Authors Accepted Manuscript

Associations between
inflammatory markers
schizophrenia

sleep quality
in patients

and
with

Shih-Hua Fang, Katsuhiko Suzuki, Chin Leong

Lim, Ming-Shun Chung, Po-Wen Ku, Li-Jung
Chen
www.elsevier.com/locate/psychres

PII:
DOI:
Reference:

S0165-1781(16)30127-5
http://dx.doi.org/10.1016/j.psychres.2016.09.032
PSY9966

To appear in: Psychiatry Research

Received date: 22 January 2016
Revised date: 7 September 2016
Accepted date: 20 September 2016
Cite this article as: Shih-Hua Fang, Katsuhiko Suzuki, Chin Leong Lim, MingShun Chung, Po-Wen Ku and Li-Jung Chen, Associations between sleep quality
and inflammatory markers in patients with schizophrenia, Psychiatry Research,
http://dx.doi.org/10.1016/j.psychres.2016.09.032
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Title page
Associations between sleep quality and inflammatory markers in patients with schizophrenia
Shih-Hua Fanga, Katsuhiko Suzukib, Chin Leong Limc, Ming-Shun Chungd, Po-Wen Kue,f,
Li-Jung Chenf,g
a

Institute of Athletics, National Taiwan University of Sport, No 16, Sec 1, Shuan-Shih Road,
Taichung, 404, Taiwan. (shfang@ntupes.edu.tw)

Faculty of Sport Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama,

359-1192, Tokorozawa, Japan. (katsu.suzu@waseda.jp)

Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang

Avenue, 639798, Singapore. (fabianlim@ntu.edu.sg)

Jianan Psychiatric Center, Ministry of Health and Welfare, 80, Lane 870, Zhongshan Road,
Tainan 717, Taiwan. (mschung3@gmail.com)

Graduate Institute of Sports and Health, National Changhua University of Education, 1,

Jin-De Road, Changhua, 500, Taiwan (powen.ku@gmail.com)

Department of Epidemiology and Public Health, University College London, London, 1-19
Torrington Place, London, WC1E 6BT, UK.

Department of Exercise Health Science, National Taiwan University of Sport, No 16, Sec 1,
Shuan-Shih Road, Taichung, 404, Taiwan (ljchen@ntupes.edu.tw)

Corresponding author: Li-Jung Chen (e-mail: ljchen@ntupes.edu.tw).

Address: No 16, Sec 1, Shuan-Shih Road, Taichung, 404, Taiwan.
Tel: 886-4-22213108; Fax: 886-4-22258026
Associations between sleep quality and inflammatory markers in patients with schizophrenia
1

Abstract
Sleep disorder is a risk factor for several systemic inflammation-related diseases and
there are extensive data showing that schizophrenia is associated with chronic low-grade
systemic inflammation. This study investigated the associations between sleep quality and
inflammatory markers in patients with schizophrenia, which has not been examined before.
Sleep quality (total sleep time, sleep efficiency, sleep onset latency, total activity counts,
wake after sleep onset, number of awakening, and average length of awakening) was
measured using actigraphy in 199 schizophrenia inpatients. The state of inflammation was
measured using blood concentration of white blood cells (WBC) and neutrophils, together
with neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). The results
showed that total sleep time was negatively associated with NLR and PLR, and sleep
efficiency was negatively associated with neutrophil counts and NLR. Sleep onset latency,
total activity counts, wake after sleep onset, and number of awakening were positively
associated with WBC and neutrophil counts. The average length of awakening was positively
associated with NLR and PLR. This is the first report to suggest that improving sleep quality
may modulate the state of inflammation in patients with schizophrenia.
Key words: Insomnia; Actigraphy; White blood cell; Neutrophil-lymphocyte ratio;
Platelet-lymphocyte ratio

Associations between sleep quality and inflammatory markers in patients with

schizophrenia
1. Introduction
Sleep is an important and complex restorative process for homeostasis regulation of
the physiological systems (Banks and Dinges, 2007) and sleep loss can alter both cellular
(e.g., neutrophils, macrophages, T and B lymphocytes) (Born et al., 1997; Lasselin et al.,
2015) and molecular mediators of inflammation (e.g., proinflammatory cytokines and
acute phase proteins) (Vgontzas et al., 1999; Mullington et al., 2010; Chennaoui et al.,
2011). Besides immunomodulation, sleep loss also alters neurobehavioral functions
through proinflammatory cytokines, such as tumor necrosis factor (TNF)-a and its soluble
receptors, and interleukin (IL)-6, which mediate the link between the immune system and
central nervous system-related behaviors (Mullington et al., 2001). Sleep disruption also
promotes the development of cardiometabolic diseases (Faraut et al., 2012; Rangaraj and
Knutson, 2016) and the progression of autoimmune diseases, such as systemic lupus
erythematosus (Palma and Tufik, 2010), rheumatoid arthritis (Mahowald et al., 1989) and
experimental autoimmune encephalomyelitis (He et al., 2014). In healthy humans, four
hours of sleep deprivation increased the concentrations of white blood cells (WBC) and
the granulocyte subset, neutrophils (Kuhn et al., 1969; Heiser et al., 2000; Boudjeltia et al.,
2008; Faraut et al., 2011). Evidence supporting the association between sleep quality and
3

immune cell counts was based mainly on self-reported questionnaires (Perez de Heredia
et al., 2014; Manzar et al., 2016) that only measured total sleep time. The validity of these
questionnaires for measuring sleep quality is doubtful as self-reported sleep quality was
not significantly correlated with objectively measured sleep quality using actigraphy
(Bender et al., 2008). Moreover, sleep quality comprises several subparameters besides
total sleep time, such as sleep efficiency, sleep onset latency, and number and length of
awakening, which are not measured with self-reported questionnaires for sleep quality
measurement.
Blood cell counting, using commercial hemo-analyzer systems, is a convenient and
routine clinical examination procedure that provides information on cell composition in
blood, such as red blood cells, WBC, neutrophils, lymphocytes and platelets. These
measurements allow the derivation of neutrophil-lymphocyte ratio (NLR) as a marker for
systemic inflammatory response (Zahorec, 2001) and platelet-lymphocyte ratio (PLR) as a
prognostic marker for both aggregation and inflammation pathways (Smith et al., 2009).
Both NLR and PLR have been used as inflammatory biomarkers for predicting the
severity of a variety of diseases, such as metabolic disease (Buyukkaya et al., 2014),
cancer (Proctor et al., 2011; Guthrie et al., 2013; Baranyai et al., 2014; Krenn-Pilko et al.,
2014), coronary artery disease (Lange et al., 2010; Yuksel et al., 2015), and obstructive
sleep apnea syndrome (Altintas et al., 2015; Koseoglu et al., 2015; Oyama et al., 2015;
4

