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Senior House Officer, Ablett Psychiatric Unit, Glan Clwyd Hospital and Department of Psychological Medicine, University of Wales College of Medicine (UWCM) Academic Unit
Professor of Psychological Medicine, Department of Psychological Medicine, UWCM Academic Unit, Wrecsam
Consultant Psychiatrist
Consultant Psychiatrist, Ablett Psychiatric Unit, Glan Clwyd Hospital, Bodelwyddan, Denbighshire LL18 5UJ (tel: 01745 585484; fax: 01745 534405)
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Abstract |
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 Top Abstract IntroductionMethodResultsDiscussionReferences |
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The aim of the study was to investigate the use of clozapine in treatment-resistant schizophrenia and its impact on hospitalisation rates when prescribed in accordance with National Institute for Clinical Excellence (NICE) guidelines. Case records were examined of patients admitted to the psychiatric unit of Glan Clwyd Hospital between 1996 and 2001.
RESULTS
Of 59 patients identified as having treatment-resistant schizophrenia, 83% had been considered for clozapine, 48% were taking clozapine, 20% had refused the drug and 15% had stopped taking it because of side-effects. The mean annual hospitalisation rate for patients receiving clozapine for a minimum of 3 years was 13.5 days, markedly lower than those not receiving this drug (34.0 days, P=0.03). Older patients were less likely to have been offered clozapine (P=0.006).
CLINICAL IMPLICATIONS
This study supports the NICE guidelines recommending clozapine for patients with treatment-resistant disease. Clozapine is offered less often to older patients; factors influencing this require investigation.
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Introduction |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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Meta-analyses suggest that clozapine is more effective than other antipsychotics in treatment-resistant schizophrenia (Tuunainen et al, 2003; Wahlbeck et al, 2003). However, many patients either refuse clozapine or discontinue it because of current practice, which requires hospitalisation for the commencement of treatment and repeated venepuncture, as well as the risk of adverse effects. The greater efficacy of clozapine is thought to shorten or prevent psychiatric hospitalisation over the longer term, but evidence for this is limited (Aitchison & Kerwin, 1997). Most studies are of less than 1 year’s duration, and usually measure relapse rate rather than the annual hospitalisation rate (Wahlbeck et al, 2003). We therefore decided to investigate if adherence to NICE guidelines confers benefits in terms of a sustained reduction in hospitalisation rates.
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Method |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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Inclusion and exclusion criteria
Records were examined for inclusion according to the criteria listed in
Table 1. This identified
patients who were under the continuing care of a general adult psychiatrist
and were therefore likely to have records with sufficient data to establish a
diagnosis of treatment-resistant schizophrenia.
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Data extraction and outcome measures
Case records were obtained, and in-patient notes and clinic correspondence
examined. Data extracted included the patient’s gender and age; which of
the four consultant psychiatrists was responsible for care; current
antipsychotic medication; and whether the patient fulfilled NICE criteria for
treatment-resistant schizophrenia; if so, whether the patient was taking
clozapine and when was it started; had the patient been offered clozapine but
refused; had the patient discontinued clozapine; and had the patient not been
offered clozapine (no documentation).
Annual hospitalisation rate
The annual hospitalisation rate (AHR) was calculated by summation of the
number of days spent in hospital over a 7-year period (1996-2002 inclusive) or
since first presentation, if this was later than 1996, and was expressed as
the mean annual number of days each patient was hospitalised. Only patients
known to the service for a minimum of 3 years were included in this
calculation, and the effect of clozapine on the AHR was calculated only if the
drug had been prescribed for at least 3 years. This was to determine the
long-term effect on hospitalisation rates, and to allow determination of the
annual rate without denominator bias.
Statistical analysis
Data were collated using Microsoft Excel 2000 and analyses undertaken using
unpaired t-tests and 
2 tests as appropriate. Data are
presented as means with 95% confidence intervals.
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Results |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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Study sample
Sample demographics and fulfilment of NICE criteria for a diagnosis of
treatment-resistant schizophrenia are summarised in
Table 2. The sample varied in
age (range 22-72 years); the majority (71%) were male, and most (65%)
fulfilled the NICE criteria. Diagnosis of treatment-resistant schizophrenia
(TRS) did not vary with age (t=0.96, d.f.=91, P=0.34),
gender (proportion with TRS: male 65%, female 65%; 2=0.004,
d.f.=1, P=1.00) or consultant psychiatrist responsible for care
(proportion with TRS with each consultant: 52%, 76%, 64% and 66%;
2=3.14, d.f.=3, P=0.37).
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Of patients who met the NICE criteria for treatment-resistant schizophrenia, 28 (48%) were received clozapine, 12 (20%) had been offered clozapine but refused, 9 (15%) discontinued clozapine owing to adverse reactions and 10 (17%) had not been offered clozapine. Hence, 83% of these patients had been offered clozapine in accordance with NICE guidelines. The 10 patients who had not been offered clozapine were significantly older than those who were taking, had refused or had discontinued clozapine (mean difference 10.7 years, 95% CI 3.3-18.1; t=2.88, d.f.=57, P=0.006).
