Psychiatry Research 246 (2016) 1–8

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Schizophrenia, smoking status, and performance on the matrics

Cognitive Consensus Battery
Alexandra C. Reed a, Josette G. Harris a, Ann Olincy a,b,n
a
Center for Schizophrenia Research, Department of Psychiatry, University of Colorado, 13001 East 17th Place, Aurora CO 80045, USA
b
Health Sciences Center, Veterans Affairs Medical Research Service, Denver, CO, USA

art ic l e i nf o a b s t r a c t

Article history: Cognitive deficits and high rates of nicotine dependence are consistently documented in the schizo-
Received 19 December 2015 phrenia literature. However, there is currently no consensus about how regular smoking influences
Received in revised form cognition in schizophrenia or which cognitive domains are most affected by chronic smoking. Previous
21 August 2016
studies have also failed to disambiguate the effects of chronic nicotine from those of acute exposure. The
Accepted 27 August 2016
current study uses a novel approach to testing nicotine addicted patients at a time-point between acute
Available online 9 September 2016
enhancement and withdrawal and implements the MATRICS Cognitive Consensus Battery (MCCB) to
Keywords: compare the overall cognitive performance of regular smokers (n¼ 40) and nonsmokers (n¼36) with
Schizophrenia schizophrenia. Controlling for age, gender, and education, smokers with schizophrenia were significantly
Nicotine
more impaired on a visual learning task, the Brief Visuospatial Memory Test-Revised (BVMT-R), than
Smoking
their nonsmoking peers. Among smokers, smoking behavior (i.e., exhaled carbon monoxide levels of
MATRICS
Cognition smokers) predicted BVMT-R T score; greater smoking was associated with more impaired visual learning.
Self-Medication Negative symptom severity was not predictive of greater visual learning deficits in smokers or non-
smokers. Future longitudinal research will be required to determine if there is a dose-response re-
lationship between chronic nicotine and visual learning impairment in patients at various stages of
psychotic illness.
& 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction impacting sustained attention (Sacco et al., 2005) and visuospatial

Individuals with serious mental illness (SMI) abuse nicotine-
containing tobacco products at high rates. Experts estimate that
65–90% of patients with schizophrenia are regular smokers (Aubin
et al., 2012). The dramatic association between SMI and nicotine
use has spurred research and debate over nicotine's effects on
attention and cognition. Empirical investigations of both the short-
term and long-term effects of nicotine on cognitive functions have
yielded mixed results. One theory suggests that nicotine self-ad-
ministration is a form of self-medication for the negative symp-
toms and cognitive deficits associated with psychotic disorders
(Kumari and Postma, 2005; Evans and Drobes, 2009).
Acute nicotine can improve the performance of patients with
schizophrenia on cognitive tasks including measures of novelty
detection memory (Jubelt et al., 2008), spatial organization and
verbal memory (Smith et al., 2002), and sustained attention (Barr
et al., 2008). Withdrawal can induce cognitive impairments,
n
Correspondence to: Department of Psychiatry, University of Colorado Denver,
13001 East 17th Place, Aurora, CO 80045, Mail Stop F546, USA.
E-mail addresses: alexandraclairereed@gmail.com (A.C. Reed),
josette.harris@ucdenver.edu (J.G. Harris), ann.olincy@ucdenver.edu (A. Olincy).
working memory (George et al., 2002).
However, the cognitive effects of chronic nicotine use in this
population are less clear. Existing cross-sectional studies have
crucial methodological and sampling differences. The definitions
of “smoker,” “nonsmoker,” and “former smoker,” change with each
investigation. Studies have employed a wide range of cognitive
batteries representing diverse cognitive domains, varying in
duration, order of testing, and comparability. Differences between
smoking and non-smoking groups on clinical measures of symp-
tomology and severity of illness are inconsistent across studies.
Additionally, when to allow the use of nicotine is critical and
varies.
One of the first studies to compare the cognitive performance
of smokers with schizophrenia (n ¼ 23, Mage¼ 43.9) to non-
smoking outpatients (n ¼ 8, Mage ¼41.5) was George et al. (2002).
Smokers were determined to have a Fagerstrom Test for Nicotine
Dependence (FTND) score greater than 5, carbon monoxide (CO)
level greater than 10 ppm, cotinine levels of more than 150 ng/ml
(plasma) and 600 ng/ml (urine), and reported smoking at least 20
cigarettes per day. Nonsmokers and smokers were evaluated on
the computerized Stroop Color Word Test (SCWT) and the Vi-
suospatial Working Memory (VSWM) task. At baseline evaluations,

