Psychiatric Bulletin (2001) 25: 174-177. doi: 10.1192/pb.25.5.174
© 2001 The Royal College of Psychiatrists
Psychiatric Bulletin (2001) 25: 174-177
© 2001 The Royal College of Psychiatrists
Use of a prescribing protocol in routine clinical practice
experience following the introduction of donepezil
Richard Prettyman, Senior Lecturer and
Jaiker Jari, Consultant
University of Leicester, Division of Psychiatry for the Elderly, the
Bennion Centre, Glenfield General Hospital, Groby Road, Leicester LE3
9DZ
1 The protocol currently followed in Leicestershire is a modified version of
the 1997 protocol but the principal components are essentially the same. 
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Abstract
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AIMS AND METHOD
Following the introduction of donepezil into clinical practice a protocol
for prescribing it was developed in Leicestershire. A prospective clinical
audit was undertaken to monitor compliance with the protocol, which also
provided an opportunity to evaluate the outcome of therapy in routine clinical
practice.
RESULTS
Overall there was close adherence to the protocol by the clinicians and
clinical factors, as well as organisational and resource-related factors, were
important in determining who received treatment. The principal outcome
measures (Mini-Mental State Examination, Barthel ADL Index and Clinical
Dementia Rating Scale) did not demonstrate any significant treatment
effect.
CLINICAL IMPLICATIONS
This study demonstrates the feasibility and acceptability of using a
protocol-based approach to manage the introduction of new drug treatments in
psychiatry.
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Introduction
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Donepezil was the first drug to receive a licence in the UK (in the spring
of 1997) for the treatment of Alzheimer's disease. At the time there was only
one published clinical trial using the drug
(Rogers & Friedhoff, 1996)
and this had shown only modest improvement in cognitive performance in
patients with Alzheimer's disease. It was estimated that the annual cost of
drug treatment (excluding any other costs, e.g. investigations) would be about
£1000 per patient. As a result there was widespread uncertainty among
both clinicians and health service managers in many parts of the country
concerning the cost-effectiveness of providing this treatment
(Alzheimer's Disease Society,
1997). Thus, in some parts of the country the policy was simply
not to prescribe, while in other areas local guidelines were developed for
prescribing donepezil (Harvey,
1999).
In Leicestershire it was decided that donepezil should be available but the
treatment should be targeted at patients for whom there is evidence of
benefit. To achieve this a local protocol for prescribing cholinesterase
inhibitors was developed and employed from the outset (see Appendix). One of
the requirements of the protocol was that the pattern of use of donepezil and
compliance with the protocol should be monitored. As a consequence a
prospective clinical audit was undertaken. The audit also provided an
opportunity to examine systematically the outcome of therapy in a routine
clinical setting, an area in which there are few published data at
present.
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Method
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Setting
The audit was carried out at the Bennion Centre, Glenfield Hospital,
Leicester. This is the base hospital for oldage psychiatric services covering
the western half of the city of Leicester and Leicestershire, with a catchment
population of approximately 70 000 persons aged 65 and over.
Subjects and procedures
All patients initially considered for donepezil treatment between 1 August
1997 and 31 July 1998 were included in the audit. They received a standardised
assessment of dementia severity, cognitive and functional status and other
parameters. This included the Clinical Dementia Rating Scale (CDR;
Hughes et al, 1982),
Mini-Mental State Examination (MMSE;
Folstein et al, 1975),
Barthel ADL (activities of daily living) Index (BAI;
Mahoney & Barthel, 1964)
and a check-list covering various non-cognitive features of dementia. Case
notes were reviewed to determine the basis for the diagnosis of probable
Alzheimer's disease. Following the initial assessment those who then went on
to receive the treatment were reassessed 8-12 weeks later with the same
measures. In addition, pre- and post-treatment questionnaires were sent to
each patient's main carer to assess their knowledge and expectations of
treatment.