Yenigun and Karamanli, 2015). Both NLR and PLR are present in chronic systemic
inflammation (Proctor et al., 2011) and the systemic inflammatory response is associated
with a variety of malignancies (Lian et al., 2015). The links between NLR, PLR and
malignancies suggest that higher levels of NLR or PLR are generally associated with
poorer clinical outcomes in patients.
Schizophrenia is a pheomorphic and heterogeneous phenotype and is also associated
with a state of chronic low-grade systemic inflammation (Miller et al., 2011; Khandaker
et al., 2012; Khandaker et al., 2013; Khandaker et al., 2015). The manifestation of
low-grade inflammation is consistent with the findings that patients with schizophrenia
have significantly higher NLR than in healthy controls (Semiz et al., 2014). Elevated
serum concentrations of both C-reactive protein (CRP) and WBC were associated with
more severe cognitive impairments and psychopathology and poorer quality of life in
patients with schizophrenia (Fan et al., 2007; Fan et al., 2010; Faugere et al., 2015;
Micoulaud-Franchi et al., 2015; Bulzacka et al., 2016). Insufficient sleep duration
promotes cardiometabolic disease risk that was accompanied by increased concentrations
of inflammatory markers (Grandner et al., 2013). In addition, sleep loss also directly alters
the concentrations of circulating WBC, proinflammatory cytokines and soluble cytokine
receptors, which are involved in the initial activation of the immune response (Mullington
et al., 2001). However, no studies have examined the relationship between sleep quality
5

and inflammatory markers (e.g. WBC, neutrophil counts, NLR and PLR) in patients with
schizophrenia. Therefore, the aim of this study was to measure sleep quality objectively,
using actigraphy, and to investigate the associations between the sub-indices of sleep
quality with inflammatory markers in patients with schizophrenia.
2. Methods
2.1 Participants
Participants for this study were recruited from the chronic psychiatric wards at
Jianan Mental Hospital, Taiwan. The diagnosis for schizophrenia was performed by a
licensed psychiatrist according to the Diagnostic and Statistical Manual of Mental
Disorders (4th edition) (DSM-IV). The patients were included in the study if their mental
states were stable and the dosage for their antipsychotic medicine was not changed for 3
months. Patients with neurological disorders and were unable to walk independently or
communicate proficiently were excluded from the study. There were 200 potential
inpatients who met the inclusion criteria in the study and 199 of them provided their
written informed consent to participate in this study.
The Control group comprised 60 healthy participants, who were recruited from the
staffs of two hospitals and two universities. The profile of participants in the Control
group was comparable with the schizophrenia patients in terms of gender and age
distribution, and BMI ranges. The healthy participants had no history of psychiatric
6

disorder and consumption of psychoactive medications and did not performed shift-work
before participating in the study (Chen et al., 2016b). The experimental design and
procedures for this study were approved by the Institutional Review Board of Jianan
Mental Hospital.
2.2 Demographic variables and health-related behaviors
Personal information on age, gender, smoking habits, alcohol consumption, and
education background was self-reported using questionnaires. Physical activity was
measured using the wActiSleep-BT ActiGraph (Pensacola, FL, USA) and the sleep period
was excluded when calculating the estimated energy expenditure of physical activity. The
association between actigraphy-derived physical activity and cognitive performance in
patients with schizophrenia was based on published norms (Chen et al., 2016b). The daily
meals of the schizophrenia patients were prescribed by the hospital nutritionists, and were
not considered in this study.
2.3 Sleep Quality Measurement
The magnitude of sleep disturbance/disruption was measured using the same
procedures described in our previous study (Chen et al., 2016a). The participants wore the
actigraph accelerometer (wActiSleep, Pensacola, FL, USA) on the wrist of the
non-dominant hand for a week. During this period, the accelerometer was removed
intermittently when the participants took their showers and during water activities. The
7

accelerometers were initialized, downloaded and analyzed using ActiLife software

version 6 (ActiGraph LLC), based on the Cole-Kripke algorithm (ActiGraph Software
Department, 2012). According to the ActiGraph Software Department ActiLife 6 users
manual, the sleep efficiency of 85% or more are considered to be normal sleepers. Sleep
quality was indicated based on total sleep time, sleep efficiency, sleep onset latency, total
activity counts, wake after sleep onset, number of awakening, and average length of
awakening.
2.4 Covariates
The effects due to the severity of the psychopathology and type and dosage of
medications taken by the patients were controlled by treating these variables as covariates.
The positive and negative syndrome scale (PANSS) was administered by psychiatric
nurse practitioners in the hospital and was used to assess the severity of symptoms and
general psychopathology states in the schizophrenia patients (Kay et al., 1987). The
PANSS consists of three subscales, namely, Positive Symptoms, Negative Symptoms, and
General Psychopathology. Since collinearity was found between Negative Symptoms and
General Psychopathology in the regression model, a total PANSS score was used in the
analyses.
Information on the use of antipsychotics medications and sleeping pills was
collected through hospital records. There were 20 types of the first and second generation
8

antipsychotics medication used and medical comorbidity were determined by the doctors.
All the medication consumed were converted into a daily equivalent dosage of
chlorpromazine (Gardner et al., 2010) and the daily equipotent dosage of lorazepam to
represent the antipsychotic effects. This was calculated according to the defined daily
dose (DDD) of WHO Collaborating Centre for Drug Statistics Methodology
(http://www.whocc.no/ddd/definition_and_general_considera/).
2.5 Blood sampling
Venous blood samples were taken before breakfast, at 0700 h, on the first day of
each week from a forearm vein using venipuncture. The blood samples were collected in
ethylene diamine tetra acetic acid disodium salt (EDTA) monovette tubes (Sarstedt,
Germany). WBC, neutrophil, lymphocyte, and platelet counts were determined using an
automated blood cell counter (KX-21N, Sysmex Corporation, Kobe, Japan). The
concentrations for triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and
fasting glucose (FG) and the data of body weight, height, waist circumference, and
systolic/diastolic blood pressure (SBP/DBP) were obtained through regular health checks
in the hospital, taken 1 month before the study.
2.6 Data analyses
The seven sleep indices had missing data for 26.6% in the original dataset, which
exceeded the acceptable criteria (<10%) and the missing data pattern shown from the
9