http://dx.doi.org/10.1016/j.psychres.2016.08.062
0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.
2 A.C. Reed et al. / Psychiatry Research 246 (2016) 1–8
it was unclear when the smokers had last smoked. Nonsmokers
had significantly higher total scores on the Positive and Negative
Syndrome Scale (PANSS) than smokers and significantly more
negative symptoms. In contrast, smokers reported significantly
more depression on the Beck Depression Inventory (BDI) than
their nonsmoking peers. George et al. (2002) observed that smo-
kers had better VSWM performance than nonsmokers. However,
this difference failed to reach statistical significance (p¼ 0.20).
These results were negative, perhaps due to the small sample size
of the non-smoking group.
To further clarify how chronic smoking affects cognitive func-
tioning in adult outpatients with schizophrenia, Wing et al. (2011)
compared the performance of current smokers (n ¼38,
Mage ¼41.9), former smokers (n ¼16, Mage ¼42.5), and never
smokers (n ¼26, Mage ¼42.5) on a neuropsychological battery.
Current smokers had FTND scores of at least 5, CO level of greater
than 10 ppm, and were smoking at least 10 cigarettes per day.
Former smokers had quit smoking at least 6 months before study
enrollment, and never smokers had smoked fewer than 100 life-
time cigarettes. Both former smokers and never smokers had CO
levels that were less than 10 ppm. Importantly, current smokers
were not deprived of nicotine more than 30 min throughout
cognitive testing. The cognitive battery was composed of the
Conners’ Continuous Performance Test (CPT), the SCWT, and the
Wisconsin Card Sorting Test (WCST) to examine sustained atten-
tion, response inhibition and processing speed, and cognitive
flexibility respectively. Although the schizophrenia groups were
similar in negative and positive symptoms, current smokers had
significantly lower IQ than former smokers. Controlling for IQ,
never smokers demonstrated lower CPT hit rate and slower reac-
tion time on SCWT (across congruent, neutral, and incongruent
trials) than former or current smokers. The authors came to the
same conclusion as George et al. (2002), that never smokers with
schizophrenia have more severe cognitive deficits than current or
former smokers with this disorder (Wing et al., 2011). However,
they did not replicate the neurocognitive findings as they selected
different cognitive tests. Furthermore, there were disparate find-
ings on the one task that was shared between studies (SCWT),
possibly due to differences in sample size and clinical character-
istics (differences between groups on depression, PANSS and ne-
gative symptoms).
A third study, Morisano et al. (2013), used the same criteria for
their smoking and nonsmoking groups as Wing et al. (2011) except
that smokers had at least 15 cigarettes per day. As in Wing et al.
(2011), smokers (n ¼ 32, Mage ¼41.3) and nonsmokers (n ¼15,
Mage ¼39.9) were similar for positive and negative symptoms,
and smoking participants did not go longer than 30 min without
smoking during the cognitive testing. The neurocognitive assess-
ment included CPT, Trail Making Test, WCST, VSWM, Digit Span,
and the California Verbal Learning Test (CVLT-II). Smoking patients
outperformed nonsmoking patients on specific domains of the
CVLT-II; smokers correctly recalled more items after short and long
delays when semantic cues were provided and when a forced
choice between words was offered (during recognition). Although
Morisano et al. (2013) had similar design and sample to Wing et al.
(2013), and demonstrated worse cognition in non-smokers with
schizophrenia, they did not replicate the specific finding of lower
CPT hit rate. The authors cite “methodological, statistical and po-
pulation differences between this and other studies” to explain the
discrepancies (Morisano et al., 2013, p. 51).
Cumulatively, the results of Morisano et al. (2013) Wing et al.
(2011) and George et al. (2002) suggest chronic nicotine has po-
sitive effects on cognitive functioning in schizophrenia. However,
some suggest that chronic nicotine may further impair cognitive
deficits. In a large sample of male Han Chinese inpatients with
schizophrenia, Zhang et al., (2002) compared the performance of
nonsmokers with schizophrenia to smokers with schizophrenia on
the Repeatable Battery for the Assessment of Neuropsychological
Status (RBANS). Current smokers (n ¼456) were defined as in-
dividuals who smoked at least one cigarette per day for at least a
year. Nonsmokers (n ¼124) were made up of former smokers (n
¼20) (individuals who had previously smoked at least one cigar-
ette per day and successfully quit for at least a year) and never
smokers (n ¼104) (participants who reported smoking less than
100 lifetime cigarettes). Smokers (Mage ¼48.6) were significantly
older than nonsmokers (Mage ¼46.3). Current smokers were al-
lowed to smoke before testing and were offered smoking breaks
during the test session. As in George et al. (2002), Zhang et al.
(2012) found that their nonsmokers had significantly more nega-
tive symptoms than their smoker group. However, the study's
primary finding was that smokers scored significantly lower than
nonsmokers on the RBANS total score and two subscales: Vi-
suospatial /Constructional and Immediate Memory. The perfor-
mance differences on the RBANS total score and on the Visuos-
patial/Constructional index remained significant even when the
authors controlled for differences in age, number of hospitaliza-
tions, PANSS total score, negative symptoms, antipsychotic drugs,
and anticholinergic drugs. These findings are incompatible with
George et al. (2002), in which smokers outperformed nonsmokers
on visuospatial memory tasks.
Further investigations comparing smokers with schizophrenia
to nonsmokers with schizophrenia include a study by Iasevoli
et al. (2013) which examined cognitive differences in outpatients
with treatment resistant schizophrenia (TRS). TRS patients were
defined as individuals who had not responded to, “at least two or
three antipsychotic agents” (Iasevoli et al., 2013, p 1114). Their
nonsmoking group (n ¼28) smoked less than 100 lifetime cigar-
ettes and less than one cigarette per day at the time of enrollment
and their smoker group (n ¼31) smoked more than one cigarette
each day for more than one year. Smokers (Mage ¼37.61) and
nonsmokers (Mage ¼ 36.67) enrolled were slightly younger than
previously tested groups. Smoker TRS patients had significantly
higher scores on the total PANSS than nonsmokers. This difference
was driven by high negative symptom ratings in the smoker TRS
patients. Although the authors state that all smoking participants
had their last cigarette, “within 1 h from assessments,” (Iasevoli
et al., 2013, p1115) the PANSS and the Personal and Social Perfor-
mance Scale (PSP) were completed before the cognitive testing,
which was assessed with the Brief Assessment of Cognition in
Schizophrenia (BACS). Cognitive domains assessed by the BACS
were the following: verbal memory by the List Learning task,
working memory by the Digit Sequencing task, verbal fluency by
the Category Instances task, processing speed by the Symbol
Coding task, problem solving by the Tower of London task, and
motor speed by the Token Motor task. Smokers and nonsmokers
with TRS performed similarly on the BACS with an important ex-
ception; smokers performed significantly worse than nonsmokers
in the problem solving domain. Across both the nonsmoker and
smoker groups, poorer cognitive performance was associated with
more severe negative symptoms. The authors state their results
may indicate that smokers with TRS schizophrenia are more cog-
nitively impaired than TRS nonsmokers. Although this is a similar
finding to Zhang (2012), of more severe deficits in smokers, the
samples differed in the distribution of negative symptoms be-
tween groups and highlighted different domains where cognitive
deficits were most pronounced.
Based on the current literature, it is unclear how chronic
smoking influences cognition in schizophrenia. There is also little
consensus over which cognitive domains are most affected by
chronic nicotine abuse and how chronic smoking relates to clinical
symptomology. Most prior studies targeting these questions have
allowed patients to smoke before or during testing to avoid testing
 A.C. Reed et al. / Psychiatry Research 246 (2016) 1–8 3

