A Case of Clozapine Induced Acute Renal Failure

There have been a few case reports that clozapine, an atypical antipsychotic, caused acute renal failure of interstitial type. Here we report a case of a 38-year-old Korean male patient with treatment-resistant bipolar I disorder who developed acute renal failure after the initiation of treatment with clozapine. We describe the clinical and laboratory findings of the case and discuss the measures for early detection of this life threating condition. Within our knowledge, this is the first report of clozapine-induced acute renal failure in South Korea.     

The clinical use of plasma clozapine levels in a maximum security setting

Background. Research suggests a correlation between clozapine dose, plasma level and therapeutic response. Plasma clozapine levels may, therefore, be useful in practice. Little evidence exists, however, on the indications for, and outcome of, levels being undertaken or their use in maximum security settings. Objective. To determine if plasma clozapine levels are useful in clinical practice by analysing their use at the maximum-security State Hospital, Carstairs. Methods. All plasma clozapine levels (until March 2004) undertaken at the State Hospital, clinical indication and outcome were analysed by retrospective case note analysis. These results were compared with the published literature. Results. A total of 140 plasma clozapine levels were analysed. The average level was 0.61 mg/l and dose was 622.9 mg/day. The indications for and consequences of levels are demonstrated. A positive correlation of 0.217 was calculated. Conclusion. This paper shows that plasma clozapine levels are most useful in managing side effects and suspected non-compliance. Plasma clozapine levels are, therefore, useful in clinical practice.     

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 )     

Progressive ratio performance following challenge with antipsychotics, amphetamine, or NMDA antagonists in adult rats treated perinatally with phencyclidine

Rationale Previous research has shown that rats exposed perinatally to phencyclidine (PCP) exhibited neuroanatomical abnormalities and altered cognition. In addition to cognitive deficits, schizophrenic patients may also exhibit negative symptoms such as lack of motivation.Objectives In this study, we used a progressive ratio (PR) schedule of food reinforcement to assess motivation following early exposure to PCP.Methods Male rat pups were injected SC with 10 mg/kg PCP on postnatal days (PN) 7, 9, and 11. On PN 120, they began training in a PR 5 schedule of food reinforcement.Results Significant PCP effects on acquisition and baseline performance were not noted. After acquisition of the task, challenges with PCP, dizocilpine, amphetamine, haloperidol, and clozapine resulted in dose-dependent decreases in response rates of similar magnitudes in both groups. In rats that continued to respond at higher doses, PCP, dizocilpine, and clozapine failed to alter breakpoints. In contrast, a 5.6 mg/kg dose of amphetamine selectively increased breakpoints in PCP-treated rats, although very few rats responded at this dose. Haloperidol decreased breakpoints in most rats at non-sedating doses.Conclusions These results suggest that a regimen of perinatal PCP administration sufficient to disrupt cognition did not alter motivation for food reinforcement, regardless of whether rats also received challenges with NMDA antagonists or antipsychotics. Interpretation of amphetamines high dose effects on breakpoints was complicated by the failure of many rats to respond at this dose. Further research is needed to determine whether negative symptoms such as social withdrawal may be modeled within this neurodevelopmental approach to schizophrenia.     

Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine

Treatment of schizophrenics with some antipsychotic drugs has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. Some of these drugs also inhibit glucose transport in rat pheochromocytoma (PC12) cells. The current study was designed to examine the effects of the atypical antipsychotic drugs--risperidone, clozapine and analogs of clozapine on glucose uptake in PC12 cells. Glucose transport was measured in cells incubated with vehicle or drug over a range of concentrations (0.2-100 microM). Uptake of 3H-2-deoxyglucose was measured over 5 min and the data were normalized on the basis of total cell protein. Risperidone and clozapine inhibited glucose transport in a dose-dependent fashion with IC(50)'s estimated to be 35 and 20 microM, respectively. The clozapine metabolite, desmethylclozapine, was considerably more potent than the parent drug, whereas clozapine N-oxide was essentially inactive. The structural analogs of clozapine, loxapine and amoxapine, both inhibited glucose transport with amoxapine being the least potent. The ability of the drugs to inhibit glucose transport was significantly decreased by including 2-deoxyglucose (5 mM) in the uptake medium. Schild analysis of the glucose sensitivity of clozapine, loxapine and risperidone indicated that 2-deoxyglucose non-competitively antagonized the inhibitory effects of these drugs. Moreover, clozapine and fluphenazine inhibited glucose transport in the rat muscle cell line, L6. These studies suggest that the drugs may block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in cells derived from both peripheral and brain tissue. Furthermore, this work may provide clues about how the antipsychotic drugs produce hyperglycemia in vivo.     