Littles MCAR (missing completely at random) test was not random (Chi-Square=218.23,
df=175, p<0.015) (Cohen et al., 2002). Therefore, all variables with missing values were
computed and replaced with the expectation maximization (EM) estimation of the IBM
SPSS Missing Value Analysis (n=199).
Descriptive statistics for demographic variables, sleep indices, and inflammatory
parameters were used to characterize the participants. Differences in sleep parameters
between individuals with and without schizophrenia were examined using independent
t-tests. Pearson correlation analyses were performed to test the univariate associations
between sleep indices and inflammatory parameters. Multivariate linear regression
analyses were conducted for predicting inflammatory parameters. Due to the collinearity
between some sleep indices, separate regression analyses were performed for each of the
sleep indices and inflammatory parameters. All the regression models were adjusted for
the effects of age, gender, education background, smoking, alcohol consumption, physical
activity, metabolic parameters (waist circumference, SBP, DBP, serum TG, HDL-C, and
FG), and medical conditions (years since illness onset, duration of hospitalization,
PANSS score, chlorpromazine equivalent doses, and lorazepam equivalent doses). As the
data were not normally distributed, all the inflammatory parameters were transformed to
natural log before performing the Pearson correlations and subsequent regression
analyses.
10

This study consisted of four dependent variables for inflammatory markers and
seven independent variables for sleep indices. Bonferroni correction was used to reduce
the inflation of type one error from the large number of correlation coefficients (alpha =
0.05/(4*7) = 0.0018). Therefore, a p-value < 0.002 was considered as statistically
significant in Pearson correlation analyses and regression models. All statistical analyses
were conducted with IBM SPSS statistics 20.0 (Chicago, IL, USA).
3. Results
There were 199 schizophrenia inpatients (122 men and 77 women) and 60 healthy
participants (34 men and 26 women) involved in this study. These two groups had similar
characteristics in terms of age, BMI and waist circumference (Table 1) and the patients
had lower physical activity level than the healthy participants. The clinical state and the
antipsychotics drugs used and their frequencies are shown in Table 2. The schizophrenia
patients had a mean PANSS score of 63.0 20.0 and the top five most commonly used
drugs are risperidone (29.6%), clozapine (27.1%), sulpiride (15.6%), haloperidol (15.1%)
and olanzapine (9.0%).
Table 1
Table 2
The data on sleep quality and blood parameters are presented in Table 3. The
hospital nurses recorded the patients sleep conditions (sleep or awake) at 30-min
11

intervals and the participants were also asked to keep a diary to record the time they went
to bed and woke up in the morning. These data were cross-checked against the actigraphic
records to ensure consistency between these two sleep tracking tools. In this study, 38
patients did not wear the actigraph recorder because they felt suspicious of the device.
Five devices were damaged during the study and the data were not available. Data from
ten patients were not used because they had less than three nights of complete data. In
total, completed sleep data were obtained from 146 patients.
The patients spent 502.9 81.6 min/day in sleep, which was significantly longer
than the healthy control participants (380.5 71.6 min/day) (p<0.001). Compared with
the healthy participants, the sleep onset latency and average length of awakening were
significantly longer (p<0.001), number of awakening (p<0.001) and total activity counts
(p=0.020) were significantly higher in the schizophremia patients. Furthermore, sleep
efficiency in both the patients (89.2 4.6 %) and the healthy participants (86.3 6.6 %)
fell within the normal range of sleep efficiency.
Table 3
The correlation coefficient between sleep indices and inflammatory markers is
summarized in Table 4. Total sleep time was negatively associated with NLR (p<0.001)
and PLR (p<0.001), and sleep efficiency was negatively associated with neutrophil count
(p<0.001) and NLR (p<0.001). Sleep onset latency, total activity counts and wake after
12

sleep onset were positively associated with both WBC (all p<0.001) and neutrophil counts
(all p<0.001). The number of awakening was positively associated with WBC (p<0.001),
and average length of awakening was positively associated with NLR (p<0.001) and PLR
(p<0.001).
Table 4
The fully adjusted linear regression models are presented in Table 5. Total sleep
time was negatively associated with both NLR (p<0.001) and PLR (p<0.001), and sleep
efficiency was negatively associated with neutrophil counts (p=0.002) and NLR
(p=0.001). Total activity count was positively associated with neutrophil counts (p=0.001),
and average length of awakening was positively associated with NLR (p<0.001) only. The
scatter plots between inflammatory markers and sleep parameters are shown in Figure 1.
Table 5
4. Discussion
This study examined the associations between sleep indices and inflammatory
markers in patients with schizophrenia using both Pearson correlation analyses and the
fully adjusted linear regression models. The key finding is that longer sleep time and
higher sleep efficiency, which promote sleep quality, were negatively associated with
neutrophil counts, NLR and PLR, which are markers of inflammation. Conversely, higher
sleep onset latency, total activity counts, number and length of awakening and wake after
13

sleep onset, which compromise sleep quality, were positively associated with WBC and
neutrophil counts. Although the patients slept 32% longer than the healthy participants
daily, their sleep quality was worse than the healthy adults. In addition, increasing length
of awakening, which reduces sleep quality, was also positively associated with NLR and
PLR. These results suggest, for the first time, that poorer sleep quality is associated with
an elevated state of inflammation in schizophrenia patients.
In this study, the schizophrenia patients had a mean PANSS score of 63.0 20.0,
which is comparable with other studies that also investigated the relationship between
sleep and inflammation in schizophrenia patients e.g., mean PANSS 71.1 24.4 (Faugere
et al., 2015), 68.5 18.2 (Micoulaud-Franchi et al., 2015), and 59 21 (Fan et al., 2007).
It was well established that sleep is impaired in schizophrenia patients, and treatments
with olanzapine, clozapine, or risperidone can improve sleep quality (Wichniak et al.,
2011; Kluge et al., 2014). Sleep efficiency in our schizophrenia patients (89.2 4.6 %)
was almost the same as the patients that were treated with medications in previous studies
(Wichniak et al., 2011; Kluge et al., 2014), which adds to the evidence that support the
association between the state of psychopathology and quality of sleep. This evidence
implies that management of sleep and improving sleep quality may be important
considerations in the treatment for schizophrenia.
The patients in our study slept significantly longer than the healthy subjects by 32%,
14

