Pretreatment Serum MCP-1 Level Predicts Response to Risperidone in Schizophrenia.
Schizophrenia is a chronic debilitating disease with a prevalence of 1% worldwide.  The pathogenesis of schizophrenia still remains unclear. Currrently, the hypothesis of Th1/Th2 cell dysfunction presents mild inflammation in schizophrenia patients,  which is characterized by the elevation of pro-inflammatory cells with a drop in anti-inflammatory cells.  Studies have shown resemblance of the cytokine network in schizophrenia to a state of acute stress, in which proinflammatory cytokines, such as Interleukin-1[alpha] (IL-1[beta]) and tumor necrosis factor-[alpha] (TNF-[alpha]), were elevated. [3-5] IL-1 and TNF-[alpha] were generated by T cells or monocyte/macrophages. They also activated the intracellular NF-[kappa]B signaling pathway,  whose general activation was commonly associated with autoimmune disease.  All of these results support the hypothesis regarding schizophrenia as an autoimmune disease. Additionally, cytokine monocyte chemokine protein 1 (MCP-1), also called C-C motif chemokine ligand 2 (CCL2), has now being drawing attention in research. MCP-1 is involved in the defect of Th2 cell polarity  and also affects the generation of interleukin-4 (IL-4), interferon-[gamma] (IFN-[gamma]), and interleukin-12 (IL-12).  The alterations of peripheral IL-4, IFN-[gamma], and IL-12 levels in schizophrenia patients indicates that MCP-1 might be associated with Th1/Th2 dysfunction in schizophrenia.  More interestingly, some studies showed the SNP (single nucleotide polymorphism) subtypes, rs4795893, rs1024611, rs4586 and rs2857657, of CCL2, the coding gene of MCP-1, were associated with treatment resistance of risperidone in the Han Chinese population. 
Previous studies demonstrated some association between cytokines IL-1[beta], TNF-[alpha] and MCP-1 and schizophrenia, however, few studies have focused on predicting response to antipsychotics by testing peripheral blood cytokines. Risperidone and olanzapine are both second generation antipsychotics, but they are greatly different in structure with different mechanisms.  They are one of the most widely used medications in the same class, therefore it is meaningful to study them. We performed a cross-sectional and a perspective natural observational cohort study on schizophrenia patients who were first-episode and drug-naive or un-medicated over the past 6 months. Here, we investigate cytokine levels at baseline to compare the cytokine levels in schizophrenia patients and Healthy controls (HCs), thereafter to explore cytokine levels at baseline in predicting response to antipsychotics.
2. Subjects and Methods
2.1 Study Design
Cross-sectional study design was applied to compare the difference in serum level of cytokines, IL-1[beta], TNF-[alpha] and MCP-1, between schizophrenia patients and HCs. We studied the role of those cytokines in the pathogenesis of schizophrenia. We also performed a perspective natural observational study to follow schizophrenia patients with risperidone or olanzapine monotherapy up to 4 weeks afterwards, to explore the relationship between the baseline level of cytokines, IL-1[beta], TNF-[alpha] and MCP-1, and the response to risperidone and olanzapine.
Patients were recruited from the inpatient units of Shanghai Mental Health Center, and HCs were volunteers recruited through advertisement. All subjects were recruited from October 2016 to May 2017. The present study was approved by the Shanghai Mental Health Center ethics committee. All participants or their legal guardians provided written informed consent to participate in this study.
The inclusion criteria for schizophrenia patients were the following: (a) Meeting diagnostic criteria for schizophrenia according to the ICD-10 ; (b) aged from 18 to 65, Han Chinese; (c) first-episode and drug-naive or un-medicated with neuroleptics except benzodiazepines over the past 6 months; (d) using olanzapine or risperidone monotherapy after recruitment. The exclusion criteria were the following: (a) presence of comorbid psychotic disorder, psychotic symptoms, psychoactive substance dependency or abuse, personality disorder, or mental retardation; (b) currently suffering from a severe medical condition, such as cancer autoimmune diseases, infection or neurological diseases; (c) metabolic or endocrine diseases, such as diabetes mellitus and dyslipidemia; (d) in use of glucose, lipid-lowering drugs, immunosuppressants, or special diet that affects the level of glucose and lipid; (e) currently pregnant or lactating.
