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.     

左旋千金藤啶碱与氯氮平治疗精神分裂症双盲对照研究

目的：探讨中药提取物左旋千金藤啶碱（L－SPD）对精神分裂症的治疗效果及副作用。方法：采用双盲，双模拟，氯氮平对照，随机入组方法，实验期六周，疗效评定采用简明精神病评定量表（BPRS），阳性症状量表（SAPS），阴性症状量表（SANS）及四级临床疗效评定标准，不良反应采用副作用量表（TESS）评定。结果：左旋千金藤啶碱与氯 平治疗精神分裂症总体疗效相当，均明显地消除阴，阳性症状（P＞0．05），千金藤副作用明显少于氯氮平治疗精神分裂症总体疗效相当，均能明显地消除阴，阳性症状（P＞0．05），千金藤副作用明显少于氯氮平（P＜0．05），结论：左旋千金藤啶碱对精神分裂症有显著疗效，且副作用更少。     

The relationship of clozapine and haloperidol treatment response to prefrontal,hippocampal, and caudate brain volumes

OBJECTIVE: The study was designed to assess the predictive relationship between brain structure volume and positive and negative symptom response to clozapine and haloperidol. METHOD: Partially responsive outpatients with schizophrenia who participated in a 10-week, parallel-group, double-blind comparison of clozapine and haloperidol and who had an available magnetic resonance imaging scan were included in the current study. Prefrontal gray and white matter, hippocampal, and caudate volumes were manually measured. The Scale for the Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS) were used to assess symptom changes. The Simpson-Angus Rating Scale was used to assess extrapyramidal symptoms. RESULTS: Twenty-two patients randomly assigned to clozapine and 23 patients assigned to haloperidol met study entry criteria. There were significant interactions between treatment and right prefrontal gray matter volume for BPRS total score and SANS total score. There were no significant treatment-by-brain structure interactions for BPRS positive symptom items. Right prefrontal gray matter volume was also related to differential treatment effects for the BPRS subscales of anxiety/depression and hostility and the Simpson-Angus Rating Scale akathisia item. CONCLUSIONS: These results suggest that there is a differential interaction among clozapine and haloperidol, brain structure, and treatment response. Partially responsive patients with larger brain volumes may be more likely to experience the benefits of clozapine treatment, but they may be more vulnerable to side effects and experience a subsequent worsening of their symptoms when treated with haloperidol.     

Efficacy of electroconvulsive therapy combined with antipsychotic medication in treatment-resistant schizophrenia: a prospective,open trial

This study examined the short-term efficacy of electroconvulsive therapy (ECT) combined with antipsychotic medication in treatment-resistant schizophrenia (TRS). Fifteen patients with TRS from an in-patient psychiatric rehabilitation unit participated. Patients completed a course of ECT consisting of 8 to 20 sessions, while their antipsychotic medications were continued throughout the study. Patients were assessed at baseline, 1 week, 1 month, and 2 months after their last ECT session. Assessment instruments included the Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Rating Scale, Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Clinical Global Impression (CGI), Nurses' Observation Scale for In-Patient Evaluation, and occupational therapists' rating of the patients' functioning with respect to work, social, and leisure activities. Compared with the baseline assessment, at each posttreatment evaluation, patients showed statistically significant improvement in the GAS and CGI. In addition, they were significantly better in terms of BPRS and SANS scores, as well as work performance and social functioning at the 2-month post-ECT evaluation.     

Insight in persons with schizophrenia: effects of switching from conventional neuroleptics to atypical antipsychotics

The primary aim of our study is to evaluate the level of insight during the switch from a classical antipsychotic drug to a atypical neuroleptic. Twenty-two schizophrenic patients were admitted to the study, 9 were male and 13 were female. Standardized questionnaire were: Scale for Assessment of Negative Symptoms (SANS), Scale for Assessment of Positive Symptoms (SAPS), Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessing the three components of Insight (SAI). All patients were receiving haloperidol at time of recruitment. Eight patients were switched to clozapine, 3 to risperidone and 11 to olanzapine. The global function, measured with BPRS, increased after administration of atypical antipsychotics. The positive and negative symptoms were reduced. The level of insight was increased after the administration of the atypical antipsychotics. The cognitive effect of the atypical antipsychotics changed the level of insight and augmented the compliance.     

