Clozapine treatment and discontinuation in Iceland: A national longitudinal study using electronic patient records

Background: Clozapine is the only drug approved for treatment-resistant schizophrenia. There is evidence that clozapine is underutilized. Aims: To evaluate the initiation and discontinuation of clozapine at Landspitali University Hospital in Iceland and the prevalence of antipsychotic polypharmacy in clozapine-treated patients. Methods: The study is a part of an ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients on clozapine or who have been on clozapine by using a keyword search in the electronic health records and by reviewing their medical records. Results: Mean age at first treatment with clozapine was 37.8 years. Mean follow-up period on clozapine was 11 years. After 20 years of treatment 71.2% of patients were still on clozapine. After one year of treatment 84.4% of patients were still receiving clozapine treatment. We estimate that 11.4% of patients with schizophrenia in Iceland are taking clozapine and that 16% have been treated with clozapine at some point. Polypharmacy is common, since nearly 2/3, 65.6%, of patients taking clozapine use at least one other antipsychotic and 16.9% are also receiving depot injections. Conclusions: We need to increase the awareness of psychiatrists in Iceland with regard to treatment with clozapine, since only about half of the estimated population of patients with treatment-resistant schizophrenia in Iceland have ever been treated with clozapine. Nearly two thirds of patients who are prescribed clozapine in Iceland remain on it long-term.     

Smoking and therapeutic response to clozapine in patients with schizophrenia.

BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS: We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS: Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS: Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.     

No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population

The serotonin hypothesis in schizophrenia had regained interest with the superior efficacy of clozapine in the refractory schizophrenic patients. Among the serotonin receptors, the serotonin 2A (5HT2A) receptor subtype is the most widely studied. Previous studies on the association between a silent mutation polymorphism of the 5HT2A gene (102T/C) and schizophrenia or clozapine response have yielded conflicting findings. Therefore, we investigated whether these genetic variants of the 5HT2A receptor are associated with schizophrenia or with response to clozapine treatment in a Chinese population. Ninety-seven schizophrenic patients and 101 control subjects were included in the study. The receptor variants were found at similar frequencies in schizophrenic patients and healthy control subjects. Also, we did not find the variants to influence the response to clozapine in schizophrenic patients. We suggest that the assessment method of clozapine response and the ethnicity may influence the result.     

Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial

RATIONALE: Risperidone augmentation of clozapine in refractory schizophrenia has theoretical but only inconsistent support from clinical trials. OBJECTIVES: To examine if adding risperidone to stable yet symptomatic schizophrenia outpatients on optimized clozapine monotherapy improves psychopathology. METHODS: We conducted a double-blind placebo-controlled parallel-group trial of a fixed dose of 4 mg/day risperidone added for 6 weeks in 24 outpatients with schizophrenia. RESULTS: Subjects who received risperidone showed a non-significant decrease in PANSS total score. The PANSS disorganized thought subscale improved significantly (beta=-3.3079, p=0.047). CONCLUSIONS: Our trial does not support the routine addition of risperidone to clozapine in refractory schizophrenia patients. However, much larger trials are needed to conclusively settle the question of added efficacy from this combination.     

Marked hypofrontality in clozapine-responsive patients

Previous data show that the effects of clozapine on regional brain activity are different from those of other antipsychotic agents. It seemed of interest to study the brain activity patterns after treatment with clozapine, since this drug might correct basal deficits directly related to schizophrenia or instead induce changes that would in some way compensate distant abnormalities. In order to study the activity pattern resulting from clozapine treatment we have used FDG-PET and statistical parametric mapping (SPM) to explore the functional status of patients after chronic treatment with this drug, We compared their metabolic activity with normal controls and neuroleptic-naive (NN) patients, with the aim to identify if a reversion of pre-existing deficits or a induction of different changes was the result of clozapine administration. We compared metabolic patterns in 23 treatment-resistant (TR) patients after 6 months of treatment with clozapine, eighteen healthy subjects, and 17 NN schizophrenia patients. After treatment with clozapine, TR patients showed a clear hypofrontality and caudate hypometabolism in comparison with both the controls and NN patients, and also a lower thalamic activity than the healthy controls. In conclusion, our results support a preferential role for prefrontal regions and their subcortical connections in the mechanism of action of clozapine, resulting in a clearly hypofrontal state as compared to both controls and schizophrenia patients without previous treatment.     

Obsessive-compulsive symptoms and disorder in patients with schizophrenia treated with clozapine or haloperidol

We conducted a cross-sectional study to compare the prevalence and severity of obsessive-compulsive symptoms (OCSs) and obsessive-compulsive disorder (OCD) in patients with schizophrenia treated with clozapine or haloperidol. Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorders-patient edition was used to diagnose schizophrenia and OCD. Sixty subjects, 40 of them using clozapine and 20 using haloperidol, completed the Yale-Brown Obsessive-Compulsive Scale, the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression. The prevalence of OCD in patients taking clozapine was 20%, whereas the prevalence of patients taking haloperidol was 10%, although this difference was not statistically significant (P = .540). However, patients using clozapine showed higher severity of OCSs than patients using haloperidol (P = .027) did. When schizophrenia patients were divided according to the presence or absence of OCD or OCSs, patients with schizophrenia and OCD or OCSs showed higher severity of schizophrenia symptoms when compared to those with schizophrenia without OCD and OCSs (P = .002). A PANSS total score higher than 70 and the use of antidepressants were predictors of the presence of OCSs or OCD. Schizophrenia patients taking clozapine had higher severity scores both in obsessive-compulsive and schizophrenia rating scales. These results may support an association between the exacerbation of obsessive-compulsive phenomena and the use of clozapine.     

