Comprehensive Psychiatry 90 (2019) 82–87 Contents lists available at ScienceDirect Comprehensive Psychiatry journal homepage: www.elsevier.com/locate/comppsych Changes in serum TNF-α, IL-18, and IL-6 concentrations in patients with chronic schizophrenia at admission and at discharge Yayan Luo 1,HongboHe1, Jie Zhang, Yufen Ou, Ni Fan ⁎ The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Liwan District, Guangzhou, Guangdong Province 510370, China article info abstract Objective: Schizophrenia is correlated with aberrant cytokine concentrations. The goal of our study was to detect the serum concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-18, and IL-6 concentrations in patients with chronic schizophrenia in the acute relapse state at admission and at discharge and to analyze the correlations between the three cytokine concentrations with psychosis symptoms. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to analyze serum concentrations of TNF-α,IL-18, and IL-6 in 68 patients with chronic schizophrenia at admission and at discharge and in 80 controls. The Positive and Negative Syndrome Scale (PANSS) was used to analyze psychosis symptoms of the patients. Results: Serum concentrations of TNF-α, IL-18, and IL-6 in patients at admission were significantly elevated com- pared to those in controls. After treatment, IL-6 concentrations in patients at discharge were significantly reduced compared to those in patients at admission, and IL-6 concentrations showed no significant difference between patients at discharge and controls. In contrast, TNF-α and IL-18 concentrations showed no significant difference between patients at discharge and patients at admission, and TNF-α and IL-18 concentrations in patients at dis- charge were still significantly elevated compared to those in controls. IL-6 concentrations in patients at admission showed a positive correlation with negative scores, and IL-6 concentrations in patients at discharge showed positive correlations with positive, negative, and total scores. Reduction in IL-6 concentrations showed positive correlations with reduction in positive, negative, and total scores in patients at discharge. Conclusion: Serum concentrations of TNF-α, IL-18, and IL-6 were significantly elevated in patients with chronic schizophrenia in the acute relapse state.Aftertreatment,IL-6concentrations in patients at discharge were significantly reduced compared to these in patients at admission. © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction as primary changed proinflammatory cytokines in patients with schizo- phrenia [5–9]. Schizophrenia (SZ) is a serious psychotic disease that occurs in nearly TNF-α, IL-18, and IL-6 are multifunctional proinflammatory cyto- 1% of the population worldwide [1]. Schizophrenia is manifested as dis- kines that are secreted primarily through monocytes and macrophages. turbed thinking, perception, belief, language, and social activities that These three cytokines play key roles in moderating the complicated occur during late adolescence or early adulthood and persist throughout events implicated in immunity and inflammation. The key roles of the life of the affected individuals [2]. Immune system dysfunction has TNF-α, IL-18, and IL-6 in regulating the excitability transmission of been implicated in the pathogenesis of schizophrenia [3]. The inflamma- neuron cell and neurotransmitter metabolisms make them primary tory immune response regulated by cytokines may contribute to the psy- candidates for schizophrenia pathogenesis [10]. Patients with chronic chopathology of schizophrenia through multidimensional mechanisms schizophrenia exhibited elevated serum concentrations of IL-6, TNF-α, affecting neurodevelopment, synaptic plasticity, and neurotransmission sIL-2R, IL-1β, and IL-18 [6,11–17]. Previous studies have shown that [3,4]. In particular, increasing evidence has concentrated on the actions IL-6 was likely to be a state-associated marker, which was elevated of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-18 during the acute exacerbation state and normalized after antipsychotic treatment. These findings suggested that IL-6 concentrations could be Abbreviations: ELISA, enzyme-linked immunosorbent assay; PANSS, Positive and influenced by treatment or disease state [6,9,18–20]. Moreover, IL-6 Negative Syndrome Scale; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin 6; IL-18, concentrations were positively correlated with positive symptoms and interleukin-18; sIL-2R, soluble IL-2 receptor. negative symptoms in schizophrenia [21,22]. The reduction in IL-6 ⁎ Corresponding author at: The Affiliated