) 2.0 (1.6–2.4)a
Ever smokers in males

Srinivasan and Thara, 2002 India 52 (149 / 286) 38 (86 / 224) 1.7 (1.2–2.5)a
Itkin et al., 2001 Israel 71 (22 / 31) 62 (20 / 32) 1.5 (0.51–4.2)a
Diwan et al., 1998 USA 95 (60 / 63) 70 (14 / 20) 8.6 (1.9–38.5)a
Ever smokers in females

Itkin et al., 2001 Israel 39 (13 / 33)b 58 (22 / 38) 0.47b(0.18–1.2)a
a
Confidence intervals, CIs, computed from two-way cross-tabulations (SPSS Inc., 1999).
b
group individuals were computed along with their 2.6. Statistical control of confounding variables
95% confidence intervals (CIs). ORs comparing
heavy smoking prevalences among smokers, cessation In most countries, gender is a major confounder in
rates in ever smokers and prevalences of ever smokers smoking behavior studies. Other potential confound-
were similarly computed. ers reported to be associated with smoking behaviors
When the general population was used as a control are medication dose, age, race, duration of hospital-
group, a bootstrap confidence interval for each OR ization, use of alcohol or illegal drugs, and polydipsia.
(Simon, 1999) was computed. Also, a weighted One way to control for confounders when comparing
average of all ORs for a particular smoking behavior schizophrenia patients and controls is to match the
was computed. Schizophrenia sample sizes were used distribution of the confounders in the control sample
as weights (Wilcox, 2001). This weighted average with that in the patient sample. For instance, to control
measured the association between smoking behaviors for gender, samples of patients and controls with
and schizophrenia in the worldwide population, similar gender proportions may be obtained. For
attaching most importance to those schizophrenia many practical reasons, this type of control is not
studies with the largest sample sizes. Confidence usually performed, especially with a large number of
intervals for weighted averages of ORs were com- confounders.
puted by using the delta method (Casella and Berger, Another way to control for confounders is through
2002). sample stratification; that is, a separate analysis within
When patients with other mental illnesses were each combination of levels of the confounding
used as a control group, CIs were computed using variables. This method is also impractical with a large
SPSS (SPSS Inc., 1999); the OR measuring the number of confounders and usually yields ORs
worldwide association between a smoking behavior computed with very small sample sizes. However, a
and schizophrenia was computed by combining all substantial number of studies reviewed for this meta-
studies of that smoking behavior. This procedure also analysis reported sufficient information to compute
gave most importance to largest sample sizes. ORs stratified by gender, although most studies did
not allow stratifying for other potential confounding 3.1.1. Males

variables. The studies in Table 2 investigated a total of 3634
The best way to control for confounders is by schizophrenia males (71% were current smokers)
performing logistic regressions in which all con- from 18 different nations. Twenty-nine out of 32
founders are included as independent variables and ORs comparing current smoking in schizophrenia
current smoking (or another dichotomous smoking males versus males from the general population were
behavior variable) is included as the dependent significantly greater than 1 (ranged between 0.55 to
variable. Logistic regression yields ORs that are 34.2). The weighted average of all ORs was 7.2 (CI,
adjusted for the included confounders. Unfortunately, 6.1–8.3).
we found very few schizophrenia studies that con-
trolled for confounding factors by using logistic 3.1.2. Females
regression. Importantly, unadjusted or non-stratified The studies in Table 3 investigated a total of 2106
ORs assume that confounding variables are similarly schizophrenia females (44% were current smokers)
distributed across schizophrenia and control samples. from 15 different nations. Twenty out of 25 ORs
This questionable assumption justifies the use of comparing current smoking in schizophrenia females
logistic regression or stratification. versus females from the general population were
This article provides separate sections for current significantly greater than 1 (ranged 0.40–7.8). The
smoking, heavy smoking, high nicotine dependence, weighted average of all ORs was 3.3 (CI, 3.0–3.6).
smoking cessation and ever smoking. In each section, In summary, studies from countries on four
individuals from the general population and non- continents undoubtedly suggest that current smoking
schizophrenia psychiatric patients are treated as is associated with schizophrenia when compared with
different control groups. Studies controlling for the general population, even after controlling for
confounders are highlighted. gender.
3.2. Comparing current smoking in schizophrenia

