Plasma clozapine levels and clinical response in treatment-refractory Chinese schizophrenic patients

PURPOSE: To evaluate clinical efficacy of clozapine in relation with its plasma level in a group of Chinese patients with treatment-resistant schizophrenia. In addition, the relationship between plasma level and side effects were examined. METHOD: Fifty-one patients with treatment-resistant schizophrenia were put on a fixed dose of clozapine at 300 mg/day for 6 weeks. Non-responders to week 6 received 500 mg/day in subsequent 6 weeks. Responders to week 6 continued to receive 300 mg/day. Clozapine plasma levels were checked at weeks 6 and 12. FINDINGS: No association was found between clozapine plasma level, response and side effects. Sodium valproate was found to elevate clozapine plasma level while lowering norclozapine/clozapine ratio. CONCLUSION: Clozapine plasma level was not found to be associated with response and side effect in Chinese treatment-resistant schizophrenic patients. Various explanations were postulated for the lack of relationship observed between clozapine plasma level and response in this population.     

Effect size of symptom status in withdrawal of typical antipsychotics and subsequent clozapine treatment in patients with treatment-resistant schizophrenia

OBJECTIVE: In light of the efficacy of newer antipsychotic agents and the possibility that drug withdrawal may negatively affect subsequent drug response, concern has arisen that the use of placebo in schizophrenia research may be unethical. This study examines the effect size of symptom exacerbation during drug washout with placebo and the effects of drug washout on the efficacy of subsequent drug treatment. METHOD: Fifty patients with treatment-resistant schizophrenia hospitalized on a research unit participated in a double-blind longitudinal study of the effects of drug washout after chronic treatment with a typical antipsychotic and before prospective treatment with clozapine. Brief Psychiatric Rating Scale (BPRS) scores were analyzed to examine drug effects and effect sizes for baseline treatment with a typical antipsychotic (>6 months treatment), drug washout with placebo (mean=34 days), early treatment with clozapine (mean=42 days, mean dose=345.0 mg/day), and optimal clozapine treatment (mean=83 days, mean dose=450.5 mg/day). RESULTS: Patients' BPRS total, positive, and negative symptom scores significantly increased during placebo washout, compared with baseline treatment, and significantly decreased with administration of clozapine, compared with placebo washout and baseline treatment. However, 30% of patients showed some symptom improvement during placebo washout. The effect sizes for the BPRS total score were 0.63 for baseline treatment versus placebo washout, 1.10 for optimal clozapine treatment versus placebo washout, and 0.82 for optimal clozapine treatment versus baseline treatment. CONCLUSIONS: Symptom exacerbation induced by drug withdrawal in patients with treatment-resistant schizophrenia did not impede subsequent responsiveness to clozapine. The effect size for clozapine, compared with typical antipsychotics, suggests that the drug-washout longitudinal design is useful for establishing a drug-free baseline and for investigating drug response, while requiring relatively few subjects.     

A new therapeutic approach tp drug-resistant schizophrenia: clozapine. Long-term prospective study in 16 patients]

Clozapine, a dibenzodiazepine derivative, has potent antipsychotic activity; but bone marrow suppression resulting in agranulocytosis has been associated with clozapine treatment and has restricted the administration of this drug to treatment-resistant schizophrenic patients. This report describes preliminary results of an open prospective study of the effects of clozapine on symptomatology and social function in 16 treatment-resistant schizophrenic patients. Authors prospectively followed up for 18 months 16 DSM III-R schizophrenic patients who had failed to respond to various neuroleptics (n: 7.2 +/- 2.8); when clozapine treatment was initiated, the mean duration of the illness was 14.2 (+/- 6.7) years. Total BPRS, BPRS "positive" and "negative" symptoms scores were used for evaluation. Social integration and side effects were also studied. 14 of 16 patients are still receiving clozapine; 1 out of 14 patients has a more than 60% decrease in total BPRS, 11 out of 14 have 30 to 60% decrease in total BPRS and 2 out of 14 have less than 30% decrease in total BPRS. Improvements in both total and positive symptoms BPRS scores were observed within the first month of treatment (p < 0.001); improvement in negative symptoms was noted within the third month (p < 0.02). At the end of the follow up period, 43% of patients showed marked improvement in family life and 21% found a job during the study. Beyond noteworthy improvement of clinical symptoms in these patients who presented with severe schizophrenia, clozapine also significantly reduced the use of concomitant medication. Side effects are studied but none required treatment disruption; neurological side effects were less reported than with usual neuroleptics. It is concluded that clozapine offers particular benefits for some treatment-resistant schizophrenic patients; however the increased comparative risk requires a restricted use of clozapine to selected patients.     

Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia. METHOD: In a randomized, double-blind, placebo-controlled 12-week trial, 40 patients unresponsive or partially responsive to clozapine monotherapy received a steady dose of clozapine combined with either placebo (N=20) or up to 6 mg/day of risperidone (N=20). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), among other measures. Movement disorders were assessed with the Simpson-Angus Rating Scale. RESULTS: From baseline to week 6 and week 12, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo. The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo. Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12. Clozapine/risperidone treatment did not induce additional weight gain, agranulocytosis, or seizures compared with clozapine/placebo treatment. CONCLUSIONS: In patients with a suboptimal response to clozapine, the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia. The combination appears to be safe and well tolerated. Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.     

Clozapine in treatment-resistant patients with schizophrenia,schizoaffective disorder,or psychotic bipolar disorder: a naturalistic 48-month follow-up study

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of clozapine in patients with treatment-resistant schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. METHOD: 101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34); schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with psychotic features (N = 37) were naturalistically treated with clozapine at flexible doses over a 48-month period. Data were collected from 1994 to 2000. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness scale total predicted scores over time were estimated with random-effects regression models. Time to response to clozapine, defined as 50% reduction of BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier method. Survival curves were compared using the log-rank test. RESULTS: The BPRS total predicted score halved its baseline value in 3 months for bipolar disorder patients, in 6 months for schizoaffective disorder patients, and in 24 months for schizophrenia patients. The proportion of subjects who satisfied the criterion for response to clozapine after 48 months of follow-up was significantly (p <.01) higher in the schizoaffective and bipolar disorder groups (90.0% and 83.8%, respectively) than in the schizophrenia group (64.7%). Baseline scores on the Global Assessment of Functioning (GAF) showed low levels of psychosocial and occupational functioning in all 3 groups. After 48 months of treatment, GAF scores showed a functional improvement in all 3 groups, with significantly (p <.01) greater improvement in the bipolar disorder group compared with the other groups. CONCLUSION: The findings of this study confirm the efficacy and safety of clozapine for treatment-resistant patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Patients with schizoaffective disorder and those with bipolar disorder show greater clinical improvement than those with schizophrenia. Patients with bipolar disorder have the shortest time to response and the highest psychosocial and occupational functioning levels. Patients with schizoaffective disorder have the lowest treatment discontinuation rate.     

The effects of clozapine on levels of total cholesterol and related lipids in serum of patients with schizophrenia: a prospective study

OBJECTIVE: To investigate the effects of 12 weeks of clozapine treatment on levels of cholesterol and related lipids in patients with schizophrenia. DESIGN: Prospective study. SETTING: University department associated with a teaching hospital. PARTICIPANTS: Eight patients (6 women and 2 men) with a clinical diagnosis of schizophrenia consistent with DSM-IV criteria. The patients were classified as treatment-resistant and had not responded to treatment with at least 2 conventional antipsychotics. INTERVENTIONS: Current antipsychotic medications were tapered and treatment with clozapine was initiated. OUTCOME MEASURES: Cholesterol and serum lipid levels, as well as Brief Psychiatric Rating Scale (BPRS) scores were measured before and after 12 weeks of treatment with clozapine. RESULTS: Clozapine treatment significantly improved the BPRS scores but did not significantly alter serum lipid levels, except triglyceride levels, which increased. CONCLUSION: The previously reported lower levels of cholesterol in treatment-resistant patients with schizophrenia cannot be attributed to the effects of clozapine administration. Further research is required to support and clarify the effects of antipsychotic drugs on lipid levels.     

