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Decreased interleukin-10 serum levels in first-episode drug-naïve schizophrenia: Relationship to psychopathology
Schizophrenia Research, Volume 156, Issue 1, June 2014, Pages 9–14
Many lines of findings support the hypothesis of the inflammation-related pathways in the multifactorial pathogenesis of schizophrenia (SZ). Interleukin-10 (IL-10), a potential anti-inflammatory cytokine, was found to be altered in chronic patients with SZ. The aim of this study was to assess the serum levels of IL-10 in first-episode and drug-naïve (FEDN) patients with SZ and its relationships with the psychopathological parameters. Serum IL-10 levels were analyzed using established procedures in 128 FEDN patients with SZ and 62 healthy controls. Schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive factor derived from the five factor model of the PANSS. Compared to the healthy controls, the patients exhibited a significant decrease in IL-10 levels. Serum IL-10 was inversely correlated with the PANSS negative symptom, as well as with the PANSS cognitive factor subscores in patients. Our results suggested that decreased IL-10 may be implicated in the negative symptom and cognitive impairment at the acute stage of schizophrenia episode.
Keywords: Schizophrenia, Cytokines, Interleukin-10, Psychopathology, Cognition, Immune function.
Many lines of findings have supported the hypothesis of the inflammation-related pathways in the multifactorial pathogenesis of schizophrenia (SZ) (Dean, 2011 and Na et al, 2014). For example, the presence of a dysregulation of cytokine profiles has been observed in patients with SZ, including decrease of the level of mitogen-induced lymphocyte proliferation ( Chengappa et al., 1995 ), increase of the numbers of total T and T-helper cells ( Muller et al., 1993 ) and increases of the serum levels of interleukin-1 (IL-1), IL-1 receptor antagonist (IL-1RA), IL-6, IL-6 receptors and tumor necrosis factor-alpha (TNF-alpha) (Ganguli et al, 1993, Rapaport and Stein, 1994, Maes et al, 1995, Naudin et al, 1996, Maes, 1997, Rapaport et al, 1997, and Lin et al, 1998), which all indicated a disorder of immune system in patients with SZ (Bocchio Chiavetto et al, 2002 and Zhang et al, 2002). The most recent meta-analysis of immune cell parameters in schizophrenia showed that there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients. Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis ( Miller et al., 2013 ), suggesting abnormal blood lymphocyte parameters and immune system dysfunction in schizophrenia.
Cytokines are important mediators of the cross-talk between the central nervous system and immune system. Effective immune response is mainly mediated by two mutually exclusive sets of cytokines: Th1-type and Th2-type. Th1 cells produce interferon-γ (IFN-γ), IL-2 and TNF, and evoke cell-mediated immunity and phagocyte-dependent inflammation. Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, evoke strong antibody responses but inhibit phagocytic activity (Romagnani, 2000 and Bocchio Chiavetto et al, 2002). A previous hypothesis proposed that TNF, IL-1, IL-2, IFN-alpha and IFN-γ produced by chronically activated macrophages and T-lymphocytes were the fundamental mediators of schizophrenia ( Smith and Maes, 1995 ). Schwarz et al. (2001) proposed the Th2-hypothesis, arguing that immunological findings in a subgroup of SZ patients can be interpreted as a shift from Th1-like cellular to Th2-like humoral immune reactivity. Based on these hypotheses, two meta-analyses have been performed to investigate these associations of aberrant cytokine levels with schizophrenia (Potvin et al, 2008 and Miller et al, 2011). The first meta-analysis, by Potvin et al. (2008) , found a significant increase in blood levels of IL-1RA, sIL-2R, and IL-6 in patients with SZ. The second meta-analysis, by Miller et al. (2011) , found significant increases in macrophage derived cytokines IL-1 β, IL-6, and TNF-α, as well as the Th1-derived cytokines IFN-γ and IL-12 in first-episode psychosis (FEP) patients with SZ and acutely relapsed AR inpatients with SZ. Such patterns are largely consistent with the macrophage–T-lymphocyte theory, but with less consistent evidence in favor of Th2-hypothesis ( Miller et al., 2011 ). Moreover, the Th1 vs Th2 distinction for cytokine responses seems to oversimplify the immune response in SZ. In recent years, the classic paradigm of Th1/Th2 cell-mediated immunity has been evolved to include novel subsets of Th cell, such as T helper type 3 cells (Th3) and T helper cells 17 (Th17) cells (Miller et al, 2011 and Severance et al, 2013). Moreover, the same cytokine may be produced by several different Th cell subsets ( Miller et al., 2011 ). Th3 cells exert their action primarily by secreting transforming growth factor beta-1 (TGF-β1) that suppresses the production of Th-1 cytokines ( Kim et al., 2004 ). Th17 cells mainly produce the pro-inflammatory cytokine interleukin-17 (IL-17), implicated in various immune and inflammatory processes ( Ding et al., 2014 ). Interestingly, two recent studies show activation of Th3 and Th17 in SZ, which was lowered after treatment with antipsychotics (Kim et al, 2004 and Ding et al, 2014).
