Siobhan Gee

Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation.

BACKGROUND Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians. AIMS To determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment. METHOD Clinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010. RESULTS Complete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, P<0.001) but did not differ by gender or ethnicity. CONCLUSIONS Substantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.

Augmentation of clozapine with a second antipsychotic - a meta-analysis

Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic – a meta‐analysis.

Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis

OBJECTIVE Certain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear. METHOD Outcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 × 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined. RESULTS Nineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients. CONCLUSIONS In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.

Factors predicting use of laxatives in outpatients stabilized on clozapine.

Constipation is a common and sometimes fatal side effect of clozapine treatment. In this study, we aimed to identify factors associated with clozapine-induced constipation. Data on 202 outpatients stabilized on clozapine treatment were collected. Of these, 71 patients (35%) had a current prescription for laxatives (a proxy for the presence of constipation). Mean clozapine dose was 400.4 mg/day in those prescribed laxatives and 390.1 mg/day in those not prescribed laxatives (p = 0.67), while mean clozapine plasma concentration was 0.53 mg/l and 0.49 mg/l, respectively (p = 0.29). Patients using laxatives had on average 29% higher norclozapine concentrations (mean = 0.34 mg/l) than those who did not use laxatives (mean = 0.27 mg/l; p = 0.046). Laxative use was more common in female patients (49.1%) than male patients (29.1%; p < 0.01). Prescribers should be vigilant for constipation at any dose or plasma concentration of clozapine and should be mindful that male patients may be undertreated. Norclozapine concentrations may predict clozapine-induced constipation.

Granulocyte colony stimulating factor (G-CSF) can allow treatment with clozapine in a patient with severe benign ethnic neutropaenia (BEN): a case report.

Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

Effects of a smoking ban on clozapine plasma concentrations in a nonsecure psychiatric unit

Background: Tobacco smoke is known to affect plasma levels of some drugs, including the antipsychotic clozapine. The effects of suddenly stopping smoking on patients who take clozapine can be severe, as plasma concentrations are expected to rapidly rise, potentially leading to toxicity. A ban on smoking at South London and the Maudsley NHS Foundation Trust (SLaM) was implemented in 2014, and this was expected to affect the plasma concentrations of clozapine for inpatients at the time. This study aimed to determine whether plasma concentrations of clozapine were affected, and additionally, in line with observations from other authors, whether levels of reported violence would also be affected. Methods: The smoking habits of all patients at SLaM who smoked and were prescribed clozapine were recorded both before and after the ban. The Glasgow Antipsychotic Side Effect Scale for Clozapine (GASS-C) scale was used to evaluate side-effect burden. Clozapine doses and plasma concentrations were also collected. Results: In total, 31 patients were included in this study. The mean clozapine dose before the ban was 502 mg/day, and this did not change significantly after the ban. Similarly, there were no significant changes in clozapine or norclozapine plasma concentrations, or in GASS-C scores. There was no change in the amount of tobacco patients reported smoking before or after the ban. A modest but statistically significant reduction in violent incidences was observed. Conclusions: Our data suggest that a ban on smoking for patients taking clozapine on open wards at inpatient hospital sites had little impact on clozapine plasma concentrations, because patients continued to smoke tobacco if allowed to leave. Smoking bans may result in a reduction in violent incidences.

Factors associated with changes in hospitalisation in patients prescribed clozapine

Objective: The objective of this study was to examine whether delays in clozapine treatment affect outcomes once clozapine is started and identify factors that affect these outcomes. Method: Patients starting clozapine in a four year period at South London and the Maudsley NHS Foundation Trust were included. Clinical details were gathered from clinical notes. Primary outcome was net change in inpatient admissions comparing the periods before and after clozapine was started. Results: There was no significant association between the length of clozapine delay (mean clozapine delay = 3.93 years) and number or length of inpatient admissions once clozapine had been started (mean net change in days of admission = 16.74 days), F value = 0.901, p = 0.345. Clozapine reduced the total number of bed days per year, but only if treatment was continued – stopping resulted in inpatient admissions returning to pre-clozapine levels. Younger patients had a greater reduction in bed days when taking clozapine (p = 0.027). Conclusion: Clozapine reduces the number of inpatient days, regardless of the chronicity of the illness at the time clozapine was started. Continued compliance with clozapine is necessary to maintain this benefit. Reduction in bed days is greater in younger patients, suggesting early initiation of clozapine may be beneficial.

Augmentation of clozapine with a second antipsychotic - a meta-analysis: Augmentation of clozapine with a second antipsychotic

Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic – a meta‐analysis.

Long-term follow-up of clozapine prescribing:

Objective: Clozapine is uniquely effective for treatment-resistant schizophrenia, and so treatment continuation is essential. We aimed to identify factors associated with an increased likelihood of clozapine discontinuation in a cohort of patients in South East London. Methods: We gathered demographic and treatment information such as duration of illness and antipsychotic treatment history. t-tests, chi-square tests and binary logistic regression were used to compare patients who continued and discontinued clozapine during the study and to identify predictor variables for discontinuation. Results: Out of the study population of 133 patients, 48 discontinued clozapine at least once during the study period. The majority of these (75%) stopped treatment within the first 4 years of clozapine therapy. Age, ethnicity, diagnosis and antipsychotic treatment history were not predictive of the risk of clozapine discontinuation. However, male patients were more likely to stop taking clozapine (χ2 = 6.81, p = 0.009). The odds of discontinuing clozapine were 2.15 times higher for male patients. The most common reason for discontinuation was patient refusal of treatment. Conclusion: We found that patients who discontinue clozapine are more likely to be male, but no other demographic variable was found to predict treatment cessation. Discontinuation usually occurred due to patient refusal of treatment.

Patient attitudes to clozapine initiation

Clozapine is widely underused. No study has assessed views of patients suitable for, but not yet receiving, clozapine. We aimed to assess views of clozapine in patients eligible for clozapine but not yet prescribed it by conducting semistructured interviews with acutely unwell hospital in-patients. We interviewed 61 of 116 eligible patients and 50 (82%) answered all questions. At interview, 33 (54%) of 61 participants had heard of clozapine and 17 (30%) of 57 participants said they would take it if asked. Overall, 31 (57%) of 54 respondents said blood testing would not preclude them taking clozapine. The necessity for hospital admission was seen as the greatest barrier to receiving clozapine – 25 (49%) of 51 respondents stated this would be a reason for their refusing clozapine. Concerns about adverse effects of clozapine were considered sufficient to refuse clozapine in 23 (43.4%) of 53 respondents. Overall, 12 (24%) of 50 respondents felt that clozapine would be helpful to them. Patients’ acceptance of clozapine is likely to be improved by offering the opportunity to start clozapine at home and by improved education about the therapeutic benefits of clozapine and the management of its adverse effects. Blood testing does not appear to be an important barrier to the initiation of clozapine.