patients when they are in withdrawal; nicotine withdrawal wor- Table 2

sens cognitive performance (AhnAllen et al., 2008; Sacco et al., Antipsychotic Medications of All Participants.
2005; George et al., 2002). However, this methodology introduces
Antipsychotic Medication Smokers Nonsmokers (n¼ 36)
a confound. It obscures the unknown effects of chronic smoking (n¼ 40)
with the known enhancing effects of acute nicotine.
The present study takes a novel approach to finding the “sweet No Antipsychotics 1 2
Risperidone Only 6 10
spot” for cognitive testing with patients who are using nicotine. To
Risperidone, Aripiprazole 2 0
avoid testing participants who were in acute enhancement or Risperidone, Asenapine 0 1
withdrawal, we chose to administer cognitive measures at least Risperidone, Quetiapine 1 0
30 min after our participants smoked their last cigarette. Our aim Risperidone, Olanzapine 1 0
was to test our participants when nicotinic receptors were at a Olanzapine Only 5 8
Olanzapine, Aripiprazole 1 0
stage between acute activation and desensitization. The current
Olanzapine, Quetiapine 1 0
study also employs the Measurement and Treatment Research to Quetiapine Only 3 1
Improve Cognition in Schizophrenia Consensus Cognitive Battery Quetiapine Fumarate Only 0 1
(MATRICS CCB, Nuechterlein et al., 2008) a test battery, which was Quetiapine, Asenapine 1 0
Aripiprazole Only 2 3
specifically designed to aid the development of pharmacological
Ziprasidone Only 1 0
treatments for the neurocognitive deficits in schizophrenia (Green Ziprasidone, Quetiapine Fumarate 1 0
et al., 2004). The MCCB is a new gold standard for schizophrenia Paliperidone Palmitate 2 1
research as it affords comparisons of overall cognitive functioning Asenapine 0 2
(composite score) and performance across seven distinctive cog- Lurasidone 0 1
Haloperidol Only 2 3
nitive domains (e.g., speed of processing, attention/vigilance, Fluphenazine Only 2 1
working memory, verbal learning, visual learning, reasoning and Perphenazine Only 3 0
problem solving, and social cognition). The purpose of this study Loxapine 1 0
was to determine whether chronic smoking was associated with Haloperidol, Perphenazine 1 0
Ziprasidone, Thiothixene 1 0
significantly diminished or enhanced cognitive functioning in a
Haloperidol, Risperidone 1 0
sample with schizophrenia. Olanzapine, Lurasidone, Fluphenazine 1 0
Decanoate
Perphenazine, Asenapine, Quetiapine 0 1
Perphenazine, Olanzapine 0 1
2. Methods