3. Current smoking versus other severe mental illnesses
3.1. Comparing current smoking in schizophrenia Fourteen out of the 18 ORs described in Table 4
versus the general population were significantly greater than 1. The stability of the
ORs about 2 is noteworthy. From the 18 ORs, 12 lay
Table 1 describes 42 samples from 20 different between 1.5 and 3.0. Combining these studies, the
nations and investigated a total of 7593 schizophre- sample-size-weighted average OR for current smok-
nia patients (62% were current smokers). Current ing in schizophrenia versus other severe mentally ill
smoking prevalences for schizophrenia patients were patients was 1.9 (CI, 1.7–2.1, Table 4).
significantly higher than those for people from the
general population, regardless of country, except in 3.2.1. Males
two studies: one from Japan, where current smoking Eleven out of the 14 ORs in male samples from
prevalences in the general population are relatively 8 different countries were significantly greater than
high (particularly in males) and another from 1 (Table 5). The combined male OR was 2.3 (CI,
Colombia, where they are relatively low. The 2.0–2.7).
individual study ORs ranged between 0.74 and
26.0 (Table 1). The weighted average of the ORs 3.2.2. Females
comparing prevalences for schizophrenia patients Only 3 out of the 8 ORs in female samples from 5
versus the general population was 5.3 (CI, 4.9– different countries were significantly greater than 1
5.7). This suggests that the odds that patients with (Table 5); but the combined female OR was signifi-
schizophrenia be current smokers are 5.3 times cant, 1.8 (CI, 1.5–2.3). The lack of significance in
higher than people from the worldwide general most female ORs may reflect the relatively small
population. sample sizes.
Thus, the association between schizophrenia and phrenia and current smoking holds after controlling for
current smoking is consistently observed in samples other variables that are also associated with current
from several different countries and has a relatively smoking.
constant strength across different cultures, suggesting A study of 136 US adults with mental retardation
that this association may have a biological component (Hymowitz et al., 1997) also supported the robustness
that manifests itself despite a variety of cultural of the association between schizophrenia and current
factors affecting smoking behavior. As described smoking. After adjusting for confounders, the OR
below, the increased current smoking prevalences in comparing current smoking in mentally retarded with
schizophrenia patients are the results of both an schizophrenia versus other mentally retarded patients
increase in ever smoking and a decrease in smoking was 3.5 (95% CI, 1.1–11.4).
cessation.
3.3. Adjusting odds ratios of current smoking for 4. Heavy smoking among smokers
confounding variables
4.1. Comparing heavy smoking among smokers with
Only one study with normal controls, performed schizophrenia versus smokers from the general
in Spain, controlled for confounding variables using population
logistic regression (Gurpegui et al., 2005). The OR,
adjusted for confounding variables, was 3.5 (CI, Table 6 describes 6 studies from 4 different
2.3–5.3). countries. Although there was not a consistent
Three studies, two in US hospitals and one in a definition of heavy smoking across these studies, the
Spanish hospital, used logistic regression to compare ORs were always significantly greater than 1, ranging
schizophrenia patients with other institutionalized between 1.9 and 6.4. This suggests that the odds that
patients (de Leon et al., 1995, 2002a; LLerena et al., smokers with schizophrenia be heavy smokers are
2003). The adjusted OR for the combination of data significantly greater than those of smokers from the
from the two US studies (in same catchment area and general population. According to 3 studies, this
with similar designs) was 2.2 (CI, 1.6–3.1) (de Leon conclusion may still be valid within males (Table 6)
et al., 2002a) and for the Spanish study was 2.3 (CI, and according to 2 of 3 studies, this conclusion was
1.1–4.6) (LLerena et al., 2003). Thus, after controlling valid within females, too.
for potential confounding variables, the odds that