but had poorer quality of sleep in terms of longer sleep onset latency and average length
of awakening, higher total activity counts and number of awakening, and sleep efficiency
was equivocal between the two groups. These results support the use of actigraphy to
measure sleep quality in both patients and healthy individuals as sleep duration alone does
not truly reflect the wakefulness during sleep e.g., onset latency, activity counts and
length of wakening. Sleep efficiency is also not an independent indicator of sleep quality.
Previous studies have shown that total (Christoffersson et al., 2014) and one
(Lasselin et al., 2015) to three nights (Boudjeltia et al., 2008) of sleep deprivation were
significantly associated with increases in WBC and neutrophil counts, within the normal
range, in healthy men. However, the associations between sleep quality and immune cell
counts in these studies were based mainly on self-reported questionnaires (Perez de
Heredia et al., 2014; Manzar et al., 2016) that only measured total sleep time but not
objectively measured sleep quality using actigraphy. Therefore, we are not aware of
previous studies showing the relationship between inflammation markers and sleep
quality in the general population. Previous results concurred with our findings that a
reduction in total sleep time was associated with higher values of NLR and PLR in
patients with schizophrenia. Taken together, this evidence suggests the associations
between sleep quality and PANSS scores may be mediated by the inflammatory pathway.
A reduction in sleep duration and sleep deprivation can increase the risk of inflammation
15

in patients with schizophrenia and that maintaining a regular sleep routine with adequate
sleep duration may be helpful in improving the clinical state of patients with
schizophrenia by modulating the inflammatory response in patients.
Our study is the first to report a positive association between WBC, neutrophil
counts and the sleep indices of sleep onset latency, total activity counts, wake after sleep
onset, and number of awakening in patients with schizophrenia. Overall, the magnitude of
the associations between total sleep time and inflammatory markers (NLR and PLR) was
moderate. In addition, sleep efficiency, total activity counts, and average length of
awakening were weakly to moderately-associated with inflammatory markers (neutrophil
counts and NLR). The physiological mechanisms underlying the interplay between sleep
quality indicators and the inflammatory pathway are not well understood presently. We
speculate that poorer sleep quality and a higher degree of wakeful events during sleep
could have activated a mild degree of sympathetic activity through the hypothalamus
pituitaryadrenergic pathway, which is known to promote leukocytosis and the
inflammatory response (Rangaraj and Knutson, 2016). Acute sleep loss increases the
concentrations of circulating catecholamines (Dimitrov et al., 2010) and enhances the
production of proinflammatory cytokines, including TNF-a and IL-6 (Besedovsky et al.,
2012). Shorter sleep time of < 4 h also rapidly increased the activation of the transcription
factor NF-kB, which is a key molecule in the inflammatory signalling pathway in blood
16

mononuclear cells (Irwin et al., 2008). In schizophrenia patients, increased concentrations

of proinflammatory cytokines, acute phase proteins and WBC are also associated with
more severe psychopathology (Fan et al., 2007; Fan et al., 2010; Muller et al., 2013). The
evidence presented supports the notion that changes in endocrine and proinflammatory
cytokine responses due to sleep loss may be involved in the recruitment of leukocytes
(Dimitrov et al., 2010) and poor sleep quality can lead to the higher state of systemic
inflammation that may induce more severe psychopathology in patients with
schizophrenia.
NLR and PLR were used recently as surrogate markers of systemic inflammatory
responses in patients with a variety of diseases e.g. metabolic disease (Buyukkaya et al.,
2014) and coronary artery disease (Lange et al., 2010; Yuksel et al., 2015). There is also
increasing evidence that NLR is an important marker of inflammation and can be used to
predict clinical outcomes in a variety of cancers (Guthrie et al., 2013). NLR was elevated
in patients with advanced or more aggressive tumor stages and a higher PLR value was
positively associated with greater severity of atherosclerosis in coronary artery disease
(Yuksel et al., 2015). However, limited studies have examined the relationships between
neuropsychiatric disorders and NLR and PLR. In addition, clozapine and other
antipsychotic drugs may induce transient neutropenia for the patients (Rettenbacher et al.,
2010). However, we did not observe any effects of these drugs on NLR or PLR. Our
17

results suggest NLR and PLR can possibly be used as surrogate indicators for systemic
inflammation in schizophrenia patients and that suppression of inflammation may be
useful for the treatment of schizophrenia.
The strength of our study lies in the use of an objective measure of sleep quality and
multiple markers of inflammation. Statistical measures were applied to control for a
number of confounding factors among patients with schizophrenia. However, our study
also has several limitations. The results in this study were based on a cross-sectional
design, which would have been more robust if the study was conducted using a
prospective long-term cohort. In addition, it is not possible to establish causality between
the variables investigated with the current study design. Although we tried to control for
the effects of several covariates, schizophrenia patients often have high rates of medical
comorbidity (e.g. diabetes, hyperlipidaemia and cardiovascular diseases), which may
influence immune responses measured in our subjects (Lambert et al., 2003). The
analyses of more inflammatory markers like CRP, interleukins or TNF-a in future studies
would help to shed more light on the effects of comorbidities on immune response in
schizophrenia patients. Although we have the data on sleep quality of the healthy
participants, the hematologic parameters of these participants were not measured, which
could have shed more light on the associations reported between sleep and inflammation.
The effects of sleep apnoea and other sleep disorders are relatively unknown in
18

schizophrenia patients and should be further investigated as sleep apnoea is also

associated with inflammation and is also common in schizophrenia (Szaulinska et al.,
2015). In conclusion, the present study showed that objectively measured sleep quality is
positively associated with WBC and neutrophil counts, and NLR and PLR. These results
suggest that improving sleep quality in schizophrenia patients may help to suppress
inflammatory response, and may have important implications in clinical management of
the condition.
Ethical approval
All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national research
committee and with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards.
Conflict of Interest
The authors declare that they have no conflict of interest.
Acknowledgements
We thank the National Taiwan University of Sport and Taiwan Ministry of Science
and Technology (MOST 104-2628-H-028-001-MY2) for funding the research. The
sponsors had no role in study design, data collection, data analysis, data interpretation, or
in the writing of the report.
19

