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.     

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.     

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.     

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。     

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.     

利培酮和氯氮平对首发精神分裂症患者血浆细胞因子的影响

目的 比较利培酮和氯氮平对首发精神分裂症患者血浆细胞因子影响的差异。方法 用酶联免疫吸附法(ELISA)测定利培酮和氯氮平两组各30例患者治疗6周前后的血浆白细胞介素-2(IL-2)、可溶性白细胞介素-2受体(sIL-2 R)、白细胞介素-6(IL-6)及可溶性白细胞介素-6受体(sIL-6R)的浓度,两组间进行比较,每组治疗前后各自进行比较。结果 两组间比较,血浆细胞因子水平无显著性差异(P>0.05);治疗前后各自进行比较,每组血浆IL-2及sIL-6R水平显著下降(P<0.05),IL-6水平显著升高(P<0.05),sIL-2R治疗前后无显著性差异(P>0.05)。结论 利培酮和氯氮平治疗均对首发精神分裂症患者的IL-2、IL-6及sIL-6R水平产生显著性影响,对sIL-2R水平影响不显著;利培酮和氯氮平对首发精神分裂症患者细胞因子水平的影响基本一致。     

Plasma-soluble interleukin-2 and transferrin receptor in schizoprenia and major depression

This study was carried out to examine some components of in vivo immune function in major depression and schizophrenia. Toward this end, plasma concentrations of interleukin-1 (IL-1) and IL-6, soluble IL-2 receptor (sIL-2R), and transferrin receptor (TfR) were measured in 28 normal controls, 11 schizophrenics and 13 major-depressed patients. Schizophrenic and major-depressed patients showed significantly higher plasma sIL-2R and TfR than normal controls. There was a trend toward higher plasma IL-6 in the psychiatric patients, and particularly in schizophrenic patients, than in normal volunteers. In normal controls and in the total study group, there were highly significant and positive correlations between plasma TfR and sIL-2R concentrations. It is suggested that schizophrenia and major depression are characterized by immune disorders that may indicate activation of cell-mediated immunity such as T-cell activation.     

In-vitro Immunomodulatory Effects of Haloperidol and Perazine in Schizophrenia

Summary: 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.     

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.     

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.     

Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.

It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of cytokines and soluble cytokine receptors in psychiatric patients (N = 361) upon hospital admission and compared the results to those obtained in healthy controls (N = 64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-alpha, sTNF-R p75, IL-6) or benzodiazepines (TNF-alpha, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-alpha and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned cytokines and cytokine receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression.     

Plasma soluble interleukin-2-receptor in depression: relationships to plasma neopterin and serum IL-2 concentrations and HPA-axis activity

The present study examined the plasma concentration of the soluble interleukin-2-receptor (sIL-2R) in depressed subjects in relation to hypothalamic pituitary adrenal (HPA) axis function and plasma neopterin and serum IL-2 concentrations. Plasma sIL-2R concentration was significantly higher in depressed patients (n = 47) than in controls (n = 19). There were no significant correlations between plasma sIL-2R and severity of illness. In the depressed subjects, there was a highly significant relationship between plasma sIL-2R and neopterin concentrations. Depressed patients with pathologically increased plasma neopterin levels had significantly higher plasma sIL-2R values than those with normal serum neopterin. There were no significant relationships between plasma sIL-2R and indices of HPA-axis function in depression. There was no significant effect of dexamethasone administration on sIL-2R levels. Significantly more depressed subjects had measurable serum IL-2 levels than normal controls. Our data support the notion that a moderate activation of cell-mediated immunity may play a role in the pathophysiology of depression.     

氯氮平对精神分裂症患者血清白细胞介素6的影响

目的：探讨女性首发精神分裂症患者氯氮平治疗前后血清白细胞介素6(IL-6)变化及其与氯氮平血药浓度的关系。方法：采用酶联免疫吸附法测定20例精神分裂症患者治疗前及治疗第1、2、4周血清IL-6，同时用高效液相色谱法测定血清氯氮平浓度，以20名女性健康者血清IL-6作对照，用阳性与阴性症状量表(PANSS)评定治疗前与治疗第4周患者的精神症状。结果：患者组治疗前血清IL-6显著高于正常对照组，治疗第1、2、4周IL-6显著低于对照组；患者组治疗后各时点IL-6与氯氮平血清浓度无显著相关；氯氮平治疗4周后，PANSS减分率与IL-6减分率无显著相关。结论：女性首发精神分裂症患者IL-6水平与健康女性差异显著，氯氮平可显著降低女性精神分裂症患者IL-6水平，精神分裂症症状改善与IL-6变化无显著相关。     