schizophrenia patients be current smokers continued 4.2. Comparing heavy smoking among smokers with
to be about 2 times higher than that of non- schizophrenia versus other severe mental illnesses
schizophrenia patients.
One can argue that antipsychotic treatment may When studying males and females combined,
explain the association between current smoking and only 2 out of 5 ORs were significantly different
schizophrenia. In the 3 above studies in hospitalized from 1 (Table 7). When studying males alone, only
patients (de Leon et al., 1995, 2002a; LLerena et al., 2 out of 7 ORs were significantly different from 1.
2003), the association between current smoking and It cannot be ruled out that lack of power may be a
antipsychotic medication did not explain the associa- problem; when 5 male studies using the same
tion between current smoking and schizophrenia. definition were combined, the sample-size-weighted
Moreover, the association between current smoking average OR was significant 1.5 (1.05–2.2). When
and antipsychotic medication disappeared after con- studying females alone, no OR of 4 was signifi-
trolling for other factors including schizophrenia. The cantly different from 1 (Table 7). Therefore, many
association between current smoking and schizophre- of the ORs in Table 7 do not substantiate the
nia remained after adjusting for substance abuse hypothesis that prevalences of heavy smoking
(OR = 2.7; CI, 1.6–4.4) in the only study (de Leon et among schizophrenia and other severe mentally ill
al., 2002a) that adjusted for substance abuse. In smokers are significantly different from each other.
summary, the consistent association between schizo- New studies with larger samples and consistent
definitions of heavy smoking are needed to provide metabolite. Olincy et al. (1997) showed that 20
a more definitive answer. smokers with schizophrenia had significantly higher
urine cotinine concentrations when compared with a
4.3. Adjusting odds ratios of heavy smoking for control group of 20 matched smokers including more
confounding variables than half with psychiatric history but no psychosis
history. This small sample did not allow an adequate
Only one Spanish study performed a logistic control for confounding variables.
regression that compared heavy smoking in schizo- In summary, worldwide studies demonstrate that
phrenia versus normal control smokers (Gurpegui et schizophrenia smokers smoke heavier than smokers
al., 2005). The OR, adjusted for confounding varia- from the general population. However, there is no
bles, was 2.2 (CI, 1.1–4.4). consistent evidence that schizophrenia smokers smoke
A logistic regression analysis of heavy smoking more heavily than smokers with other severe mental
using a combination of the 2 US samples described in illnesses. Only a relatively small number of studies
de Leon et al. (1995, 2002a) provided an adjusted OR have reported significant differences in heavy smok-
of 1.8 (CI, 1.1–3.0) comparing schizophrenia smokers ing between smokers with schizophrenia and those
versus other institutionalized patients who smoke. with other severe mental illness. Alcohol and drug
However, using the same definition of heavy smoking abuse are associated with heavy smoking. It cannot be
(z 30 cig/day), LLerena et al. (2003) did not find a ruled out that this association explains the positive
significant difference in heavy smoking between results associating heavy smoking and schizophrenia.
Spanish schizophrenia and other institutionalized To definitely demonstrate an association between
smokers, not even after controlling for potential heavy smoking and schizophrenia among smokers, a
confounding variables. In summary, the worldwide large study using reliable, stable biological measures
evidence concerning differences in heavy smoking such as plasma cotinine concentrations and including
between schizophrenia and non-schizophrenia smok- large samples of schizophrenia patients and other
ers is inconsistent and inconclusive. severe mentally ill patients is required. Ideally one
should compare schizophrenia to other homogenous
4.4. Other definitions of heavy smoking group of patients such as bipolar or major depressive
disorder. Using heterogeneous samples of severe