2.1. Participants
into groups based on smoking status. Current smokers were de-
Seventy-Six current smokers, former smokers, and never fined as individuals who had smoked at least one cigarette per day
smoking participants with schizophrenia or schizoaffective dis- and had been smoking at least one month (n ¼40). Detailed
order, between ages 20 and 62 inclusive, Mage ¼ 45 years smoking histories were obtained from 92.5% of current smokers
(SDage ¼12.92 years), were recruited from the community, the (Table 1). Former smokers were participants who reported no
Denver VA, and the University of Colorado School of Medicine's smoking within the last month, but previous lifetime smoking of
outpatient psychiatric clinic (Table 1). Diagnoses of schizophrenia at least one cigarette per day for at least a month (n ¼ 8). Never
and schizoaffective were confirmed by SCID-I administration at smokers reported no lifetime nicotine use or quit attempts (n
the screening visit (First et al., 1997). Participants were divided ¼28). Former smoking and never smoking statuses were con-
firmed by exhaled carbon monoxide levels of less than 10 ppm.
Table 1 Due to a small sample size of former smokers, former smokers and
Demographics of Smokers and Nonsmokers with Schizophrenia. never smokers were treated as one group, current nonsmokers (n
¼36), for all major analyses.
Characteristic Smokers (n ¼ 40) Nonsmokers Test for At the time of study enrollment, 3 participants were not on
(n ¼ 36) significance
antipsychotic medications (1 smoker, 2 nonsmokers), 13 partici-
Gender 8 Female 11 Female X2(1, n ¼ 76) ¼ pants were on typical antipsychotics (9 smokers, 4 nonsmokers),
32 Male 25 Male 1.13, p o 0.29 55 patients were on atypical antipsychotics (27 smokers, 28 non-
Diagnosis 29 Schizophrenia 27 Schizophrenia X2(1, n ¼ 76) ¼ smokers), and 5 participants were on a combination of typical and
11 Schizoaffective 9 Schizoaffective 0.06, p o 0.81
atypical antipsychotic medications (3 smokers, 2 nonsmokers)
Age (years) 44.20 7 13.30 45.14 7 12.66 t(74) ¼ 0.31, p ¼
Mean 7 SD 0.75 (Table 2). Only decisionally capable individuals were eligible to
Education 12.65 7 2.26 14.32 7 1.98 t(74) ¼ 3.41 p ¼ participate. Exclusion criteria were current substance abuse or
(years) 0.001n dependence, positive urine drug screen, current use of smokeless
Mean 7 SD tobacco or nicotine replacement therapy (e.g., e-cigarettes, chew,
Cigarettes per 20.08 7 11.23 – –
day
nicotine gum or patch), pregnancy, neurological disorder, history
Mean 7 SD of severe head trauma, and current suicidal ideation. The study
Range 4.00  60.00 – – was approved by the Colorado Multiple Institutional Review
Pack years Board. Prospective participants received a complete description of
Mean 7 SD 22.64 7 20.47 – –
the study, were asked questions to ensure their understanding of
Range 0.06  90.00 – –
Pre-MCCB CO the procedures, and provided written informed consent at the
level screening visit. Patients received compensation for participation
(ppm) 24.83 7 17.47 2.06 7 1.22 – and travel to and from the study was provided if required.
Mean 7 SD 3.00  89.00 0.00 – 6.00 – After consent procedures, clinical assessments were performed
Range
by a research psychiatrist (A.O.). All participants completed the
n
Indicates a significant difference po 0.05, smokers were significantly less Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962),
educated than nonsmokers. the Scale for the Assessment of Negative Symptoms (SANS)
4 A.C. Reed et al. / Psychiatry Research 246 (2016) 1–8

Table 3
Clinical Symptoms and MCCB Scores of Smokers and Nonsmokers (mean 7 SD).

Measure Nonsmokers N ¼ 36 Mean 7 SD Smokers N¼ 40 Mean 7 SD t df p

Scale for the Assessment of Negative Symptoms

Total SANS Score 4.25 7 2.79 5.28 7 2.99 1.54 74 0.127
Affective flattening 0.67 7 0.99 0.58 7 0.96 0.41 74 0.682
Alogia 0.19 7 0.58 0.35 7 0.74 1.02 74 0.312
Anhedonia 1.94 7 1.37 2.25 7 1.30 1.00 74 0.321
Avolition/Apathy 1.44 7 1.03 2.10 7 1.24 2.50 74 0.015nn
Brief Psychiatric Rating Scale
BPRS Total Score 35.50 7 7.65 36.63 7 9.83 0.55 74 0.577
Calgary Depression Scale for Schizophrenia
CDSS Total Score 3.53 7 3.71 4.00 7 4.15 0.52 72.5 0.604
MCCB Domain Score (age, gender and education corrected)
Speed of Processing (TMT, BAC SC, and Fluency) 38.36 7 11.41 36.28 7 14.15 0.70 74 0.485
Attention/Vigilance (CPT-IP) 36.19 7 13.36 35.30 7 14.16 0.28 74 0.778
Working Memory (WMS-III and LNS) 42.75 7 12.28 40.00 7 13.96 0.91 74 0.367
Verbal Learning (HVLT-R) 41.56 7 10.56 40.60 7 9.66 0.41 74 0.681
Visual Learning (BVMT-R) 46.00 7 10.69 37.43 7 13.36 3.07 74 0.003n
Reasoning and Problem Solving (NAB Mazes) 56.67 7 16.37 51.00 7 13.53 1.65 74 0.103
Social Cognition (MSCEIT) 42.42 7 12.39 38.88 7 12.00 1.27 74 0.210
MCCB Overall Composite (All tests) 36.97 7 12.49 31.35 7 14.66 1.79 74 0.078

nn
SANS subscale Avolition/Apathy did not remain statistically significant after Bonferroni alpha-level correction p o0.01.
n
MCCB Visual Learning remained statistically significant after Bonferroni alpha-level correction p o 0.00625.