Correlations of Kynurenic Acid, 3-Hydroxykynurenine,sIL-2R,IFN-α, and IL-4 with Clinical Symptoms During Acute Relapse of Schizophrenia

Several lines of evidence suggest that up-regulation of immune response and alterations of kynurenine pathway function are involved in pathogenesis of schizophrenia. Correlations among clinical status (using PANNS, SANS and SAPS scales) and blood levels of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and levels of selected immunoactive molecules, soluble interleukin-2 receptor (sIL-2R), interferon-α (IFN-α) and IL-4 were analyzed in 51 chronic schizophrenia patients during acute relapse, after four weeks of therapy and at remission. KYNA levels were significantly lower in comparison with controls (N=45) throughout the study, whereas 3-HK did not differ from controls at admission and during therapy, but increased at remission. The KYNA/3-HK ratio and IL-4 levels, but not sIL-2R and IFN-α levels, were consistently decreased in schizophrenia patients at all analyzed time points. KYNA level and KYNA/3-HK ratio measured at admission correlated negatively with the duration of illness, whereas 3-HK level correlated negatively with the improvement of SANS score at discharge. sIL-2R level before treatment was positively linked with number of relapses. In the subgroup of patients with poor response to pharmacotherapy, treated with clozapine later on, initial KYNA level and the ratio KYNA/3-HK correlated negatively with number of relapses. Positive association of sIL-2R level with number of relapses was also evident in this subgroup. Furthermore, among these patients, starting IFN-α level was negatively linked with the improvement of total PANSS score at discharge. Presented here data support the concept of disturbed kynurenine pathway function in schizophrenia and suggest that assessment of KYNA and 3-HK levels during acute relapse might be useful in prediction of response to antipsychotic therapy. Deficit of peripheral KYNA and higher 3-HK levels could be associated with more severe symptoms of schizophrenia. Further studies with larger samples size are needed to validate our results.     

Monocytic, Th1 and th2 cytokine alterations in the pathophysiology of schizophrenia

A growing body of evidence suggests that changes in the serum levels and cellular production of various cytokines are associated with the immunological abnormalities of schizophrenia. Several studies have examined alterations in T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in schizophrenia. We explored monocytic, Th1 and Th2 cytokines in 43 schizophrenia patients and 50 normal controls. The mitogen-induced production of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-4, gamma-interferon (IFN-gamma) and IL-2 was measured with enzyme-linked immunosorbent assays before and after antipsychotic treatment. IL-6 and TNF-alpha production by schizophrenic patients was significantly higher than by normal controls, while IL-2, IL-4 and IFN-gamma production was significantly lower in schizophrenic patients. After 6 weeks of antipsychotic treatment, IL-6 and TNF-alpha production was significantly decreased, while IL-4, IFN-gamma and IL-2 productions were not significantly changed. Our results suggest that increased monocytic cytokines and decreased Th1 and Th2 cytokines may be associated with the immunopathogenesis of acute psychotic schizophrenia, and that antipsychotics may play an important role in immune response by decreasing elevated monocytic cytokines.     

抑郁症首次发病维吾尔族、汉族患者血清白介素-2、6及其可溶性受体水平的对照研究

目的:探讨抑郁症首次发病的维吾尔族(维族)、汉族患者血清白介素(IL)-2、IL-6及其可溶性受体(sIL-2R、sIL-6R)水平的变化。方法:对117例首次发病的抑郁症患者(抑郁症组,维族亚组57例,汉族亚组60例)给予文拉法辛治疗4周。治疗前后采用汉密尔顿抑郁量表(HAMD)-17项评定病情,采用酶联免疫吸附法(ELISA)检测血清IL-2、IL-6及sIL-2R、sIL-6R水平;并与性别、年龄相匹配的正常对照组(维族、汉族各55例)比较。结果:抑郁症维族及汉族亚组HAMD评分治疗后较治疗前显著下降(P均0.01),两亚组间差异无统计学意义。抑郁症组治疗前血清IL-2、IL-6及sIL-2R、sIL-6R水平明显高于正常对照组(P均0.01),且IL-2、sIL-6R水平在维族与汉族亚组间差异有统计学意义(P均0.01);治疗后血清IL-2、IL-6及sIL-2R、sIL-6R水平较治疗前明显下降(P均0.01)。结论:维族和汉族抑郁症患者均有免疫失调;文拉法辛治疗能改善抑郁症病情及免疫失调。     

