In-vitro immunomodulatory effects of haloperidol and perazine in schizophrenia.

There are some reports describing concurrent changes in lymphocytic and monocytic activities in schizophrenia. In this study we investigated T cell activity in schizophrenic patients by measuring the release of interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) by T cells and the percentages of CD4+ and CD8+ cells in blood. The release of IL-2 and sIL-2R by T cells was evaluated in dilute whole blood after in-vitro stimulation with phytohemagglutinin. IL-2 levels and the percentage of CD4-cells tended to decrease and sIL-2R levels decreased significantly in schizophrenic patients. Haloperidol and perazine significantly decreased IL-2 levels and increased sIL-2R levels and the percentage CD4-cells. IL-2 and sIL-2R levels were lower in patients with a predominance of positive symptoms. The neuroleptic-induced increase in sIL-2R levels was higher in patients with a predominance of positive symptoms compared with those in whom both positive and negative symptoms were severe. The study has shown that T-cell activity is reduced in schizophrenia and that neuroleptics may have immunomodulatory properties.     

Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine

The purpose of this study was to investigate immune-inflammatory markers in schizophrenia and the effects of chronic treatment with clozapine, an atypical antipsychotic agent, on these variables. Toward this end, we measured interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and sIL-2R in the blood of 26 normal controls and 14 schizophrenic patients before and after treatment with clozapine. The sIL-2R and IL-6 levels were significantly higher in younger (<35 years) schizophrenic subjects than in normal controls and older (≥ 35 years) schizophrenic subjects. The sIL-6R levels were significantly lower in schizophrenic subjects than in normal controls. Chronic treatment with clozapine significantly increased the blood concentration of sIL-2R; the increases in the latter were significantly related to the dose of clozapine but not to changes in severity of positive or negative symptoms. We conclude that: (a) schizophrenia in younger people is accompanied by increased IL-6 and sIL-2R secretion; and (b) subchronic treatment with clozapine increases sIL-2R levels. Increased plasma sIL-2R may be one mechanism by which neuroleptics exhibit their immunosuppressive effects.     

Immune disturbances during major depression: upregulated expression of interleukin-2 receptors

We determined the following immune parameters in drug-free, major depressed patients and in age- and sex-matched healthy controls: the number and percentage of interleukin-2 receptor (IL-2R) bearing cells (CD25+, anti-TAC), serum circulating levels of soluble (s)IL-2Rs, the pre- and postdexamethasone phytohemagglutinin (PHA)-induced accumulation of sIL-2Rs in culture supernatant, and the number of T helper (CD4+) and T suppressor (CD8+) cells. In comparison with normal volunteers, patients with major depression had a higher number and percentage of CD25+ cells, higher concentrations of serum circulating sIL-2Rs, higher supernatant sIL-2Rs after stimulation with PHA, and a higher number of CD4+ cells. The CD4+/CD8+ ratio and the number of CD4+ cells were significantly and positively related to the number of cells expressing the CD25+ antigen. These results may indicate that depressed patients display an increased number of T cells in an early phase of activation.     

Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients with schizophrenia

There are a number of indications that schizophrenia is associated with changes in the immune system. Although functional studies have mostly demonstrated decreased in vitro production of IL-2 by peripheral blood mononuclear cells (PBMCs) stimulated with mitogen, the reason is unclear. The aim of the study was to explore the relationship between IL-2 production and CD4+ cells which mainly secret IL-2 in non-Caucasian patients with schizophrenia. Blood CD4+ cells and mitogen-stimulated IL-2 secreting cells identified by an immunohistochemical study with the alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique, and in vitro IL-2 production with radioimmunometric assay (RIA) were measured in 30 schizophrenic patients and 30 normal control subjects matched for sex, age and race. The results showed that blood CD4+ cells and mitogen-induced IL-2 secreting cells and IL-2 production were significantly lower in schizophrenic subjects than in the normal controls. There was significantly positive correlation between CD4+ cells and IL-2 production in normal controls but not in patients. These findings suggest that immune disturbance may be present in schizophrenic patients. The lower in vitro IL-2 production is probably related to the decreased number of T-cells that secret IL-2, as well as to the intrinsic disorder of the patients' T cells.     

Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The SIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.     

Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients

A number of immunological parameters were studied in 82 DSM-III-R diagnosed schizophrenic patients (53 first drug-naive and 29 medicated chronic patients) as well as 62 healthy blood donors. The serum levels of interleukin-2 (IL-2), interleukin-1 beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) were measured and correlated with cellular immunity, as assessed by the autologous mixed lymphocyte reaction (AMLR). T lymphocyte subsets were also examined. The above immune parameters were reassessed in a subgroup of 11 first-episode, drug-naive patients 1month after neuroleptic medication. IL-2 serum levels were significantly lower, and IL-1beta and TNF-alpha were significantly higher in schizophrenic patients compared with healthy donors (P<0.001); no significant difference was observed between the two patient groups (medicated and not medicated). Abnormal cytokine serum levels were associated with decreased AMLR responses in vitro. Increased percentages of activated CD4+ and CD16+ natural killer cells, as well as cells expressing ICAM-1 adhesion molecules and IL-2 specific receptors, were detected in the patients. Immunophenotype studies revealed a higher percentage of cells expressing IL-2 receptors in medicated chronic schizophrenic patients compared with drug-naive patients. The abnormal cytokine production in vivo, along with the low AMLR responses in vitro, and the high percentage of activated CD4+ lymphocytes presented in this study suggest alterations in the immune system of schizophrenic patients (medicated or not medicated) consistent with immune activation.     

Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.     

Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients

In an attempt to define potential immunological dysfunctions in schizophrenia, we determined the production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon- (IFN-), and soluble IL-2 receptor (sIL-2R) in a whole-blood assay after stimulation with phytohemagglutinin (PHA) as well as the serum concentrations of sIL-2R. Because CD₄ ⁺CD45RO⁺T cells are the main producers of IFN-, we determined the percentage of these cells, as well as of pan T, CD4⁺T, and CD8⁺T cells, by flow cytometry. A whole-blood count was performed in addition. Two groups of patients were examined, paranoid-type and residual-type schizophrenics. The numbers of both monocytes and neutrophils, but not of lymphocytes, were increased significantly in the schizophrenic sample. The IFN- production of the schizophrenics as a whole group, and of the paranoid patients, was reduced significantly in comparison with the control group (p0.05). The residual patients produced less IFN- than the controls, but more than the paranoid patients. The latter differences did not reach statistical significance. The production of IL-4, which physiologically antagonizes the production of IFN-, was not significantly higher in the patient group. No changes in the lymphocyte subpopulations were observed. The production of IL-2 showed a trend toward reduction in paranoid patients, but not in residual schizophrenics. The serum sIL-2R levels were elevated slightly in schizophrenics when compared with controls. In order to rule out a possible effect of cortisol on cytokine production, 20 schizophrenic were compared with 20 age- and gendermatched controls. However, neither elevated cortisol levels were detected in the schizophrenic sample, nor significant intercorrelations between cortisol levels and cytokine production, or levels of sIL-2R, respectively. In summary, our data reinforce the possibility of immune dysfunction in schizophrenia and point to the possible relevance of disease subgroups in this respect.     

脑胶质细胞瘤病人IL-2和sIL-2R表达及细胞免疫功能变化的意义

目的 研究脑胶质细胞瘤病人外周血中自细胞介素2（IL-2）、可溶性白细胞介素2受体（sIL-2R）的表达以及红细胞免疫和T淋巴细胞亚群的变化规律．探讨它们之间的相互关系。方法 对55例脑胶质瘤病人及55例健康献血员．采用酶联免疫吸附（ELISA）法测定血清IL-2、sIL-2R含量，免疫黏附法测定红细胞免疫活性及其调节功能，链亲和素一过氧化物酶（SP）一步法测定CD3、CD4、CD8细胞数。结果 脑胶质细胞瘤组IL-2含量较对照组显著性降低（P〈0.01），sIL-2R则显著性升高（P〈0．01）；红细胞C3b受体（RBC-C3bR）、红细胞免疫调节促进因子（RFER）亦显著性降低（P〈0．01），而红细胞免疫复合物（RBC-ICR）、红细胞免疫调节抑制因子（RFm）则显著性升高（P〈0．01）；CD3、CD4细胞数显著性降低（P〈0．001），而CD8无显著性差异（P〉0．05）。结论 脑胶质细胞瘤病人存在免疫功能低下；检测血清IL-2和sIL-2R含量、红细胞免疫功能及T细胞亚群活性，对脑胶质细胞瘤病人的免疫机制研究具有重要意义。     

A longitudinal study on IL-2, sIL-2R, IL-4 and IFN-gamma in multiple sclerosis CSF and serum.

The cerebrospinal fluid (CSF) and serum levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were longitudinally investigated in 20 multiple sclerosis (MS) patients. There were 80 paired CSF and serum samples (range 2-8 per patient) covering a 1-5 year (mean 2.5 year) period. Increased levels of IL-2 and sIL-2R were found in 56 and 71%, respectively, of MS sera. In all patients, one or several sera (totally 89%) exhibited values above the normal range for either one of the components or both. The occurrence of IL-2 or sIL-2R positive CSF specimens was much lower, 15 and 9%, respectively. Only 3 MS sera (from one patient) had clearly detectable IL-4 and no CSF samples were definitely positive. IFN-gamma was undetectable in all serum and CSF specimens. No correlations were found between the immunological parameters and the clinical disease activity. The cytokine patterns in MS give strong support for the presence of a systemic T-cell activation. Furthermore, the data argue for a predominant activation of an IL-2- and sIL-2R-producing but not IL-4-producing T-helper (Th) lymphocyte subpopulation, Th1/CD4 + CD45R + cells.     

Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients

Activation of the inflammatory response system has been reported in schizophrenia. Levels of serum IL-1 receptor antagonist (IL-1ra) and soluble IL-2 receptor (sIL-2R(alpha)) were studied in 32 schizophrenic and 22 age- and sex-matched healthy subjects before and after an 8-week treatment protocol. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). At weeks 0 and 8, sIL-2R(alpha) levels were significantly higher than in the schizophrenic patients, as well as in a neuroleptic-naive subgroup, than in controls. Patients' sIL-2R(alpha) levels did not vary significantly between weeks 0 and 8. IL-1ra levels in controls did not differ significantly from those in patients at week 0 but were significantly lower at week 8. The patients' serum IL-1ra levels varied significantly between weeks 0 and 8. IL-1ra levels were significantly higher in the subgroup of neuroleptic-naive patients at week 0 than in controls. Levels of sIL-2R(alpha) at week 0 were positively correlated with PANSS positive and negative symptom scores at week 8, and levels at week 8 were positively correlated with PANSS total, positive symptom, and negative symptom scores at week 8. IL-1ra levels at week 0 were positively correlated with PANSS scores at week 8. There were positive correlations between both delta (baseline values minus endline values) IL-1ra and delta sIL-2R(alpha) levels and delta PANSS negative symptoms. The results provide evidence for immune activation in some schizophrenic patients and suggest that medication differentially affects the production of sIL-2R(alpha) and IL-1ra.     

重症肌无力患者细胞免疫水平的检测及临床意义

目的 :探讨周围血中 T细胞亚群、NK细胞、细胞膜白细胞介素 - 2受体、可溶性白细胞介素 - 2受体的阳性细胞与 MG发病及临床疗效的关系。方法 :1.应用流式细胞仪检测外周围血 m IL- 2 R(CD2 5)阳性细胞、NK(CD5 6 )和T细胞亚群 (CD3 、CD4、CD8)的相对计数。 2 .用富氏双抗体夹心 EL ISA方法检测血清 s IL- 2 R。结果 :1.MG患者血清s IL- 2 R水平明显高于健康对照组 ,激素治疗后较治疗前明显下降 ;2 .NK和 CD4阳性细胞在治疗前均明显高于正常 ,治疗后明显下降 ;3.CD3 阳性细胞在激素治疗前后无明显改变 ;4.m IL- 2 R(CD2 5)阳性细胞数无明显改变。结论 :1.血清中的 s IL- 2 R,NK细胞的测定可对该病进行动态观察 ;2 .CD4增高 ,CD8下降提示免疫功能紊乱 ;3.m IL- 2 R阳性细胞百分率不能直接反映 MG的免疫功能紊乱。     

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders

Background

Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology.

Methods

Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis > alcohol > cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n = 24) was 466.6 mg ± 227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes.

Results

On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p = 0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p < 0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r = − 0.524; p = 0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms.

Conclusion

These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.     

脑出血患者周围血T淋巴细胞亚群及sIL—2R水平的研究

目的：探讨脑出血患者的细胞免疫功能及其临床意义。方法：对４６例脑出血患者及４２例正常对照组外周血Ｔ淋巴细胞亚群及血清可溶性白细胞介素－２受体（ｓＩＬ－２Ｒ）水平进行检测,并对其中２１例脑出血患者恢复期外周血Ｔ淋巴细胞亚群及血清ｓＩＬ－２Ｒ水平进行了复查。结果：脑出血急性期外周血ＣＤ３数量明显低于对照组,ＣＤ４与对照组比较无显著性差异,ＣＤ８明显高于对照组,ＣＤ４／ＣＤ８比值则显著低于对照组,血清ｓＩＬ－２Ｒ水平显著高于对照组;病情重者、预后差者周围血ＣＤ３数量明显少于病情轻者、预后好者,ＣＤ８数量明显多于病情轻者、预后好者,ＣＤ４／ＣＤ８比值显著低于病情轻重、预后好者,血清ｓＩＬ－２Ｒ水平显著高于病情轻重、预后好者;脑出血组恢复期与急性期比较,周围血ＣＤ３数量明显增多,ＣＤ８明显减少,ＣＤ４／ＣＤ８比值明显升高     

