A mixed methods analysis of clozapine errors reported to the National Reporting and Learning System.

PURPOSE: To review and analyse medication errors related to clozapine, an atypical antipsychotic, that were reported to the National Reporting and Learning System (NRLS). METHODS: Following extraction of one year of clozapine related errors from the NRLS, a qualitative analysis (thematic analysis and re-classification) and quantitative analysis was performed. An incident was considered a clozapine error if there was a failure in its medication process (i.e. an error in the prescribing, dispensing, preparing, administering, monitoring or advising of clozapine). RESULTS: "Issues with stock/supply/ordering" was the most common theme derived from the qualitative thematic analysis (n = 338), followed by wrong dose/strength/frequency (n = 221) and medication omissions (n = 202). Most errors occurred in the "administration/supply" medication stage. Over half of reported clozapine incidents involved people 26 to 55 years old (n = 830) and 82% of errors were reported by mental health services (n = 1270). Only 1.5% of reports were classed as moderate/severe harm. CONCLUSION: Issues with availability, stock, and supply were found to be the most common causes. This usually entailed a lack of stock to fulfil a patient's dose/supply. Such incidents could potentially be reduced by improved management of the supply process, and liaison between pharmacy and clinical staff. The implementation of emergency drug cupboards at the discretion of an on-call pharmacist may prove to be a preventative measure for such errors. Despite the potential adverse effects associated with clozapine, very few incidents led to moderate/severe harm. Encouragement of NRLS reporting is recommended for incidents of all degrees of harm.

Clozapine dose for schizophrenia.

BACKGROUND: Schizophrenia and related disorders such as schizophreniform and schizoaffective disorder are serious mental illnesses characterised by profound disruptions in thinking and speech, emotional processes, behaviour and sense of self. Clozapine is useful in the treatment of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms (such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what dose of clozapine is most effective with the least side effects. OBJECTIVES: To compare the efficacy and tolerability of clozapine at different doses and to identify the optimal dose of clozapine in the treatment of schizophrenia, schizophreniform and schizoaffective disorders. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (August 2011 and 8 December 2016). SELECTION CRITERIA: All relevant randomised controlled trials (RCTs), irrespective of blinding status or language, that compared the effects of clozapine at different doses in people with schizophrenia and related disorders, diagnosed by any criteria. DATA COLLECTION AND ANALYSIS: We independently inspected citations from the searches, identified relevant abstracts, obtained full articles of relevant abstracts, and classified trials as included or excluded. We included trials that met our inclusion criteria and reported useable data. For dichotomous data, we calculated the relative risk (RR) and the 95% confidence interval (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) again based on a random-effects model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We identified five studies that could be included. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). Four of the five included studies were based on a small number of participants. We rated all the evidence reported for the main outcomes of interest as low or very low quality. No data were available for the main outcomes of global state, service use or quality of life. Very low dose compared to low doseWe found no evidence of effect on mental state between low and very low doses of clozapine in terms of average Brief Psychiatric Rating Scale-Anchored (BPRS-A) endpoint score (1 RCT, n = 31, MD 3.55, 95% CI -4.50 to 11.60, very low quality evidence). One study found no difference between groups in body mass index (BMI) in the short term (1 RCT, n = 59, MD -0.10, 95% CI -0.95 to 0.75, low-quality evidence). Very low dose compared to standard doseWe found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS-A endpoint score (1 RCT, n = 31, MD 6.67, 95% CI -2.09 to 15.43, very low quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI -0.76 to 0.96, low-quality evidence) Low dose compared to standard doseWe found no evidence of effect on mental state between low doses and standard doses of clozapine in terms of both clinician-assessed clinical improvement (2 RCTs, n = 141, RR 0.76, 95% CI 0.36 to 1.61, medium-quality evidence) and clinically important response as more than 30% change in BPRS score (1 RCT, n = 176, RR 0.93, 95% CI 0.78 to 1.10, medium-quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 57, MD 0.20, 95% CI -0.84 to 1.24, low-quality evidence).We found some evidence of effect for other adverse effect outcomes; however, the data were again limited. Very low dose compared to low doseThere was limited evidence that serum triglycerides were lower at low-dose clozapine compared to very low dose in the short term (1 RCT, n = 59, MD 1.00, 95% CI 0.51 to 1.49). Low dose compared to standard doseWeight gain was lower at very low dose compared to standard dose (1 RCT, n = 27, MD -2.70, 95% CI -5.38 to -0.02). Glucose level one hour after meal was also lower at very lose dose (1 RCT, n = 58, MD -1.60, 95% CI -2.90 to -0.30). Total cholesterol levels were higher at very low compared to standard dose (1 RCT, n = 58, n = 58, MD 1.00, 95% CI 0.20 to 1.80). Low dose compared to standard doseThere was evidence of fewer adverse effects, measured as lower TESS scores, in the low-dose group in the short term (2 RCTs, n = 266, MD -3.99, 95% CI -5.75 to -2.24); and in one study there was evidence that the incidence of lethargy (RR 0.77, 95% CI 0.60 to 0.97), hypersalivation (RR 0.70, 95% CI 0.57 to 0.84), dizziness (RR 0.56, 95% CI 0.39 to 0.81) and tachycardia (RR 0.57, 95% CI 0.45 to 0.71) was less at low dose compared to standard dose. AUTHORS' CONCLUSIONS: We found no evidence of effect on mental state between standard, low and very low dose regimes, but we did not identify any trials on high or very high doses of clozapine. BMI measurements were similar between groups in the short term, although weight gain was less at very low dose compared to standard dose in one study. There was limited evidence that the incidence of some adverse effects was greater at standard dose compared to lower dose regimes. We found very little useful data and the evidence available is generally of low or very low quality. More studies are needed to validate our findings and report on outcomes such as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life. There is a particular lack of medium- or long-term outcome data, and on dose regimes above the standard rate.