IL-10 is an important Th2-type cytokine, produced by activated macrophages, T regulatory, B regulatory, and Th2 lymphocytes, and inhibits expression of other pro-inflammatory cytokines such as IFN-γ, IL-2, and TNF-α in Th1 cells. Interestingly, Th3 cells, involved in mucosal immunity and protection, produce IL-10 (Miller et al, 2011 and Severance et al, 2013). Hence, IL-10 contributes to dampen the immune and inflammatory response, being a potential anti-inflammatory mediator ( Moore et al., 2001 ), which determines immune regulation and the balance between inflammatory and anti-inflammatory responses ( Potvin et al., 2008 ). Also, IL-10 may be part of the compensatory anti-inflammatory response syndrome, a counter-regulatory response to the primary inflammatory response (Woiciechowsky et al, 1999 and Miller et al, 2011). In addition, previous studies have found that IL-10 and IL-10 receptors are synthesized in the brain including microglia and astrocyte ( Ledeboer et al., 2002 ). Hence, they are also considered to be an important modulator of inflammatory response in the central nervous system (CNS) ( Strle et al., 2001 ), functioning to maintain a balance between pro- and anti-inflammatory cytokine levels in the CNS ( Sawada et al., 1999 ).
Several previous studies have shown a relationship between IL-10 and SZ, with contradictory results. For example, Maes et al. (2002) and Kunz et al. (2011) reported that patients with SZ exhibited significantly increased IL-10 serum levels. Moreover, increased serum levels of IL-10 were observed in SZ patients, specifically in more severe cases (Rothermundt et al, 1996 and Cazzullo et al, 1998). However, some authors failed to replicate these findings in patients with SZ (O'Brien et al, 2008 and Kubistova et al, 2012), or even found decreased serum IL-10 levels in paranoid SZ ( Kaminska et al., 2001 ) or in patients with SZ at late stage ( Pedrini et al., 2012 ). A recent study found no significant differences in IL-10 gene expression in peripheral blood cells between patients with SZ and healthy controls ( Freudenreich et al., 2010 ). Thus, the picture emerging is that IL-10 levels deserve further examination in the peripheral blood of patients with SZ.
Only a few studies have reported serum IL-10 levels in FEDN patients with SZ (Kubistova et al, 2012 and Pedrini et al, 2012). However, these studies featured small sample sizes. We recruited a larger sample of FEDN patients (n = 128) in the present study, which might provide us an enough power to elucidate the following questions: (1) whether serum IL-10 levels were altered in FEND patients at the onset of psychosis; (2) whether there was a relationship between IL-10 levels and psychopathological parameters, using the Positive and Negative Syndrome Scale (PANSS) ( Kay et al., 1987 ).
2. Material and methods
One hundred and twenty-eight (73 male and 55 female) FEND Chinese Han patients were followed for 3 months as inpatients after admission to Henan Zhumadian Hospital, a Henan-province owned psychiatric hospital in order to establish a DSM-IV diagnosis of schizophrenia using the Structured Clinical Interview for DSM-IV (SCID). Each subject filled out a detailed questionnaire that recorded general information, sociodemographic characteristics, and medical and psychological conditions. Additional information was collected from available medical records and collateral data (from family and/or treating clinician). Patients who previously had taken any antipsychotic, antidepressant or mood stabilizing drugs were excluded from the study. Patients were re-evaluated three months later for FEDN schizophrenia using the SCID, and diagnosed with schizophrenia only if both evaluations concluded the same. Using this method of diagnosis, 3 patients were excluded from this study. The patients had a mean age of 25.8 ± 9.4 years (range: 14–48 years), a mean duration of illness of 23.4 ± 19.1 months and a mean education of 7.1 ± 3.1 years.
