Authors Accepted Manuscript

Cognitive dysfunction correlates with elevated

serum S100B concentration in drug-free acutely
relapsed patients with schizophrenia

Song Chen, Li Tian, Nan Chen, Meihong Xiu,

Zhiren Wang, Guigang Yang, Chuanyue Wang,
Fude Yang, Yunlong Tan
www.elsevier.com/locate/psychres

PII: S0165-1781(16)30004-X
DOI: http://dx.doi.org/10.1016/j.psychres.2016.09.029
Reference: PSY9963
To appear in: Psychiatry Research
Received date: 3 January 2016
Revised date: 4 September 2016
Accepted date: 20 September 2016
Cite this article as: Song Chen, Li Tian, Nan Chen, Meihong Xiu, Zhiren Wang,
Guigang Yang, Chuanyue Wang, Fude Yang and Yunlong Tan, Cognitive
dysfunction correlates with elevated serum S100B concentration in drug-free
acutely relapsed patients with schizophrenia, Psychiatry Research,
http://dx.doi.org/10.1016/j.psychres.2016.09.029
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Cognitive dysfunction correlates with elevated serum S100B

concentration in drug-free acutely relapsed patients with schizophrenia

Song Chena,b, Li Tiana,c , Nan Chena, Meihong Xiua, Zhiren Wanga, Guigang Yanga,
Chuanyue Wangb, Fude Yanga,*, Yunlong Tana,*

a
BeijingHuiLongGuan Hospital, Peking University, Beijing, China
b
Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital,

Capital Medical University, China; Center of Schizophrenia, Beijing Institute for Brain Disorders,

Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology,

China
c
Neuroscience Center, University of Helsinki, Helsinki, Finland

*Corresponding authors
Fude Yang
Beijing HuiLongGuan Hospital, Peking University, Changping District, Beijing,
China
TEL: +86 10 62715511-6251
FAX: +86 10 62710156
E-mail: yangfd200@126.com
Yunlong Tan
Beijing HuiLongGuan Hospital, Peking University, Changping District, Beijing,
China
TEL: +86 10 62715511-6523
FAX: +86 10 62712052
E-mail: yltan21@126.com

Running title: Relationship between S100B and cognitive dysfunction in

schizophrenia
Abstract

S100B, a biomarker of glial dysfunction and blood-brain barrier (BBB) disruption,

has been proposed to be involved in the pathophysiology of schizophrenia. In the
present study, we aimed at exploring the association of serum S100B levels with
cognitive deficits using MATRICS Consensus Cognitive Battery (MCCB) in
schizophrenia, by excluding the impact of antipsychotics. Sixty-two unmedicated
patients with schizophrenia during their acute phases were divided into a drug-nave
group (n=34) and a drug-free group (n=28). S100B serum concentrations were
measured and MCCB was administered to all of the patients. Forty healthy controls
donated their blood samples for S100B assessment. The results indicated that serum
S100B was significantly elevated in the drug-naive/free acute-stage schizophrenic
patients when compared to the healthy controls. In the drug-free group, the serum
S100B level was an independent contributor to the global cognitive dysfunctions,
particularly for the speed of processing, attention/vigilance, visual learning and
reasoning/problem solving subscores. Nevertheless, no significant associations
between S100B and MCCB composite score or any cognitive domain subscore were
observed in the drug-nave group. These findings support the hypothesis that glial
dysfunction and associated marker protein S100B may contribute to the
pathophysiologic development of neurocognitive deficits in the relapsed individuals
with schizophrenia.

