Psychopharmacology
DOI 10.1007/s00213-014-3525-2
ORIGINAL INVESTIGATION
Smoking improves divided attention in schizophrenia
Eike Ahlers & Eric Hahn & Thi Minh Tam Ta &
Elnaz Goudarzi & Michael Dettling & Andres H. Neuhaus
Received: 22 December 2013 / Accepted: 26 February 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract
Rationale Smoking is highly prevalent in schizophrenia, and
there is evidence for beneficial effects on neurocognition.
Smoking is therefore hypothesized a self-medication in
schizophrenia. Although much effort is devoted to character-
ize those cognitive domains that potentially benefit from
smoking, divided attention has not yet been investigated.
Objectives The aim of this study was to analyze the interac-
tional effects of diagnosis of schizophrenia and smoking his-
tory on divided attention.
Methods We investigated behavioral measures of divided
attention in a sample of 48 schizophrenic patients and 48
controls (24 current smokers and non-smokers each) carefully
matched for age, sex, education, verbal IQ, and smoking
status with general linear models.
Results Most important within the scope of this study, significant
interactions were found for valid reactions and errors of omis-
sion: Performance substantially increased in smoking schizo-
phrenic patients, but not in controls. Further, these interactions
were modified by sex, driven by female schizophrenic patients
who showed a significant behavioral advantage of smokers over
non-smokers, other than male schizophrenic patients or healthy
controls who did not express this sex-specific pattern.
Conclusions Results suggest a positive effect of smoking
history on divided attention in schizophrenic patients. This
study provides first evidence that the complex attention do-
main of divided attention is improved by smoking, which
further substantiates the self-medication hypothesis of
smoking in schizophrenia, although this has been shown
Eike Ahlers and Eric Hahn contributed equally to this work.
E. Ahlers (*) : E. Hahn : T. M. T. Ta : E. Goudarzi : M. Dettling :
A. H. Neuhaus
Department of Psychiatry, Charité University Medicine, Campus
Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany
e-mail: eike.ahlers@charite.de
mainly for sustained and selective attention. Gender-specific
effects on cognition need to be further investigated.
Keywords Nicotine . Tobacco . Cigarettes . Divided
attention . Attention . Dopamine . Cognition . Schizophrenia .
Prefrontal cortex . Sex difference
Introduction
Smoking prevalence is higher in patients with schizophrenia
than in the general population and also compared with other
psychiatric disorders. Moreover, schizophrenic patients show
heavier smoking patterns compared to the general population
(Winterer 2010). One explanation, which is supported by a
plethora of findings, is that tobacco smoking is a form of self-
medication, related to schizophrenia symptoms. For instance,
schizophrenic patients who smoke high-nicotine cigarettes
compared to denicotinized cigarettes performed better in a
verbal memory task and appeared to have transiently reduced
negative symptoms (Smith et al. 2002). Leonard et al. (2007)
could show that variations in the gene coding for nicotinic
alpha7 receptors were associated with a deficit of P50 auditory
sensory gating and schizophrenia. Other researchers found that
nicotine could temporarily improve a number of neurocognitive
deficits associated with schizophrenia, suggesting that nicotine
intake enhances at least some cognitive domains in schizo-
phrenic patients (Depatie et al. 2002; Avila et al. 2003; Sacco
et al. 2005). Own research supports this line of evidence and
suggests that smoking is related with an improvement of selec-
tive attention in schizophrenia (Hahn et al. 2012).
In general, attention deficits form a core cognitive domain
in schizophrenia that may be alleviated by nicotine consump-
tion. For instance, Jacobsen et al. (2004) reported that nicotine
differentially improved performance of schizophrenic patients
during a dichotic two-back task, depending on whether or not