Brain Hospital of Guangzhou Medical levels in patients with schizophrenia was associated with the alleviation University, 36 Mingxin Rd, Liwan District, Guangzhou, Guangdong 510370, China. E-mail address: [email protected] (N. Fan). of negative symptoms [23]. Furthermore, high IL-6 concentrations at 1 These authors contributed equally to this work. baseline were associated with therapy resistance and long duration of https://doi.org/10.1016/j.comppsych.2019.01.003 0010-440X/© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Y. Luo et al. / Comprehensive Psychiatry 90 (2019) 82–87 83 hospitalization [13,24]. Together, these results suggested that IL-6 may the blood samples at 4000 rpm for 15 min; the serum was then sepa- be implicated in the response of the patient to antipsychotic therapy rated and stored at −80 °C before use. and could be regarded as a potential marker of cure response in schizo- Serum TNF-α, IL-18, and IL-6 concentrations were tested using phrenia. In contrast, TNF-α was likely to be considered as a trait marker, eBioscience ELISA kits (catalog numbers: BMS223, BMS213, and which shows no significant alterations after antipsychotic treatment BMS267, respectively, eBioscience, San Diego, USA). The sensitivities [9,19,20]. Compared with the more frequently analyzed cytokines, the were 0.13 pg/mL for TNF-α, 0.03 pg/mL for IL-6, and 9 pg/mL for IL- reports on the effect of antipsychotics on IL-18 are limited. A previous 18. The range of the standard curves varied from 0.31 to 20 pg/mL for study indicated that IL-18 exhibited a positive correlation with general TNF-α, from 0.09 to 5 pg/mL for IL-6, and from 19.5 to 1250 pg/mL for psychopathology of patients with chronic schizophrenia, but anti- IL-18. Duplicate tests were performed for standards and samples. Absor- psychotics have no effects on IL-18 concentrations [17]. bance at 450 nm was measured using a microplate reader. In the present study, the serum cytokine concentrations of TNF-α, IL-18, and IL-6 and psychosis symptoms of patients with schizophrenia 2.3. Data analysis were assessed during the first week of admission as baseline and in the week before the discharge. The aims of our study were to assess the All data were analyzed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA). following in patients with chronic schizophrenia in the acute relapse The difference in gender between patients and healthy subjects was state: (1) the serum levels of inflammatory cytokines TNF-α, IL-18, determined by the chi-square test. The difference in age between pa- and IL-6 at admission and at discharge; (2) the correlation of inflamma- tients and healthy subjects was determined using independent t-test. tory cytokine concentrations at admission with the duration of admis- The difference of cytokine concentrations between patients at admis- sion; (3) the correlation of the cytokine levels at admission and at sion and patients at discharge was evaluated by the paired t-test. The discharge with the severity of the psychotic symptoms; and (4) the difference of cytokine concentrations between healthy subjects and association of the changes in these cytokine concentrations with the patients at admission or at discharge was evaluated by a covariance alleviations of psychotic symptoms. analysis with age and gender as covariates. Pearson's correlation analy- sis was performed to determine the correlation between cytokine con- 2. Methods centrations with demographic and clinical characteristics in patients with schizophrenia. Further multiple linear regression analysis was 2.1. Subjects applied to detect the correlation between cytokine concentrations with demographic and clinical characteristics in patients with schizo- Sixty-eight inpatients with chronic schizophrenia in the acute relapse phrenia. All of the presented variables from Table 1 were included in re- state were recruited from the Affiliated Brain Hospital of Guangzhou gression models. Categorical variables were converted into dummy Medical University as described in previous studies [6,9,13]. The inclusion variables in regression models. Multiple comparisons were corrected criteria for all patients were as follows: (1) diagnosed as schizophrenia on by Bonferroni's corrections [26]. p b 0.05 was considered significant. the basis of International Classification of Diseases-tenth edition (ICD-10) diagnostic criteria; (2) free of currently occurring allergies, autoimmune 3. Results disorders, and infections; (3) free of immunosuppressive or anti- inflammatory agent use; and (4) free of past history of substance use. 3.1. Clinical characteristics The diagnosis of these