Efficacy of electroconvulsive therapy in treatment-resistant schizophrenia: a prospective open trial

There is a lack of controlled trials examining the effectiveness of electroconvulsive therapy (ECT) combined with olanzapine or risperidone in treatment-resistant schizophrenia (TRS). The authors conducted a prospective, open, controlled trial of ECT in TRS in a long-term psychiatric rehabilitation unit in Hong Kong. Thirty patients with TRS from an inpatient psychiatric rehabilitation unit participated in this study. All subjects were resistant to a host of antipsychotic medications given singly or in different combinations. In addition, they were also resistant to or they refused clozapine treatment. Fifteen patients completed a course of ECT consisting of 8-20 sessions. Fifteen patients who refused ECT formed the control Subjects were assessed at baseline, 1 week, 1 month, and 2 months after their last ECT. Assessment instruments included the Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Rating Scale (HDRS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Clinical Global Impression (CGI), CGI Severity of Illness [CGI(SOI)], CGI Global Improvement [CGI(GI)], Nurses' Observation Scale for Inpatient Evaluation (NOSIE-30), and occupational therapists' rating of the subjects' functioning with respect to work (OT-W), social (OT-S), and leisure (OT-L) activities. In comparison with the control group, the ECT group showed statistically significant improvement only in the GAS and CGI at each posttreatment evaluation. There was a trend for ECT to reduce positive and negative symptoms, although the rate of improvement did not reach statistically significant levels. ECT augmentation of risperidone and olanzapine is of marginal efficacy compared to reports of the greater augmentation of these antipsychotics with other agents.     

工娱疗法合并氯氮平治疗慢性精神分裂症的对照研究

目的探讨工娱疗法合并氯氮平治疗慢性精神分裂症的效果。方法将112例服用氯氮平治疗的慢性精神分裂症患者随机分为工娱治疗组和对照组。工娱治疗组进行为期16周的训练。采用简明精神症状量表（BPRS）、阴性症状量表（SANS）、临床疗效总评量表（CGI）进行临床效果评定，日常生活能力量表（ADL）来评定患者的日常生活能力。用药物依从性量表来判断患者的服药情况。结果治疗16周末，治疗组患者的服药依从性。慢性精神分裂症阴性症状的缓解，患者的日常生活能力的提高都优于对照组P〈0．05）。结论工娱疗法有助于慢性精神分裂症的治疗和康复。     

Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison

BACKGROUND: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. METHODS: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. RESULTS: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. CONCLUSIONS: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.     

Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials

OBJECTIVE: The authors conducted a review and meta-analysis of studies that compared the efficacy and tolerability of typical and second-generation antipsychotics for patients with treatment-resistant schizophrenia. METHOD: A systematic search revealed 12 controlled studies (involving 1,916 independent patients), which were included in the review. For the seven studies that compared clozapine to a typical antipsychotic, a meta-analysis was performed to examine clozapine's effects on overall psychopathology, response rate, extrapyramidal symptoms, and tardive dyskinesia. RESULTS: The meta-analysis confirmed that treatment-resistant schizophrenic patients have more favorable outcomes when treated with clozapine rather than a typical antipsychotic, as reflected by Brief Psychiatric Rating Scale total score, categorical response rate, Scale for the Assessment of Negative Symptoms score, Simpson-Angus Rating Scale score, and compliance rate. Clozapine also conferred benefits on the sickest treatment-resistant schizophrenic patients. Patients treated with olanzapine also had more favorable outcomes with regard to categorical response and compliance rates. CONCLUSIONS: In the aggregate, the results of a meta-analysis indicated that clozapine exhibits superiority over typical antipsychotics in terms of both efficacy (as measured by improvement in overall psychopathology) and safety (in terms of reduced extrapyramidal side effects). However, the magnitude of the clozapine treatment effect was not consistently robust. Efficacy data for other second-generation antipsychotics in the treatment of patients with refractory schizophrenia were inconclusive. There is, therefore, a growing need to consider new and different treatment strategies, whether they be adjunctive or monotherapeutic, for schizophrenia that continues to be resistant or only partially responsive to treatment.     

Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine

OBJECTIVE: Treatment options are very limited for individuals with schizophrenia resistant to clozapine. We tested the hypothesis that amisulpride augmentation would lead to an improvement in these patients. METHOD: This was an open non-randomized study. Thirty-three patients with sub-optimal response to clozapine were commenced on amisulpride in addition to clozapine. Clinical status was evaluated at baseline, 3 and 6 months using the Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Calgary Depression Scale, Calgary Anxiety Scale and various side effect rating scales. RESULTS: Twenty-eight subjects completed 6 months treatment on clozapine and amisulpride. There was a statistically significant improvement in the mean scores for PANSS, SANS and GAS at follow-up and no significant changes in side effect ratings. CONCLUSION: Co-administration of amisulpride, in a group of patients partially or non-responsive to clozapine, may lead to a substantial improvement in positive and negative symptoms, without worsening the side effect burden.     

Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.     

Smoking in chronic schizophrenic inpatients in taiwan

OBJECTIVE: This study investigated the prevalence of smoking and its association with the clinical characteristics of Chinese inpatients with chronic schizophrenia. METHOD: Schizophrenic patients hospitalized in chronic wards were assessed using Brief Psychiatric Rating Scale (BPRS), Abnormal Involuntary Movements Scale (AIMS) and Folstein Mini-Mental Status Examination (MMSE) testing. RESULTS: Of 257 patients, 105 smoked and 4 had ceased. Males exhibited a higher prevalence of smoking than females (p < 0.001). Smoking was not significantly associated with age at onset (AAO), chlorpromazine equivalents, MMSE, AIMS, BPRS positive symptom subscale, BPRS negative symptom subscale or total BPRS scores. Smokers had higher BPRS general subscales. CONCLUSION: Compared to the general population, smoking prevalence was slightly higher in schizophrenic males, double in schizophrenic females, but no difference in refractory schizophrenic clozapine users. Smoking did not affect patient AAO or daily antipsychotic dose. Patients with a higher BPRS general subscale may smoke to relieve affective symptoms.     

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.     

Clozapine-induced weight gain predicts improvement in psychopathology

BACKGROUND: Some, but not all, previous studies have indicated that weight gain is associated with greater improvement in psychopathology during clozapine treatment. Possible reasons for the inconsistent results include failure to adjust for initial body weight and level of psychopathology, differences in trial duration, outcome measures, reliability of assessment, concomitant medications and clozapine dosage. The purpose of this study was to test the hypothesis that clozapine-induced weight gain is related to antipsychotic efficacy at 6 weeks and 6 months after adjusting for initial body weight and severity of illness. METHODS: Weight and psychopathology were determined in 74 patients with schizophrenia or schizoaffective disorder at baseline and after 6 weeks and 6 months of open treatment with clozapine monotherapy. The primary measures of psychopathology were the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms subscales, Schedule for Assessment of Negative Symptoms (SANS), Schedule for Assessment of Positive Symptoms (SAPS) and Global Assessment of Function Scale (GAFS). RESULTS: Significant improvement in the key measures of psychopathology was noted at 6 weeks and 6 months. Mean weight gains at 6 weeks and 6 months were 3.7+/-5.7 S.D. and 7.3+/-7.9 S.D. kg, respectively, with the increase between 6 weeks and 6 months being significant. Age, but not gender, initial body weight, clozapine dosage or plasma levels predicted weight gain at both time points. At 6 weeks and 6 months, after adjustment for age, initial weight and level of psychopathology, the percentage change in weight significantly predicted the improvement in the BPRS Total and Positive symptoms subscale, the SANS Global score, as well as other measures of psychopathology. CONCLUSIONS: Increase in weight with clozapine predicted improvement in psychopathology. This suggests that effects of clozapine on neurotransmitters which influence weight gain, e.g. 5-HT(2C) and 5-HT(1a) antagonism, in association with individual variations in these receptors and others molecules, e.g. peptides and transporters, due to polymorphisms or post-translational editing of mRNAs, may also contribute to the improvement in psychopathology.     