奥氮平合并氯氮平对男性难治性精神分裂症阴性症状的疗效及安全性的研究

目的观察奥氮平合并氯氮平治疗男性以阴性症状为主的难治性精神分裂症的疗效以及安全性。方法对43例男性原服用氯氮平且以阴性症状为主的难治性精神分裂症患者合并奥氮平5～20mg／d治疗8周,同时于2周内将氯氮平减量且氯氮平剂量2周后不再变化,并于合并治疗前及后2周、4周、8周评定阳性症状与阴性症状量表（PANSS）、副反应量表（TESS）。结果合并奥氮平治疗后2周、4周、8周末PANSS总分和TESS评分较合并前有明显差异。结论奥氮平合并氯氮平对于男性难治性精神分裂症患者的阴性症状有明显的改善,副反应也有减少。     

Add-on of aripiprazole improves outcome in clozapine-resistant schizophrenia

Although clozapine proved effective in treating 30-50% of the cases of resistant schizophrenia, its clinical use is hampered by significant side effects. To overcome this problem, augmentation with other atypical antipsychotics has been attempted, with conflicting results. A clozapine-aripiprazole combination showed interesting properties, due to the favourable complementary pharmacodynamic receptor profile and to the negligible metabolic interactions. In this retrospective case series, we investigated the change in BPRS scores and metabolic features like BMI, fasting glucose, total and LDL cholesterol, triglycerides, functional outcome HoNOS Rome and PSP scores after aripiprazole augmentation in 16 persons with treatment-resistant schizophrenia who were already treated with clozapine. The results demonstrated a statistically significant improvement in metabolic indices, psychopathology and functional outcome measures from baseline to endpoint (6 weeks) after augmentation with aripiprazole. Statistically significant correlations were observed between psychopathological and behavioural measures at baseline and at endpoint. Linear regression analysis defined a tripartite model, in which item HoNOS Rome 11, measuring autonomy in everyday life, explained nearly half of functional outcome PSP score predictive variance, together with BPRS total psychopathology score and HoNOS Rome total social functioning score. Adequately conducted randomised double-blind studies should provide further specific data highlighting the role of a clozapine-aripiprazole combination in improving functional outcome of persons with treatment-resistant schizophrenia.     

Augmentation with amisulpride for schizophrenic patients nonresponsive to antipsychotic monotherapy

Despite the effectiveness of antipsychotic medications in treatment of schizophrenia, about 30% of patients who receive an adequate treatment have significant persisting symptoms. The problem of treatment-resistant psychosis is an important and difficult one. The aim of this study was to retrospectively evaluate the efficacy and safety of amisulpride augmentation in treatment-resistant schizophrenic patients. To the best of our knowledge, this is the first report about resistant schizophrenic and schizoaffective patients treated with the combinations of risperidone and amisulpride and ziprasidone and amisulpride. Data were collected from patient records. A total of 15 resistant schizophrenic patients (7 men, 8 women, 54.0 +/- 16.9 years old) were included in the study. Before addition of amisulpride, the patients were treated with monotherapy by atypical neuroleptics (clozapine, olanzapine, risperidone, or ziprasidone). The mean amisulpride dose was 693.3 +/- 279.6 mg/d. The mental state of 12 (80%) patients treated with combination was improved. Three (20%) patients showed no change in their mental state. Only 2 patients treated with a combination of risperidone and amisulpride had mild side effects. The results are preliminary and require confirmation in a randomized controlled trial. The authors suggest that amisulpride may be a promising option as an augmentation strategy in treatment-resistant schizophrenic patients.     

A three-year naturalistic follow-up of patients receiving clozapine: Report from India

INTRODUCTION: Clozapine is a first-line drug for treatment-resistant schizophrenia, but studies dealing with long-term outcome are lacking, so we decided to carry out such a study. METHODS: Patients with treatment-resistant schizophrenia who were recruited in an open-label study three years ago were re-evaluated using the same parameters: BPRS, PANSS and a side-effect rating checklist. RESULTS: Nineteen out of 25 patients who participated in the initial study were available for re-evaluation. Two patients had changed to conventional neuroleptic medication, and were excluded from the study. A significant reduction in psychopathology was observed in 85% of patients. An improvement in social functioning was evident, with seven patients pursuing a career independently, and another six working with their family members since being started on clozapine. All the patients were on clozapine monotherapy, and the average daily dose was 248.21 mg. No patient required hospitalization and there was no incidence of granulocytopenia. CONCLUSIONS: A significant improvement in the psychopathology and social functioning of patients was observed with much lower doses of clozapine than has been reported elsewhere. The doses used for maintenance were lower than those used in the acute phase of treatment. (Int J Psych Clin Pract 2002; 6: 167-171 )     

Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial

INTRODUCTION: Only limited data are available on the effectiveness of augmented antipsychotics to clozapine therapy in chronic schizophrenia. We conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of augmentation with the atypical neuroleptic amisulpride to clozapine in a small sample group of patients. METHODS: 16 patients with the DSM-IV diagnosis of chronic schizophrenia and partially responsive to clozapine participated in this pilot study. Patients on a steady dose of clozapine randomly received either clozapine and amisulpride 400 mg/day (n=7) or clozapine and amisulpride 600 mg/day (n=6) or clozapine and placebo for 6 weeks (n=3). Efficacy measures were BPRS, CGI, GAF and MADRS score. Side effects and prolactin levels were obtained. Primary outcome measure were BPRS score changes. RESULTS: The beneficial effect of augmented amisulpride at a daily dose of 600 mg was observed in the mean scores of secondary outcome measures, as assessed by GAF, CGI and MADRS. Measures of primary objectives failed to improve significantly. No reduction in BPRS total score was achieved due to lack of power of the study, whereas the BPRS subscore "activity" had a tendency to improve. Amisulpride was more beneficial in a higher than a lower dose. No severe side-effects occurred, but tremor, bradykinesia, akathisia and elevated prolactin levels were recorded. DISCUSSION: Augmented amisulpride improved the global outcome of patients suffering from chronic schizophrenia in this pilot study and tended to be a helpful treatment option in cases of partial or non-responsiveness to clozapine. Limitations emerge from the small sample size and lack of power. Further investigation requires a larger number of patients to be included.     

Augmenting atypical antipsychotic medications with clozapin

Typical antipsychotic medications have considerably improved clinical outcome of patients suffering from schizophrenic psychoses, but up to 40% of the cases show treatment resistant symptoms. Even therapy with atypical antipsychotic drugs such as risperidone, quetiapine, olanzapine, sulpiride, amisulpride, and ziprasidone often fails to reach complete remission due to resistant, positive or negative symptoms or dose-limiting side effects. As this also holds true in the case of monotherapy with clozapine, a substance known to be effective against treatment-resistant schizophrenia, increasing numbers of patients receive atypical antipsychotic drugs in addition to clozapine. This review systematically evaluates case reports and clinical investigations on the use of clozapine combined with risperidone, olanzapine, quetiapine, sulpiride, amisulpride, or ziprasidone. Details on indication, methodology, and effects of the investigations are summarized. Only one double blind, placebo-controlled trial on the combination with sulpiride exists within a number of altogether 31 publications about 1182 treatments. Favorable effects on positive and/or negative symptoms or improvements of clozapine-induced side effects were described for every combination approach. In some cases pharmacokinetic interactions or serious unfavorable effects occurred. In conclusion it might be accepted that most of the combination therapies follow a neurobiological rational. There a major differences in the level of evidence that they are safe, tolerable and effective. We discuss criteria for the indication for augmenting clozapine therapy and the differential indication for existing alternatives. Additional randomized prospective trials are needed in order to evaluate these strategies systematically.     

氯丙嗪宝刀不老——与氯氮平疗效的对照观察

目的;了解氯丙嗪与氯氮平治疗以阳性症状为主的精神分裂症的临床疗效与副反应。方法：选择符合ＣＣＤＭ－２－Ｒ诊断标准,同时符合Ａｎｄｒｅａｓｅｎ阳性神经分裂症标准的２００例病人,随机均分为单用氯丙嗪或氯氮平治疗两组,以简明精神病量表（ＢＰＲＳ）评定疗效,以不良反应症状量表（ＴＥＳＳ）观察副反应。     

Favourable results in treatment-resistant schizophrenic patients under combination of aripiprazole with clozapine

Clozapine is still the gold standard in treatment-resistant schizophrenia. However, a substantial amount of patients do not fully recover on clozapine monotherapy. Though there is still a lack of randomised controlled studies of combination strategies in treatment-resistant schizophrenia, they are widely used. Aripiprazole is a relatively new therapeutic option due to its partial D2 agonism. Both clozapine and aripiprazole, though having a generally favourable side-effect profile, may lead to insufficient response and might provoke side effects in monotherapy. We report the case of four patients in whom we observed a distinct clinical improvement with respect to positive and negative symptoms without major side effects under a combination of clozapine and aripiprazole. The combination of clozapine action and aripiprazole-mediated D₂ receptor regulation could be responsible for the described favourable effects and for the increase of D₂ receptor blockade after adding aripiprazole to clozapine observed in one patient. A combination of clozapine and aripiprazole may be an effective therapeutic strategy for some schizophrenic patients, leading to a good response with respect to positive and negative symptoms without the occurrence of major side effects.     