(Andreasen,1982) and the Calgary Depression Scale for Schizo-
phrenia (CDSS) (Addington, Addington, and Schissel, 1990) (Ta-
ble 3). On the first study visit, participants also completed health
history questionnaires, a current medications list, and provided
urine samples that were screened for recreational drugs and
pregnancy.
Cognitive measures were administered at a second study visit.
Smoking participants were not instructed to abstain or change
their normal smoking routine before this study visit. A trained
research assistant recorded vital signs (blood pressure and pulse)
and CO level (Vitalograph Breath CO carbon monoxide monitor,
Lenexa, KS) before cognitive testing began.
2.2. Cognitive measures: MCCB
The MATRICS Consensus Cognitive Battery, a brief cognitive test
battery specifically designed for use in schizophrenia clinical trials
and cognitive remediation research (MCCB Forms A and B:
Nuechterlein et al., 2008), was administered individually to all
participants. To reduce the potential for participant discomfort and
nicotine withdrawal effects on cognitive testing, the MCCB was
administered within two hours of the participant's arrival. Smok-
ing participants who requested a smoke break before the cognitive
testing session were allowed to smoke; however, participants who
smoked were required to wait at least 30 min before beginning the
cognitive testing.
The MCCB takes approximately 65 min to complete and is
composed of ten subtests, which map on to seven cognitive do-
mains. These domains are 1. Speed of processing (comprised of
Brief Assessment of Cognition in Schizophrenia: Symbol Coding,
Category Fluency: Animal Naming, and the Trail Making Test: Part
A), 2. Attention/Vigilance (comprised of the Continuous Perfor-
mance Task-Identical Pairs), 3. Working memory (comprised of the
Wechsler Memory Scale Spatial Span and the Letter-Number
Span), 4. Verbal learning (comprised of the Hopkins Verbal
Learning Test), 5. Visual learning (comprised of the Brief Visuos-
patial Memory Test-Revised), 6. Reasoning and problem solving
(composed of the Neuropsychological Assessment Battery: Mazes),
and 7. Social cognition (comprised of the Mayer-Salovey-Caruso
Emotional Intelligence Test: Managing Emotions). Raw scores were
double-checked and corrected by a second rater. Scores from each
test were double entered into the MCCB computer scoring
program to produce t-scores, percentiles, and composite scores
corrected for age, gender, and education level.
2.3. Statistical analyses
Statistical analyses were completed using SPSS version 22.0.
Significance was set at p o0.05. A one-way ANOVA with a post
hoc Tukey HSD test was used to evaluate group differences be-
tween current smokers, former smokers, and never smokers on
our MCCB outcomes. No difference was found between former and
never smokers in the post hoc analysis; therefore we collapsed the
groups and performed other tests on two groups, current smokers
(n ¼40) and nonsmokers (n ¼36). Categorical data were analyzed
using X2 test and two-tailed independent samples t-tests were
used to evaluate for group differences on continuous demographic
variables. Independent two-tailed t-tested were also used to de-
termine group differences on the MCCB total and 7 individual
domains. Although there are 10 subtests on the MCCB, which yield
raw scores individually, several related subtests measuring the
same functional cognitive domains were grouped for analysis. To
control for multiple comparisons, Bonferroni corrections were
applied to the resulting seven MCCB cognitive domain tests. The
alpha level was divided by the number of comparisons (i.e., the
Bonferroni alpha level was 0.05/8 measures or 0.00625).
T-tests were also used to determine relationships between
group (smoking status), gender, clinical symptoms, and cognitive
test scores. Tests of clinical ratings with multiple domain scores
were also Bonferroni corrected. Relationships between significant
domain scores and carbon monoxide levels were assessed using
Pearson's product moment correlation coefficients. The relation-
ships between significant cognitive domains and negative symp-
toms were also assessed with correlations.
3. Results
3.1. Demographics
Smokers and nonsmokers did not differ in age or gender dis-
tribution (Table 1). However, nonsmokers completed significantly
more years of education than smokers with schizophrenia, t(74) ¼
3.41 p ¼0.001. This is consistent with the fact that in the general
 A.C. Reed et al. / Psychiatry Research 246 (2016) 1–8
population, smoking is associated with lower educational attain-
ment (Latvala et al., 2014; Wagenknecht et al., 1990). Although the
authors of the MCCB suggest controlling only for age and gender
when deriving normative scores for clinical trials for schizophrenia
(Nuechterlein and Green, 2006), all MCCB scores used in this study
were corrected for age, gender, and education level. This choice
was made because nonsmokers and smokers had statistically
significantly different levels of educational attainment. As there
were a number of older people in the sample, we additionally
conducted an ANCOVA to assess the effect of the covariate age on
the dependent variable BVMT-R and the independent variable
smoking status. There was no significant effect of age as a cov-
ariate F(1,73) ¼3.024, p ¼0.086, N.S. Thus we felt it was appro-
priate to include the entire sample regardless of age.
Nonsmoking and smoking participants had similar levels of
negative symptoms (total SANS), psychiatric symptoms (total