HCs were matched with the patient group on age, gender, education years and BMI. The exclusion criteria were the following: (a) currently suffering from a severe medical condition; (b) currently suffering from a psychotic disorder; (c) family history of psychotic disorder; (d) pregnant or lactating women.
Demographic data, including name, age, education years, height and weight, and clinical correlates were collected at baseline and 4-weeks' follow-up. Positive and Negative Syndrome Scale (PANSS) were employed to assess the psychopathological symptoms of patients. All interviewers were trained with professional PANSS scale and undergone assessment of consistency.
After strict screening, 64 patients were included in our study. 26 patients were involved in risperidone group, including 15 males and 11 females, whose mean(sd) age was 29.77(12.07). 38 patients were involved in olanzapine group, including 24 males and 14 females, whose mean(sd) age was 30.17(10.89).
2.3 Cytokine Assays
All peripheral blood samples were collected after an overnight fast between 06:00-07:00 a.m. 2 ml of blood was sampled into anticoagulant-free tubes before serum was isolated (centrifugation at 3000 rpm for 20 min at 4 [degrees]C). The separated serum was stored at -80 [degrees]C until being thawed for cytokine analysis.
Multiplex technology was applied to test several cytokines simultaneously.  Human Premixed Multi-ANAlyte kits for measuring cytokines and Tecan magnetic washing plate were purchased from Bio-Rad (Luminex, Austin, TX, USA).
2.4 Statistical Analyses
Statistical analyses were carried out using SPSS 20.0 for Windows (SPSS, Inc., Chicago, IL, USA). Figures were made by software GraphPad Prism 6.0. The normal distribution of data was tested using the Kolmogorov-Smirnov one-sample test. All data were normally distributed and reported as mean(sd). Cytokine comparisons between groups were analyzed by independent sample t tests. Intra-group comparisons were tested by paired t test. Correlation was tested by Pearson and Spearman correlation analysis. Stepwise linear regression analysis was performed to control the confounders and evaluate the variables that might affect response. Significance was defined as p<0.05 (twotailed).
3.1 Comparison of serum cytokines between schizophrenia and HC
After strict screening procedures, sixty-four patients with schizophrenia were included in our study, including 39 males and 25 females, with a mean(sd) age of 29.61(11.16) and mean(sd) BMI of 21.10(2.70). Fifty-three HCs were in the control group, including 35 males and 18 females, with a mean(sd) age of 32.25(10.46) and mean(sd) BMI of 21.41(1.74).
Significantly higher baseline level of MCP-1 was found in patients with schizophrenia than HCs. But levels of IL-1[beta], TNF-[alpha] were not different between the two groups (table 1).
3.2 Analysis of response to 4-weeks' olanzapine and risperidone monotherapy
Because there was no difference in duration of illness, gender, age, education years, baseline BMI, baseline PANSS scores, and cytokine levels between the olanzapine and risperidone groups (table 2), we examined the two groups of patients together and found significant reduction after treatment (table 3). According to a response criterion of a 30% reduction in symptoms  (reduction rate = (baseline score - followup score) / (baseline score - 30) x 100%), we had total of 37 (57.8%) responders at the 4-week follow-up, including 22 (57.9%) responders in the olanzapine group and 15 (57.7%) responders in the risperidone group.
We defined PANSS reduction as scores at 4-weeks' follow-up minus scores at baseline. There was no significant difference in PANSS total score, PANSS positive score (PANSS-P) and PANSS general score (PANSS-G) between the olanzapine and risperidone groups. But we found PANSS negative score (PANSS-N) higher in the olanzapine group than in the risperidone group (t=2.03, p=0.047) (table 3).