Annual hospitalisation rates
Patients with schizophrenia who did not fulfil the NICE criteria for
treatment-resistant schizophrenia (n=32) had an annual
hospitalisation rate of 14.2 days (Table
2). Patients with treatment-resistant disease who refused to take,
could not tolerate or had not been offered clozapine (n=22) had a
rate of 34.0 days, whereas those who tolerated and continued clozapine
(n=12) had a rate of 13.5 days. Thus, long-term treatment with
clozapine was associated with a mean reduction in hospitalisation of 20.5 days
(95% CI 2.1-39.0; t=2.26, d.f.=32, P=0.03). This represents
a reduction in AHR of 60%. Because the patients receiving clozapine were
significantly younger than those not taking it, age was examined as an
independent variable; however, there was no significant correlation between
age and AHR in the treatment-resistant group (r=0.22,
t=1.30, d.f.=32, P=0.20) or among those taking clozapine
(r=0.45, t=1.68, d.f.=11, P=0.12).
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Discussion |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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Long-term clozapine therapy was associated with a reduction of 21 days per year in bed occupancy. Moreover, this study did not include patients receiving clozapine prior to 1996 who were not admitted between 1996 and 2001; thus, the actual effect of clozapine in reducing hospitalisation rates is likely to have been underestimated.
The benefits of clozapine include quality-of-life gains as a result of reduced hospitalisation, given the preference of most patients for community living. This benefit must be balanced against the inconvenience of venepuncture, concerns over adverse effects and the increased burden on community teams required to monitor clozapine therapy. One UK study estimated a reduction in AHR from 49 days to 39 days with clozapine, based on retrospective interviews of 26 patients, their keyworkers or both (Aitchison & Kerwin, 1997). Theoretical modelling of the effect of clozapine (Duggan et al, 2003) suggests AHR would be reduced by 21 days from 130 days for all patients with schizophrenia; our data indicate similar reductions for patients with treatment-resistant disease (Table 2).
Limitations
To determine the long-term effect of clozapine on annual hospitalisation
rates, we needed to study patients receiving clozapine or known to services
for at least 3 years. This limited our sample size considerably, which must be
taken into consideration when interpreting the data. There was also
significant loss to follow-up (35%); patients out of area subsequently
requiring hospitalisation are not included. Since a cohort study cannot
establish causality, the observed association between reduced hospitalisation
and clozapine therapy may have other explanations. Patients receiving
clozapine long-term are generally compliant with oral medication regimens;
those requiring depot antipsychotics might benefit from clozapine but are not
prescribed it because of poor oral compliance. Thus, the reduction in hospital
admission for patients taking clozapine may reflect a patient group more
likely to comply with treatment and who may receive more psychosocial support,
as they are reviewed more frequently by community mental health teams (because
of the need for venepuncture).
Further research
This study demonstrates an association between long-term clozapine therapy
and reduced hospitalisation; more studies are required to confirm
reproducibility across regions. Our results accord with the finding that
clozapine therapy reduces in-patient costs, while increasing out-patient and
laboratory costs (Aitchison & Kerwin,
1997). Further work is required to establish procedures for
starting clozapine therapy in the community; initial results are promising
(O’Brien & Firn,
2002). This approach might increase patient acceptance, as some
are reluctant to enter hospital for the purpose of commencing clozapine
therapy.
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Acknowledgments |
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References |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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ALVIR, J. M. J., LIEBERMAN, J. A., SAFFERMAN, A. Z., et al
(1993) Clozapine-induced agranulocytosis: incidence and risk
factor in the United States. New England Journal of
Medicine, 329, 162
-167.
DUGGAN, A., WARNER, J., KNAPP, M., et al
(2003) Modelling the impact of clozapine on suicide in patients
with treatment-resistant schizophrenia in the UK. British Journal
of Psychiatry, 182, 505
-508.
KILIAN, J. G., KERR, K., LAWRENCE, C., et al (1999) Myocarditis and cardiomyopathy associated with clozapine. Lancet, 354, 1641 -1645.[Medline]
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE (2002) Guidance on the Use of Newer (Atypical) Antipsychotic Drugs for the Treatment of Schizophrenia. NICE Technology Appraisal Guidance, No. 43. London: NICE.
O’BRIEN, A. & FIRN, M. (2002) Clozapine
initiation in the community. Psychiatric Bulletin,
26, 339
-341.
TUUNAINEN, A., WAHLBECK, K. & GILBODY, S. M. (2003) Newer atypical antipsychotic medication versus clozapine for schizophrenia (Cochrane Review). Cochrane Library, issue I. Oxford: Update Software.
WAHLBECK, K., CHEINE, M. & ESSALI, M. A. (2003) Clozapine versus typical neuroleptic medication for schizophrenia (Cochrane Review). Cochrane Library, issue 1. Oxford: Update Software.
WORLD HEALTH ORGANIZATION (1992) International Statistical Classification of Disease and Related Health Problems (ICD-10) . Geneva: WHO.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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