氯氮平治疗难治性精神分裂症相关研究进展

本文旨在阐述氯氮平治疗难治性精神分裂症(Treatment-resistent schizophrenia,TRS)的效果及可能机制.本文系统收集各方面的文献以总结当前氯氮平的独特作用机制,包括:作用于γ-氨基丁酸(GABA)和谷氨酸受体,影响细胞因子及小胶质细胞细胞因子,平衡患者大脑炎症进程,影响突触连接性与可塑性进...     

齐拉西酮、氯氮平治疗的卫生经济学比较

目的:比较齐拉西酮和氯氮平在治疗难治性精神分裂症时的卫生经济学。方法:将85例难治性精神分裂症患者随机分为齐拉西酮组43例,氯氮平组42例,疗程6个月。采用阳性与阴性症状量表(PANSS)、治疗中出现的症状量表(TESS)进行评定;调查住院2年内因患精神分裂症所花费成本及治疗恢复后所获得的收入,进行比较。结果:两组疗效相当,但齐拉西酮组不良反应明显少于氯氮平组(P<0.01)。齐拉西酮组的直接费用比氯氮平高,平均工作时间较氯氮平组长,效益比值明显比氯氮平组大(P<0.01)。结论:齐拉西酮治疗难治性精神分裂症疗效与氯氮平相当,不良反应较氯氮平轻,服药依从好,总的经济价值高于氯氮平。     

精神分裂症药物治疗的德尔菲法调查

目的:调查国内精神分裂症的药物治疗现状,取得国内专家对精神分裂症药物治疗的共识,为规范精神分裂症药物治疗提供参考依据。方法:通过德尔菲法(Delphi法)选择来自我国不同省市精神专科三级医院临床专家,进行两轮专家咨询,采用描述性统计分析的方法对专家基本情况、专家意见集中程度进行分析,对问卷的各个项目采用频数的描述性分析,总结出临床治疗指导意见。结果:(1)两轮调查共有48名专家参与,来自18个省市,职称全部为副高及以上,平均从业29年以上。两轮调查的积极系数为100%。(2)调查取得了6种不同情况下抗精神病药选用顺序的推荐意见。在涉及用药及换药时机、合并用药、难治性精神分裂症治疗、非药物增效治疗、药物维持治疗等5个方面共19项治疗意见中,有11项的认同率超过2/3,达到专家共识。结论:国内精神分裂症药物治疗的专家共识是6种情况下抗精神病药前3位的推荐用药、11条具体推荐意见;存在争议的问题是合用情感稳定剂时机、超说明书用药、维持治疗时间、前驱期是否用药、难治性精神分裂症治疗方案、长效针急性期是否应用、氯氮平疗效欠佳时治疗方针、难治性精神分裂症是否应用重复经颅磁刺激。     

氯氮平对难治性精神分裂症的疗效与D_2受体基因的关系

目的 :探讨与氯氮平对难治性精神分裂症疗效有关的 D2 受体基因的基因型以及其他相关因素。　方法 :抽取 10 0例难治性精神分裂症患者 ,给予氯氮平≥ 40 0 mg/ d治疗 2个月。用阳性症状与阴性症状量表 (PANSS)评定氯氮平疗效 ,用多聚酶链式反应扩增及限制性片段长度多态性 (PCR-RFL Ps)技术测定所研究对象的基因型和等位基因。　结果 :发现氯氮平对难治性精神分裂症患者的疗效与患者性别明显相关 ,而与 D2 受体基因无关。　结论 :氯氮平对男性难治性精神分裂症患者疗效较好 ,但难以通过检测 D2 受体基因来预测氯氮平对难治性患者的疗效。     

无抽搐电休克联合氯氮平治疗难治性精神分裂症临床观察

目的探讨无抽搐电休克(MECT)联合氯氮平对难治性精神分裂症的临床疗效。方法选取符合《中国精神障碍分类与诊断标准(第3版)》(CCMD-3)难治性精神分裂症断标准的患者91例,采用随机数字表法分为观察组(n=46)和对照组(n=45),给予对照组单纯氯氮平25mg,每天睡前服用,观察组在此基础上接受MECT治疗。于治疗前后采用阳性和阴性症状量表(PANSS)评定临床疗效,采用症状量表(TESS)评定不良反应。结果治疗12周后,观察组和对照组总有效率比较差异有统计学意义(91.3%vs.71.1%,P0.05);观察组治疗后的PANSS总评分为(32.7±3.8)分,不良反应发生率为15.2%,低于对照组的(56.6±4.5)分和37.8%,差异有统计学意义(P0.05)。结论 MECT联合氯氮平对难治性精神分裂症疗效和安全性均优于单用氯氮平。     