Sixty-two healthy volunteers (male, 38 and female, 24) were recruited by advertisements at the local community. They had a mean age of 28.8 ± 8.4 years and a mean education of 7.7 ± 3.1 years. They were matched for gender and age with the above FEDN patients. Current mental status and personal or family history of any mental disorder were assessed by unstructured interviews. None of them presented a personal or family history of psychiatric disorder.
All subjects were Han Chinese recruited at the same period from the same area. We obtained a complete medical history, physical examination and laboratory tests from patients and control subjects. All were in good physical health and any subjects with abnormalities were excluded. Neither patients nor control subjects suffered from drug or alcohol abuse/dependence. The Institutional Review Board for both the Beijing Hui-Long-Guan and the Zhumadian hospitals approved the research protocol, and all subjects provided written informed consent.
2.2. Serum IL-10 ELISA
The blood samples were taken at the time of admission when all subjects were drug-naïve. Serum samples were collected between 7 a.m. and 9 a.m. following an overnight fast. The serum was separated, aliquoted, and stored at − 70 °C before use.
Serum IL-10 levels were measured in all subjects on the same day by sandwich enzyme-linked-immunosorbent serologic assay (ELISA) using a commercially available kit (R&D systems Inc., America) after all the samples had been collected and stored at − 70 °C. A full description of the assays has been given in our previous report (Tan et al, 2005 and Zhang et al, 2007). All samples were assayed by a research assistant blind to the clinical situation. The identity of all subjects was indicated by a code number maintained by the investigator until all biochemical analyses were completed. Inter- and intra-assay variation coefficients were 7% and 5%, respectively. The sensitivity of the assay was 0.1 ng/ml.
2.3. Clinical assessment
Four psychiatrists who had simultaneously attended a training session in the use of the Positive and Negative Syndrome Scale (PANSS) ( Kay et al., 1987 ) rated patients on this scale. After training, repeated assessment showed that the inter-observer correlation coefficient was maintained at > 0.8 for the PANSS total score. The patients' psychopathology was assessed on the day of the blood sampling.
The five factor model of the PANSS includes five factors commonly labeled as ‘positive’, ‘negative’, ‘cognitive’, ‘depression’ and ‘excitement’ (Citrome et al, 2011, Wallwork et al, 2012, and Rodriguez-Jimenez et al, 2013). Recently, Wallwork et al. (2012) have proposed a new consensus model of the cognitive factor that is only made up of three PANSS items: ‘Conceptual disorganization’ (P2), ‘Difficulty in abstract thinking’ (N5), and ‘Poor attention’ (G11) ( Wallwork et al., 2012 ).
2.4. Data analysis
Demographic and clinical variables of the patient and healthy control groups were compared usingt-test or analysis of variance (ANOVA) for continuous variables and chi-squared for categorical variables. Since the IL-10 variables were normally distributed in patients and normal controls (Kolmogorov–Smirnov one sample test; both p > 0.05), the principal outcome analysis consisted of one-way analysis of variance (ANOVA). Where there was significance in ANOVA, the effect of sex, age, education, smoking, and body mass index (BMI) was tested by adding these variables to the analysis model as covariates. Relationships between variables were assessed with Pearson's product moment correlation coefficients. We used stepwise multiple regression analysis with IL-10 as the dependent variable to investigate the impact of age, gender, duration of illness, age of onset and symptoms on the PANSS and its subscales. Data were presented as mean ± SD. Differences at p < 0.05 were considered to be significant.
3.1. Demographic data
Table 1 shows the demographic data of the subjects in the present study. Patients with SZ and control groups were matched with respect to age, gender, education, body mass index (BMI) and smoking. There were no significant relationships between IL-10 levels and any of the demographic variables, including gender, smoking and age, either for the whole group or when the normal controls and patients were examined separately (all p > 0.05). A possible influence of BMI on IL-10 was investigated by calculating Pearson correlation coefficients in control subjects, showing no association (r = 0.27, p = 0.84). Age of onset of psychosis, duration of illness, and family history of psychosis did not significantly correlate with IL-10 levels in the patient group.