References
ActiGraph Software Department, 2012. ActiLife 6 user's manual. ActiGraph Software
Department, Pensacola, FL, USA.
Altintas, N., Cetinoglu, E., Yuceege, M., Acet, A.N., Ursavas, A., Firat, H., Karadag, M.,
2015. Neutrophil-to-lymphocyte ratio in obstructive sleep apnea; a multi center,
retrospective study. Eur Rev Med Pharmacol Sci 19 (17), 3234-3240.
Banks, S., Dinges, D.F., 2007. Behavioral and physiological consequences of sleep
restriction. J Clin Sleep Med 3 (5), 519-528.
Baranyai, Z., Krzystanek, M., Josa, V., Dede, K., Agoston, E., Szasz, A.M., Sinko, D.,
Szarvas, V., Salamon, F., Eklund, A.C., Szallasi, Z., Jakab, F., 2014. The
comparison of thrombocytosis and platelet-lymphocyte ratio as potential
prognostic markers in colorectal cancer. Thromb Haemost 111 (3), 483-490.
Bender, B.G., Ballard, R., Canono, B., Murphy, J.R., Leung, D.Y., 2008. Disease severity,
scratching, and sleep quality in patients with atopic dermatitis. J Am Acad
Dermatol 58 (3), 415-420.
Besedovsky, L., Lange, T., Born, J., 2012. Sleep and immune function. Pflugers Arch 463
(1), 121-137.
Born, J., Lange, T., Hansen, K., Molle, M., Fehm, H.L., 1997. Effects of sleep and
circadian rhythm on human circulating immune cells. J Immunol 158 (9),
4454-4464.
Boudjeltia, K.Z., Faraut, B., Stenuit, P., Esposito, M.J., Dyzma, M., Brohee, D., Ducobu,
J., Vanhaeverbeek, M., Kerkhofs, M., 2008. Sleep restriction increases white blood
cells, mainly neutrophil count, in young healthy men: a pilot study. Vasc Health
Risk Manag 4 (6), 1467-1470.
Bulzacka, E., Boyer, L., Schurhoff, F., Godin, O., Berna, F., Brunel, L., Andrianarisoa, M.,
Aouizerate, B., Capdevielle, D., Chereau-Boudet, I., Chesnoy-Servanin, G.,
Danion, J.M., Dubertret, C., Dubreucq, J., Faget, C., Gabayet, F., Le Gloahec, T.,
Llorca, P.M., Mallet, J., Misdrahi, D., Rey, R., Richieri, R., Passerieux, C., Roux,
P., Yazbek, H., Leboyer, M., Fond, G., 2016. Chronic Peripheral Inflammation is
Associated With Cognitive Impairment in Schizophrenia: Results From the
Multicentric FACE-SZ Dataset. Schizophr Bull 42 (5), 1290-1302.
Buyukkaya, E., Karakas, M.F., Karakas, E., Akcay, A.B., Tanboga, I.H., Kurt, M., Sen, N.,
2014. Correlation of neutrophil to lymphocyte ratio with the presence and severity
of metabolic syndrome. Clin Appl Thromb Hemost 20 (2), 159-163.
Chen, L.J., Fox, K.R., Ku, P.W., Chang, Y.W., 2016a. Effects of Aquatic Exercise on
Sleep in Older Adults with Mild Sleep Impairment: a Randomized Controlled Trial.
Int J Behav Med 23 (4), 501-506.
20

Chen, L.J., Steptoe, A., Chung, M.S., Ku, P.W., 2016b. Association between
actigraphy-derived physical activity and cognitive performance in patients with
schizophrenia. Psychol Med 46 (11), 2375-2384.
Chennaoui, M., Sauvet, F., Drogou, C., Van Beers, P., Langrume, C., Guillard, M., Gourby,
B., Bourrilhon, C., Florence, G., Gomez-Merino, D., 2011. Effect of one night of
sleep loss on changes in tumor necrosis factor alpha (TNF-alpha) levels in healthy
men. Cytokine 56 (2), 318-324.
Christoffersson, G., Vagesjo, E., Pettersson, U.S., Massena, S., Nilsson, E.K., Broman,
J.E., Schioth, H.B., Benedict, C., Phillipson, M., 2014. Acute sleep deprivation in
healthy young men: impact on population diversity and function of circulating
neutrophils. Brain Behav Immun 41, 162-172.
Cohen,

J., Cohen, P., West, S.G., Aiken, L.S., 2002. Applied multiple
regression/correlation analysis for the behavioral sciences (3rd ed.). Routledge,
London.

Dimitrov, S., Lange, T., Born, J., 2010. Selective mobilization of cytotoxic leukocytes by
epinephrine. J Immunol 184 (1), 503-511.
Fan, X., Liu, E.Y., Freudenreich, O., Park, J.H., Liu, D., Wang, J., Yi, Z., Goff, D.,
Henderson, D.C., 2010. Higher white blood cell counts are associated with an
increased risk for metabolic syndrome and more severe psychopathology in
non-diabetic patients with schizophrenia. Schizophr Res 118 (1-3), 211-217.
Fan, X., Pristach, C., Liu, E.Y., Freudenreich, O., Henderson, D.C., Goff, D.C., 2007.
Elevated serum levels of C-reactive protein are associated with more severe
psychopathology in a subgroup of patients with schizophrenia. Psychiatry Res 149
(1-3), 267-271.
Faraut, B., Boudjeltia, K.Z., Dyzma, M., Rousseau, A., David, E., Stenuit, P., Franck, T.,
Van Antwerpen, P., Vanhaeverbeek, M., Kerkhofs, M., 2011. Benefits of napping
and an extended duration of recovery sleep on alertness and immune cells after
acute sleep restriction. Brain Behav Immun 25 (1), 16-24.
Faraut, B., Boudjeltia, K.Z., Vanhamme, L., Kerkhofs, M., 2012. Immune, inflammatory
and cardiovascular consequences of sleep restriction and recovery. Sleep Med Rev
16 (2), 137-149.
Faugere, M., Micoulaud-Franchi, J.A., Alessandrini, M., Richieri, R., Faget-Agius, C.,
Auquier, P., Lancon, C., Boyer, L., 2015. Quality of life is associated with chronic
inflammation in schizophrenia: a cross-sectional study. Sci Rep 5, 10793.
Gardner, D.M., Murphy, A.L., ODonnell, H., Centorrino, F., Baldessarini, R.J., 2010.
International consensus study of antipsychotic dosing. American Journal of
Psychiatry 167 (6), 686-693.
Grandner, M.A., Sands-Lincoln, M.R., Pak, V.M., Garland, S.N., 2013. Sleep duration,
21

cardiovascular disease, and proinflammatory biomarkers. Nat Sci Sleep 5, 93-107.