they were smokers. In contrast, healthy controls performed
worse after a nicotine challenge. In a naturalistic study, ciga-
rette smoking first-episode schizophrenic patients had a supe-
rior performance compared to non-smoking patients in the
selective and sustained attention measures (Segarra et al.
2011). Nicotine exposure to non-smoking schizophrenic pa-
tients (Harris et al. 2004; Barr et al. 2008) and nicotine
application after abstinence (Sacco et al. 2005) also demon-
strated an improvement of attention deficits by nicotine.
To the best of our knowledge and in contrast to the well-
studied domain of sustained attention, investigations focusing on
divided attention in this context are largely lacking. This is a
crucial knowledge gap, given that divided attention contributes
to cognition-based diagnostic classification of schizophrenia more
than most attention domains (Shen et al. 2013). Divided attention
refers to the ability to process more than one task at a time and can
be further conceptualized as within-modal and cross-modal divid-
ed attention, depending on whether received stimuli belong to one
or more modalities. The dopaminergic system has been identified
as one of the key players involved in attention processes and gains
importance with increasing levels of task complexity, i.e., when
“executive aspects as divided attention” are required (Coull
et al. 1997). Nicotine affects cognition via presynaptic dopa-
mine release, preferentially in prefrontal areas; accordingly,
prefrontal neuronal activity is modulated by nicotine consump-
tion, especially anterior cingulate cortex and prefrontal cortex
areas (Rezvani and Levin 2001; Newhouse et al. 2004; Hahn
et al. 2009). Consistently, functional magnetic resonance im-
aging (fMRI) data on divided attention tasks showed activa-
tions of ACC and prefrontal cortex areas (Vohn et al. 2007) that
contain a relatively dense array of D1 receptors, as suggested
by autoradiography studies (Palomero-Gallagher et al. 2009).
Although much effort is devoted to characterize cognitive
domains that might potentially benefit from smoking, divided
attention has not yet been systematically investigated. In this
study, we analyzed the interactional effects of diagnosis and
smoking on divided attention in a large cohort of schizophren-
ic patients and carefully matched healthy control participants
in a cross-sectional design.
Materials and methods
Participants
We investigated a sample of 48 clinically stable patients (29
females, 19 males) meeting Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition (DSM-IV) criteria for
schizophrenia. Current regular substance intake other than
nicotine as well as histories of severe medical disorder, severe
neurological disorder, or electroconvulsive therapy led to ex-
clusion from this study. Other exclusion criteria were current
intake of benzodiazepines, presence of extrapyramidal
Psychopharmacology
symptoms, and prescription of biperiden. All patients were
recruited from the inpatient and outpatient units of the
Department of Psychiatry, Campus Benjamin Franklin,
Charité University Medicine, Berlin, Germany. All patients
had unrestricted access to cigarettes and a smoker’s room.
All patients received typical or atypical antipsychotic medica-
tion; calculation of chlorpromazine equivalents followed the
suggestion of Andreasen et al. (2010). Positive and Negative
Syndrome Scale (PANSS) ratings were performed by authors
EH and TMTT within 1 week after neuropsychological testing.
Forty-eight healthy controls (23 females, 25 males) were
matched for age and variables related to smoking behavior,
including smoking status, severity of nicotine dependence,
and lifetime nicotine consumption. No control participant
had a history of substance abuse other than tobacco smoking,
any psychiatric axis I disorder according to DSM-IV, or any
other severe medical or neurological disorder and had never
received any psychopharmacological treatment. A reported
first-degree family history of psychiatric illness also led to
exclusion from the study. All control participants were exam-
ined by a certified psychiatrist prior to inclusion in this study.
Participants were classified as non-smokers (<5 cigarettes
in lifetime) or smokers (daily smoking for at least 24 months);
former/abstinent smokers were not included in this study.
Cross-sectional estimates of severity of nicotine dependence
were provided by the Fagerstroem Test for Nicotine
Dependence (Heatherton et al. 1991) as well as the total
number of cigarettes smoked per day. Longitudinal measures
of life-time nicotine consumption were provided by quantify-
ing years of cigarette smoking as well as cigarette pack years
that were calculated as 20 cigarettes per day times the number
of years as a smoker (Lu et al. 2011).
All participants were right-handed and reported normal or
corrected-to-normal vision. As an estimate of verbal IQ, a
multiple choice vocabulary test (Lehrl et al. 1995) was ap-
plied. Clinical and demographic data of patients and controls
stratified by smoking status are summarized in Table 1. All
participants gave written informed consent before participat-
ing in this study. The study protocol was approved by the
ethics committee of the University Hospital Benjamin
Franklin, Charité University Medicine, Berlin, Germany, and
the study was conducted in accordance with the Declaration of
Helsinki and its amendments.
Cognitive testing
Prior to the experiment, participants were allowed to smoke ad
libitum. Testing was done after approximately 1 h of nicotine
abstinence, thus minimizing both acute nicotine and nicotine
withdrawal effects (Stein et al. 1998).
The effect of smoking on divided attention was analyzed
using the applicable subtest of the test for attention performance
(Testbatterie zur Aufmerksamkeitsprüfung, TAP; Zimmermann
Psychopharmacology