Keywords: Drug-nave, Drug-free, Schizophrenia, Cognition, MATRICS Consensus

Cognitive Battery (MCCB), S100B

1. Introduction
 Cognitive impairment has been well validated in the patients with schizophrenia.
The most pronounced cognitive deficits include selective and sustained attention,
processing speed, verbal memory, working memory, executive function and social
cognition (Barch and Ceaser, 2012; Green et al., 2004; Medalia and Choi, 2009).
Although cognitive dysfunction as a core characteristic of schizophrenia has received
extensive attention and research, the underlying neurobiological mechanisms remain
mostly unknown. Recent conceptualization of involvement of neurodevelopment,
neuroplasticity and neuroinflammation in the pathophysiology of cognitive
impairments in schizophrenics provides an insight into exploring the disease
mechanisms (Na et al., 2014; Skaper et al., 2014; Steullet et al., 2014). S100B, a
calcium-binding protein, is predominantly produced by astrocytes, and is also
expressed in other brain cells such as oligodendrocytes, microglial or even neurons
(Steiner et al., 2007). Glial, especially astrocytic, dysfunction appears to play an
important role in the pathogenesis of schizophrenia (Bernstein et al., 2014; De Keyser
et al., 2008; Hercher et al., 2014); therefore, astrocyte-derived S100B protein was
considered as a neurobiological marker of astrocytic response in schizophrenics
(Rothermundt et al., 2004). S100B can act in both autocrine and paracrine manners to
regulate cell proliferation, differentiation and neuroprotection in the brain at pico- to
nano-molar concentrations (Rothermundt et al., 2003). On the contrary, excessive
S100B (at micro-molar concentrations) is neurotoxic and promotes neurodegeneration
and apoptosis, by inducing the overexpression of inducible nitric oxide synthase
and/or pro-inflammatory cytokines (Hu et al., 1996). In other words, increased S100B
contributes to the imbalanced neuroinflammation and is also described as the
C-reactive protein of the brain (Sen and Belli, 2007).

In healthy aging adults (between the ages of 43 and 84 years), serum S100B was
reported to be positively correlated with cognitive performance (Lam et al., 2013).
However, in the individuals with cognitive decline-related diseases, such as
circulatory arrest, stroke, traumatic brain injury, Alzheimer's disease and mood
disorders, studies have showed that S100B serum levels are significantly increased
when compared to healthy controls (Schroeter et al., 2013; Sun and Feng, 2014;
Yardan et al., 2011). Moreover, higher levels of S100B are correlated with lower total
scores of cognitive performance in subcortical vascular dementia and comorbid brain
abnormalities caused by rheumatoid arthritis (Hamed et al., 2012; Levada and Trailin,
2012).

S100B may also play role in the pathophysiology of schizophrenia. Several

studies have consistently demonstrated elevated levels of S100B in the peripheral
blood or cerebrospinal fluid (CSF) of patients with schizophrenia (Aleksovska et al.,
2014). Furthermore, persistently high S100B concentrations correlate with memory
impairments in the patients with chronic schizophrenia (Pedersen et al., 2008). Risk
variants in the S100B gene, including the A allele of rs9722, the G allele of rs1051169,
and the AG haplotype, are also associated with elevated S100B level and poor
performance on cognitive tasks in people with schizophrenia (Zhai et al., 2011).
Despite these evidences, to our best knowledge, no study has yet examined the
relationship between serum S100B level and cognition in schizophrenic patients using
a comprehensive cognitive assessment battery. The MATRICS (Measurement and
Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive
Battery (MCCB) provides a reliable and valid assessment of cognition across all
cognitive domains, including speed of processing, attention and vigilance, working
memory, verbal learning, visual learning, reasoning and problem solving, and social
cognition (Nuechterlein et al., 2008), and therefore was chosen in our current study.
The reliability and validity of the Chinese version of MCCB has been confirmed (Zou
et al., 2009). Given the influence of antipsychotics on S100B levels and cognitive
functions (Zhang et al., 2010), acute schizophrenic patients who were drug-nave or
drug-free for at least one month were involved in this study. As mentioned above, we
hypothesize that elevated serum S100B level is inversely related to cognitive ability
as assessed by the MCCB in non-medicated schizophrenia.
2. Methods
2.1. Participants
For inclusion in the study, patients had to fulfill all of the following criteria: (1)
Provision of informed consent prior to any study-specific procedure; (2) Male and
female patients aged over 18 and inclusive; (3) Meet the Diagnostic and Statistical
Manual of Mental Disorders, fourth Edition (DSM-IV) for schizophrenia by
agreement of two senior psychiatrists, using the Structured Clinical Interview for
DSM-IV (SCID); (4) Antipsychotic drugs were stopped at least one month prior to
this study; (5) Education level was more than 3 years; (6) Physically healthy; (7) No
history of neurological disorders or head trauma; (8) Patients were able to understand
and comply with all study procedures, as judged by the investigator. Subjects with
current DSM-IV diagnosis other than schizophrenia were excluded from the study.
Clinical psychopathological symptoms were evaluated by the Positive and Negative
Syndrome Scale (PANSS), which were measured independently by two psychiatrists
on the day of blood sample collection. To ensure consistency and reliability of ratings
across the study, both senior psychiatrists were trained before the study began. After
training, a correlation coefficient > 0.8 was maintained for the PANSS total scores.
Forty physical healthy controls were recruited from the local community. None of the
control subjects had any mental disorder or was taking medications. This study was
approved by the ethics committee of Beijing Huilongguan Hospital in accordance
with the Declaration of Helsinki.

