Karl Winckel

Increasing Clozapine Dispensing Trends in Queensland, Australia 2004-2013.

INTRODUCTION Clozapine is the most effective treatment for treatment-resistant schizophrenia but its use is suboptimal. METHODS Clozapine dispensing data from Queensland, Australia were extracted (2004-2013). The number of people dispensed clozapine each year and mean maintenance doses were calculated. The 18-week and 5-year cessation and treatment interruption rates were calculated using Kaplan-Meier analysis. RESULTS Clozapine dispensings increased 36.4% (p<0.001) from 44 to 60 people per 100,000. This was estimated as 8.3% of people with schizophrenia and 33.3% of people with treatment resistant schizophrenia dispensed clozapine in 2013. Mean maintenance dose did not significantly change (364-399 mg) over 5 years of treatment. One in 7 (14.2%) people ceased within the first 3 weeks. 3-quarters (72.7%) reached maintenance therapy. The 5-year actuarial estimate of the proportion of people a) dispensed clozapine was 0.610 (S.E. 0.011) and b) with an interruption to treatment was 0.422 (S.E. 0.013). DISCUSSION The number of patients being dispensed clozapine increased between 2004 and 2013 but clozapine is still underused. Increased use combined with continued monitoring for adverse effects will improve quality use of clozapine.

Comparison of prescribing criteria in hospitalised Australian elderly

The Beers criteria (2003) and McLeod criteria (1997) have been applied internationally to quantify inappropriate prescribing in elderly populations. Similarly, guidelines have been published locally by the National Prescribing Service (NPS). Objective This study aimed to adapt, evaluate and compare the utility of these three established criteria in measuring prescribing appropriateness in a sample of hospitalised elderly patients. Methods Initial refinement of the criteria produced versions applicable to Australian practice. Inpatient records of 202 patients aged 65 years or older in six wards of the Princess Alexandra Hospital, Brisbane, Australia, were reviewed using the adapted criteria. ‘Potentially inappropriate’ prescribing was descriptively analysed using relevant denominators. Results The adapted criteria collectively listed 70 ‘potentially inappropriate’ medicines or drug groups and 116 ‘potentially inappropriate’ prescribing practices. Patients (mean age 80.0; SD=8.3 years) were prescribed, a median of eight medicines (SD=4.0). At least one ‘potentially inappropriate’ medicine was identified in 110 (55%) patients. ‘Potentially inappropriate’ prescribing practices averaged 1.1 per patient (range 1-6). The adapted Beers criteria identified more ‘potentially inappropriate’ medicines/practices (44%, 101/232) than the McLeod criteria (41%) and NPS criteria (16%). Aspirin, benzodiazepines, beta-blockers and dipyridamole were most commonly identified. Conclusion The Beers and McLeod criteria, developed internationally, required considerable modification for local prescribing. The three criteria differed in their focus and approaches, such that development and validation of national criteria, using the key features of these models, is recommended. There is potential to apply validated guidelines in clinical practice and review of prescribing, but only to supplement clinical judgement.

The impact of clozapine on hospital use: a systematic review and meta-analysis

The objective of this study was to perform a systematic review and meta‐analysis of studies reporting the impact of clozapine on hospital use in people with a psychotic illness.

Glucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes

Clozapine is the most effective antipsychotic, but its use is tempered by adverse metabolic effects such as weight gain, glucose intolerance and type II diabetes. Current interventions do not facilitate compelling or sustained improvement in metabolic status. Recent studies suggest that glucagon-like peptide-1 (GLP-1) may play a key role in clozapine’s metabolic effects, possibly suggesting that clozapine-associated obesity and diabetes are mediated independently through reduced GLP-1. As a result, GLP-1 agonists could show promise in reversing antipsychotic-induced metabolic derangements, providing mechanistic justification that they may represent a novel approach to treat, and ultimately prevent, both diabetes and obesity in patients on clozapine. GLP-1 agonists are already used for diabetes, and they provide a unique combination of glycaemic improvement and metabolically relevant weight loss in diabetic and non-diabetic patients, in the context of a currently favourable safety profile. Using GLP-1 agonists for clozapine-associated obesity and diabetes could be a potentially effective intervention that may reduce cardiometabolic morbidity and mortality in this vulnerable patient population.