齐拉西酮与氯氮平治疗精神分裂症对照研究

目的：探讨齐拉西酮治疗精神分裂症的疗效和不良反应。方法：将60例符合中国精神障碍分类与诊断标准第3版的精神分裂症患者,随机分为齐拉西酮组和氯氮平组,疗程6周,用阳性与阴性症状量表（PANSS）评定疗效,用治疗中出现的症状量表（TESS）观察不良反应,分别于治疗前、治疗2周、治疗4周评定1次一结果：两组疗效差异无显著性（P〉0．05）,齐拉西酮不良反应显著少于氯氮平。结论：齐拉西酮对精冲分裂症的疗效与氯氮平相当,不良反应较小,服药依从好,可作为分裂症的首选药物。     

齐拉西酮与氯氮平、利培酮对精神分裂症患者脂代谢影响的对照研究

目的探讨氯氮平、利培酮、齐拉西酮三种抗精神病药物对精神分裂症患者脂代谢的影响。方法将符合CC-MD-3精神分裂症诊断标准的187例精神分裂症患者随机分成氯氮平、利培酮、齐拉西酮3组,分别给予单药治疗6个月。于治疗前及治疗第1、2、3、6个月末监测血脂、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL))等项指标,同时评定症状程度。结果治疗后较治疗前氯氮平组、利培酮组在血脂各指标数值均增加,且在体质量、TC项,差异具有统计学意义(P<0.05);氯氮平组在TG、LDL项,利培酮组在TG项差异具有统计学意义(P<0.01);齐拉西酮组在血脂各项指标上,治疗前后差异无统计学意义(P>0.05)。结论氯氮平、利培酮对患者的血脂代谢均有影响,且氯氮平的影响大于利培酮,齐拉西酮的影响则不显著。     

奥氮平和氯氮平治疗精神分裂症老年患者的对照研究

目的：对比奥氮平与氯氮平治疗精神分裂症老年患者的疗效和安全性。方法：对64例精神分裂症老年患者分别给予奥氮平、氯氮平治疗，其中奥氮平组30例，氯氮平组34例，疗程8周。以阳性症状和阴性症状量表(PANSS)、临床疗效总评量表(CGI)、简明精神病评定量表(BPRS)评定临床疗效。以副反应量表(TESS)和实验室监测评价安全性。结果：治疗结束时，两组PANSS和BPRS总分较治疗前显著降低，组间差异无显著性。两组间从治疗第1周起各时点PANSS减分率差异有显著性。临床有效率：奥氮平组76．7％，氯氮平组64．7％，两组相仿。奥氮平组不良反应较氯氮平组少，常见不良反应为胆碱能作用、嗜睡、体重增加和一过性肝酶升高等。结论：奥氮平治疗精神分裂症的疗效与氯氮平相似，某些不良反应较氯氮平轻而少；是一种安全有效、服用方便的新型抗精神病药。     

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.     

奥氮平与氯氮平治疗难治性精神分裂症对照研究

目的评价奥氮平治疗难治性精神分裂症的疗效及安全性。方法将64例难治性精神分裂症患者随机分为研究组和对照组,分别予以奥氮平和氯氮平治疗8周,采用PANSS量表和TESS量表评定疗效和不良反应。结果奥氮平组治疗前后PANSS减分率为39.3%,有效率为72.8%;氯氮平组治疗前后PANSS减分率为36.6%,有效率为59.4%。奥氮平组未见严重的不良反应。结论奥氮平与氯氮平治疗难治性精神分裂症均有良好疗效,奥氮平的副作用小,病人依从性好。     

维思通与氯氮平治疗精神分裂症对照分析

用维思通治疗精神分裂症３３例，与用氯氮平治疗的３１例进行对照研究。两组以阴性症状量表（ＳＡＮＳ），阳性症状量表（ＳＡＰＳ），简明精神病量表（ＢＰＲＳ）和副反应量表进行盲式评分。结果显示：虽然氯氮平对治疗阴性阳性症状均有较好疗效，但维思通更明显优于氯氮平，且副作用较小。本文对维思通的疗效，临床应用，副作用，作用机理进行了讨论。