Difference between treatment-resistant schizophrenia and clozapine-resistant schizophrenia

We read the impressive review article “Clozapine resistant schizophrenia: Newer avenues of management” with great enthusiasm and appreciation. The author believes that preventing clozapine resistance from developing may be the most effective treatment strategy for patients with clozapine-resistant schizophrenia (CRS), and optimizing clozapine treatment is a key component. Disentangling the differences between treatment-resistant schizophrenia and CRS is important for studies addressing treatment strategies for these difficult-to-treat populations.     

Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders.

BACKGROUND: The increase or emergence of obsessions was compared in young patients with recent-onset schizophrenia or other psychotic disorders taking clozapine and other antipsychotic drugs. METHOD: We conducted a retrospective cohort study. Subjects were 121 consecutively admitted patients diagnosed with DSM-III-R schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychotic disorder not otherwise specified. Obsessions were diagnosed according to DSM-IV criteria. RESULTS: More clozapine-treated subjects (20.6%) than subjects treated with other antipsychotic drugs (1.3%) experienced an emergence or increase of obsessions (p<.01). CONCLUSION: Use of clozapine is associated with the emergence or increase of obsessions in early-phase schizophrenia.     

氯氮平和维思通对精神分裂症认知功能的影响

目的：比较氯氮平和维思通对精神分裂症对知功能的影响,以阴性症状为主。方法对５７例接受氯氮平或维思通治疗的精神分裂症病人,采用韦氏记忆量表,数字划销测验、威斯康星卡片分类测验评估其治疗前和治疗８周后记忆、注意及执行功能。结果氯氮平和维思通能显著改善记忆,注意及执行功能,氯氮平对以阳性症状为主分裂症的注意改善优于维思通,维思能对以阴性症状为主分裂症图片成绩优于氯氮平,结论两种药物均有助于改善精神分理解     

Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response

GDNF (glial-cell-line derived neurotrophic factor) is a potent neurotrophic factor for dopaminergic neurons. Neuropsychiatric diseases and their treatments are associated with alterations in the levels of both GDNF and its receptor family (GDNF family receptor alpha or GFRA). GFRA1, GFRA2 and GFRA3 are located in chromosomal regions with suggestive linkage to schizophrenia. In this study we analyzed polymorphisms located in all four known GFRA genes and examined association with schizophrenia and clozapine response. We examined SNPs across the genes GFRA1-4 in 219 matched case-control subjects, 85 small nuclear families and 140 schizophrenia patients taking clozapine for 6 months. We observed that GFRA3 rs11242417 and GFRA1 rs11197557 variants were significantly associated with schizophrenia after combining results from both schizophrenia samples. Furthermore, we found an overtransmission of the G-C GFRA1 rs7920934-rs730357 haplotype to subjects with schizophrenia and association of A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 with schizophrenia in the case-control sample. On the other hand, GFRA2 variants were not associated with schizophrenia diagnosis but subjects carrying T-G-G rs1128397-rs13250096-rs4567028 haplotype were more likely to respond to clozapine treatment. The statistical significance of results survived permutation testing but not Bonferroni correction. We also found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia.     

Effects of venlafaxine treatment on clozapine plasma levels in schizophrenic patients

Depressive symptoms are found at any stage of schizophrenia, and antidepressant medication may be beneficial. Selective serotonin reuptake inhibitor antidepressants have been considered safe in schizophrenia but in combination with clozapine, that is widely used in chronic treatment-resistant schizophrenia, remarkable pharmacokinetic interactions can occur causing an elevation in clozapine plasma levels. To investigate this further, the plasma levels of clozapine were measured in 11 schizophrenic male patients with depressive symptoms who were administered both clozapine and venlafaxine. Low to moderate doses of venlafaxine did not seem to have any significant effect on clozapine plasma levels.     