Guthrie, G.J., Charles, K.A., Roxburgh, C.S., Horgan, P.G., McMillan, D.C., Clarke, S.J.,
2013. The systemic inflammation-based neutrophil-lymphocyte ratio: experience
in patients with cancer. Crit Rev Oncol Hematol 88 (1), 218-230.
He, J., Hsuchou, H., He, Y., Kastin, A.J., Mishra, P.K., Fang, J., Pan, W., 2014. Leukocyte
infiltration across the blood-spinal cord barrier is modulated by sleep
fragmentation in mice with experimental autoimmune encephalomyelitis. Fluids
Barriers CNS 11 (1), 27.
Heiser, P., Dickhaus, B., Schreiber, W., Clement, H.W., Hasse, C., Hennig, J.,
Remschmidt, H., Krieg, J.C., Wesemann, W., Opper, C., 2000. White blood cells
and cortisol after sleep deprivation and recovery sleep in humans. Eur Arch
Psychiatry Clin Neurosci 250 (1), 16-23.
Irwin, M.R., Wang, M., Ribeiro, D., Cho, H.J., Olmstead, R., Breen, E.C., Martinez-Maza,
O., Cole, S., 2008. Sleep loss activates cellular inflammatory signaling. Biol
Psychiatry 64 (6), 538-540.
Kay, S.R., Flszbein, A., Opfer, L.A., 1987. The positive and negative syndrome scale
(PANSS) for schizophrenia. Schizophrenia Bulletin 13 (2), 261-276.
Khandaker, G.M., Cousins, L., Deakin, J., Lennox, B.R., Yolken, R., Jones, P.B., 2015.
Inflammation and immunity in schizophrenia: implications for pathophysiology
and treatment. Lancet Psychiatry 2 (3), 258-270.
Khandaker, G.M., Zimbron, J., Dalman, C., Lewis, G., Jones, P.B., 2012. Childhood
infection and adult schizophrenia: a meta-analysis of population-based studies.
Schizophr Res 139 (1-3), 161-168.
Khandaker, G.M., Zimbron, J., Lewis, G., Jones, P.B., 2013. Prenatal maternal infection,
neurodevelopment and adult schizophrenia: a systematic review of
population-based studies. Psychol Med 43 (2), 239-257.
Kluge, M., Schacht, A., Himmerich, H., Rummel-Kluge, C., Wehmeier, P.M., Dalal, M.,
Hinze-Selch, D., Kraus, T., Dittmann, R.W., Pollmacher, T., Schuld, A., 2014.
Olanzapine and clozapine differently affect sleep in patients with schizophrenia:
results from a double-blind, polysomnographic study and review of the literature.
152 (1), 255-260.
Koseoglu, S., Ozcan, K.M., Ikinciogullari, A., Cetin, M.A., Yildirim, E., Dere, H., 2015.
Relationship Between Neutrophil to Lymphocyte Ratio, Platelet to Lymphocyte
Ratio and Obstructive Sleep Apnea Syndrome. Adv Clin Exp Med 24 (4),
623-627.
Krenn-Pilko, S., Langsenlehner, U., Thurner, E.M., Stojakovic, T., Pichler, M., Gerger, A.,
Kapp, K.S., Langsenlehner, T., 2014. The elevated preoperative
platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients. Br J
22

Cancer 110 (10), 2524-2530.

Kuhn, E., Brodan, V., Brodanova, M., Rysanek, K., 1969. Metabolic reflection of sleep
deprivation. Act Nerv Super (Praha) 11 (3), 165-174.
Lambert, T.J., Velakoulis, D., Pantelis, C., 2003. Medical comorbidity in schizophrenia.
Med J Aust 178 Suppl, S67-70.
Lange, T., Dimitrov, S., Born, J., 2010. Effects of sleep and circadian rhythm on the
human immune system. Ann N Y Acad Sci 1193, 48-59.
Lasselin, J., Rehman, J.U., Akerstedt, T., Lekander, M., Axelsson, J., 2015. Effect of
long-term sleep restriction and subsequent recovery sleep on the diurnal rhythms
of white blood cell subpopulations. Brain Behav Immun 47, 93-99.
Lian, L., Xia, Y.Y., Zhou, C., Shen, X.M., Li, X.L., Han, S.G., Zheng, Y., Mao, Z.Q.,
Gong, F.R., Wu, M.Y., Chen, K., Tao, M., Li, W., 2015. Application of
platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and
prognostic prediction in patients with resectable gastric cancer. Cancer Biomark
15 (6), 899-907.
Mahowald, M.W., Mahowald, M.L., Bundlie, S.R., Ytterberg, S.R., 1989. Sleep
fragmentation in rheumatoid arthritis. Arthritis Rheum 32 (8), 974-983.
Manzar, M.D., Rajput, M.M., Zannat, W., Hameed, U.A., Al-Jarrah, M.D., Spence, D.W.,
Pandi-Perumal, S.R., BaHammam, A.S., Hussain, M.E., 2016. Association
between sleep quality and inflammatory complement components in collegiate
males. Sleep Breath 20 (2), 867-872.
Micoulaud-Franchi, J.A., Faugere, M., Boyer, L., Fond, G., Richieri, R., Faget, C.,
Cermolacce, M., Philip, P., Vion-Dury, J., Lancon, C., 2015. Elevated C-reactive
protein is associated with sensory gating deficit in schizophrenia. Schizophr Res
165 (1), 94-96.
Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., Kirkpatrick, B., 2011. Meta-analysis of
cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol
Psychiatry 70 (7), 663-671.
Muller, N., Myint, A.M., Krause, D., Weidinger, E., Schwarz, M.J., 2013.
Anti-inflammatory treatment in schizophrenia. Prog Neuropsychopharmacol Biol
Psychiatry 42, 146-153.
Mullington, J.M., Hinze-Selch, D., Pollmacher, T., 2001. Mediators of inflammation and
their interaction with sleep: relevance for chronic fatigue syndrome and related
conditions. Ann N Y Acad Sci 933, 201-210.
Mullington, J.M., Simpson, N.S., Meier-Ewert, H.K., Haack, M., 2010. Sleep loss and
inflammation. Best Pract Res Clin Endocrinol Metab 24 (5), 775-784.
Oyama, J.I., Nagatomo, D., Yoshioka, G., Yamasaki, A., Kodama, K., Sato, M., Komoda,
H., Nishikido, T., Shiraki, A., Node, K., 2015. The relationship between neutrophil
23