When schizophrenia and non-schizophrenia smok- mentally ill patients may have contributed to the
ers are compared using other definitions of heavy inconsistency of published data. New studies will also
smoking, the results are still inconsistent. Using the have to control for potential confounding variables
Elgin Repetitive Behavior Scale and after controlling such as male gender and substance use.
for confounders, de Leon et al. (2002a) did not find a
significant difference in heavy smoking between US
schizophrenia and other institutionalized smokers. 5. High nicotine dependence among smokers
Two Spanish studies compared the mean daily
number of cigarettes smoked by schizophrenia versus The FTND may reflect nicotine dependence and its
non-schizophrenia smokers. While one found a brain disturbances better than heavy smoking.
significant difference (Arias-Horcajadas et al., 1997), Unfortunately, very few studies of the association
the other did not (Herrán et al., 2000). Nonetheless, a between schizophrenia and tobacco smoking have
Swiss (Etter et al., 2004) and a Greek study (Beratis et used the FTND (or its briefer version HSI). Etter et al.
al., 2001) suggested that schizophrenia smokers (2004) found that Swiss schizophrenia smokers had
smoke on average more cigarettes than smokers from higher HSI scores than smokers from the Swiss
the general population. Unfortunately, these studies general population.
did not control for potential confounding variables. Similarly a Spanish study (Gurpegui et al., 2005)
Only one study has used urine cotinine concentration found that 173 schizophrenia smokers had higher
as a biological measure of the severity of smoking scores than 100 control smokers using FTND scores
(Olincy et al., 1997). Cotinine is the main nicotine (6.8 F 2.3 versus 3.3 F 2.9; t = 10.3, df = 168.3,
p b 0.001) and HSI scores (4.6 F 1.4 versus 2.4 F 2.2; ORs comparing cessation rates in schizophrenia
t = 9.4, df = 149.8, p b 0.001). smokers versus smokers from the general population
Two studies in US (Diwan et al., 1998; de Leon et was 0.19 (CI, 0.14–0.24).
al., 2002b) and one in Israel (Itkin et al., 2001) did not Four studies suggested that cessation rates for
find significant differences in the mean FTND scores schizophrenia males are significantly smaller than
of schizophrenia versus mood-disordered smokers males from the general population (weighted OR 0.10,
from same treatment settings. CI 0.06–0.14; Table 8). Also, 3 studies suggested a
De Leon et al. (2002c) studied high nicotine trend for schizophrenia females to have smaller
dependence (FTND z 6) in samples of severely cessation rates than females from the general pop-
mentally ill smokers and controls from US and Spain. ulation, particularly when they were combined
In both countries, mentally ill smokers had signifi- (weighted OR 0.46, CI 0.23–0.69; Table 8).
cantly higher frequencies of high nicotine dependence The adjusted OR of smoking cessation after
than those of general population smokers. In neither controlling for gender and educational level was
country, a significant difference in the frequencies of 0.06 (CI, 0.02–0.14) in Spanish schizoprenia patients
high nicotine dependence between schizophrenia and and normal controls (Gurpegui et al., 2005).
mood disordered smokers was found. Interestingly,
US and Spanish mentally ill smokers did not 6.2. Comparing smoking cessation rates among
significantly differ from each other in high nicotine smokers with schizophrenia versus other severe
dependence frequencies. Gurpegui et al. (2005) found mental illnesses
a higher prevalence of high nicotine dependence in
schizophrenia outpatient smokers when comparing Three of the 4 available studies suggested a trend
with voluntary controls who smoked (adjusted for schizophrenia patients to have smaller cessation
OR = 5.1; CI, 2.7–9.5). Within the same schizophrenia rates than non-schizophrenia patients, but only the
sample, high FTND scores were associated with poor- study with the largest sample size reached significance
outcome schizophrenia (Aguilar et al., 2005). (Poirier et al., 2002; Table 9). Combining the 4 studies
In summary, a few studies suggest that although provided a significant result (weighted OR = 0.55, CI
schizophrenia smokers are more nicotine dependent 0.33–0.90).