氯氮平致粒细胞缺乏症危险因素的对照研究

目的 探讨氯氮平治疗引起的粒细胞缺乏症的危险因素,方法 采用１：２病例对照方法和计算Ｘ＾２ＯＲ值,分析了１３例氯氮平致粒细胞缺乏症患者及其对照组中暴露因子的差异,结果 两组在病毒性肝炎病史（Ｐ〈０．０２５）早期感冒或类感冒现象（Ｐ〈０．０１）,影响造血系统药物应用史（Ｐ〈０．００５）,三因素之间有明显差异,而合并用药,免疫病史,ＥＥＧ异常,化学毒物或放射线接触史之间则无明显差异,结论 病毒性肝炎史     

Clozapine-induced elevated C-reactive protein and fever mimic infection

Clozapine-induced fever has been reported frequently, but clozapine-induced elevated serum C-reactive protein (S-CRP) over 100 mg/L with early onset, without associated myocarditis, has not been reported in the literature. In this case report, we present a case of an 80-year-old Slovenian female with dementia and psychotic symptoms who developed elevated S-CRP (122 mg/L) and fever (38.2°C) on the seventh day with 25 mg of clozapine daily, which improved after clozapine discontinuation. The patient did not have symptoms and signs of infection. This case report can be used to remind clinicians of keeping in mind the potential of clozapine associated with very high elevated S-CRP with fever, which can be easily confused with more serious conditions.     

利培酮并小剂量氯氮平治疗精神分裂症对照研究

目的探讨早晨服一次利培酮联合每晚服一次氯氮平对精神分裂症的临床疗效.方法按入院顺序分层随机法将病人分为研究组(早晨服利培酮并晚上服氯氮平组)和两个对照组(利培酮组和氯氮平组);进行10周对照观察;用四级临床疗效评定法结合简明精神病量表(RPRS)评分评定疗效.结果研究组的起效时间为7.67±2.33天.明显优于氯氮平组的11.56±4.11天(P＜0.05),略优于利培酮组的10.48±3.50天,但无统计学意义(P＞0.05);三组的痊愈率、显进率及显效率均相当;研究组对焦虑抑郁、活力缺乏症状群起效快于氯氮平组,对兴奋、敌对猜疑症状群起效快于利培酮组(P＜0.05);不良反应的发生率较氯氮平组明显减少.结论早晨服一次利培酮联合晚上服小剂量氯氮平的用药方法治疗精神分裂症起效快,疗效好,不良反应少,能综合两者优点,克服两者的缺点;该用药方法值得在临床工作中推广应用.     

Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy

ObjectiveWe tested the hypothesis that fasting blood glucose and insulin levels are higher in schizophrenic subjects on clozapine monotherapy compared with healthy controls and they correlate with anthropometric measurements, laboratory tests and body composition.MethodsData for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed.ResultsPatients taking clozapine had higher fasting levels of glucose (103.5 ± 31.6 vs. 87.8 ± 11.7 mg/dL, z = −2.03, p = 0.04), there was no difference for insulin concentrations and markers of insulin resistance. In the clozapine group glucose levels correlated with clozapine dose (R = −0.43, p = 0.03), while insulin levels correlated with weight (R = 0.66, p < 0.001), body mass index (R = 0.54, p = 0.007), abdominal (R = 0.53, p = 0.007) and waist (R = 0.43, p = 0.04) circumference, total body fat (R = 0.51, p = 0.01), and uric acid levels (R = 0.50, p = 0.01). In the clozapine group insulin levels were lower in subjects with body mass index <25 kg/m² (7.0 ± 3.3 vs. 13.4 ± 8.8 μU/mL, p = 0.04) and in subjects without abdominal obesity (6.3 ± 2.4 vs. 13.3 ± 8.6 μU/mL, p = 0.03).ConclusionsWe found higher blood glucose levels in subjects taking clozapine and no differences in blood insulin levels between subjects with schizophrenia and controls. Associations between blood insulin levels and abdominal/waist circumferences support the role of abdominal obesity as an important risk factor of insulin resistance.     

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.