to lymphocyte ratio, endothelial function, and severity in patients with obstructive

sleep apnea. J Cardiol 67 (3), 295-302.
Palma, B.D., Tufik, S., 2010. Increased disease activity is associated with altered sleep
architecture in an experimental model of systemic lupus erythematosus. Sleep 33
(9), 1244-1248.
Perez de Heredia, F., Garaulet, M., Gomez-Martinez, S., Diaz, L.E., Warnberg, J.,
Androutsos, O., Michels, N., Breidenassel, C., Cuenca-Garcia, M., Huybrechts, I.,
Gottrand, F., Ferrari, M., Santaliestra-Pasias, A.M., Kafatos, A., Molnar, D.,
Sjostrom, M., Widhalm, K., Moreno, L.A., Marcos, A., Group, H.S., 2014.
Self-reported sleep duration, white blood cell counts and cytokine profiles in
European adolescents: the HELENA study. Sleep Med 15 (10), 1251-1258.
Proctor, M.J., Morrison, D.S., Talwar, D., Balmer, S.M., Fletcher, C.D., O'Reilly, D.S.,
Foulis, A.K., Horgan, P.G., McMillan, D.C., 2011. A comparison of
inflammation-based prognostic scores in patients with cancer. A Glasgow
Inflammation Outcome Study. Eur J Cancer 47 (17), 2633-2641.
Rangaraj, V.R., Knutson, K.L., 2016. Association between sleep deficiency and
cardiometabolic disease: implications for health disparities. Sleep Med 18, 19-35.
Rettenbacher, M.A., Hofer, A., Kemmler, G., Fleischhacker, W.W., 2010. Neutropenia
induced by second generation antipsychotics: a prospective investigation.
Pharmacopsychiatry 43 (2), 41-44.
Semiz, M., Yildirim, O., Canan, F., Demir, S., Hasbek, E., Tuman, T.C., Kayka, N., Tosun,
M., 2014. Elevated neutrophil/lymphocyte ratio in patients with schizophrenia.
Psychiatr Danub 26 (3), 220-225.
Smith, R.A., Bosonnet, L., Raraty, M., Sutton, R., Neoptolemos, J.P., Campbell, F.,
Ghaneh, P., 2009. Preoperative platelet-lymphocyte ratio is an independent
significant prognostic marker in resected pancreatic ductal adenocarcinoma. Am J
Surg 197 (4), 466-472.
Szaulinska, K., Plywaczewski, R., Sikorska, O., Holka-Pokorska, J., Wierzbicka, A.,
Wichniak, A., Sliwinski, P., 2015. Obstructive sleep apnea in severe mental
disorders. Psychiatr Pol 49 (5), 883-895.
Vgontzas, A.N., Papanicolaou, D.A., Bixler, E.O., Lotsikas, A., Zachman, K., Kales, A.,
Prolo, P., Wong, M.L., Licinio, J., Gold, P.W., Hermida, R.C., Mastorakos, G.,
Chrousos, G.P., 1999. Circadian interleukin-6 secretion and quantity and depth of
sleep. J Clin Endocrinol Metab 84 (8), 2603-2607.
Wichniak, A., Skowerska, A., Chojnacka-Wojtowicz, J., Taflinski, T., Wierzbicka, A.,
Jernajczyk, W., Jarema, M., 2011. Actigraphic monitoring of activity and rest in
schizophrenic patients treated with olanzapine or risperidone. J Psychiatr Res 45
(10), 1381-1386.
24

Yenigun, A., Karamanli, H., 2015. Investigation of the relationship between

neutrophil-to-lymphocyte ratio and obstructive sleep apnoea syndrome. J Laryngol
Otol 129 (9), 887-892.
Yuksel, M., Yildiz, A., Oylumlu, M., Akyuz, A., Aydin, M., Kaya, H., Acet, H., Polat, N.,
Bilik, M.Z., Alan, S., 2015. The association between platelet/lymphocyte ratio and
coronary artery disease severity. Anatol J Cardiol 15 (8), 640-647.
Zahorec, R., 2001. Ratio of neutrophil to lymphocyte counts--rapid and simple parameter
of systemic inflammation and stress in critically ill. Bratisl Lek Listy 102 (1),
5-14.
Table 1 Mean SD of demographics, anthropometry and physical activity profiles
Characteristics (Mean SD or %)

Patients (n=199)

Healthy control (n=60)

Sex (Male) (%)

61.3

56.7

Alcohol (Never) (%)

83.4

85.0

Smoke (Never) (%)

57.3

81.7

Age (years)

44.0

9.9

41.1

9.6

Education (years)

11.4

2.2

14.9

3.5

Height (cm)

164.6

8.9

164.4

6.6

Weight (kg)

66.0

13.5

65.7

13.7

BMI (kg/m )

24.3

4.3

23.9

3.7

Waist circumference (cm)

86.8

11.1

81.0

10.5

567.0 367.7

904.1

558.8

Physical activity (Kcal)

Abbreviations: BMI: Body mass index

25

Table 2 The clinical state profiles

Characteristics (Mean SD or %)

Patients (n=199)

PANSS all

63.0

20.0

PANSS-P

15.4

5.7

PANSS-N

16.9

6.2

PANSS-G

30.7

10.7

Years since illness onset

23.8

6.5

Hospitalization (month)