than smokers from the general population, schizo- Four studies consistently suggested that male
phrenia smokers may not be significantly more schizophrenia smokers have more difficulties quitting
nicotine dependent than smokers with other severe smoking than male smokers with other severe mental
mental illnesses. These inconclusive results for illnesses (Table 9). Combining the 4 studies, it is
nicotine dependence are analogous to those for heavy obtained that cessation rates for male schizophrenia
smoking. patients are significantly smaller than male non-
schizophrenia patients (OR = 0.34, CI 0.22–0.54). On
the other hand, data comparing smoking cessation
6. Smoking cessation rates rates in schizophrenia versus non-schizophrenia
females is meager and not definitive (Table 9).
6.1. Comparing smoking cessation rates among As a summary, the fact that all odds ratios in
smokers with schizophrenia versus smokers from the Table 8 are smaller than 1 confirms that schizophre-
general population nia smokers have more difficulties quitting smoking
than smokers from the general population. Moreover,
Six studies from 5 countries suggested that smok- only very few schizophrenia patients are successful
ing cessation rates for schizophrenia patients were in quitting smoking. Also, the data in Table 9
significantly smaller than the general population suggests that male schizophrenia smokers have more
(Table 8). Combining these 6 studies, the cessation difficulties quitting smoking than male smokers with
rate for schizophrenia patients was 9% versus other mental illnesses. The combined cessation rate
cessation rates between 14% and 49% for the general in male schizophrenia patients (18%) was signifi-
population. The sample-size-weighted average of the cantly smaller than that of male non-schizophrenia
patients (38%). For more conclusive results, espe- 7.2. Comparing ever smoking in schizophrenia versus
cially on females, new and larger studies are other severe mental illnesses
required. Ideally, studies should use multivariate
techniques such as logistic regression to control for Four of the 5 studies described in Table 11 showed
co-morbid substance use and other potential con- a trend for schizophrenia patients to have a higher
founding variables. prevalence of ever smoking than non-schizophrenia
Smoking cessation rates in Tables 8 and 9 are patients, although 2 of the 5 studies did not reach
naturalistic. A limited number of studies describing significance. When the 5 studies were combined, the
pharmacological and non-pharmacological treatments prevalence of ever smoking in schizophrenia patients
for smoking have reported very low cessation rates in was significantly higher than non-schizophrenia
schizophrenia patients. For a review of treatment– patients (OR = 2.0; CI, 1.6–2.4).
intervention studies, see McChargue et al. (2002).
7.2.1. Males
Four studies compared ever smoking in male
7. Ever smoking schizophrenia versus male non-schizophrenia patients
(Table 11). In all 4 studies, the prevalence of ever
7.1. Comparing ever smoking in schizophrenia versus smoking was higher in schizophrenia patients,
the general population although only 2 studies reached significance. Com-
bining the 4 studies, the prevalence of ever smoking in
In 8 out of the 9 studies described in Table 10, the male schizophrenia patients was significantly higher
OR comparing ever smoking in schizophrenia patients than in male non-schizophrenia patients (OR = 2.0; CI,
versus the general population was significantly greater 1.5–2.7).
than 1. The sample-size-weighted average of the 9
ORs was 3.1 (CI, 2.4–3.8). Only one study (Gurpegui 7.2.2. Females
et al., 2005) provided an adjusted OR after controlling There were 2 studies comparing ever smoking in
for confounding variables, 1.4 (CI, 0.91–2.2) that did female schizophrenia and non-schizophrenia patients
not reach significance. (Table 11). Both have small sample sizes and did not
reach significance. One of the studies (Itkin et al.,
7.1.1. Males 2001) included a rather atypical sample of female
Table 10 describes 4 male studies comparing schizophrenia patients who had an unusual ethnic
prevalences of ever smoking in schizophrenia patients background and an unusual low prevalence of current