3.3 Pretreatment levels of cytokine and response to risperidone or olanzapine
In the analysis of correlation, we found that PANSS-G was negatively correlated with baseline level of MCP-1 in the risperidone group (r = -0.658; p=0.0003), but not with baseline levels of IL-1[beta] and TNF-[alpha] in the same group. The correlation remained significant after using stepwise linear regression to control for the sociodemographic and clinical confounders, such as gender, age, education, BMI, and duration of illness (adjusted [R.sup.2] = 0.409, [beta] = -0.658, p = 0.0003). In the olanzapine group, no significant correlation was found between cytokines and reduction of 3 PANSS factors (figure 1). There was no correlation between baseline level of 3 cytokines and PANSS total reduction in the two groups. But we found a tendency of correlation between baseline level of MCP-1 and PANSS total reduction in the risperidone group (r = -0.36, p= 0.075). Using socio-demographic and clinical confounders, such as gender, age, education, BMI, and duration of illness as independent variables, we also found the duration of illness could serve as a predictor for PANSS total reduction (adjusted [R.sup.2] = 0.077, [beta] = -0.303, p = 0.015) and PANSS-G reduction (adjusted R2 = 0.087, [beta] = -0.334, p= 0.040).
4.1 Main findings
According to the main results of our present study, (1) pretreatment level of MCP-1 was higher in schizophrenia patients than HCs; (2) pretreatment MCP-1 level was negatively correlated with PANSS-G reduction in the risperidone group, indicating that pretreatment serum level of MCP-1 could serve as a biomarker predicting response to risperidone treatment. Additionally, our results showed (1) olanzapine was superior in response of negative symptoms than risperidone; (2) duration of illness could be a predictor indicating the response to olanzapine treatment.
Our result was consistent with a large-sample study that showed a higher MCP-1 level in chronic schizophrenia than HCs [17.] But participants in their study were chronic schizophrenia patients with no washout of medications. In our study, all of our patients recruited had been un-medicated at least 6 months in order to exclude the effect of antipsychotics on cytokine levels.
The sample size is small, so further large-sample studies are needed to confirm our results. Therefore, we need to be cautious when explaining the results and generalizing the findings of this study.
To consider the factors of physical condition and the effect of medication on cytokines, all patients were matched in age, gender, BMI and education with HCs. Moreover, all patients were first-episode and drug-naive or un-medicated for over 6 months before they were recruited.
It is worth noting that pretreatment level of MCP-1 was significantly correlated with response to risperidone mono-treatment in schizophrenia patients. Higher levels of pretreatment MCP-1 indicated poorer response to risperidone treatment. For fortification purposes, we controlled confounders such as gender, age, BMI, duration of illness and education years, the only variable that remained with a predictive effect was MCP-1, whose higher level indicated less PANSS-G reduction in the risperidone group. A study on Han Chinese patients with schizophrenia found that SNP subtype of CCL2 gene, the coding gene of MCP-1, rs4795893, rs1024611, rs4586 and rs2857657 appeared more frequently in patients who were resistant to risperidone treatment.  This finding provided evidence supporting our present results. However, the underlying mechanism of how MCP-1 influences response to risperidone is still unclear. Some studies showed that cytokines were involved in the regulation of many neuronal functions thus representing the pathogenetic link to schizophrenia.  Other studies also found that receptors of MCP-1, CC chemokine receptor type 1 (CCR1) and CC chemokine receptor type 2 (CCR2), were expressed on the ventral midbrain of humans. CCL2 also played a role in development and differentiation of midbrain dopaminergic neurons.  Those studies indicate the potential role of MCP-1 in dopaminergic neuron growth. In a study of rats, long term intracranial injection of CCL2 activated dopamine release in the nigrostriatal area.  However, no finding has been reported on the effect of MCP-1 on the mesolimbic or mesocortical dopaminergic pathways.