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.     

Electroconvulsive therapy in first-episode schizophrenia

Knowledge about the efficacy of electroconvulsive therapy (ECT) on schizophrenia comes from chronic patients and little known on young, first-episode patients. The aim of this study is to evaluate short-term and long-term efficacy of ECT in patients with first-episode schizophrenia.In the first phase of the study, 90 hospitalized, first-episode patients with schizophrenia were enrolled; psychopathology was evaluated with Brief Psychiatric Research Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), and Scale for the Assessment of Negative Symptoms (SANS) on admission and discharge. Antipsychotics were first-line treatment for most of the patients, but medication for nonrespondent catatonic patients and patients who had violent behaviors were treated with ECT. The patients who met the remission criteria were intended to a 1-year follow-up after discharge. BPRS, SAPS, and SANS were monthly recorded during the follow-up. Differences in clinical characteristics, relapse, and rehospitalization rates were analyzed in patients with or without ECT treatment.Thirteen patients were treated with ECT. They were low educated and were more likely nonparanoid subtypes (catatonic, disorganized). The ECT group had higher BPRS scores on admission and their hospitalization period was longer than the antipsychotic group. On the contrary, BPRS and SAPS scores of the ECT group were lower at discharge. The ECT group presented shorter follow-up duration than the antipsychotic group during the follow-up period. In conclusion, the efficacy of ECT was very satisfactory in acute term in first-episode schizophrenia, but the same efficacy was not continuous during the 1-year follow-up.     

Relations among clinical scales in schizophrenia

OBJECTIVE: Clinical scales have become established as tools to quantify phenomenological features of schizophrenia. The goal of this study was to examine relations among the following: the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the deficit-nondeficit classification. METHOD: Forty-seven patients with schizophrenia were recruited according to specific inclusion and exclusion criteria. The standardized assessment procedures were administered by a trained psychiatric research team. RESULTS: Examination of the BPRS showed that the patients had highest scores on the thought disorder factor and the symptoms specific to schizophrenia. Classification of patients as having the positive, negative, or mixed type of schizophrenia resulted in a finding of seven with the positive, seven with the negative, and 33 with the mixed type. The division of patients into those with the deficit syndrome (N = 29) and those without (N = 18) was related to symptom specificity and to positive and negative symptoms. Deficit syndrome patients had more symptoms specific to schizophrenia, fewer nonspecific symptoms, and, as expected, greater severity of negative symptoms. Cluster analysis revealed three clusters of patients: those with low negative symptom scores and high scores on specific symptoms (the majority were without the deficit syndrome); those with high scores on negative, positive, and specific symptoms (the majority had the deficit syndrome); and those with lower scores on specific symptoms and high scores on negative and positive symptoms (the majority had the deficit syndrome). CONCLUSIONS: The scales showed some overlap but also seemed to measure complementary aspects of the phenomenology of schizophrenia. Subtypes of patients identified by the combined use of these scales may differ in underlying pathology.     