versus the general population. The sample-size- smoking that was lower than the general female
weighted average of the 4 ORs was 7.3 (CI, 1.04– population in that country (de Leon and Diaz, 2002;
13.6). Only one study (Gurpegui et al., 2005) Einat, 2002).
provided an adjusted OR after controlling for con- In summary, in spite of the limited number of
founding variables, 1.2 (CI, 0.65–2.1) that did not studies, the fact that most of the ORs in Tables 10 and
reach significance. 11 are greater than 1 suggests that schizophrenia
patients have higher prevalences of ever smoking than
7.1.2. Females the general population and, more importantly, than
Table 10 describes 3 female studies comparing severe mentally ill patients recruited in comparable
prevalences of ever smoking in schizophrenia patients settings. Thus, schizophrenia patients have an in-
versus the general population. In the 3 studies the creased risk of starting daily smoking.
prevalence for female schizophrenia patients was
higher, although one study did not reach significance 7.3. Smoking initiation and vulnerability to
(Gurpegui et al., 2005). The average of 3 ORs was 2.8 schizophrenia
(CI, 1.2–4.4). Only one study (Gurpegui et al., 2005)
provided an adjusted OR, 1.5 (CI, 0.81–2.9) that did A number of studies provide evidence supporting
not reach significance. the view that vulnerability to schizophrenia (rather
than schizophrenia itself) is associated with ever by the authors) that schizophrenia illness includes the
smoking. Examples are 7 studies that reported the precursors, these changes happen much earlier than
proportion of schizophrenia patients who started smoking initiation and one must consider increased
smoking before the onset of their illness (Campo- smoking initiation in schizophrenia patients as another
Arias et al., 1998; Kelly and McCreadie, 1999; Beratis early sign of the illness.
et al., 2001; Liao et al., 2002; de Leon et al., 2002b; Two studies (Weiser et al., 2004; Zammit et al.,
Uzun et al., 2003; Gurpegui et al., 2005). The average 2003) focusing on male conscripts provided a cross-
reported proportion was relatively high, 77% (range, section of smoking behavior at time of conscription
49–90%). Furthermore, a small study of first psy- and the development of schizophrenia after follow-up.
chotic episodes suggested that most schizophrenia These studies were limited by the exclusion of males
patients start to smoke before the onset of their illness who started schizophrenia before conscription, all
(McEvoy and Brown, 1999). Another study of first females, and by the lack of information on smoking
episode patients using plasma cotinine levels found initiation in males after 20 years old. According to
that schizophrenia patients have the highest preva- results in de Leon et al. (2002b) and Gurpegui et al.
lence of current smoking (42%, 13 / 31) when com- (2005), that information is crucial to establishing
pared with mood disorders (25%, 3 / 12) and matched significant differences between male controls and
controls (3%, 1 / 40) (Reddy et al., 2003). male schizophrenia patients. In the Israeli study of
Only two studies have used multivariate techniques 14,288 male conscripts, 28% reported smoking at
to compare the age of onset of daily smoking in least 1 cigarette per day (Weiser et al., 2004). The
schizophrenia patients versus people from the general prevalence of schizophrenia after 4–16 years of
population or versus patients with other mental follow-up was 0.3%. The adjusted relative risk of
illnesses (de Leon et al., 2002b; Gurpegui et al., schizophrenia in smokers versus non-smokers was 1.9
2005). The first, a US study (66 schizophrenia patients, (CI, 1.1–3.6). Moreover, there was a dose effect; the
51 patients with mood disorders and 404 controls), relative risk was 1.4 (CI, 0.48–4.3) in those smoking
suggested that, after an age of about 20 years old, a 1–9 cigarettes/day and 2.3 (CI, 1.2–4.3) in those
person with schizophrenia or with vulnerability to smoking z 10 cigarettes/day (Weiser et al., 2004).
schizophrenia has a higher risk of initiation of daily These results were not replicated in a cohort study in
smoking than controls of comparable age, gender and Swedish male conscripts aged 18–20 years that