To the best of our knowledge, no previous study has focused on prediction of serum MCP-1 levels in response to risperidone. If our results could be confirmed in further studies with a larger sample, serum MCP-1 level would probably be a viable biomarker predicting response to risperidone in patients with schizophrenia. Meanwhile, MCP-1 could be a potential target in the mechanism of pathogenesis and treatment of schizophrenia, and is worth further exploration.
Special thanks to Doctor Guoqing Zhao, Zongfeng Zhang, Professor Guanning Lin, Attending doctor Caojun Ji, Fellow doctor Mengjuan Xing, Nurse Xiaonan Fan, Nurse Yujun Sun, Nurse Jialin Zhuang, Nurse Haitao Jiang, Xingshuo Li and Jinrui Rao at Shanghai Mental Health Center for providing help on the present study.
Funding for this study provided by: The National Key Research and Development Program (2017YFC0909200); National Natural Science Foundation of China (NSFC, 81171266, 81271481, 81571326, 81500976); Ministry of Science and Technology Precision Medicine Project; Shanghai Key Laboratory of Psychotic Disorders (13dz2260500); Shanghai Municipal Planning Commission of Science and Research Fund (20154Y0194)
Conflict of interest statement
Authors declare no conflict of interest related to this manuscript.
All participants or their legal guardians provided written informed consent to participate in this study.
The present study was approved by the Shanghai Mental Health Center ethics committee.
Yezhe Lin, Yuan Shi, Zhiguang Lin, Yanmin Peng and Yousong Su were responsible for clinical data collection and lab experiments.
Yezhe Lin and Yanmin Peng managed the literature search and the statistical analyses.
Donghong Cui, Yezhe Lin, and Cuizhen Zhu were involved in formulating concepts and editing the manuscript.
Donghong Cui and Jinghong Chen were responsible for study design and revising.
All authors have contributed to and have approved the final manuscript.
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Yezhe Lin has a Bachelor's degree of medicine (M.B.B.S). She graduated from the Shanghai Jiao Tong University School of Medicine in 2014. Afterwards, she studied as a graduate student at affiliated Mental Health Center of Shanghai Jiao Tong University School of Medicine until 2017. She began her residency at the Shanghai Mental Health Center in 2017 and is now working as a full-time resident doctor in the department of general psychiatry at Shanghai Mental Health Center. She is interested in transitional medicine and clinical studies, especially studies on the side effects of neuroleptics.
Yezhe LIN (1,2), Yanmin PENG (1,2), Cuizhen ZHU (1,2), Yousong SU (1), Yuan SHI (1,2), Zhiguang LIN (1), Jinghong CHEN (1,3*), Donghong CUI (1,2,3*)
(1) Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
(2) Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
(3) Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
(*) correspondence: Donghong Cui. E-mail: firstname.lastname@example.org; Jinghong Chen. E-mail: email@example.com. Mailing address: No.3210 Humin Road, Shanghai, China. Postcode: 201108.