Clozapine and negative symptoms. An open study

1. Clozapine, the first atypical antipsychotic, has demonstrated an efficacy in the treatment of resistant schizophrenia. But one of the major challenge in the treatment of schizophrenia remains the lack of efficacy of antipsychotics on negative symptoms of schizophrenia. 2. The authors studied the efficacy of clozapine in an open study in a population of 51 patients, who met the DSM IV criteria for schizophrenia. Using the positive and negative symptom scale (P.A.N.S.S.), and the Extra Pyramidal Symptoms Rating Scale (E.S.R.S.), we try to identify the specificity of the action of clozapine on the different symptomatic dimensions of schizophrenia. 3. The efficacy of clozapine was clinically significant on the negative symptomatology but was delayed compared to the efficacy on the other dimensions of symptomatology evaluated using the PANSS. 4. Nine patients, were considered as deficit patients; in this sample clozapine also demonstrated a significant efficacy on negative symptoms. The efficacy of clozapine did not seem to be a consequence of the better neurological tolerance of this antipsychotic evaluated with ESRS.     

Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome

OBJECTIVE: Clozapine is a unique atypical antipsychotic with superior efficacy in treatment-resistant schizophrenia. Plasma concentration of clozapine and its major metabolite N-desmethylclozapine (NDMC) as well as the ratio of NDMC to clozapine have been reported to be predictors of clozapine response. Here we evaluate these as well as other measures in an effort to find predictors of response to clozapine in our early-onset treatment-refractory population. METHOD: Fifty-four children and adolescents participated in double-blind (n = 22) or open-label (n = 32) clozapine trials. Clinical evaluations took place at baseline, week 6 on clozapine, and at 2- to 6-year follow-up. The data were analyzed in relation to demographics, age at onset, IQ, clozapine dose, and plasma concentrations of prolactin, clozapine, NDMC, and NDMC/clozapine ratio. Stepwise regression and correlation analyses were performed to find predictors of treatment response. RESULTS: Clinical improvement after 6 weeks of clozapine treatment, as measured by the percentage of improvement on the Brief Psychiatric Rating Scale and the Scale for the Assessment of Positive Symptoms, was strongly associated with the NDMC/clozapine ratio at the 6-week time point (Pearson correlation coefficient: r = 0.41; p < .01 for Brief Psychiatric Rating Scale and r = 0.43; p < .01 for Scale for the Assessment of Positive Symptoms). Although the rate of side effects was higher than that typically found in the adult population, it did not appear to be related to clozapine dose, clozapine or NDMC plasma concentrations, or NDMC/clozapine ratio. Outcome at long-term follow-up, as measured by Children's Global Assessment Scale, was associated with lesser illness severity at baseline and with greater improvement during the initial 6 weeks of clozapine treatment. CONCLUSIONS: The NDMC/clozapine ratio may be a valuable predictor of response to clozapine and may suggest new approaches to clozapine treatment.     

文拉法辛联合氯氮平治疗精神分裂症阴性症状的疗效

目的 观察文拉法辛缓释片合并氯氮平治疗精神分裂症阴性症状的疗效和不良反应.方法 采用单纯随机化法,将107例精神分裂症患者分为研究组（文拉法辛缓释片＋氯氮平）和对照组（氯氮平＋安慰剂）.于治疗前、治疗第2、4、8周末以阳性和阴性症状量表（PANSS）和阴性症状量表（SANS）评定疗效,于治疗第2、4、8周末以药物副反应量表（TESS）评定不良反应.结果 治疗4、8周末,研究组PANSS总分和阴性因子分与对照组比较,差异有统计学意义（P〈0.05）;研究组SANS总分和部分因子分与对照组比较,差异有统计学意义（P〈0.05）.治疗后第2、4、8周末,研究组TESS评分均明显低于对照组,差异有统计学意义（P〈0.05）.结论 文拉法辛缓释片治疗精神分裂症安全有效,协同氯氮平治疗精神分裂症阴性症状可增加疗效.