Treatment of clozapine-associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: study protocol for a pilot randomised controlled trial

Background Clozapine causes significant metabolic disturbances including obesity and type 2 diabetes. Recent evidence that reduced glucagon-like-peptide-1 (GLP-1) may contribute to aetiology of clozapine-associated metabolic dysregulation suggests a potential therapeutic role for GLP-1 agonists. Method This open-label, pilot randomised controlled trial evaluates the effect of exenatide in clozapine-treated obese adults who have schizophrenia, with or without poorly controlled diabetes. Sixty out-patients will be randomised to once weekly extended release exenatide or treatment as usual for 24 weeks. Aims To evaluate the feasibility of larger studies regarding methodology, acceptability, tolerability and estimate efficacy for glycaemic control or weight loss. Secondary outcomes are psychosis severity and metabolic parameters. Conclusions This is the first trial investigating GLP-1 agonists for glycaemic control and weight loss in clozapine-treated patients with either diabetes or obesity. Clozapine-associated obesity and diabetes with exenatide (CODEX) will provide proof-of-concept empirical evidence addressing whether this novel treatment is practical and worthy of further investigation. Declaration of interest A.W.R. has received speaker honoraria and travel grants from AstraZeneca, BoehringerIngelheim, Eli Lilly, MSD, Novo Nordisk and Sanofi and has participated on advisory panels for MSD and Novo Nordisk. Copyright and usage

Clozapine-induced myocarditis: separating the wheat from the chaff

There has been increased awareness of clozapine-induced myocarditis since the publication of the review of fifteen clozapine-induced myocarditis cases reported to the Australian Adverse Drug Reaction Committee (Kilian et al., 1999). Rates of clozapineinduced myocarditis appear to be higher in Australia than in other countries (Lambert, 2010: 24). Whilst recognition of this problematic adverse effect is encouraged, concern has been raised about possible over diagnosis (Ronaldson et al., 2010). Misdiagnosis may be due to two factors: insufficient data to support a diagnosis of myocarditis; or where there is sufficient data to support the diagnosis but there is an alternative primary cause such as a viral respiratory tract infection. We recently reviewed 20 cases with a recorded diagnosis of clozapine-induced myocarditis at a large tertiary referral hospital in Brisbane (reported between 2005 and 2013). We reviewed clinical information in the patient’s chart against the comprehensive set of diagnostic criteria for clozapine-induced myocarditis developed by Ronaldson et al. (2010). We found that 13/20 (65%) cases did not meet the Ronaldson criteria for a diagnosis of clozapine-induced myocarditis. Whilst an elevated troponin was present in 17/20 (85%) cases, other parameters were either not assessed or not indicative of myocarditis. Electrocardiogram abnormalities were only present in 12/20 (60%) cases, fever in 12/20 (60%) and a heart rate >100bpm in 11/20 (55%) cases. Additionally, 5/20 (25%) cases had documented upper respiratory tract infections, which was an alternate possible cause of the myocarditis. No cardiac MRI or cardiac biopsies were performed in any of these cases. These findings suggest that the veracity of the diagnoses of clozapineinduced myocarditis may be suboptimal. Appropriate clinical investigations to clarify and confirm the diagnosis were not done, or not recorded in clinical notes. There are substantial short and long term ramifications of clozapine cessation in people with treatment resistant schizophrenia including acute relapse of psychotic symptoms, deterioration in function and loss of access to the gold standard treatment. Close communication between psychiatrists and cardiologists is essential to reduce the risk of inappropriate myocarditis diagnosis. People with treatment resistant schizophrenia who have ceased clozapine following a presumptive diagnosis of clozapine-induced myocarditis may benefit from revisiting this diagnosis. If the diagnosis of clozapine-induced myocarditis is in question, they may be eligible for a closely monitored clozapine rechallenge.

Treatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX)

Clozapine causes obesity and type 2 diabetes (T2DM). Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (e.g. exenatide) can counter clozapine‐associated GLP‐1 dysregulation in animals, and may be beneficial in people on clozapine. This randomized, controlled, open‐label, pilot trial evaluated weekly exenatide for weight loss among clozapine‐treated obese adults with schizophrenia, with or without T2DM. A total of 28 outpatients were randomized to once‐weekly extended‐release subcutaneous exenatide or usual care for 24 weeks. The primary outcome was proportion of participants with >5% weight loss. All 28 participants completed the study; 3/14 in the exenatide group and 2/14 in the usual care group had T2DM. Six people on exenatide achieved >5% weight loss vs one receiving usual care (P = .029). Compared with usual care, participants on exenatide had greater mean weight loss (−5.29 vs −1.12 kg; P = .015) and body mass index reduction (−1.78 vs −0.39 kg/m2; P = .019), and reduced fasting glucose (−0.34 vs 0.39 mmol/L; P = .036) and glycated haemoglobin levels (−0.21% vs 0.03%; P = .004). There were no significant differences in other metabolic syndrome components. Exenatide may be a promising therapeutic agent for glycaemic control and weight loss in clozapine‐treated people with obesity, and could assist in reducing clozapine‐associated cardio‐metabolic morbidity and mortality.

Clozapine in the community: Improved access or risky free-for-all?

Australian & New Zealand Journal of Psychiatry, 49(10) Clozapine is the most effective treatment for people with treatmentresistant schizophrenia (Conley and Buchanan, 1997; Kane et al., 1988). Unfortunately, clozapine’s efficacy is tempered by potentially fatal adverse drug reactions (ADRs) which require regular blood monitoring. Concerns about these ADRs, in particular neutropenia and agranulocytosis, led to clozapine being restricted to prescribing by psychiatrists and dispensing by pharmacists in hospitals.

T160. TREATMENT OF CLOZAPINE-ASSOCIATED OBESITY AND DIABETES WITH EXENATIDE (CODEX) IN ADULTS WITH SCHIZOPHRENIA: A RANDOMISED CONTROLLED TRIAL

Abstract Background Clozapine is the most effective anti-psychotic for treatment refractory schizophrenia, but causes significant metabolic disturbances including obesity and type 2 diabetes. The metabolic adverse reactions may be mediated in part by clozapine induced dysregulation of Glucagon-like-peptide-1 (GLP-1). GLP-1 is an intestinal epithelial derived peptide, released with ingestion of food, that triggers satiety, reduces glucagon production, promotes insulin production and slows gut motility. Clozapine has been shown to interfere with GLP-1 function in animal models, leading to metabolic dyregulation including obesity and preference for high calorie meals. Administration of exogenous GLP-1 agonists such as exenatide to animals have been shown to counter this effect of clozapine. Exenatide subcutaneous weekly injections may assist obese people on clozapine lose weight. Methods This randomised, controlled, open-label, pilot trial aimed to evaluate the effect of exenatide on weight loss among clozapine-treated obese adults who have schizophrenia, with or without stable diabetes. Twenty-eight out-patients were randomised to once weekly extended release sub-cutaneous exenatide or treatment as usual for 24 weeks. This trial examined the safety, tolerability and acceptability of exenatide among obese people with schizophrenia on clozapine, with an evaluation of change in weight, glycaemic control, psychosis severity and metabolic parameters. Results All 28 participants completed the study. (Exenatide=14 (3 T2DM), control=14 (2 T2DM)). Six people on exenatide achieved >5% weight loss, compared to only 1 control (p=0.029). Mean weight loss was greater for exenatide than control at week 24 (-5.29kg vs -1.12kg, p=0.015) as were. BMI (-1.78 vs -0.39 p=0.019), fasting glucose (-0.34 vs 0.39, p=0.036) and HbA1c (-0.21 vs 0.03, p=0.004). There was no significant difference for other metabolic syndrome components. There were higher rates of transient nausea (n=8), vomiting (n=7) and diarrhoea (n=7) in the exenatide group. Discussion Exenatide is a promising therapeutic agent for glycaemic control and weight loss in clozapine-treated people with obesity. These results suggest good tolerability and a consistent and favourable pattern of weight loss effects with exenatide. GLP-1 agonists could assist in reducing the cardio-metabolic associated morbidity and mortality secondary to clozapine.

Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993–2014

RationaleClozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia.MethodsUsing data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993–2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia.ResultsThere were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five reported deaths from neutropenia and cardiomyopathy.ConclusionsThe rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.