and Fimm 1992). The test was run on a personal computer and
presented on a 17-in. cathode ray tube monitor. Behavioral
responses were collected via a response key. Participants per-
formed a dual task that requiring simultaneous reactions to
visual and auditory stimuli. During the test, varying numbers
of crosses simultaneously appeared on the screen, while at the
same time high and low tones were presented in sequence.
Participants were instructed to press the response key whenever
four crosses formed a square on the screen or when the same
tone was presented twice in a row. Following a training session
of ten trials, 50 test trials were presented. Outcome measures
were mean reaction time, valid reactions, anticipations, errors
of commission, errors of omission, and lapses of attention.
Additionally, all participants were tested with a basic neuropsy-
chological test battery (see Table 1) including a multiple-choice
vocabulary test to estimate (pre-morbid) verbal intelligence
(Lehrl et al. 1995), the Digit Symbol Test, and the Trail
Making Test.
mean reaction time, valid reactions, anticipations, errors of
commission, errors of omission, and lapses of attention with
separate 2×2×2 analyses of covariance (ANCOVAS) that in-
cluded “Diagnostic group,” “Sex,” and “Smoking status” as
fixed factors and “Fagerstroem score” as covariate. For all
ANCOVAs, partial eta-squared served as an estimator of effect
size, i.e., the proportion of variance accounted for by the model.
Tests were performed as two-tailed tests with an alpha level set
at p<0.05.
Results
According to the nicotine self-medication hypothesis in
schizophrenia and for the sake of clarity in presenting the
results, we will here focus on those dependent variables that
showed an interaction of “Diagnostic group”דSmoking sta-
tus,” i.e., valid reactions and errors of omission.

Statistical analyses Valid reactions

Statistical calculations were conducted using IBM SPSS 19.0 ANCOVA indicated a significant main effect of “Diagnostic
(SPSS Inc., Chicago, IL, USA). Demographic, basic neuropsy- group” (F(1, 95)=18.728; p<0.001; η2 =0.177), where schizo-
chological, and clinical data were analyzed with χ2 test and t phrenic patients had fewer valid reactions than healthy controls
tests for independent samples, as appropriate. We analyzed (26.62±4.9 vs. 30.06±2.1). Another significant main effect

Table 1 Summary of demographic, basic neuropsychological, and clinical data

Schizophrenia Control

Smokers Non-smokers Total Smokers Non-smokers Total

N (female/male) 24 (15/9) 24 (14/10) 48 (29/19) 24 (10/14) 24 (13/11) 48 (23/25)

Age (years) 33.6±10.6 37.8±10.5 35.7±10.6 35.0±6.9 32.6±9.6 33.8±8.3
Education (years) 14.0±1.9 13.6±2.0 13.7±1.9 13.7±1.9 14.8±2.2 14.3±2.1
Verbal IQ 107.9±12.6 108.3±13.2 108.1±12.8 107.1±11.4 113.8±15.0 110.4±13.6
Digit Symbol Test 45.8±8.8 45.8±10.9 45.8±9.8a 56.4±10.1b 64.3±7.1b 60.3±9.5a
Trail Making Test—A 34.3±11.0 35.8±12.5 35.1±11.7a 27.2±6.0 26.0±5.0 26.6±5.5a
Trail Making Test—B 85.9±23.1 85.3±32.0 85.6±27.5a 66.9±17.0b 57.1±13.9 62.0±16.1a
Cigarette pack years 12.6±10.8 – – 10.3±8.2 – –
Years of smoking 10.7±7.0 – – 15.1±9.6 – –
Cigarettes per day 22.5±12.3 – – 16.0±11.5 – –
FTND score 5.8±1.9c – – 3.4±2.2c – –
DOI (months) 78.1±90.7 114.9±90.0 96.5±91.3 – – –
N episodes 3.7±4.0 4.2±3.3 3.9±3.7 – – –
PANSS positive scale 12.3±3.8 14.1±4.5 13.2±4.2 – – –
PANSS negative scale 15.2±5.0 16.5±5.2 15.9±5.1 – – –
PANSS general scale 30.6±7.8 32.9±9.4 31.8±8.6 – – –
CPZ equivalents (mg/day) 475.0±313.1 500.2±322.1 487.6±414.5 – – –