Increased serum interleukin-1beta and interleukin-6 in elderly, chronic schizophrenic patients on stable antipsychotic medication

In schizophrenia, alterations of proinflammatory cytokine levels have been reported and related to the disease and psychopathology. However, only limited conclusions can be drawn in view of confounding factors such as infection, age, sex, smoking, and antipsychotic medication. Chronic schizophrenic patients with a long-term disease process and medication period have not been investigated so far. We have measured serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)α in 41 elderly, chronic schizophrenic patients and 23 age- and sex-matched controls using enzyme-linked immunosorbent assay (ELISA). We assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine, and the two main clozapine metabolites, desmethylclozapine and clozapine metabolite N-oxide, by high-pressure liquid chromatography (HPLC). IL-1β and IL-6 levels were increased in treatment-resistant schizophrenic patients compared with healthy controls, whereas TNFα showed no difference. We did not find statistically significant differences of cytokine levels between medication groups and there was no correlation with serum levels of antipsychotics or psychopathological rating scores. Elevations of IL-1β and IL-6 in elderly chronic schizophrenic patients may be related to an active disease process lasting until old age. Despite missing correlations, long-term treatment effects in treatment-resistant patients may have affected TNFα, leading to control levels. Post-mortem and animal studies should clarify the presence of altered immune function in the brain as well as the effect of cytokine levels in relation to neurodevelopmental disturbances and schizophrenia-associated behavior.     

氯氮平对精神分裂症血清IL-2、IL-6的影响及临床意义

目的探讨氯氮平对精神分裂症患血清白介素-2（IL-2）、白介素-6（IL-6）水平的影响及与精神症状、体型指数变化的关系。方法选择住院的符合中国精神障碍分类与诊断标准第3版精神分裂症诊断标准的病人35例，阳性与阴性症状量表（PANSS）评分≥60分，予氯氮平治疗10周，分别于治疗前及治疗第10周末采用PANSS评估精神症状，采用酶联免疫吸附法（ELIAS）测定血清IL-2、IL-6水平。同时记录体型指数（BMI）。选取健康志愿35例作对照组，样本采集与检测同患组。结果治疗前精神分裂症患组血清IL-2水平显高于对照组（t=2．93，P=0．006），IL-6水平与对照组比较无显差异（P〉0．05）；氯氮平治疗10周末血清IL-2水平比治疗前显下降（t=3．51，P=0．001）;血清IL-6水平与治疗前相比显增高（t=2．53，P〈0．05）。治疗后精神分裂症患组体型指数显高于治疗前（t=6．02，P〈0．01）。治疗前血清IL-2水平与阳性症状评分呈显正相关（r=0．36，n=35，P=0．042）。与阴性症状、一般病理性症状、PANSS总分及体型指数均无显相关性（P〉0．05）。治疗前血清IL-6水平与各组精神症状及体型指数均无显相关性（P〉0．05）。治疗后血清IL-2下降值与阳性症状减分值呈显正相关（r=0．35，n=35，P=0．042）；IL-6增加值与各组精神症状减分值及体型指数增加值均无显相关性（P〉0．05）。结论氯氮平对精神分裂症患血清IL-2、IL-6水平有显影响，其临床意义可能与精神症状的变化有关，与氯氮平引起的体型指数变化无关。     

Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor

There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment.     

Plasma concentrations of amino acids in chronic schizophrenics treated with clozapine.

Peripheral amino acid changes have been reported in schizophrenia, but results are not consistent. We measured serum levels of different amino acids in 11 neuroleptic-resistant schizophrenic patients before and after clozapine treatment and in 11 age- and sex-matched healthy subjects. The schizophrenic patients exhibited significantly higher levels of serum aspartate, glutamate, isoleucine, histidine and tyrosine and significantly lower concentrations of serum asparagine, tryptophan and serine. In patients, the ratio between tryptophan and large neutral amino acids (LNAA) was significantly lower than in matched controls, whereas the tyrosine/LNAA ratio did not differ significantly. Moreover, 12 weeks of clozapine administration significantly reduced serum levels of glutamate but did not restore the values observed in normal controls, nor did it affect other amino acid concentrations. These data show changes in serum amino acids that may influence central serotonergic, dopaminergic and glutamatergic transmission in neuroleptic-resistant schizophrenics.