利培酮联合氯氮平治疗难治性精神分裂症临床研究

目的探讨利培酮联合氯氮平治疗难治性精神分裂症的疗效及安全性。方法对40例难治性精神分裂症患者,给予利培酮联合氯氮平治疗8周、12周。采用阳性与阴性症状量表、副反应量表评定临床疗效及不良反应。结果利培酮联合氯氮平治疗难治性精神分裂症的显效率为42.5%,有效率为57.5%。有效剂量利培酮为1mg~4mg/d,氯氮平为100mg~350mg/d,不良反应轻微且发生率低,均可耐受,经对症处理后均可缓解或消失。结论利培酮联合氯氮平治疗难治性精神分裂症疗效显著,安全性高,依从性好,可作为难治性精神分裂症的治疗方法。     

利培酮和氯氮平治疗难治性精神分裂症的随机对照研究

目的　比较氯氮平和利培酮治疗难治性精神分裂症的疗效。方法　共入组 72例符合难治性精神分裂症的病人 ,采用随机表单双数办法决定服用氯氮平和利培酮治疗 ,利培酮组为 38例 ,氯氮平组为 34例。观察期为 12周 ,分别于入组前、服药 4周末、8周末和 12周末时采用阳性症状和阴性症状量表 (PANSS)及功能总体评定量表 (GAF)评定疗效、治疗中需处理的不良反应症状量表 (TESS)评定副反应。结果　两组治疗前PANSS总分、阳性症状分、阴性症状分及一般精神病理分、GAF、TESS总分比较 ,经t检验 ,差异无显著性 (P >0 0 5 ) ;治疗第 4周、第 8周、第 12周末的评分与治疗前相比较 (除第 4周末利培酮组阴性症状总分外 ) ,经配对t检验 ,差异有显著性。第 4周末、第 8周末氯氮平组在GAF的改善与利培酮组相比结果的差异有显著性 ,第 12周末氯氮平组在阳性症状、一般精神病理总分减分率和GAF的改善与利培酮组相比结果的差异有显著性。氯氮平组在第 8周末和第 12周末TESS总分都显著高于利培酮组。结论　氯氮平和利培酮治疗TRS病人均有效 ,氯氮平可作为TRS病人治疗的一线用药 ,利培酮可用于不能耐受氯氮平副反应的TRS病人     

丁螺环酮对难治性精神分裂症治疗的增效作用

目的:探讨丁螺环酮对难治性精神分裂症(TRS)治疗的增效作用与安全性。方法:80例TRS患者随机分入合用组(氯氮平+丁螺环酮)和氯氮平组,每组40例,观察治疗12周。采用阳性和阴性症状量表(PANSS)和治疗中出现的症状量表(TESS)分别评定临床疗效和不良反应。结果:在治疗2、4、12周,合用组临床疗效优于对照组(P均<0.05);两组干预后各因子积分和总分均较入组前显著下降(P均<0.001);阳性因子积分和总分,干预与时间存在交互效应(P<0.01);总分存在组间差别(P<0.05);同期对照比较,除入组后8周阴性因子积分和12周阴性因子和一般精神病理因子积分外,其余各时点各因子积分和总分,合用组减分幅度大于对照组(P<0.05)。不良反应总发生率两组间差异无显著性(P>0.05)。结论:丁螺环酮对氯氮平治疗难治性精神分裂症有一定的增效作用,且不增加不良反应。     

氯氮平合并无抽搐电休克治疗难治性精神分裂症的对照研究

目的 评价氯氮平合并无抽搐电休克(MECT)治疗难治性精神分裂症的疗效和安全性.方法 将60例难治性精神分裂症患者随机分为研究组和对照组,分别给予氯氮平合并无抽搐电休克、氯氮平治疗,疗程12周,采用阳性与阴性症状量表(PANSS)及治疗中出现的症状量表(TESS)评定疗效和不良反应.结果 研究组显效率为43.3%,有效率为76.7%;对照组显效率16.7%,有效率53.3%,两组显效率和有效率均有显著性差异(P<0.05).PANSS总分及各因子分从治疗4～6周起两组即有显著性差异(P<0.05或P<0.01);两组副反应比较差异无显著性(P>0.05).结论 氯氮平合并无抽搐电休克治疗难治性精神分裂症疗效优于单用氯氮平,且显效快,副作用少,安全性高,是治疗难治性精神分裂症的较好选择.     