BPRS), and depression (CDSS) (Table 3). Smokers were more
symptomatic then nonsmokers on the avolition/apathy subscale of
the SANS, t(74) ¼2.50, p ¼0.015. However, this finding did not
survive Bonferroni correction (α ¼0.01).
3.2. Hypothesis Testing
Table 3 compares cognitive domain scores on the MCCB by
smoking status. While smokers achieved lower average overall
composite scores than nonsmokers on the MCCB, this difference
was not statistically significant (p¼ 0.078). Average scores across
all of the distinct MCCB domains were lower for smokers than
nonsmokers; however, differences in speed of processing, atten-
tion/vigilance, reasoning/problem solving, working memory, ver-
bal learning, and social cognition failed to reach significance.
Smokers (M ¼37.43, SD ¼13.36) were significantly more im-
paired than nonsmokers (M ¼46.00, SD ¼10.69) on the visual
learning domain (BVMT-R task), t(74) ¼3.07, p ¼0.003 (Fig. 1). This
finding remained statistically significant when participants who
were not on antipsychotic medication (n ¼ 3) were excluded, and
it survived Bonferroni correction.
A one-way ANOVA was used to determine if former smokers
performed differently from never smokers or current smokers on
the BVMT-R. Although there was a statistically significant differ-
ence between groups, (F(2, 73) ¼4.94, p ¼ 0.010)), this indicated
the significantly lower scores of smokers compared to never
smokers on the BVMT-R. A Tukey HSD post-hoc test revealed no
60
* tested by the MCCB, the only statistically significant difference by
BVMT-R Scores
40
20
0 et al., 2002), which suggests that smokers with schizophrenia are
Smokers Nonsmokers
Fig. 1. Comparison of schizophrenia smokers to nonsmokers on the BVMT-R scores
(Mean 7 SD).
5
90
80
70
CO Level (ppm)
60
50
40
30
20
10
0
0 10 20 30 40 50 60 70
BVMT-R T-Score
Fig. 2. Correlation between carbon monoxide levels in schizophrenia smokers and
visual learning as measured by the BVMT-R T score.
statistically significant differences between former smokers and
either current smokers or never smokers on BVMT-R T scores
(p ¼0.081).
Gender distribution did not differ between smoking and non-
smoking groups and BVMT-R score was not significantly different
by gender t(74) ¼0.375, p ¼ 0.71. Non-smoking females out-
performed smoking females on the BVMT-R t(17) ¼ 2.23, p ¼0.040
and non-smoking males outperformed smoking males t(55) ¼2.33,
p¼ 0.023. There were no significant differences on visual learning
by gender within groups; nonsmoking male and females per-
formed similarly on the BVMT-R, t(34) ¼0.10, p¼ 0.921, as did
smoking males and females, t(38) ¼ 0.958, p ¼0.34. Nor did females
smoke significantly less than males based on pretest CO levels,
t(38) ¼1.244, p ¼0.22.
For the current smoker only group, MCCB BVMT-R T-scores
were negatively correlated with pretest carbon monoxide levels,
r(40) ¼  0.32, p ¼0.045 (Fig. 2).
Despite the trend-level finding that smokers had more avoli-
tion and apathy on the SANS than the nonsmokers, higher levels of
avolition/apathy in smokers were not associated with greater vi-
sual learning impairment r(40) ¼  0.16, p ¼0.31 or higher CO le-
vels r(40) ¼  0.16, p ¼0.32. Similarly, higher levels of avolition/
apathy were not predictive of lower BVMT-R scores in nonsmoking
participants, r(36) ¼ 0.06, p ¼0.72.
4. Discussion
The present study examined cognitive differences in non-
smokers and chronic smokers with schizophrenia. Although non-
smoking participants outperformed their smoking peers on the
overall composite and all seven of the unique cognitive domains
smoking status was in the visual learning domain. Smokers with
schizophrenia had more severe visual learning deficits than non-
smokers. Additionally, there was a significant negative correlation
between smoking behavior and visual learning; among regular
smokers, more smoking (indicated by higher CO levels) predicted
greater impairment on the visual learning task. Finally, the present
study also found that smokers with schizophrenia had higher
ratings of avolition and apathy on the SANS than nonsmokers,
although this finding did not survive conservative Bonferroni
correction.
Generally, our findings are a departure from some of the pre-
vious literature (Morisano et al., 2013; Wing et al., 2011; George
more cognitively intact than nonsmokers across a variety of do-
mains. However, it is appropriate to be skeptical of studies that
claim chronic smokers have enduring, “relative enhancements”
6 A.C. Reed et al. / Psychiatry Research 246 (2016) 1–8
compared to nonsmokers as many of these studies fail to dis-
ambiguate the effects of “chronic” nicotine from the enhancing
effects of acute nicotine. Our findings do not resemble those of
Morisano et al. (2013), Wing et al. (2011), or George et al. (2002),
because of a crucial methodological difference; smokers in the
present study did not smoke within 30 min of cognitive testing
and were abstinent throughout the MCCB, while smokers in prior
studies received acute nicotine before and during cognitive test
batteries.
Though it is challenging to directly compare prior studies, as
they did not rely on the same cognitive measures or recruit
identical schizophrenia samples, it is noteworthy that the cogni-
tive tasks chosen by Morisano, Wing, and George largely measured
domains that have been shown to improve with acute nicotine
administration (i.e., working memory, attention, and inhibition)
(Barr et al., 2008; Jubelt et al., 2008; Smith et al., 2002). It seems
likely that allowing participant smoking before and during testing