14.2

17.0

1.1

1.3

Lorazepam equivalent doses

Chlorpromazine equivalent doses

847.6 783.8

Antipsychotic drug used frequencies (%)

Amisulpride

2.5

Aripiprazole

2.5

Chlorpromazine

2.0

Clopenthixol

1.5

Clozapine

27.1

Fluphenazine

0.5

Fluvoxamine

1.0

Haloperidol

15.1

Loxapine

1.0

Olanzapine

9.0

Risperidone

29.6

Quetiapine

6.5

Sulpiride

15.6

Trifluoperazine

1.0

Ziprasidone

1.0

Zotepine

5.5

Lozapine

3.5

Flupentixol

7.0

Clothiapine

2.0

Fluanxol

1.0

Abbreviations: PANSS: Positive and negative syndrome scale

26

Table 3 Mean SD of sleep indices and immune cell counts

Characteristics (MeanSD)
Sleep indices
Total sleep time (min)
Sleep efficiency (%)
Sleep onset latency (min)

Patients (n=199)

Healthy control (n=60)

502.9
89.2
14.3

81.6
4.6
5.7

18992.7
22.2
5.3
3.1
2.1

Neutrophil (x10 /mm )

Lymphocyte (x103/mm3)
Platelet (x103/mm3)

6.8
4.0
2.0
240.7

73.1

NLR
PLR

3.5
138.4

9.7
72.2

Total activity counts

Wake after sleep onset (min)
Number of awakening
Average length of awakening (min)
Hematologic parameters
WBC (x103/mm3)
3

42600.1
58.1
11.8
5.9

380.5 71.6
86.3 6.6
4.2 3.1
36022.5
54.7
20.2
2.8

17272.2
25.4
8.0
1.1

1.6

0.9

Abbreviations: WBC: white blood cell, NLR: neutrophil-lymphocyte ratio, PLR:

platelet-lymphocyte ratio

27

<0.001
0.003
<0.001
0.020
0.358
<0.001
<0.001

Table 4 Correlations between sleep indices and inflammatory markers among patients with
schizophrenia
Variables

WBC

(p)

Total sleep time

0.090

(0.205)

Sleep efficiency

-0.153

(0.031)

Sleep onset latency 0.246 (<0.001)*

Total activity

0.233 (0.001)*

Wake after sleep

(min)

0.239 (0.001)*

counts

Number of
awakening
Average length of
awakening (min)

0.262 (<0.001)*
-0.106

(0.137)

Neutrophil
(p)

-0.062

NLR

(p)

PLR

(p)

(0.386) -0.258 (<0.001)* -0.299 (<0.001)*

-0.248 (<0.001)* -0.246 (<0.001)* -0.163

(0.022)

0.266 (<0.001)* 0.142

(0.045) -0.004

(0.950)

0.276 (<0.001)* 0.152

(0.033) 0.045

(0.530)

0.269 (<0.001)* 0.155

(0.028) 0.023

(0.752)

0.201

(0.004) -0.001

(0.984) -0.080

(0.264)

0.027

(0.705) 0.284 (<0.001)* 0.247 (<0.001)*

A p-value less than 0.002 was considered as statistically

significant. Abbreviations: WBC: white blood cell, NLR:
neutrophil-lymphocyte ratio, PLR: platelet-lymphocyte
ratio

28

Table 5 Multivariate regressions between sleep indices and inflammatory markers among
patients with schizophrenia
Varia
bles

WBC
R
2

Total

Bet
a

Neutrophil

R
2

NLR

Bet
a

R
2

PLR

Bet
a

R
2

Bet
a

14

0.0 1.0

0.3

11

-0.

-1.

0.1

19

-0.

-4.

<0.0

23

-0.

-4.

<0.0

.3

78

13

.6

104

33

84

.4

322

32

01*

.5

349

82

01*

15

-0.

-1.

0.0

15

-0.

-3.

0.0

16

-0.

-3.

0.00

16

-0.

-2.

0.03

.5

132

90

60

.2

219

12

02*

.2

230

30

1*

.0

150

15

onset

17

0.1 2.8

0.0

14

0.2 2.9

0.0

12

0.1

1.6

0.10

14

-0.

-0.

0.86

latenc

.5

97

05

.8

08

03

.5

17

.0

012

17

17

0.2 2.8

0.0

15

0.2 3.3

0.0

12

0.1

1.6

0.09

14

0.0 0.3

0.70

.5

01

05

.8

36

01*

.5

21

.0

28

after

17

0.1 2.7

0.0

15

0.2 3.0

0.0

12

0.1

1.8

0.06

14

0.0 0.2

0.84

sleep

.3

93

06

.1

16

03

.8

31

.0

14

er of

17

0.2 2.6

0.0

12

0.1 1.8

0.0

11

-0.

-0.

0.94

14

-0.

-0.

0.57

awake

.0

07

09

.3

48

69

.2

006

069

.1

045

57

length

14

-0.

-0.

0.5

11

0.0 0.9

0.3

18

0.2

4.0

<0.0

17

0.2 2.9

0.00

of

.0

045

61

44

.2

75

24

.4

93

01*

.8

15

sleep
time
Sleep
efficie
ncy
Sleep

y
Total
activit
y
count
s
Wake

onset
Numb

ning
Avera
ge
9

awake
ning
A p-value less than 0.002 was considered as statistically significant. Abbreviations: WBC: white
blood cell, NLR: neutrophil-lymphocyte ratio, PLR: platelet-lymphocyte ratio. All the models
generated were adjusted for age, sex, education, alcohol consumption, cigarette smoking, physical
activity (Kcal), medication (Chlorpromazine equivalent doses and Lorazepam equivalent doses),
Number of metabolic syndromes, duration of hospitalization, years since illness onset, and the
29

positive and negative syndrome scale.

Highlights

Total sleep time was negatively associated with neutrophil-lymphocyte ratio and
platelet-lymphocyte ratio, and sleep efficiency was negatively associated with
neutrophil counts and neutrophil-lymphocyte ratio.

Higher sleep onset latency, sleep activity counts, number of awakening and wake after
sleep onset, which compromise sleep quality, were positively associated with the
inflammatory markers of WBC and neutrophil counts.

Improving sleep quality in patients with schizophrenia may modulate the state of
inflammatory in patients with schizophrenia.

30

Figure 1: Scatter plot between inflammatory markers and sleep parameters