FTND Fagerstroem Test for Nicotine Dependence, DOI duration of illness, PANSS Positive and Negative Syndrome Scale, CPZ chlorpromazine
a
Significant between-group differences: schizophrenia vs. control total
b
Significant between-group differences: smokers vs. non-smokers controls
c
Significant between-group differences: schizophrenia vs. control smokers
 Psychopharmacology

was found for “Smoking status” (F(1, 95)=5.175; p<0.05;
η2 =0.056), where non-smokers had fewer valid reactions than
smokers (27.40±5.2 vs. 29.28±2.5). When following the in-
teraction of “Diagnostic group”דSmoking status” (F(1, 95)=
5.508; p<0.05; η2 =0.060), we found that smoking schizo-
phrenic patients performed significantly better than non-
smoking patients (28.44±2.4; T(46)=2.769; p<0.01) while
there was no difference between smokers and non-smokers in
healthy controls (30.13±2.3 vs. 30.00±2.0; see Fig. 1a). This
interaction was further modified, thus resulting in a tripartite
interaction of “Diagnostic group”דSmoking status”דSex”
(F(1, 95)=7.114; p<0.01; η2 =0.076), which was driven by
female schizophrenic patients who showed a significant be-
havioral advantage of smokers over non-smokers (28.53±2.4
vs. 22.86±6.7; T(27)=3.081; p<0.01), other than male schizo-
phrenic patients (28.30±2.4 vs. 27.50±3.7) or healthy controls
(female 29.20±3.1 vs. 30.54±1.9; male 30.79±1.3 vs. 29.36±
2.0; see Fig. 1b) who did not express this sex-specific pattern.
Errors of omission
When examining errors of omission, we observed a similar
pattern with significant main effects of “Diagnostic group”
(schizophrenia vs. control 4.00±4.7 vs. 1.02±1.5; F(1, 95)=
15.647; p< 001; η2 = 0.152) and “Smoking status” (non-
smokers vs. smokers 3.48±4.8 vs. 1.54±2.0; F(1, 95)=
9.135; p<0.005; η2 =0.095). The interaction of “Diagnostic
group”דSmoking status” (F(1, 95)=6.129; p<0.05; η2 =
0.066) was based on a superior performance of smoking vs.
non-smoking schizophrenic patients (2.21±2.2 vs. 5.79±5.8;
T846)=−2.816; p<0.01); there was no difference between
smokers and non-smokers in healthy controls (0.88±1.6 vs.
1.17±1.4; see Fig. 2a).
Again, the interaction of “Diagnostic group”דSmoking
status” was modified by the factor “Sex” (F(1, 95)=4.478;
p<0.05; η2 =0.049) that was driven by female schizophrenic
patients who showed a clear behavioral advantage of smokers
over non-smokers (2.13±2.2 vs. 7.36±7.0). This difference
was not present in male schizophrenic patients (2.33±2.4 vs.
3.60±2.7) or in healthy controls (female 1.50±2.3 vs. 0.85±
1.1; male 0.43±0.6 vs. 1.55±1.7; see Fig. 2b).
Discussion
This is the first study aiming at investigating the effects of
smoking history on performance in a cross-modal divided
attention task in schizophrenia compared with matched
healthy controls. We conducted a cross-sectional study to
address the question, whether divided attention is affected