改良电抽搐治疗难治性精神分裂症的作用

目的:评估氯氮平合并改良电抽搐(MECT)治疗对难治性精神分裂症的临床疗效及安全性。方法:74例难治性精神分裂症患者随机分为两组,联合治疗组37例,在应用氯氮平的基础上联合MECT治疗;单药治疗组37例,仅给予氯氮平治疗;观察12周。分别于治疗前及治疗后4周、8周、12周末采用阳性和阴性症状量表(PANSS),治疗中出现的症状量表(TESS)评定其临床疗效和不良反应;治疗前及治疗结束后ld、1周、2周采用韦氏记忆量表(WMS)评定MECT对记忆的影响。结果:治疗12周后,联合治疗组的PANSS减分率(46.17±16.14)%,临床总有效率为58.7%;单药治疗组的PANSS减分率(32.26±14.27)%,临床总有效率为28.9%,两组差异有显著性(P<0.05或P<0.01)。两组TESS评分差异无显著性(P>0.05)。WMS评分在治疗结束后1d明显降低(P<0.01),但在治疗1周、2周与治疗前差异无显著性(P>0.05)。结论:改良电抽搐治疗联合氯氮平对难治性精神分裂症有效、安全。     

阿立哌唑联用小剂量氯氮平治疗女性难治性精神分裂症对照研究

目的 探讨阿立哌唑联合小剂量氯氮平对女性难治性精神分裂症（TRS）的疗效和安全性。方法 将62例女性TRS患者随机分成研究组和对照组各31例,对照组采用阿立哌唑治疗,研究组采用阿立哌唑联用小剂量氯氮平治疗,观察26周。于治疗前及治疗后第8、12、26周末进行阳性和阴性综合征量表（PANSS）评定;治疗后第1、2、6、12、26周末用治疗中需处理的不良反应症状量表（TESS）评定不良反应。结果 治疗后第8、12、26周末两组PANSS总分均较治疗前下降（P〈0.01）,研究组PANSS总分低于对照组（P〈0.05）。两组间不良反应发生率比较差异无统计学意义（P〉0.05）。结论 阿立哌唑联合小剂量氯氮平治疗女性TRS更有效且安全。     

Is clozapine antisuicidal?

Suicide accounts for approximately 10% of patient deaths in schizophrenia. The atypical antipsychotic clozapine (Clozaril), successful in treatment-resistant patients with schizophrenia, may have an additional antisuicidal effect. Numerous published reports, including the collaborative International Suicide Prevention Trial, have compared mortality rates between clozapine recipients and patients receiving other forms of antipsychotic treatment and observed a significant reduction in patient risk for suicide with clozapine therapy. Preliminary reports indicate improvements in suicidality in schizophrenia patients treated with other modern atypical antipsychotics, for example olanzapine [Zyprexa], risperidone [Risperdal] and sertindole [Serdolect], but further investigation is required to clarify their role as antisuicidal drugs. It has been estimated that 53 suicides in treatment-resistant patients could have been prevented by clozapine, but the number of lives saved may be significantly higher if clozapine therapy was extended to treatment responders at a high risk for suicide.     

Effects of atypical antipsychotics on the syndromal profile in treatment-resistant schizophrenia

BACKGROUND: There has been considerable support for the observation that atypical antipsychotics have a broader range of therapeutic effects than traditional antipsychotics. We are exploring whether this expanded clinical efficacy can also be seen in patients with treatment-resistant schizophrenia. METHOD: The subjects were 157 treatment-resistant inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week double-blind trial and rated with a standard measure of clinical antipsychotic efficacy (Positive and Negative Syndrome Scale [PANSS]). Factor analysis at baseline and endpoint together with changes in 5 PANSS-derived factors were examined. Data were gathered from June 1996 to December 1999. RESULTS: The underlying PANSS factor structure, as indicated by the factor loadings, was essentially identical at baseline and endpoint. At baseline, the excitement factor was followed by the positive, negative, cognitive, and depression/anxiety factors, explaining 49.4% of the total variance. At endpoint, the positive factor was followed by the negative, excitement, cognitive, and depression/anxiety factors, explaining 55.5% of the total variance. The endpoint data indicated statistically significant (p <.05) improvements over time on the positive factor for all 3 atypicals, but not for haloperidol. The negative factor showed significant improvement for clozapine and olanzapine, with significant worsening for haloperidol. Clozapine, olanzapine, and risperidone were superior to haloperidol on the negative factor, while clozapine was also superior to risperidone. The cognitive factor showed significant improvement for all atypicals, as did the depression/anxiety factor. Only clozapine showed improvement on the excitement factor and was superior to both haloperidol and risperidone. CONCLUSIONS: Treatment with atypical antipsychotics did not substantially change the underlying PANSS 5-factor structure. However, antipsychotic treatment with all 3 atypical medications was associated with significant improvements on 3 of 5 syndromal domains (positive, cognitive, and depression/anxiety) of schizophrenia. Clozapine and olanzapine also showed improvement on the negative factor. Only clozapine was associated with improvement on the excitement domain. This finding confirms that atypicals are associated with improvement of an expanded spectrum of symptoms in treatment-resistant patients.     

Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial

OBJECTIVE: We tested the hypothesis that topiramate is more effective than placebo in reducing symptoms in patients with treatment-resistant schizophrenia when combined with ongoing antipsychotic medication. METHOD: Twenty-six hospitalized treatment-resistant patients with chronic DSM-IV-diagnosed schizophrenia participated in a randomized, double-blind, placebo-controlled trial in which 300 mg/day of topiramate was gradually added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods. Data were collected from April 2003 to November 2003. RESULTS: In intention-to-treat analysis, topiramate was more effective than placebo in reducing Positive and Negative Syndrome Scale general psychopathologic symptoms (effect size = 0.7, p = .021), whereas no significant improvement was observed in positive or negative symptoms. CONCLUSION: Glutamate antagonist topiramate may be an effective adjuvant treatment in reducing general psychopathologic symptoms in patients with schizophrenia resistant to treatment with second-generation antipsychotics.     

Effects of antipsychotic medications on quality of life and psychosocial functioning in patients with early-stage schizophrenia: 1-year follow-up naturalistic study

BACKGROUND: The relative effects of the atypical antipsychotic drugs and conventional agent on quality of life and psychosocial functioning in patients with early-stage schizophrenia is still uncertain because of an insufficient number of studies examining this issue. METHODS: In a 12 months open-label, prospective observational, multicenter study, 1029 subjects with schizophrenia or schizophreniform disorder within 5 years of onset were monotherapy with chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine or aripiprazole. The health-related quality of life and psychosocial functioning were assessed using Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), the Global Assessment Scale (GAS) and the Activities of Daily Living Scale (ADL), respectively. RESULTS: At 12 months, treatment resulted in significant improvements in all 8 domain scores of SF-36, GAS and ADL score (all P-values< .001). However, only olanzapine and quetiapine groups demonstrated greater improvement in the role-psychical score of SF-36 and GAS score than did the chlorpromazine group (all P-values ≤ .002). CONCLUSIONS: All antipsychotics may improve quality of life and social function in patients with early-stage schizophrenia, but further studies are needed to determine whether atypical antipsychotics are superior to conventional agents.     

Antipsychotic use in the treatment of outpatients with schizophrenia in the VA from fiscal years 1999 to 2006

OBJECTIVE: This study examined changes in prescribing patterns of antipsychotic medications to treat schizophrenia. METHODS: Pharmacy records for patients with schizophrenia were obtained from Department of Veterans Affairs databases. The proportion of patients prescribed specific second-generation antipsychotics or any first-generation antipsychotic was calculated per year. RESULTS: In fiscal year (FY) 2006, 78,849 veterans with schizophrenia were prescribed antipsychotic medication. For FY 1999 to FY 2006 the percentage of patients with schizophrenia who received first-generation antipsychotics decreased from 40.8% to 15.9%, but the percentage receiving olanzapine, after peaking at 32.0% in FY 2001, decreased to 19.0%. The percentage of patients given quetiapine increased from 2.5% to 18.8%; risperidone, from 25.5% to 29.7%. However, clozapine usage remained flat, at 2.0%-3.0%. Use of then-new ziprasidone and aripiprazole rose from 5.0% to 9.0%. CONCLUSIONS: Use of each antipsychotic newly marketed over eight years increased while use of risperidone was unchanged and use of olanzapine and the first-generation antipsychotics declined.     