黄芪穴位注射对慢性精神分裂症血可溶性白细胞介素2受体的影响

目的:探讨足三里穴位注射黄芪液对慢性精神分裂症患者免疫功能的影响。方法:对30例患者足三里穴位注射黄芪液,分别于注射前、注射4周和8周用酶联免疫法检测血可溶性白细胞介素2受体(sIL-2R)变化,并与30例健康者比较,进行相关因素分析。结果:穴位注射前患者sIL-2R水平显著高于健康者,注射后显著降低;老年组的sIL-2R水平明显高于青年组及中年组;氯丙嗪组sIL-2R水平明显高于氯氮平组及联合用药组;不同临床亚型组间的sIL-2R水平无显著差异。结论:足三里穴位注射黄芪液对慢性精神分裂症患者异常偏高的sIL-2R有显著改善作用。     

COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy

Abstract. Recent advances in immunological research regarding the differentiation between the type-1 and type-2 immune response are discussed. Increased levels of Interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might be the result of the activation of type-2 monocytes/macrophages, too. On the contrary, several parameters of the specific cellular immune system are blunted, e. g. the decreased type-1 related immune parameters in schizophrenic patients. This study was performed as a double-blind, placebo-controlled, randomized evaluation of risperidone and celecoxib versus risperidone and placebo. Fifty schizophrenic patients were included in the study: 25 patients received risperidone and placebo, and 25 patients received risperidone and celecoxib for 5 weeks after the wash-out period. The treatment effect was calculated by ANCOVA. In parallel, serum levels of sTNF-R1 and sIL- 2R, and the percentages of CD3⁺-, CD4⁺-, and CD19⁺ lymphocytes were estimated. As expected, both groups of schizophrenic patients showed significant improvement. However, the celecoxib add-on therapy group showed a significant group effect in the PANSS total score. The cytokines and lymphocytes reflected the type-1/type-2 balancing effects of COX-2 inhibitors. Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to the total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug shows beneficial effects on the symptomatology of schizophrenia indicates that immune dysfunction in schizophrenia is not just an epiphenomenon, but related to the pathomechanism of the disorder.The study was supported by the Theodore and Vada Stanley Medical Research Institute     

精神分裂症免疫功能与血清5-羟色胺的研究

目的:研究阴性型和阳性型精神分裂症患者免疫功能和神经生化物质改变情况及其变化规律.方法:选择阴性型和阳性型精神分裂症患者各20例以及20名正常对照者,抽取静脉血检测T细胞亚群,主要免疫球蛋白和补体C3、C4水平,和血清5-羟色胺(5-HT)水平.结果:阴性型精神分裂症患者CD 3下降,阳性型CD 3、CD 4则升高;IgG、IgA水平2种类型精神分裂症患者均显著降低;5-HT水平阳性型精神分裂症患者显著升高,阴性型精神分裂症患者显著降低.结论:精神分裂症患者伴随有免疫功能的改变,不同类型的精神分裂症其免疫应答参与机制也有不同.     

Effect of high-dose steroid therapy on T-cell subpopulations A longitudinal study in MS patients

Lymphocyte subpopulations, T cell activation antigens, and serum levels of interleukin 2 (IL-2) and soluble IL-2 receptor (sIL2R), were studied in relapsing-remitting MS (RR-MS) patients before and after high-dose steroid therapy. Prior to therapy, a minority of patients showed increased HLA-DR antigen expression, and an increased number of CD16 + and CD19+ cells. Steroid treatment induced a significant increase in HLA-DR and CD 19 expression, a significant reduction in CD 16 +, CD57 +, and CD8 + CD57 + cells, and a slight, non-significant, decrease in IL-2 and sIL-2R levels and CD25 expression on CD4 + T lymphocytes.     

Increased tumor necrosis factor-alpha concentrations with interleukin-4 concentrations in exacerbations of schizophrenia

Several studies have indicated that cytokines may be involved in the pathophysiology of schizophrenia. Previous studies, however, have yielded contradictory results; in this study we assess the plasma levels of both T-helper-1 (Th1) and T-helper-2 (Th2) cytokines in patients with acute exacerbations of schizophrenia. Plasma concentrations of interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and soluble receptor of interleukin-6 (sIL-6R) were measured with high sensitivity, enzyme-linked immunosorbent assays (ELISA) in patients with acute exacerbations of schizophrenia as compared with healthy controls. Patients with an acute exacerbation of schizophrenia had significantly increased production of TNF-alpha and significantly reduced production of IL-4 as compared with healthy subjects. No significant difference was observed in IL-6, sIL-6R, IL-8 and IL-10. Acute exacerbations of schizophrenia are associated with increased TNF-alpha concentrations (Th1) with concomitantly reduced concentrations of IL-4 (Th2) and a resulting increased TNF-alpha/IL-4 ratio.