Table 1. Comparison between baseline level of cytokines in schizophrenia patients and healthy controls Cytokine patient group, HC group, t value P value baseline (n=64) baseline (n=53) IL-1[beta] (pg/ml) 5.59(3.55) 4.67(3.34) 1.43 0.154 TNF-[alpha] (pg/ml) 4.77(2.73) 5.19(3.04) 0.79 0.434 MCP-1 (pg/dl) 3.11(1.09) 2.62(0.97) 2.62 0.010 (*) IL-1[beta], interleukin-1[beta]; TNF-[alpha], tumor necrosis factor-[alpha]; MCP-1, monocyte chemokine protein 1; (*) p<0.05; independent sample t test. Table 2. Demographic, baseline PANSS scores and cytokine levels in the olanzapine and risperidone groups Olanzapine Risperidone t or (N=38) (N=26) [chi squared] FEDN 20(52.6%) 12(46.2%) - Drug-free 30(78.9%) 17(65.4%) - duration of illness (month) 38.48(49.10) 32.08(32.17) 0.60 Gender (M/F) 24/14 15/11 0.19 Age (years) 30.17(10.89) 29.77(12.07) 0.09 Education (years) 12.42(2.69) 12.73(3.28) 0.41 BMI 21.56(2.72) 20.61(2.59) 1.21 PANSS 73.05(17.50) 69.08(11.07) 1.11 IL-1[beta] (pg/ml) 5.38(3.57) 5.90(3.55) 0.58 TNF-[alpha] (pg/ml) 4.49(2.29) 5.17(3.28) 0.98 MCP-1 (pg/dl) 3.07(0.85) 3.20(1.38) 0.44 P value FEDN - Drug-free - duration of illness (month) 0.552 (b) Gender (M/F) 0.660 (a) Age (years) 0.925 (b) Education (years) 0.681 (b) BMI 0.233 (b) PANSS 0.270 (b) IL-1[beta] (pg/ml) 0.567 (b) TNF-[alpha] (pg/ml) 0.329 (b) MCP-1 (pg/dl) 0.665 (b) BMI, body mass index; PANSS, Positive and Negative Syndrome Scale; IL-1[beta], interleukin-1[beta]; TNF-[alpha], tumor necrosis factor-[alpha]; MCP-1, monocyte chemokine protein 1; a [chi squared] test; b independent sample t test. Table 3. Psychopathological evaluation following antipsychotic treatment Total (n=64) Olanzapine (N=38) BSL FU RED p BSL FU chlorpromazine equivalent 0.0 162.4 - 0.0 178.2 (mg/d) (0.0) (66.8) (0.0) (52.3) PANSS positive 21.31 14.84 6.47 <0.001 (*a) 21.89 14.95 (6.85) (5.20) (5.09) (6.59) (5.00) PANSS negative 16.20 13.70 2.50 <0.001 (*a) 16.82 13.29 (5.75) (4.29) (5.01) (6.26) (5.02) PANSS general 33.92 27.70 6.22 <0.001 (*a) 34.34 27.87 (7.27) (5.55) (8.06) (8.84) (6.08) PANSS total 71.44 56.25 15.19 <0.001 (*a) 73.05 56.11 (15.24) (12.04) (13.79) (17.50) (13.88) Olanzapine (N=38) RED p BSL FU RED chlorpromazine - 0.0 101.6 equivalent (0.0) (26.2) (mg/d) 6.95 <0.001 (*) 20.46 14.69 5.77 PANSS positive (6.12) (7.25) (5.58) (3.00) 3.53 <0.001 (*a) 15.31 14.31 1.00 PANSS negative (5.43) (4.90) (2.92) (3.96) 6.47 <0.001 (*a) 33.31 27.46 5.85 PANSS general (10.00) (4.11) (4.89) (3.94) 16.95 <0.001 (*a) 69.08 56.46 12.62 PANSS total (17.19) (11.07) (8.94) (5.51) OLZ vs. Risp (reduction) p t p chlorpromazine equivalent - - - (mg/d) PANSS positive <0.001 (*a) 1.021 0.312 (b) PANSS negative 0.210 (*a) 2.029 0.047 (*b) PANSS general <0.001 (*a) 0.349 0.728 (b) PANSS total <0.001 (*a) 1.448 0.154 (b) PANSS: Positive and Negative Syndrome Scale; BSL: baseline; FU: follow-up; RED: reduction; a paired t test; b independent sample t test. (*) (p<0.05)
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|Title Annotation:||ORIGINAL RESEARCH ARTICLE|
|Author:||Lin, Yezhe; Peng, Yanmin; Zhu, Cuizhen; Su, Yousong; Shi, Yuan; Lin, Zhiguang; Chen, Jinghong|
|Publication:||Shanghai Archives of Psychiatry|
|Date:||Oct 1, 2017|
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