influenced smoker's scores on these measures. In addition to our
“sweet spot” approach to avoid testing patients during acute ni-
cotine enhancement or withdrawal, the present study also relied
on a more comprehensive test battery, the MCCB, to evaluate
performance across these previously tested domains and untried
others.
The only study we reviewed that did not administer acute ni-
cotine to its smoking subjects was the study of chronic tobacco use
in TRS by Iasevoli et al. (2013). Iasevoli and colleagues (2013) did
not find the difference between smokers and nonsmokers in visual
learning, indicated in the present study, because they used a
cognitive test battery, the BACS, which does not have a test that
corresponds to this cognitive domain. They did, however, find that
TRS nonsmokers outperformed chronic smokers on a problem
solving/executive function task (i.e. tower of London). The current
study did not replicate a significant problem-solving deficit in
smokers on the MCCB, perhaps because our sample was healthier
(i.e., not a TRS sample). While the significant domain between
studies is different, both studies suggest that chronic smokers are
more cognitively impaired than nonsmoking patients with
schizophrenia.
The present study is also a partial replication of Zhang et al.
(2012), which found that smokers performed significantly worse
than nonsmokers on the RBANS Visuospatial/ Constructional in-
dex. The Visuospatial/Constructional index of the RBANS is made
up of figure drawing and line orientation tasks. The BVMT-R on the
MCCB consists of an array of six figures, which are shown to the
participant for 10 s at a time over three learning trials (Nuech-
terlein and Green, 2006). After the stimulus is shown, the parti-
cipant is asked to draw the figures from memory as accurately as
possible, in their correct locations on a blank page. Both the RBANS
Visuospatial/Constructional index tasks and the BVMT-R require
overlapping skills (i.e., psychomotor skills for drawing, spatial
approximation/estimation, and visual memory). Thus, our finding
of visual learning deficits in smokers is a natural extension of
Zhang et al. (2012).
Current theories about why VSWM may be more sensitive to
chronic nicotine than other cognitive domains are highly spec-
ulative. Chronic nicotine alters dopamine (DA) regulation (George
et al., 2002) and VSWM is thought to be, at least partially de-
pendent on prefrontal cortical DA systems (Tan et al., 2014). In-
dividuals with schizophrenia typically have deficits in the number
of nicotine receptors and their functioning. This includes both high
affinity and low affinity nicotinic cholinergic receptors. Chronic
smoking decreases expression of high affinity nicotinic acet-
ylcholine receptors, which are down-regulated by chronic smok-
ing, which then further reduces DA activity (Leonard et al., 2007;
Park et al., 2000). The current study's observation of greater vi-
suospatial deficits in schizophrenic smokers may be, in part due to
cortical DA hypofunction (George et al., 2002).
DA hypofunction may extend to other brain regions including
the prefrontal cortex, which has been implicated in negative
symptoms. The global hypodominergia may explain possible re-
lationships between negative symptoms and cognition. Findings of
negative symptoms in smokers and nonsmokers are mixed. Iase-
voli et al., 2013 and the present investigation found smokers had
more severe negative symptoms than nonsmokers. Other studies
have found the opposite relationship, that nonsmokers had more
negative symptoms than smokers (George et al., 2002; Zhang
et al., 2012), or no differences between smokers and nonsmokers
(Wing et al., 2011; Morisano et al., 2013).
The studies that found differences between smokers and non-
smokers in negatives symptoms chose a variety of methods to
analyze the relationships with cognition. George et al., 2002 did
not analyze the relationship between negative symptoms and
cognition. Zhang et al., 2012 used multivariate regression analysis
and backward stepwise procedures to determine significant as-
sociations with cognitive findings, including negative symptoms
and found none. Iasevoli et al., 2013 found that there were weak
negative correlations between several cognitive domains (e.g.,
verbal memory, verbal fluency and working memory) and negative
symptoms for their smoking participants. The same weak corre-
lation between verbal fluency and negative symptoms, a more
robust correlation between negative symptoms and verbal mem-
ory, and a significant association between negative symptoms and
processing speed immerged for nonsmokers in the sample. There
was no significant association between working memory and ne-
gative symptoms for nonsmokers. The present study found no
correlations between avolition/apathy on the SANS and visual
learning on the BVMT-R in smokers or non-smokers. Further in-
vestigations of the associations between chronic smoking, cogni-
tion, and clinical symptoms are needed to clarify these relation-
ships. Tobacco smoking has been suggested to increase dopamine
release by mesocortical projections as a consequence of choliner-
gic receptor stimulation by nicotine. However, with chronic ex-
posure, it is possible that nicotine could worsen hypodominergia
by either presynaptic (i.e., reduced dopamine synthesis) or post-
synaptic (i.e., increase COMT activity and breakdown of dopamine)
mechanisms. Whether the fairly chronic sensitization of the ni-
cotinic receptors resulting in down-regulation of the receptor with