Clozapine Combination and Augmentation Strategies in Patients With Schizophrenia —Recommendations From an International Expert Survey Among the Treatment Response and Resistance in Psychosis (TRRIP) Working Group

BackgroundEvidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia.MethodsWe conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses “agree” + “strongly agree”) was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations.ResultsForty-four (first round) and 49 (second round) of 63 TRRIP members participated. Expert recommendations at ≥75% agreement included raising clozapine plasma levels to ≥350 ng/ml for refractory positive, negative, and mixed symptoms. Where plasma level-guided dose escalation was ineffective for persistent positive symptoms, waiting for a delayed response was recommended. For clozapine-refractory positive symptoms, combination with a second antipsychotic (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For negative symptoms, waiting for a delayed response was recommended, and as an intervention for clozapine-refractory negative symptoms, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilizers, and ECT met consensus criteria. For clozapine-refractory aggression, augmentation with a mood-stabilizer or antipsychotic medication achieved consensus. Generally, cognitive-behavioral therapy and psychosocial interventions reached consensus.ConclusionsGiven the limited evidence from randomized trials of treatment strategies for clozapine-resistant schizophrenia (CRS), this consensus-based series of recommendations provides a framework for decision making to manage this challenging clinical situation.     

Effectiveness and safety of antipsychotics in early onset psychoses: a long-term comparison

The effectiveness and safety of various antipsychotics was evaluated in a long-term study on 47 patients, 29 with schizophrenia and 18 with schizoaffective disorder, aged 10 to 17 years (mean 15.5) at onset. Follow-up ranged from 3 years (all 47 patients) to 11 years (19 patients). Data were collected on the following antipsychotics: haloperidol, risperidone, olanzapine, quetiapine, aripiprazole and clozapine. Cases with positive response were significantly more frequent with clozapine as compared to haloperidol, risperidone and olanzapine. Risperidone was significantly better than haloperidol at the 3-year follow-up. A comparison of the degree of clinical improvement evaluated with PANSS and CGI in patients treated with drugs in subsequent periods showed clozapine led to significantly greater improvement as compared to haloperidol, risperidone and olanzapine, and risperidone as compared to haloperidol. Data on long-term functioning significantly favored clozapine as compared to all the other drugs. Discontinuation due to side effects involved 20% patients with clozapine, lower percentage with the other drugs. The results of this study on early-onset schizophrenic and schizoaffective disorders confirm that even in the long-term, clozapine is more effective than haloperidol, risperidone and olanzapine. Despite a relevant incidence of adverse effects, clozapine seems to have unique effectiveness in treating children and adolescents with early-onset schizophrenic disorders.     

阿立哌唑与利培酮治疗精神分裂症研究

目的：评价阿立哌唑治疗精神分裂症的疗效及不良反应。方法：64例精神分裂症患者,随机分为两组,分别给予阿立哌唑与利培酮治疗8周。采用阳性与阴性症状量表（PANSS）、治疗中出现的症状量表（TESS）评定疗效及不良反应。结果：阿立哌唑组显效率为78.1%,利培酮组为75.0%。利培酮组锥体外系反应稍高于阿立哌唑组。结论：阿立哌唑与利培酮疗效相似,锥体外系反应比利培酮少,是一种有效、安全的抗精神病药物。     

Clinical predictors of therapeutic response to clozapine in a sample of Turkish patients with treatment-resistant schizophrenia

BACKGROUND: Several lines of evidence suggest that clozapine is more effective than both first- and second-generation antipsychotic drugs in treatment-resistant schizophrenia (TRS). However, clinicians appear to be hesitant to prescribe this drug. It would therefore be extremely valuable if predictors of response to clozapine could be identified. The aim of this study was to evaluate the predictive factors of clinical responses to clozapine in a group of Turkish patients with TRS. METHODS: This was a 16-week uncontrolled open study carried out among 97 TRS patients (80 males and 17 females; DSM-IV diagnosis). All patients fulfilled the criteria for refractory schizophrenia according to the UK guidelines for the National Institute of Clinical Excellence (NICE). After all previous antipsychotic medications had run their course, the patients were started on clozapine according to a standardized titration and dosage schedule. Psychopathology was evaluated before the initiation of clozapine therapy and once every 4 weeks using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment for Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. RESULTS: Of the TRS patients on clozapine, 55.7% achieved a clinical response, defined as at least a 20% decrease in BPRS. We observed a favorable effect of clozapine on both positive and negative symptoms. Logistic regression analysis showed that a good clozapine response was more likely when schizophrenia began at a later age, when negative symptoms were severe, and when patients had an early response at 4 weeks. CONCLUSION: A combination of demographic, baseline clinical, and acute treatment response variables may accurately predict response to clozapine in TRS. Priority should be given to initiating clozapine at the earliest phase of TRS, especially for patients with evident negative symptoms.