educational background (de Leon et al., 2002b). The suggested smoking may have a protective effect
second study, (250 schizophrenia patients and 290 against the development of schizophrenia in patients
controls) replicated this finding in Spain (Gurpegui et with an illness onset between 20 and 25 years of age
al., 2005). Moreover, it extended the finding by (Zammit et al., 2003).
demonstrating that after age 20, smoking initiation The increased prevalences of ever smoking in
rates were higher among 107 schizophrenia patients schizophrenia patients and the higher rates of smok-
who started daily smoking at least five years before ing initiation before schizophrenia starts suggest that
illness onset. This analysis including schizophrenia people who are going to develop schizophrenia have
patients, who started smoking as early as 5 years some risk factor that makes them more vulnerable to
before schizophrenia onset, suggests that the associa- start smoking. We have speculated that a vulnerability
tion between smoking and schizophrenia cannot be to schizophrenia may be associated with an increased
explained by the illness or prodromal period. The vulnerability to start smoking (de Leon, 1996). In a
literature describes that some schizophrenia precursors landmark study using female twins, Kendler et al.
(such as minor neurological deficits) may be present in (1993) suggested that the relationship between smok-
early childhood. However, these precursors are not ing and major depression is not a causal one (smoking
specific to schizophrenia and many subjects who did not cause major depression and major depression
present them never develop schizophrenia. Thus, it did not cause smoking). Instead, the relationship
seems reasonable to consider precursors as schizo- appears to be mediated largely or entirely through
phrenia risk factors rather than as part of the illness. familial factors, probably genetic, that influence the
Obviously, if one defends an extreme view (not shared liability to both smoking and major depression. The
relationship between mood disorders and smoking is gest that schizophrenia patients from all countries
not as strong as the relationship between schizophre- share a biological factor that makes them more
nia and smoking (Gonzalez-Pinto et al., 1998; de prone to smoke. Most studies examining ever
Leon et al., 2002b). Therefore, if genetic vulnerability smoking and two studies exploring age of smoking
may make subjects with vulnerability to mood initiation (de Leon et al., 2002b; Gurpegui et al.,
disorders more prone to become smokers, vulner- 2005) suggest that there may be genetic factors
ability to schizophrenia may also be associated with increasing the risk of both becoming a smoker and
vulnerability to smoking. In a discordant twin study developing schizophrenia. This model is supported
with 24 pairs collected from a large Veteran twin male by recent genetic studies (Freedman et al., 1997;
sample, Lyons et al. (2002) found that unaffected co- Leonard et al., 2002).
twins had a frequency of ever daily smoking (88%) There is no doubt that schizophrenia is also
similar with that in male schizophrenia probands associated with greater frequencies of heavy smok-
(83%) and higher than male twin controls (66%). The ing and high nicotine dependence in smokers and
OR of ever daily smoking was 3.7 for co-twin with lower smoking cessation rates when compared
schizophrenia probands. The schizophrenia probands with the general population. However, worldwide
and their co-twins were also more frequently unable studies do not rule out that schizophrenia smokers
to quit smoking when compared with controls and smokers with other severe mental illnesses have
(respectively, 65%, 75% and 38%). relatively similar frequencies of heavy smoking and
The studies from a schizophrenia research group high nicotine dependence. Therefore, schizophrenia
suggest that vulnerability to schizophrenia may be may not be different from other severe mental
associated with vulnerability to smoking. Freedman et illnesses in rates of heavy smoking and high
al. (1997) described a genetic neurophysiological nicotine dependence among smokers. There is some