regular cigarette smoking makes them function less well, or con-
tributes to poorer cognitive performance, is uncertain. Comparing
smokers and nonsmokers on other physiologic measures influ-
enced by nicotinic receptors, such as P50 gating or PPI could help
resolve this issue.
The present study had several limitations. Our “sweet spot”
approach to cognitive testing with smoking participants cannot
fully rule out the possibility of withdrawal effects. Because the
MCCB takes about 65 min to administer, most participants were
abstinent at least 95 min by the end of the cognitive testing ses-
sion. Previous research has suggested that nicotine withdrawal
may induce problems with VSWM in particular (George et al.,
2002; Sacco et al., 2005). However, it is unlikely that nicotine
withdrawal during the MCCB testing in this study caused the
significantly reduced visual learning performance of our smoker
group because similar deficits have been found in chronic nicotine
studies where withdrawal was impossible as acute administration
was ongoing. For example, Zhang et al. (2012) found Visuospatial/
Constructional deficits in fully satiated smokers. This suggests that
chronic nicotine use, regardless of whether acute nicotine is also
present, is independently associated with impairments on a vari-
ety of tasks that involve visual and spatial navigation, recognition,
construction, and learning.
The present study used CO to assess the intensity of smoking
because it a sensitive indicator, often called the “stethoscope of
 A.C. Reed et al. / Psychiatry Research 246 (2016) 1–8
smoking cessation” (Bittoun, 2008, p 69). CO has a half-life of ap-
proximately 5 h and is often measured to test for smoking ab-
stinence in cessation trials since a regular smoker's CO level will
return to a normal nonsmoking level within 24–48 h of abstinence
(Bittoun, 2008). However, CO is an indirect measure of nicotine
and we had to exclude participants using smokeless nicotine, (e.g.
e-cigarette, chew, patch, gum) as CO monitors are unable to detect
these sources. Although we found a significant correlation be-
tween CO and visual learning outcomes in the current study, fu-
ture investigations should also include a direct measure of nicotine
or cotinine to clarify this result.
Additionally, the present study did not systematically collect
data on participant's history of institutional stays. We also did not
assess IQ, although our analysis controlled for educational attain-
ment differences between non-smoking and smoking participants.
Though the sample included older adults, smoking and non-
smoking groups did not differ in age and neurocognitive measures
were age corrected. Exclusion criteria included current drug abuse,
dependence, and positive toxicology. However, past substance
abuse was unknown and could have differed between smoking
and nonsmoking groups, possibly accounting for cognitive differ-
ences. Although the smokers and nonsmokers were equally dis-
tributed on atypical and typical antipsychotic medications, we did
not specifically compare chlorpromazine equivalents in the two
samples as some of the subjects were unable to supply accurate
dose information. Thus, there could be dose effects on cognition
that were not detected. Lastly, our study treated former smokers
(n ¼8) as nonsmokers; as a result, it is possible our results un-
derestimate the relationship between chronic smoking and VSWM
deficits. Future studies should strive to include a distinct group of
former smokers to determine whether their cognitive perfor-
mance is similar to never smokers or current smokers and to
continue to clarify a potential dose-response relationship to cog-
nition and negative symptoms.
The present study highlights the association between chronic
smoking in schizophrenia and a specific deficit in visual learning.
However, this is a cross-sectional study design that is not meant to
infer causality of smoking in schizophrenia. Further longitudinal
studies of nicotine use in schizophrenia are warranted to de-
termine whether smoking causes cognitive deficits, exacerbates
cognitive issues, or partially remediates some pre-existing im-
pairments. By continuing to investigate the mechanisms and time-
course of nicotine's neurocognitive effects, these longitudinal
studies may yield new targets for cognitive intervention.
Funding
This work was supported by the National Institute of Health
and National Institute of Mental Health (P50MH086383) “Basic to
Clinical Neurobiology of Nicotinic Receptors in Schizophrenia” and
by Veteran's Affairs Merit Award (5101Cx000145) “Nicotinic Re-
ceptors and Schizophrenia.” Funders had no further role in the
collection, analysis or interpretation of data, or the decision to
submit this study for publication.
Contributors
Alexandra Reed and Ann Olincy were responsible for the study
design, protocol, clinical assessments, data collection, statistical
analysis, and manuscript preparation. Josette Harris was re-
sponsible for selecting the MCCB and supervised all neurocogni-
tive assessments. All authors have contributed to and approved of
the final manuscript.
7
Conflict of Interest
All of the authors declare they have no sources of conflict of
interest.
Acknowledgment
Thank you to Dr. Robert Freedman for encouraging this in-
vestigation and editing the manuscript. Special thanks to James
Saunders, Jason Smucny, Emma Lyons, Lindsay Eichman, and Holly
Gindes who assisted with data collection.
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