All patients were recruited from Beijing Huilongguan Hospital, a city-run

psychiatric hospital in Beijing, China. Seventy unmedicated patients with
schizophrenia during their acute phases were screened. Of these subjects, 2 failed the
screening, 6 did not complete the MCCB tests. Therefore, 62 patients divided into a
drug-nave group (n=34) and a drug-free group (n=28) were included in the analysis.
The drug-nave group consisted of 7 patients who had never been exposed to
antipsychotic medications and 27 patients who had received less than two weeks of
antipsychotics, while 28 medication-free patients were the ones with relapse because
of drug discontinuance. Additionally, for normal controls, we did not administer
MCCB tests.

2.2. Blood sampling and serum S100B measurements

All subjects fasted for at least 12 hours prior to blood drawing between 7:00 AM
and 9:00 AM. Blood samples were centrifuged to separate sera, and serum samples
were stored at -80C until S100B analysis. Serum S100B levels were measured in
duplicates in all subjects by sandwich ELISA using a commercially available kit
(R&D systems, Beijing, China) as described previously (Qi et al., 2009). All samples
were assayed by the same investigator, who was blind to the clinical situation. The
sensitivity of the S100B assay was 0.1 ng/ml. Inter- and intra-assay variation
coefficients were 6% and 4%, respectively.

2.3. The MCCB

The MCCB was administered by trained staff under the supervision of a
registered clinical neuropsychologist. The MCCB includes ten tests that assess
seven cognitive domains: (1) Speed of processing: Trail Making Test, part A
(TMT); Symbol Coding Subtest (SC); Category Fluency Test (CF); (2) Attention and
vigilance: Continuous Performance TestIdentical Pairs (CPT-IP); (3)
Working memory: Wechsler Memory Scale, spatial span (SS) and digit sequencing
(DS) test; (4) Verbal learning: Hopkins Verbal Learning TestRevised (HVLT-R); (5)
Visual learning: Brief Visuos-patial Memory TestRevised (BVMT-R); (6)
Reasoning and problem solving: Neuropsychological Assessment Battery, mazes
subtest (MAZES); (7) Social cognition: Mayer-Salovey-Caruso Emotional
Intelligence Test, managing emotions subtest (ME). Raw scores were converted to
normalized T-scores, and seven domain T-scores as well as a composite T-score were
acquired using the MCCB scoring program. The MCCB was administered within 48
hours after blood drawing.

2.4. Statistical analysis

Demographic variables of drug-nave, drug-free and normal control groups were
compared using analysis of variance (ANOVA) for continuous variables and
Chi-Square test for categorical variables, and Fisher's least significant difference
(LSD) test was performed for post-hoc pairwise comparisons. Analysis of covariance
(ANCOVA) was applied to compare the serum S100B levels among the three groups
with the factors that showed to be significantly different in ANOVA as covariates,
and post-hoc comparisons between groups were made using Bonferroni procedure.
Comparisons between the two groups of schizophrenic patients were assessed using
Students T-test for parametric nominal data, Mann-Whitney U test for nonparametric
nominal data, and Chi-Square test for categorical data. Relationships between
variables were assessed with Pearsons product moment correlation coefficients.
Stepwise multiple linear regression analysis using the composite or seven domains of
MCCB scores as the dependent variables was made to investigate the impact factors
including the S100B serum levels. Data analysis was performed using the IBM SPSS
Statistics 21.0. All p-values were two-tailed and statistical significance was set at
0.05.