abnormality in patients with schizophrenia (and their evidence that male schizophrenia patients have
relatives), which was temporarily corrected by a high lower smoking cessation rates than male non-
peak of nicotine. This abnormality was associated schizophrenia patients. A comparison of smoking
with a dysfunction of a specific hippocampal nicotine cessation rates in female schizophrenia versus
receptor (a7). More recently, Leonard et al. (2002) female non-schizophrenia patients needs further
found that that the presence of an a7 promoter and larger studies. This review did not try to cover
polymorphism was more frequent in schizophrenia all the complex issues regarding smoking and
patients than in controls and may be a marker for the schizophrenia. This is a focused attempt to prove
neurophysiological abnormalities that increase the risk that there is an association between schizophrenia
of schizophrenia. If vulnerability to schizophrenia is and tobacco smoking and that this association is
associated with vulnerability to smoking, non-psy- consistent across the world.
chotic relatives of schizophrenia patients should have
higher rates of smoking behavior than the general
population. As far as we know, no study has been Acknowledgements
designed to test this hypothesis, but the Kopala et al.
(2001) study on olfactory identification in members of Preliminary early versions of this article were
families with schizophrenia provides some support for presented by Dr. de Leon as lectures at John Umstead
the hypothesis: the prevalence of smoking was 69% in Hospital, Butner, NC on 8/29/02 and Burghflzli
19 psychotic members, 41% in 27 non-psychotic Hospital in Zurich, Switzerland on 7/12/03. Dr. Diaz
members and 9% in 43 matched volunteers. was partially supported by the Dirección de Inves-
tigaciones of the Universidad Nacional, Medellin,
Colombia (grants 030802738 and Apoyo a Grupos
8. Conclusions Reconocidos Colciencias 2004). Margaret T. Susce,
R.N., M.L.T., and Maria Johnson, R.N., helped with
A large number of worldwide studies describing editing of this article. Raimo K.R. Salokangas, MD,
current smoking in schizophrenia consistently sug- provided prevalences from his study published in
Finnish. Terry Kupra, PhD, provided schizophrenia Campo-Arias, A., Suárez-Jiménez, M., Haydar-Ghisays, R., 1999.
data from a Canadian study (Gerber et al., 2003) that Severidad del tabaquismo en pacientes de la consulta psiquiátr-
ica. Rev. Argent. Psiquiatr. Biol. 6, 21 – 24.
did not describe separated schizophrenia data. Warn- Campo-Arias, A., Dı́az-Martı́nez, L.A., Rueda-Jaimes, G.E., 2004.
ing for researchers who have conducted studies not Anxiety and depressive symptoms among smokers: a population
included in this meta-analysis: The authors are aware study. Medunab 7, 4 – 8.
that PubMed is biased against articles published in Caraballo, R.S., Giovino, G.A., Pechacek, T.F., Mowery, P.D.,
Richter, P.A., Strauss, W.J., 1998. Racial and ethnic differences
non-English language. To avoid this bias in future
in serum cotinine levels of cigarette smokers. JAMA 280,
updates of this meta-analysis, the authors will be 135 – 139.
willing to review published studies sent to them from Carvajal, C., Passig, V.C., San Martin, R.E., Zuñiga, S.A., 1989.
any country (all medical or scientific journals will be Prevalencia del consumo de cigarrillos en pacientes psiquia-
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Spanish version of the article and enough information Casella, G., Berger, R.L., 2002. Statistical Inference, Second
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Schizophrenia Research 76 (2005) 135 – 157

A meta-analysis of worldwide studies demonstrates an association

Keywords: Schizophrenia; Tobacco; Nicotine; Smoking; Logistic regression

Current smokers in females

Heavy smokers in males

Heavy smokers in females

Heavy smokers in males

Heavy smokers in females

Cessation rates in males

Cessation rates in females

Cessation rates in males

Cessation rates in females

Ever smokers in males

Ever smokers in females

Ever smokers in males

Ever smokers in females

not allow stratifying for other potential confounding 3.1.1. Males

3.2. Comparing current smoking in schizophrenia

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