The Effect of Clozapine on Premature Mortality: An Assessment of Clinical Monitoring and Other Potential Confounders

Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007–2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes.Key words: clozapine, mortality, clinician contact, schizophrenia, schizoaffective disorder, bipolar affective disorder     

首发首诊住院分裂症患者精神药物使用情况调查

目的 了解首发首诊住院分裂症患者精神药物的使用情况。方法 自2000年全部首次住院病例中，选择符合CCMD-2-R精神分裂样精神病标准者673例。结果 首选单一用药者587例(92．15％)，常用药物依次为氟哌啶醇占64．52％，氯氮平占14．76％，氯丙嗪占7．69％，舒必利占2．83％，其他药物的使用率均不足1％，首选联合用药者50例(7．85％)，最常见的是氯氮平联合舒必利占4．71％，合用安坦者510例(80．06％)。结论 对初治分裂症的首选用药，仍以经典抗精神病药为主，不应联合用药，必要时可舍用增效剂，氯氮平不宜做为首选用药。     

氯氮平合并碳酸锂治疗男性难治性精神分裂症的对照研究

目的比较氯氮平和氯氮平合并碳酸锂治疗男性难治性精神分裂症的疗效和不良反应．方法将72例男性难治性精神分裂症患者随机分为两组，分别应用氯氮平和氯氮平合并碳酸锂治疗8周．采用阳性和阴性症状量表（PANSS）和不良反应量表（TESS）评定疗效和不良反应。结果治疗结束时，两组PANSS因子分值较治疗前均有明显降低，且有统计学意义。氯氮平合并碳酸锂组阳性症状因子减分早于氯氮平组，且两组间有显著性差异（P〈0．05）。氯氮平合并碳酸锂组总有效率为75％，明显高于氯氮平组的47．1％（P〈0．05）。结论氯氮平合并碳酸锂治疗男性难治性精神分裂症疗效优于氯氮平。     

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。     

The effect of clozapine on the speed and accuracy of information processing in schizophrenia

1. 1. The study aimed to investigate the effects of clozapine on the speed and accuracy of information processing in patients with schizophrenia. Data are reported from 13 subjects with schizophrenia, treated with clozapine for 6.8 (± 1.8) months.

2. 2. Reaction time and accuracy of target detection on a tone detection task were measured before and during clozapine treatment, and these results were compared with a matched control group.

3. 3. Symptom severity and performance on three timed tests of cognitive function were also measured prior to clozapine treatment in the schizophrenia group, and these measures were repeated during treatment with clozapine.

4. 4. Treatment with clozapine was found to significantly improve reaction time and the accuracy of target detection in patients with schizophrenia. Despite this improvement their performance remained significantly inferior to that of a matched control group. Both positive and negative symptoms improved with clozapine treatment, as did performance on the WAIS-R digit symbol substitution test.

5. 5. Improved performance on the WAIS-R digit symbol substitution test correlated with reduction in negative symptoms, and faster reaction time showed some correlation with reduction in positive symptoms.

6. 6. The results of this pilot study indicate that treatment with clozapine can produce limited improvement in cognitive function in schizophrenia.

     

New vs. old antipsychotics: the Texas experience

A study was conducted in Texas state psychiatric facilities of 299 patients with schizophrenia who were taking clozapine, comparing them with 223 matched controls taking traditional neuroleptics. From 12 months before until 54 months after clozapine was begun, hospital bed days and the associated costs were determined for both groups. The clozapine group had appreciably fewer hospital bed days throughout the study period. Substantially fewer clozapine-treated patients than neuroleptic-treated patients required 180 continuous days of hospitalization during the study. By 48 months after initiation of clozapine, hospital inpatient costs were $27,850/patient/year lower in the clozapine group than in the traditional neuroleptic group. Agranulocytosis occurred in < 1% of patients taking clozapine; all recovered quickly. In a separate study, clozapine therapy was shown to produce a 5-fold decrease in the rate of suicide among patients with schizophrenia. Administration of clozapine appears to lower the overall cost of treating schizophrenia by reducing the costs associated with hospitalizations.     

The putative functional rs1045881 marker of neurexin-1 in schizophrenia and clozapine response

Neurexin-1 (NRXN1) modulates recruitment of NMDA receptors. Furthermore, clozapine reduces hyperactivity of NMDA receptors. Thus, regulation of the NRXN1 gene may mediate the efficacy of clozapine at reducing cortical hyperactivity. We examined the putative functional SNP, rs1045881, for association with schizophrenia, and the potential role of this SNP in clozapine response. The rs1045881 variant was not significantly associated with schizophrenia (N=302 case-control pairs), but with clozapine response (N=163; p=0.030). Baseline and BPRS scores after six months revealed a trend for rs1045881 genotype by treatment interaction (p=0.079). In the post hoc analysis, a significant association between BPRS negative symptoms score and genotype was observed (p=0.033). These results suggest that the rs1045881 NRXN1 polymorphism may influence clozapine response.     

氯氮平合并改良电抽搐治疗难治性精神分裂症的对照研究

目的评价氯氮平合并改良电抽搐治疗（MECT）难治性精神分裂症的临床疗效及安全性。方法将94例难治性精神分裂症患者按照就诊顺序分为两组,联合治疗组47例,在应用氯氮平的基础上合并MECT治疗,疗程8周;单药治疗组47例,仅给予氯氮平治疗。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。结果联合治疗组的显效率为51.1%,单药治疗组的显效率为27.7%。联合治疗组不良反应较少。结论氯氮平合并改良电抽搐治疗难治性精神分裂症有效、安全。