3. Results
Clinical and demographic characteristics for drug-nave and drug-free
schizophrenic patients along with healthy controls are presented in Table 1. Among
the three groups, gender distribution was not different (p>0.05), but there was a
significant difference in age (p<0.001). Both patient groups were older than the
controls (all p<0.001). However, the two patient groups did not significantly differ in
age.

Drug-nave and drug-free patients showed no differences in education, BMI,

PANSS total score and negative symptom subscore (all p>0.05). Drug-free patients
had longer duration of illness (p<0.001) and higher smoking rate (p<0.05) when
compared to drug-nave patients, who had significantly higher positive symptoms
(p<0.05) and general psychopathology (p<0.01) subscores than drug-free patients.

3.1. Comparisons of serum S100B among drug-nave patients, drug-free patients and
 healthy controls
There was significant difference in S100B levels among the three groups
(p<0.001). This difference remained significant after controlling for age (p<0.001).
Serum S100B concentrations in both patient groups were higher than in the healthy
controls (p<0.001). However, there was no significant difference in serum S100B
concentrations between drug-nave and drug-free patients.

Correlation analysis showed that the age, gender, education, duration of illness,
BMI and smoking status were not associated with S100B in both patient groups (all
p>0.05). Separate correlation analysis showed that serum S100B level was positively
correlated with the PANSS positive symptom subscore (r=0.388, p=0.045) in the
drug-nave group, but were not associated with any other psychopathological
parameters within either the drug-nave or drug-free group of patients (all p>0.05).

3.2. MCCB assessment in drug-nave and drug-free patients

Statistics of MCCB composite T-score and seven domain T-scores of drug-nave
and drug-free schizophrenic patients are showed in Table 2. Overall, the means of
composite MCCB scores in both patient groups were 1 SD below the Chinese norms
(a score of 50, with a standard deviation of 10). However, there was no significant
difference in any cognitive dimension between the two groups of patients with
schizophrenia (all p>0.05).

3.3. Correlation between Serum S100B levels and cognitive performance

In the drug-nave group, no significant associations between S100B and MCCB
composite score (Fig.1A) or any cognitive domain subscore were observed after
controlling for positive symptoms using partial correlation analysis (all p>0.05).
Furthermore, the positive symptoms did not show associations with the MCCB in this
group (all p>0.05).

However, for the drug-free patients, correlation analysis showed that S100B was
negatively associated with the MCCB composite score (r=-0.657, p=2.6610-4)
(Fig.1B), working memory (r=-0.494, p=0.01), reasoning/problem solving (r=-0.639,
p=3.3510-4), visual learning (r=-0.596, p=0.001) and attention/vigilance (r=-0.493,
p=0.009). Furthermore, S100B had a trend toward significant negative correlation
with the processing speed (r=-0.379, p=0.051) and verbal learning (r=-0.379,
p=0.052).

In the drug-free group, there were markedly inverse associations between the
PANSS negative subscore and the MCCB composite score and six subscores (all
p<0.05), except for the reasoning/problem solving subscore (p>0.05). On the other
hand, no significant correlations were observed between the MCCB performance and
the other demographic and psychopathological parameters (all p>0.05), except that
gender was associated with the speed of processing (r=-0.397, p=0.037). Therefore,
considering the MCCB composite score and seven subscores as the dependent
variables, and the negative subscore and S100B serum levels as the independent
variables (gender was also considered as an independent variable when the speed of
processing was regarded as a dependent variable), a stepwise multivariate linear
regression analysis demonstrated that S100B was an independent contributor to the
MCCB composite score (=-0.537, t=-3.603, p=0.001), speed of processing (=-0.524,
t=-3.473, p=0.002), attention/vigilance (=-0.493, t=-2.837, p=0.009), visual learning
(=-0.596, t=-3.709, p=0.001) and reasoning/problem solving (=-0.639, t=-4.152,
p=3.3510-4). PANSS negative subscore was found to be an independent contributor
to the MCCB composite score (=-0.359, t=-2.413, p=0.024), working memory
(=-0.542, t=-3.163, p=0.004), verbal learning (=-0.386, t=-2.092, p=0.047) and
social cognition (=-0.607, t=-3.815, p=0.001). Besides, female gender was an
independent predictor of poor performance of the processing speed (=-0.602,
t=-3.992, p=0.001).