(n = 128)
(n = 62)
|Sex (M/F)||73/55||38/24||0.58 (0.63)|
|Age (years)||25.8 ± 9.4||28.8 ± 8.4||0.31 (0.50)|
|Education (years)||7.1 ± 3.1||7.7 ± 3.1||0.07 (0.91)|
|BMI (kg/m2)||20.7 ± 2.6||22.8 ± 3.7||0.27 (0.61)|
|Smokers||37 (29.6%)||23 (37.1%)||0.26 (0.32)|
|Duration of illness (months)||23.4 ± 19.1|
|Age of onset||24.5 ± 8.6|
|Positive symptom||19.2 ± 5.6|
|Negative symptom||18.9 ± 7.0|
|General psychopathology||31.8 ± 7.3|
Note: BMI = body mass index.
3.2. Serum IL-10 levels
IL-10 serum levels were markedly lower in patients than healthy controls (39.2 ± 25.4 pg/ml vs 51.2 ± 36.6 pg/ml; F = 6.45, df = 1,187, p = 0.01) ( Fig. 1 ). When the effect of age, sex, education, smoking and BMI was examined by adding them to the ANOVA as covariates, a significant difference between patients and the normal controls was still observed (F = 6.76, df = 5,156, p = 0.03).
3.3. Symptoms and IL-10 levels
Correlation analysis showed that there was a significantly negative correlation between IL-10 and negative symptom subscore of PANSS (r = − 0.195, df = 128, p = 0.029) ( Fig. 2 ), but without a significant correlation between IL-10 and the other subscores and total score of PANSS. After controlling for sex, age, education, smoking and BMI, a significant negative correlation was still found between serum IL-10 levels and the PANSS negative subscore (r = − 0.192, df = 99, p < 0.05).
Based on the previous report, the cognitive factor is made up of three PANSS items: items P2, N5, and G11. Further correlation analysis showed that there was a significantly negative correlation between IL-10 and the cognitive factor (r = − 0.201, df = 122, p = 0.025) ( Fig. 3 ).
Stepwise multiple regression analysis including IL-10 levels (as the dependent variable) and PANSS and its subscales, together with age, gender, duration of illness, age of onset, and smoking as independent covariates identified the PANSS general psychopathology subscore as a significant predictor factor for IL-10 (beta = − 0.21, t = − 2.33, p < 0.05), whereas the other variables showed no effects (p > 0.05).
In addition, 25 (19.5%) first-episode patients and 11 (17.7%) controls were under age 18, without significant difference in proportion between them. Further analyses excluding these non-adult subjects did not change the pattern of all these results above (data not shown).
The main findings of the present study were that first, IL-10 levels were significantly decreased in these FEDN patients, and second, a significantly negative association between IL-10 and PANSS clinical phenotypes of schizophrenia was found, including negative and cognitive symptoms.
In this study, our finding of decreased serum levels of IL-10 was consistent with previous studies (Kaminska et al, 2001 and Pedrini et al, 2012). However, some studies failed to replicate the results in both medicated and unmedicated (O'Brien et al, 2008 and Kubistova et al, 2012) or even found increased IL-10 levels in patients with SZ (Maes et al, 2002 and Kunz et al, 2011). Numerous factors may have contributed to these discrepancies, such as differences in testing material (serum vs plasma), exposure to antipsychotic treatment (naive vs medicated), sampling of patients in different stages of disease progression (acute vs chronic or active phase vs remission), different illness durations, age at onset, and different ethnic origins or genetic backgrounds of the populations studied.
Several studies have shown that an activation of the inflammatory response system plays a pivotal role in the pathogenesis of schizophrenia, including the promotion of Th1 cytokine response (Smith, 1992 and Smith and Maes, 1995). IL-10 is a powerful Th2 cell cytokine produced by lymphoid cells and reduces the inflammatory actions of macrophages and T cells by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines (IL-1, TNF-alpha, IL-6, IL-8 and IL-12) ( Howard and O'Garra, 1992 ). On the basis of the role of IL-10 in anti-inflammation, our present result of decreased IL-10 supports the hypothesis that schizophrenia is accompanied by an activated macrophage immune response system, maybe through a Th1 response rather than an antibody mediated response. Moreover, finding lower levels of IL-10 in patients with SZ compared to healthy controls is in accordance with the previous reports of increased IFN-γ levels ( Miller et al., 2011 ), since recombinant human IL-10 markedly suppressed LPS-induced IFN-γ and IL-2 synthesis and release ( Marchant et al., 1994 ). Therefore, our finding of decreased IL-10 levels provides further support for the hypothesis that an abnormal immune response may play a role in some types of schizophrenia.
