A double‐blind,placebo‐controlled trial of rosiglitazone for clozapine‐induced glucose metabolism impairment in patients with Schizophrenia

Objective: The primary purpose of this 8‐week double‐blind, placebo‐controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine‐treated subjects with schizophrenia with insulin resistance. Method: Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. Results: Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non‐significant improvement in SG (0.016 ± 0.006–0.018 ± 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 ± 2.8–7.8 ± 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low‐density lipoprotein cholesterol (LDL‐C) particle number (987 ± 443–694 ± 415, effect size = 0.30, P = 0.04). Conclusion: Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.     

氯氮平在中国精神分裂症人群的群体药物动力学研究

本研究旨在考察口服氯氮平 (clozapine) 在中国精神分裂症患者中的群体药物动力学特征, 探讨各项动力学参数与人口统计学因素及CYP1A2酶基因多态性的关系, 通过建立群体药物动力学模型指导临床个体化给药。研究中采集了临床服用氯氮平的183例精神分裂症患者的626份稳态血样本资料, 随机分组为建模组 (168例) 和外部验证组 (15例)。用非线性混合效应模型 (NONMEM) 程序中的一级评估法 (first-order estimation, FO) 对建模组的数据进行分析, 估算清除率 (CL/F)、表观分布容积 (V/F) 和吸收速率常数 (K_a) 的群体值, 并且定量评价人口统计学指标和CYP1A2酶基因型因素对药物动力学参数的影响。建模中单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了经体表面积归一化的单日剂量 (DBSA) 和吸烟 (SMOK) 因素对CL/F的影响。CL/F (非吸烟组)、V/F和K_a的群体典型值分别为28.5 L·h⁻¹ (5.05%)、1 290 L (16.7%) 和2.26 h⁻¹ (fixed), 相应的个体间变异分别为42.2%和10.0%。研究发现吸烟组的清除率有所上升。观测值与预测值之间的残留误差SD为45.8 μg·L⁻¹。     

Augmentation of aripiprazole with low-dose clozapine

An issue under much clinical debate is whether treatment with two antipsychotic agents simultaneously is advantageous for optimizing response in patients whose previous monotherapy with antipsychotic agents has failed. Minimal evidence supports treatment with multiple antipsychotics, even when the agents have different mechanisms of action. The standard of care for treating schizophrenia is to first use monotherapy of adequate dosage and duration, including a trial of clozapine before adding a second agent. We report the case of a 32-year-old man whose monotherapy with various antipsychotic agents failed. During attempted conversion from aripiprazole to clozapine, the patient experienced a significant reduction in psychiatric features. Despite this improvement, the patient became resistant to the clozapine titration schedule due to complaints of sedation. Aripiprazole combined with low-dose clozapine as maintenance therapy resulted in a positive clinical outcome despite a clozapine serum level that is generally considered subtherapeutic. This case emphasizes the importance of making interventions based on individual patient response.     

The safety and tolerability of clozapine in aged patients: A retrospective clinical file review

Abstract

Objectives. A clinical file review was conducted of clozapine use in three aged psychiatry services in Melbourne, Australia, to compare its safety and tolerability with findings reported in the literature. Methods. The review period spanned the intervals from 2008 to the services' origins between 11 and 15 years earlier. The files of all patients treated with clozapine during this period were checked with respect to adverse effects and the reasons for ceasing treatment. Results. Clozapine was prescribed to 75 patients (mean age 74.2 years, range 65–89) with doses ranging from 25–800 mg daily (mean 296 mg). Treatment was stopped within the review period in 37 (49%) cases. Reasons for discontinuation included death (n=14), non-fatal adverse events (n=12), patient choice (n=8) and other factors (n=3). While none of the 14 deaths could be linked directly to treatment, orthostatic hypotension might have contributed to a single fatal cerebrovascular accident. There were three cases of “red alert” leukopenia, none of which progressed to agranulocytosis. In general, side effects were more frequent than in a previous report concerning aged patients, most probably because clozapine doses were higher. Conclusions. Most of the adverse events leading to treatment cessation occurred within the first month, emphasising the need for slow titration. Strict monitoring procedures ensured that there were no fatal haematological adverse events.     

奎的平与氯氮平治疗首发精神分裂症对照研究

目的 了解奎的平与氯氮平对精神分裂症的疗效及不良反应的差别。方法 选择符合DSM-Ⅳ和CCMD-2-R关于精神分裂症诊断标准的患者,且阳性和阴性症状量表(PANSS)评分>60分。共108例患者完成了8w的研究,其中奎的平组55例,氯氮平组53例。在治疗前及治疗后1、2、4、6w分别评定PANSS,CGI及ESPS量表。结果 奎的平对精神病性症状的总有效率与氯氮平组相比无明显差异。但奎的平对抑郁症状、攻击行为和敌意、认知功能障碍的疗效明显好于氯氮平,两组有显著性差异。在8w的治疗过程中,奎的平组的总体副反应,特别是行为障碍和肌张力障碍明显少于氯氮平组,两组有显著性差异。结论 奎的平是一种较理想的抗精神病药,对首发精神分裂症有较好的疗效和耐受性,并且起效较快,安全性高,值得临床推广使用。     

比较硫必利与氯氮平治疗精神分裂症153例

目的：比较硫必利和氯氮平治疗精神分裂症的疗效。方法：把精神分裂症病人随机分为硫必利组和氯氮平组。５９例男性和１９例女性用硫必利，ｐｏ，１０１５±３９１ｍｇ／ｄ；４９例男性和２６例女性用氯氮平，ｐｏ，４００±１１９ｍｇ／ｄ，２药均服用６ｗｋ。以ＢＰＲＳ和ＳＡＮＳ量表评定症状，ＴＥＳＳ量表评定２个药的不良反应。结果：用药６ｗｋ后，在控制兴奋躁动、减少敌对性方面硫必利不及氯氮平，但２药治疗阴性症状的效果相似。硫必利的不良反应较少。结论：硫必利与氯氮平一样对精神分裂症的阴性症状有效。     

Diet and gender moderate clozapine-related weight gain

This study examined patients with schizophrenic disorders treated with clozapine in a state hospital setting. Gender and diet affected weight gain over a six-month period. Pre-treatment weight status also related to eventual weight gain. There were no significant effects of dosage. Weight gain was most pronounced in non-dieting women. This has implications for management of patients on clozapine.     

Individualizing drug dosage by using a random intercept linear model

An algorithm for drug dosage individualization is proposed. The algorithm assumes a random intercept linear model for the log of trough-plasma-concentration-to-dosage ratio of the drug at steady-state, and aims at determining an optimum dosage for producing a trough steady-state plasma concentration within a target concentration range. The minimum number of algorithm steps necessary to find the optimum dosage is computed. Computations are illustrated for clozapine, an antipsychotic drug used to treat patients with severe schizophrenia.