4. Discussion
Our present results show that (1) serum S100B was significantly elevated in
drug-naive/free acute-stage schizophrenic patients when compared to healthy controls,
while there was no marked difference between the two groups of patients; (2)
drug-naive/free acute-stage schizophrenic patients scored lower in MCCB
performance than the Chinese norms, but the two patient groups did not significantly
differ on all of the seven MCCB domains; (3) in the drug-nave group, S100B was not
associated with any cognitive process; (4) in the drug-free group, S100B was an
independent contributor to the global cognitive dysfunctions, particularly for the
speed of processing, attention/vigilance, visual learning and reasoning/problem
solving.

Our finding that serum S100B levels were significantly higher in patients with
acute phase of schizophrenia than that in healthy controls was well consistent with
earlier studies (Rothermundt et al., 2001; Steiner et al., 2012; Zhang et al., 2010).
Also, in the chronic schizophrenics under treatment with antipsychotics, S100B levels
were reported to be higher (Zhang et al., 2010). Furthermore, the data here showed
that there was no observable difference in S100B levels between drug-nave and
drug-free patients with acute episode, while it has been shown that drug-nave
early-stage schizophrenic patients have significantly higher S100B concentrations
than medicated chronic schizophrenic patients (Zhang et al., 2010). Differences in
disparate stages of disease progression (acute relapse vs. chronic phase) and exposure
to antipsychotics (drug discontinuance vs. medicated) may contribute to this
inconsistent result.

As expected, both drug-nave and drug-free schizophrenia patients in acute phase

scored lower than the Chinese norms in MCCB performance after excluding
uncooperative participants. Given cognitive dysfunction associated with duration of
illness (Kaneda et al., 2013), we had assumed that drug-free patients would manifest
more severe cognitive impairment when compared to drug-nave ones, but no
significant difference in any domain of MCCB between the two groups was observed.
Plausible explanations could be: (1) Higher rate of smoking in the drug-free group
may be potentially beneficial to neurocognitive performance, because nicotine has
been described to improve cognitive functions in schizophrenic patients (Hambsch et
al., 2014; Harris et al., 2004; Myers et al., 2004; Smith et al., 2006); (2) Between the
two patient groups, there was no notable difference in PANSS negative symptoms,
which could definitely influence cognitive tests. On the other hand, since drug-free
patients had received systemic therapies with antipsychotics earlier, the effect of
antipsychotics on cognition is also possible (Husa et al., 2014; Keefe, 2014).

Correlation analysis together with multivariate linear regression analysis indicated

that serum S100B concentration was an independent contributor to the speed of
processing, attention/vigilance, visual learning, reasoning/problem solving and global
cognitive function as represented by the MCCB composite score in drug-free patients,
which is similar with observations in several previous studies. For example, Anya et
al. reported that chronic schizophrenic patients with high S100B levels were impaired
in verbal memory performance as compared to chronic and first-episode patients with
low S100B levels (Pedersen et al., 2008), and elevated S100B levels were associated
with visuospatial disability of schizophrenia as described by Zhai et al. (Zhai et al.,
2011). Furthermore, schizophrenic patients receiving recombinant human
erythropoietin (rhEPO) treatment showed a significant improvement in cognitive
performance (RBANS subtests and WCST-64) and a decline in serum S100B levels
(Ehrenreich et al., 2007). The close relationship between S100B and cognitive
function is further supported by a preclinical study showing that S100B deficient mice
had enhanced long-term potentiation in the hippocampal CA1 region and better spatial
memory in the Morris water maze test, whereas perfusion of hippocampal slices with
recombinant S100B protein reduced long-term potentiation in mutant slices
(Nishiyama et al., 2002). These results support the hypothesis that high levels of
S100B derived from neuroglia may play a role in the pathogenesis of
schizophrenia-related cognitive impairment, however, the exact mechanisms
responsible for this have not yet been elucidated.

