Clozapine prescribing in adolescent psychiatry: survey of prescribing practice in in-patient units

AIMS AND METHOD

Clozapine is an effective drug in treatment-resistant schizophrenia,but it seems to be prescribed for few patients under the ageof 18 years. This study reports a survey of consultant psychiatristsworking in adolescent units in the UK, looking at their useof clozapine and experience with it.

RESULTS

Out of 83 clinicians, 59 responded (71%). More than 40% of respondentsdo not use clozapine, and those who do may not always be followingbest practice recommendations. Reasons for not using clozapine,beliefs about its effectiveness and problems encountered inits use are described.

CLINICAL IMPLICATIONS

Clozapine may not always be made available to young people with treatment-resistant schizophrenia. There is a need for moreeducation, guidance and debate on clozapine use in child andadolescent psychiatry.

Introduction

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Introduction

Schizophrenia can occur in children as young as 7 years old,but is very uncommon until after puberty (Jacobsen & Rapoport, 1998;Nicolson & Rapoport, 1999; National Institute for Mental Health, 2003).Among young people the clinical features,particularly likely to be preceded by premorbid abnormalitiesin development and social adjustment, include more commonly disorganisation and affective symptoms (Nicolson et al, 2000;Schaeffer & Ross, 2002). Reduction of environmental stress,psychoeducation (of the patient, the family and the school),psychotherapy (family work and cognitive-behavioural psychotherapy),promoting continued education, and social support are all consideredimportant elements of treatment (Briess & Reveley, 1997). Nevertheless, pharmacotherapy remains the cornerstone of therapy,although side-effects and treatment resistance to antipsychoticsare more common than in adults (Clark & Lewis, 1998; Malhotra et al, 2000;Asarnow et al, 2004).

Delay in treatment is associated with poorer results, whereasearly intervention appears beneficial: the longer the durationof untreated psychosis the worse the condition becomes, withfunctional outcome appearing to decline sharply (Joyce et al, 2002; Harrigan et al, 2003). Early treatment thus has thepotential to reduce the secondary impacts of this serious mentalillness such as suicide, stigma, isolation and reduction insocial status (Duggan et al, 2003; Meltzer & Baldessarini, 2003).

Clozapine is the only drug licensed for the treatment of schizophreniain individuals as young as 16 years who are unresponsive toor intolerant of conventional medication. In the summary ofproduct characteristics by Novartis non-responsiveness is definedas ‘a lack of satisfactory clinical improvement despitethe use of adequate doses of at least two marked neurolepticsprescribed for adequate duration’. Intolerance is defined as ‘the impossibility to achieve adequate benefits withconventional neuroleptic drugs because of severe and untreatableneurological adverse reactions (extrapyramidal symptoms ortardive dyskinesia)’.

The use of clozapine is affected by several possible complications.Fits, excess salivation, drowsiness, weight gain and autonomicside-effects (blurring of vision, increased intra-ocular pressure,constipation and urinary retention) are the most common (Frazier et al, 2003; British Medical Association & Royal Pharmaceutical Society of Great Britain, 2004).Patients taking clozapinealso need regular blood tests, supervised at the time of startingthis study only by the Clozaril Patient Monitoring Service.In the UK this system, available 24 h a day, was originallydeveloped in 1990 to manage the risk of agranulocytosis associated with clozapine. It requires the patients, the responsible physiciansand the supplying pharmacies to be registered with the service.This ensures that people who develop severe complications areidentified early and that they are not exposed to the drugagain in the future, if it has to be discontinued (Atkin & O’Sullivan, 1995).In addition, for patients under 18years old taking clozapine, the advice from the original manufacturer(Novartis) is that they should have an electroencephalogram(EEG) prior to starting treatment and at regular intervalsduring the course of treatment owing to the increased incidenceof absences and seizures (Freedman et al, 1994; Fink, 2002).

According to the Clozaril Patient Monitoring Service, in April2004, out of more than 21 000 patients on the register, therewere just 88 patients under the age of 18 years in the UK.This is such a small number that it is possible that youngpeople are not being offered treatment with clozapine. Thiswould not only contravene the National Institute for ClinicalExcellence guidance on atypical antipsychotics, which statesthat ‘in individuals with evidence of treatment resistantschizophrenia clozapine should be introduced at the earliestopportunity’ (National Institute for Clinical Excellence, 2002),but it would also deprive patients of a potentiallyunique and effective treatment. Some studies in fact suggestthat its use might be worthwhile and beneficial in children and young people (Kumra et al, 1996; MacEwan & Morton, 1996;Turetz et al, 1997).

Thus there is accumulating evidence to advocate the early useof clozapine, although this medication has the potential tocause severe side-effects. This paper reports the results ofa survey of the attitudes and prescribing practices relatedto clozapine in a sample of consultants in adolescent psychiatry.