Treatment pathway and patterns of clozapine prescribing for schizophrenia in New Zealand.

OBJECTIVE: To describe the treatment pathway and patterns of clozapine use in patients with schizophrenia, including coprescribed psychotropic medications, and compare the extent of coprescribing of clozapine with that of non-clozapine schizophrenia treatment in community mental health services in the Auckland and Northland regions of New Zealand. METHODS: A retrospective chart review was conducted for adult outpatients receiving care from community mental health services on October 31, 2004. Data collected for all patients prescribed an antipsychotic included demographics (sex, age, ethnicity); principal diagnosis (Diagnostic and Statistical Manual of Mental Disorders, 4th edition); comorbid conditions; duration of mental illness; psychiatric admissions; and treatment information (psychotropic medications, with dose and route of administration). If clozapine had been started after the introduction of full government prescription subsidy (February 1999), additional data, including year of initiation and prior antipsychotic history, were collected. Analysis included all outpatients with a diagnosis of schizophrenia (including schizoaffective disorder). RESULTS: Antipsychotics were prescribed for 2796 schizophrenia patients; 32.8% were prescribed clozapine, with a mean dose of 372 mg/day and an average duration of illness of 9.7 years before starting clozapine. Patients who had started treatment after clozapine was funded by the government (59.3%) had received a median of 3 antipsychotic drugs prior to starting clozapine; most of the treatment regimens included 1 second-generation antipsychotic (91.2%). Clozapine patients were less likely to be coprescribed another antipsychotic compared with non-clozapine patients (11.7% vs 17.6%; p < 0.001). Both the clozapine and non-clozapine groups had a low total number of psychotropic medications prescribed (median 2); for clozapine patients, the second drug was most likely to be for treatment of hypersalivation. CONCLUSIONS: Outpatients with treatment-resistant schizophrenia were prescribed clozapine at expected rates; however, treatment was delayed longer than recommended. There is some evidence that access to clozapine for treatment-resistant schizophrenia has improved, possibly as the result of the introduction of government subsidy, guideline dissemination, or increasing experience of clinicians with use of clozapine. In this real-world environment, the number of concomitant psychotropic medications for outpatients with schizophrenia was found to be low; when used concomitantly with clozapine, they were most commonly used to manage adverse effects.

Clozapine use by state programs: public mental health systems respond to a new medication.

The authors present data from a national survey of state departments of mental health showing that two years after reaching the U.S. market, clozapine is available to only a small fraction of the patients whom it might benefit. The primary continuing hurdle for the public sector, where most schizophrenic patients get their care, is funding. Several arguments support the use of clozapine in state mental health systems: it is the most effective or only effective medication for many patients, it can decrease the enormous costs of schizophrenia and related disorders, and access to the medication has become an important issue for advocacy groups and other mental health activists. Two years of experience with clozapine in the Texas mental health system have shown that availability of clozapine in the community is a vital factor for successful use of the drug in hospitals. The authors discuss ways to encourage outpatient clozapine programs that are critical to successful treatment in both the hospital and the community.