However, no significant correlations between S100B and cognition performance

were detected in the drug-nave group, which was in contrast with the findings in
drug-free recurrent episode patients with schizophrenia. The exact reason for this
discrepancy is still unknown, but illness duration might play a key role. Elevated
S100B levels in drug-nave patients may not decrease to the normal level even in their
stable mental state after treatment (Qi et al., 2009; Zhang et al., 2010). Hence, the
increased S100B in the drug-free group may represent a more chronic phenomenon
that repeats over time in some patients, which could lead to gradual but irreversible
alterations of neuro-circuitry and neurochemistry in specific brain regions,
contributing, for example, to the cognitive deficits. A recent study by Milleit et al.
(Milleit et al., 2016) investigated the associations between S100B and structural white
matter abnormalities in unmedicated schizophrenia patients (first and recurrent
episode) and healthy controls. Using voxel based morphometry (VBM), they found
that the first episode patients had a negative correlation of S100B concentration to the
white matter values in the right superior temporal gyrus (STG), the right middle
temporal lobe, and a large region of the right frontotemporal white matter that
corresponds to the right superior longitudinal fasciculus. Nevertheless, recurrent
episode patients had a positive association in all of the above regions. Therefore, this
suggests S100B is involved in an ongoing and dynamic process that is related to
structural changes of brain at different stages of schizophrenia (Milleit et al., 2016),
which is a possible mechanism explaining the present results that positive correlation
between S100B concentration and positive symptoms was found only in the
drug-nave group, whereas significant negative correlation between S100B and
neurocognition performance was seen only in the drug-free group. On the other hand,
since the increase in S100B in drug-nave patients was related to positive symptoms
which may unpredictably affect cognitive performance, this could lead to the absence
of association between S100B and cognition in this group. Lastly, as all drug-free
patients were previously under systematic pharmacological treatments, we cannot
completely rule out the antipsychotics-mediated effects on the association between
S100B and cognitive performance.

The present study has certain limitations that need to be considered. First,
although this data provides preliminary evidence for the role of serum S100B as a
biomarker for neurocognitive dysfunction in drug-free acute relapse patients with
schizophrenia, a conclusive assessment is limited by the small sample size. Second,
for healthy controls, we did not implement MCCB assessment, hence the relationship
between S100B profiles and cognitive functioning in healthy young adults could not
be detected, which should be improved in future studies. Third, it is still uncertain
whether peripheral S100B reflects similar changes in the CNS, since other sources of
serum S100B could include adipocytes, melanocytes, chondrocytes and myocardium
(Donato, 2001; Schafer and Heizmann, 1996; Zimmer et al., 1995). For example,
several lines of evidence suggest that raised BMI, which is likely associated with
increased number of adipocytes, may contribute to elevated S100B serum
concentrations (O'Connell et al., 2013; Steiner et al., 2010). In contrast, another study
showed that extracranial sources of S100B do not affect serum levels in
neuropsychiatric disorders in intact subjects (without traumatic brain or bodily injury
from accident or surgery) (Pham et al., 2010). Anyway, metabolic parameters are still
important confounding factors since schizophrenia are associated with a higher risk of
obesity and metabolic syndrome, and future studies should overcome this limitation.
Finally, the cross-sectional study design that was used unfortunately does not permit
strong inferences of causality between S100B levels and cognitive performance.