Our further finding of a significant negative relationship between IL-10 and the PANSS negative subscore is to our knowledge the first demonstration of a significant correlation between serum IL-10 levels and clinical symptoms in SZ. A few studies have linked serum levels of inflammatory cytokines and clinical severity in SZ. For example, a previous study found that TNF-α was correlated with positive psychotic symptoms in SZ ( Erbagci et al., 2001 ). A recent study showed that IL-1Ra was significantly correlated with PANSS negative symptoms in SZ ( Hope et al., 2013 ). However, the exact mechanism for the association of IL-10 with the negative symptoms in SZ is still unknown. There is evidence that the negative/deficit symptom complex of SZ may be associated with low dopamine activity in the prefrontal cortex ( Weinberger and Berman, 1988 ). The recent studies have shown that injection of LPS into the substantia nigra (SN) induced a selective loss of dopaminergic neurons, but IL-10 protects against inflammation-mediated degeneration of dopaminergic neurons in SN ( Arimoto et al., 2007 ). Thus, the decreased IL-10 may alter the central dopamine function and further affect the negative symptoms in SZ. However, this is only our speculation; interaction between IL-10 and dopamine system and how they relate to negative symptoms of SZ need to be explored with further detailed investigations.
Further, cognitive impairments appear to be the core feature of schizophrenia ( Goff et al., 2011 ). Numerous studies have shown that activation of the peripheral innate immune system induces production of cytokines within the brain that can have deleterious effects on cognition ( Yirmiya and Goshen, 2011 ). Inflammatory cytokines can negatively affect hippocampal function by directly impairing long-term potentiation (LTP) ( Pickering and O'Connor, 2007 ), and evidence also shows that immune/inflammation response in the hippocampus may underlie the pathophysiology of cognitive deficits in SZ ( Hwang et al., 2013 ). A recent study has found that IL-2 levels were positively correlated with scores in the digit span test and intelligence in SZ ( Asevedo et al., 2014 ). Our recent study showed that IL-18 was positively associated with the Visuospatial/Constructional domain of cognitive deficits in SZ. Taken together, these studies suggest that immune responses may play a role in cognitive impairment in SZ.
A further finding of our present study is that there was a significant inverse relationship between IL-10 level and the PANSS cognitive factor. To our knowledge, this is the first study to investigate any association between IL-10 and cognitive symptom in SZ. A recent study found that homozygosis for the A allele of the IL-10-1082 G/A polymorphism was associated with neurodegeneration and cognitive impairment in Alzheimer's dementia ( Arosio et al., 2010 ). Another recent study showed that IL-10-1082 G/A influenced the risk of cognitive impairment in Parkinson's disease (PD) ( Nie et al., 2013 ). These studies suggest that IL-10 system may be involved in the cognitive impairment. On the other hand, many studies have shown that cognitive performances are regulated, at least partially, by dopamine neurotransmission in the dorsolateral prefrontal cortex, as well as by the interactions of this region with other brain regions, such as the parietal cortex, thalamus, and striatum ( Barch and Ceaser, 2012 ). Notably, the current view on the dopamine (DA) hypothesis of schizophrenia postulates a cortical/subcortical DA imbalance: subcortical mesolimbic DA projections might be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms, whereas mesocortical DA projections to the prefrontal cortex might be hypoactive, resulting in hypostimulation of D1 receptors, negative symptoms, and cognitive impairment ( Guillin et al., 2007 ). Studies performed in animals or in cell cultures have demonstrated the neuroprotective effect of IL-10 against glutamate-induced or hypoxic–ischemic neuronal cell death, LPS- or interferon-induced oligodendrocyte cell death and traumatic brain injury ( Arimoto et al., 2007 ). The mechanisms underlying the neuroprotective effect of IL-10 on dopaminergic neurons is probably, in part, due to suppression of microglia- or macrophage-mediated release of inflammatory mediators because IL-10 has been reported to inhibit the production of cytokines such as TNF-α, IL-1β, IL-6, PGE2, reactive oxygen species and NO in glial cells in vivo and in vitro (Molina-Holgado et al, 2001 and Arimoto et al, 2007). Therefore, it seems likely that IL-10 may influence the cognitive impairment in schizophrenia through its neuroprotective action on dopaminergic neurons. However, the exact role of IL-10 in terms of DA function and further cognition in schizophrenia remains to be clarified. It is worth mentioning that the cognitive factor used in the present study was derived from the five-factor model of PANSS scale, which is used for symptomatology. We did not use a specific cognition scale and did not present any quantitative cognitive specific scale data regarding cognition in the SZ patients or controls. Therefore, the relationship between IL-10 and cognitive performance in schizophrenia deserves further investigation using a specific cognition scale in a longitudinal and prospective study.