a b
35

30
N valid reactions

25
non-smokers
20
smokers

15

10

0
female male
Controls

35

30
*
N valid reactions

25

20 non-smokers
smokers
15

10

0
female male
Schizophrenia

Fig. 1 a Combined scatter plot of lifetime nicotine consumption in pack status. Differences in number of valid reactions in this task are driven by
years (abscissa) vs. number of valid reactions in a cross-modal divided smoking status in female schizophrenic patients. Error bars denote stan-
attention task for healthy controls and schizophrenic patients. b Controls dard error of the mean
(top) and schizophrenic patients (bottom) stratified for sex and smoking
Psychopharmacology
a b
Fig. 2 a Combined scatter plot of lifetime nicotine consumption in pack
years (abscissa) vs. number of errors of omission in a cross-modal divided
attention task for healthy controls and schizophrenic patients. b Controls
(top) and schizophrenic patients (bottom) stratified for sex and smoking
by chronic nicotine consumption, similarly to existing studies
within the sustained or the selective attention domains. We
found significant improvements of behavioral performance
regarding valid reactions and errors of omission in schizo-
phrenia, but not in healthy controls. Moreover, this dissocia-
tion was mainly driven by female schizophrenic patients.
In general, the pattern of results is consistent with studies
investigating the effect of smoking history on attention and
working memory that found beneficial effects in schizophren-
ic patients and no or detrimental effects in healthy controls
(George et al. 2002; Harris et al. 2004; Jacobsen et al. 2004;
Barr et al. 2008; Segarra et al. 2011; Hahn et al. 2012). This
dissociation may be explained by nicotine’s agonistic action
on dopaminergic neurons in the ventral tegmental area that
project to the prefrontal cortex (Imperato et al. 1986) and the
inverted U-shaped function of prefrontal dopamine receptors
(Vijayraghavan et al. 2007). As a consequence of the func-
tional prefrontal D1 deficit, schizophrenic patients are thought
to be located on the ascending left part of the inverted U
function; in contrast, healthy controls are thought to be located
around the top of the curve, corresponding to an optimal D1
receptor activation. Nicotine mediates the release of dopa-
mine, which in turn leads to a rightward shift on that curve.
Given the different starting points of schizophrenic patients
and healthy controls, this shift differentially affects D1 recep-
tor activation and, as a consequence, dopamine-mediated
8
N errors of omission
6
5
non-smokers
4 smokers
0
female male
Controls
10
9 *
8
N errors of omission
7
6 non-smokers
smokers
5
4
3
2
1
0
female male
Schizophrenia
status. Differences in number of omission errors in this task are driven by
smoking status in female schizophrenic patients. Error bars denote stan-
dard error of the mean
cognitive functions: While schizophrenic patients move to-
ward the curve maximum, controls may either show very little
effect or move toward an unfavorable D1 receptor activation
state. This mechanism is thought to underlie the growing body
of findings in schizophrenia, e.g., in working memory
(George et al. 2002) or selective attention (Hahn et al. 2012),
and may also explain unaffected behavioral measures (Hahn
et al. 2009) as well as performance decrements in healthy
controls in corresponding studies (Ernst et al. 2001;
Lawrence et al. 2002; Jacobsen et al. 2004, 2005).
Our results were mainly driven by female patients, which
may be indicative of an undetected population stratification
effect in our sample other than those demographic variables
that were controlled for across groups (smoking vs. non-
smoking; schizophrenia vs. control). In line with this thought,
Goldstein et al. (1998) studied cognition in schizophrenia and
found sex-related differences in various cognitive domains with
better performance of female compared with male schizophren-
ic patients. They discussed the heterogeneity of previously
reported data as being due to different sampling strategies; here,
differences in the clinical course of the disorder between males
and females are likely to contribute to this gender effect.
On the other hand, this result may serve as a starting point
for gender-specific effects of nicotine, similar to gender-
specific effects on cognition (Neuhaus et al. 2009). Data on
sex effects on prefrontal cognition in schizophrenia are still

controversial (Roesch-Ely et al. 2009), and studies investigat-
ing divided attention in this context are currently missing.
There is evidence, however, for an impact of sex hormones
on dopamine-dependent cognitive processes as a potential
mechanism for differences in cognitive performance.
Estradiol has been found to be associated with decision making
in a reward paradigm in rats (Uban et al. 2012). In humans,
estrogen seems to modulate working memory performance in
healthy women as a function of baseline dopamine in the
prefrontal cortex (Jacobs and D'Esposito 2011). In a recent
review, Sacher et al. (2013) conclude that there is “preliminary
evidence for neuroplastic changes across the menstrual cycle”
in various brain areas. Hence, controlling for the phase of the
menstrual cycle in female participants is warranted in the future,
and the lack of doing so most probably constitutes a method-
ological limitation, which is also true for the current study.
Two other limitations have to be acknowledged. First, no
objective control of nicotine dose is available for this study.
Although we sought to minimize both acute nicotine and
nicotine withdrawal effects by testing after approximately
1 h of nicotine abstinence, it cannot be ruled out that the
resulting data are heterogeneous due to individual smoking
habits. A control via measurement of serum cotinine or of
expired carbon monoxide levels would have been a more
favorable measure of nicotine dose than the history of
smoking behavior. Second, the cross-sectional nature of our
study does not permit to conclude whether the observed
associations between chronic smoking patterns and divided
attention in schizophrenia were caused by smoking or whether
they preceded its initiation. Pre-existing differences between
smokers and non-smokers with schizophrenia might consti-
tute unmeasured confounding variables, and other explana-
tions like the addiction vulnerability hypothesis (Chambers
et al. 2001) cannot be ruled out by the current study design.
In sum, however, first evidence is presented that divided
attention is responsive to smoking history in schizophrenia.
This study thus adds to the growing body of evidence in favor
of the self-medication hypothesis of nicotine in schizophrenia.
Acknowledgments We would like to thank all participants of this study
for contributing their time and effort. This study is part of the doctoral
thesis of Elnaz Goudarzi.
Conflict of interest There is no conflict of interest for any of the
authors.
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