To our knowledge, this is the first study to report a significant association between
serum S100B levels and a broad-spectrum measure of cognition in drug-free acutely
relapsed individuals with schizophrenia. Interestingly, this relationship has not been
observed in the drug-nave group, which might be on account of the different
neurobiological mechanisms of cognitive deficits at early stage of schizophrenia and
impact of previous antipsychotic treatment. In conclusion, these preliminary, but
encouraging data support the concept that glial marker protein S100B may be
involved in the pathophysiologic development of neurocognitive deficits in
schizophrenia. In addition, whether this association could be replicated in other
psychotic disorders is worthy of further exploration and research.

Role of funding source

 This study was funded by the Beijing Natural Science Foundation (7151005) and
the Long-Yue Project Foundation of Beijing Huilongguan Hospital (No.
2014LYYQ-01).

Competing interests

The authors reported no conflicts of interest.

Contributors

Yang FD and Tan YL designed the experimental protocol, provided the funding for
the study and were responsible for the integrity of data and the accuracy of data
analysis. Chen S, Xiu MH, Wang ZR and Yang GG were responsible for recruiting
the patients, performing the clinical rating and collecting the samples. Chen S
researched data, analyzed data and wrote the manuscript. Tian L and Chen N were
invited in evolving the ideas, analyzing data and editing the manuscript. Wang CY
contributed to the discussion and reviewed the manuscript. All authors have
contributed to and have approved the final manuscript.

Acknowledgment

The authors thank professor Xingguang Luo for the assistance in the English
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A
 B

Fig.1. Correlation analysis showed a significant negative relationship between S100B and MCCB

composite T-score (r=-0.657, p=2.6610-4) in drug-free patients with schizophrenia, but no

significant correlation between S100B and MCCB composite score (r=0.036, p=0.843) in

drug-nave schizophrenic patients.

Table 1 Characteristics of drug-nave, drug-free schizophrenic patients and healthy controls

Drug-nave Group Drug-free Group Healthy Controls t/z/F/x2Value p-Value

(n=34) (n=28) (n=40)

Age(years)a 35.0012.92*** 35.689.78*** 25.686.55 11.467 3.3210-5

Gender(Male/Female)b 14/20 10/18 20/20 1.450 0.484

Duration of illness(months,median) 24.0 73.5 NA -3.694 2.2110-4

Education(years, median) 12 12 NA -0.511 0.609

2
BMI(kg/m ) 22.203.23 23.904.23 NA -1.792 0.078

Smoker/Non-smoker 3/31(8.8%) 9/19(32.1%) NA 5.349 0.021

PANSS total 86.3213.17 79.6812.94 NA 1.993 0.051

P subscore 25.155.08 21.936.38 NA 2.211 0.031

N subscore 20.565.34 22.144.60 NA -1.237 0.221

G subscore 40.626.60 35.616.26 NA 3.046 0.003

c *** ***
S100B(ug/L) 0.240.08 0.210.07 0.110.03 34.624 7.0410-12
a
One-Way ANOVA
b
Pearson X2 test
c
analysis of covariance with age as covariate
***
indicates the comparisons between drug-nave/drug-free patients and healthy controls, and p<0.001

Table 2 Comparison of MCCB performances between drug-nave and drug-free schizophrenic patients

Cognition Drug-nave Group Drug-free Group

t Value p-Value
(n=34) (n=28)

MCCB composite score 40.2611.71 39.9812.35 0.091 0.928

Processing speed 43.089.54 43.1010.82 -0.007 0.994

Attention/vigilance 40.049.40 35.4710.12 1.841 0.071

Working memory 43.369.43 43.5212.81 -0.056 0.956

Verbal learning 40.8114.30 39.6511.88 0.341 0.734

Visual learning 43.759.97 45.0510.72 -0.496 0.622

Reasoning/problem solving 46.0414.12 47.1912.88 -0.334 0.740

Social cognition 44.5714.06 42.9713.23 0.459 0.648

HIGHLIGHTS

Serum S100B was elevated in drug-naive/free acute-stage schizophrenia patients.

For the drug-free patients, S100B was related to multiple cognitive dimensions.

For the drug-nave patients, S100B was not associated with any cognitive
dimension.

Possible reasons for this contradictory result are discussed.