Several methodological limitations of the study should be noted here. First, it has been known that there is a strong interrelationship between different cytokines. Cytokines are frequently regulated in cascades, where induction of the early cytokines serves to increase the production of later cytokines ( Kronfol and Remick, 2000 ). They are actively transported into the CNS, and activate glia cells in the CNS to produce other cytokines, and cascade of cytokine effects may be initiated by these mechanisms ( Muller and Ackenheil, 1998 ). In the present study, only IL-10 was examined, and at only one time point, which probably could not reveal in detail the observed findings of immune abnormalities in schizophrenia. These drawbacks would be remedied in the future study to investigate several relevant cytokines in schizophrenia simultaneously using a longitudinal design. Second, the cognitive factor used in the present study was derived from the five-factor model of PANSS proposed by Wallwork et al. (2012) . Its adequate psychometric properties for cognitive performance in schizophrenia have not achieved broad consensus. Moreover, the PANSS cognitive factor is a general measure of cognition, and could not test specific cognitive domains. Thus, it is worthwhile to use special cognitive tools to examine the relationship between IL-10 and the cognitive performance in future investigations. Third, IL-10 levels were analyzed in peripheral blood, and it is unknown whether blood IL-10 levels may reflect IL-10 centrally. Therefore, whether a decrease in peripheral IL-10 levels might directly influence the pathophysiology of schizophrenia also in the central nervous system remains to be determined. Fourth, a further consideration is the effects of stress on serum IL-10 levels in schizophrenia patients who experienced acute episode of clinical symptoms, since immunological aspects of the peripheral blood are more readily influenced by external conditions, including stress ( Westermann and Pabst, 1990 ). It is possible therefore that the differences in serum IL-10 levels may be related to whether subjects feel stressed by their symptoms. Further studies will need to evaluate the role of stress in these findings, for example, through the measurement of hormone level related to the hypothalamic–pituitary–adrenal (HPA) axis.
In summary, our data show that IL-10 is decreased in the acute early phase of SZ. Furthermore, the decreased IL-10 level is related to higher negative and cognitive symptom levels in patients with SZ. These results provide additional evidence that immune disturbances may be involved in the psychopathology of SZ. The relationship of IL-10 with psychopathological symptoms in SZ warrants further investigation in a larger sample of first-episode, medication-naive patients with SZ using a longitudinal design. Moreover, our current study is only limited to the Chinese Han population. The findings in our study will be highly strengthened if they could be replicated in another set of samples of a different ancestry, such as Caucasian.
Role of funding source
This work was funded by the grant from the National Natural Science Foundation of China (81000509, 81371477), the Beijing Municipal Excellent Talents Foundation (2010D003034000032), the Beijing Municipal Natural Science Foundation (7132063 and 7072035), NARSAD Independent Investigator Grant (20314), and the Stanley Medical Research Institute (03T-459 and 05T-726). These sources had no further role in the study design, data collection and analysis, decision to publish, or preparation of the article.
Xiang Yang Zhang was responsible for the study design, statistical analysis and manuscript preparation. Mei Hong Xiu, Gui Gang Yang, Chun Da Chen, Shu Ping Tan, Zhi Ren Wang and Fu De Yang were responsible for recruiting the patients, performing the clinical rating and collecting the samples. Olaoluwa Okusaga and Jair C. Soares were invited in evolving the ideas and editing the manuscript. Mei Hong Xiu and Xiang Yang Zhang were involved in writing the protocol, cowrote the paper and were responsible for providing the funding for the study. All authors have contributed to and have approved the final manuscript.
Conflict of interest
The authors have no conflicts to disclose.
The authors would like to thank Bao Hua Zhang and Song Chen for all of their hard work and significant contributions towards the study.
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a Biological Psychiatry Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China
b Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA
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