Method

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Method

The study employed a cross-sectional survey design using a questionnaire developed specifically for this project (Box 1). Questionnaireitems were generated following an examination of the evidenceavailable regarding clozapine use and through discussion withcolleagues. The questionnaire was piloted with two consultantsin child and adolescent psychiatry working in in-patient settings.Items covered four broad areas: usage, beliefs about effectiveness,prescribing practices, and side-effects and other problems encountered.

Box 1. Study questionnaire: respondents were asked to tick statements that reflected what happened in their practice

I do not useclozapine because of:

my unfamiliarity with it

the need forintensive monitoring

the patient’s age

the side-effects

thecost

I use clozapine in my practice

I use clozapine onlyin those aged 16 years or above

Before using clozapine I trytwo or more antipsychotics

One of them will have been an atypical

Oneof them will have been a depot

I try to use clozapine at theearliest opportunity

I believe clozapine is effective in thepresence of negative symptoms

I use clozapine in patients whoare intolerant of other antipsychotics

The patients receivea routine ECG and an EEG. Other EEGs are performed during thecourse of treatment

I believe clozapine reduces mortality dueto effects on suicidality

I believe clozapine reduces aggression

Beforestarting clozapine benefits and side-effects are discussed withthe patient and the family

I use doses of up to 200, 450 mgor up to 900 mg maximum

I routinely measure plasma concentrationlevels

Most common side-effects I encounter in my practiceare:

drowsiness

hypotension

absences/seizures

hypersalivation

constipation

urinaryproblems

other problems

I have had to stop clozapine becauseof severe side-effects:

reduction of white cell count

otherproblems (please state)

I find the Clozaril Patient MonitoringService useful

Any other comments

ECG, electrocardiogram;EEG, electroencephalogram.

The population sampled comprised all consultant psychiatristsworking in adolescent units in the UK. Contact details wereobtained from the unit directory of the Royal College of Psychiatrists.All of the 83 practitioners eligible to take part were contacted.The questionnaire was anonymous; no attempt was made to identifythe respondent consultants and there was no request for informationregarding individual patients. The project was submitted toand approved by the South Sheffield research ethics committee.

Results

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Results

Of the 83 consultants contacted, 59 (71%) responded, but oneperson returned a blank questionnaire. Of the 58 respondentswho provided data, 7 (12%) reported that they did not prescribeclozapine because of a lack of suitable cases and 17 (29%)reported that they just did not use it. Reasons given are summarisedin Table 1. The prescribing practices and beliefs about clozapinein the 34 (58%) respondents who reported using it are shownin Table 2.

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Table 1. Reasons for not using clozapine (n=17)

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Table 2. Respondents’ use of clozapine, beliefs and prescribing practice (n=34)

Participants were asked about side-effects and other problemsencountered when using clozapine. The most common side-effectsreported were drowsiness, reported by 25 (73%) of respondentsusing this drug; hypersalivation, 23 (68%); hypotension, 11(32%); constipation, 11 (32%); and others, including urinaryproblems, weight gain, tachycardia, diabetes and absences/seizures, reported by 7 (21%). A number of these doctors described difficultieswith prescribing this drug for young people, citing poor adherenceto treatment, particularly because of the risk of weight gain.Reductions in white cell count had been experienced by 18 ofthe 34 respondents (53%); 7 (21%) reported having to stop clozapinebecause of other serious problems such as myocarditis, arrhythmias,excessive sedation, untreatable hypersalivation, overdose andlack of adherence. Twenty-six (76%) found the patient monitoring service useful in managing their prescribing.

Discussion

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Discussion

Clozapine seems effective when used in children and adolescents,the National Institute for Clinical Excellence advocates thistreatment and there is guidance available from the ClozarilPatient Monitoring Service on its use in those under 18 yearsold. However, this is countered by possible serious complications,and clinicians may be understandably wary of using it. As pointedout by some of the participants in the study, young patients themselves may not be prepared to adhere to the monitoringregimen and put up with the likely complications at an agewhen physical appearance and well-being are particularly important.Although this was a questionnaire survey, the response rate(at 71%) was respectable. Caution needs to be exercised aboutextrapolating from these findings to all consultant adolescent psychiatrists, but it is clear that within this group of respondentsthere is a need for further debate about clozapine usage, ifyoung people with schizophrenia are to benefit from this treatment.This is particularly topical now that clozapine is availablein generic form, produced by two additional manufacturers.

The data from this survey suggest that a considerable numberof specialists in adolescent psychiatry working in in-patientunits do not prescribe clozapine. Unfamiliarity with the drugand the need for monitoring of side-effects seem to influenceits use, and it might be that clearer information about effectivenessand prescribing practices would result in increased usage.The need for information and training is emphasised by the factthat those who do use clozapine may not comply with nationallyagreed recommendations about prescribing: for example, manydo not seem to routinely request EEGs before or during thecourse of treatment.

Acknowledgments

I thank Drs A. Livesey and S. Spence from Sheffield for thecomments given during the initial part of the project. I thankProfessor D. Cottrell in Leeds for his tremendous support.

References

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