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Results
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Patient selection and characteristics
Between 1 August 1997 and 31 July 1998, 62 patients were considered for
donepezil treatment. Of these, 35 eventually received treatment. The
characteristics of the treated and untreated groups are shown in
Table 1. The groups differed
only in mean age (t=3.52, P=0.001). Reasons for eventual
non-treatment included failure to meet diagnostic or other eligibility
criteria (44%), refusal of the general practitioner to continue treatment
(30%) and other factors including problems of follow-up (26%); for example,
patient moving out of the area. Of the 35 treated patients, complete 12-week
follow-up data were available for 25 of them. Four patients had discontinued
before 12 weeks and for the remainder only incomplete data were available.
With respect to non-cognitive symptoms there were no significant
differences between the treated and non-treated groups with the exception of
weight loss and aggression, which were present in a significantly greater
number of non-treated (P<0.05; Fisher's exact test).
Therapeutic outcome
Mean changes in MMSE, BAI and CDR—SB (sum of boxes) scores were not
statistically significant (see Table
2) although a few individuals showed larger changes on one or both
measures (see Fig. 1). These
findings were broadly in line with clinicians' general impressions of a small
minority of patients demonstrating a marked overall clinical change.
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Table 2. Mean Mini-Mental State Examination (MMSE), Barthal ADL (activities of
daily living) Index (BAI) and Clinical Dementia Rating scale - sum of boxes
(CDR-SB) scores: baseline and post-treatment (n=25)
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View larger version (10K):
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Fig. 1 Change in Clinical Dementia Rating scale — sum of boxes
(CDR—SB), Mini-Mental State Examination (MMSE) and Barthel ADL
(activities of daily living) Index (BAI): post-treatment against
baseline
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Sixty-nine per cent of carers reported ‘some’ or
‘marked’ improvement (number of responders=16). The most
frequently cited areas of improvement were in mood (n=7; 44%) and
sociability (n=8; 50%). In eight cases (50%) carers stated that the
degree of improvement was less than they had anticipated.
Discontinuation of treatment
At the 12-week follow-up four of the 35 patients discontinued treatment;
two owing to side-effects (gastrointestinal), one owing to rapid deterioration
and one owing to death (unrelated to treatment). In addition to this, five
carers reported possible side-effects that were mild and transient. These
included minor gastrointestinal upset (two), insomnia (one), mood swings (one)
and muscular aches (one). As at 31 July 1999, a further 22 patients had
discontinued treatment; nine owing to lack of benefit, 12 owing to
deterioration and one owing to death (again, this was unrelated to treatment).
There were no further cases of discontinuation because of side-effects and
nine of the 35 patients who had commenced treatment were still continuing
treatment as at 31 July 1999. Of the 26 patients who had discontinued
treatment, 50% had discontinued by 30 weeks and approximately two-thirds (65%)
by 12 months.
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Conclusions
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The characteristics of the patients selected for treatment with donepezil
were broadly in line with the eligibility criteria contained in the protocol.
Acceptance of the protocol by the clinicians did not present any significant
problems despite the additional work involved in administering the rating
scales and questionnaires. During the period described, it appears that
resource-related and organisational factors were as important as clinical
factors in determining who received treatment. The total number of patients
was far less than had been originally anticipated. Although the annual cost of
prescribing donepezil has been estimated at £1000 per patient, a
significant proportion of the patients did not complete 1 full year's
treatment. Thus, the average drug cost per patient treated was significantly
less than the estimated cost.
Generally, donepezil appears to be well tolerated, with only two of the 35
patients in this series discontinuing treatment because of adverse effects.
The objective outcome measures employed in this evaluation did not demonstrate
a large treatment effect. This would be consistent with either a genuine lack
of clinical benefit; with a relative insensitivity of these measures in the
target domains together with the possibility of type two error (owing to small
numbers); or with a failure to rate those domains that may, in fact, manifest
the greatest response to treatment. The latter possibility is reinforced by
the subjective clinician and carer impressions of improvement in mood and
social functioning. Other authors have also reported noticeable improvements
in the non-cognitive features of the condition and the relief and enhancement
in quality of life experienced by the patients' carers
(Burns et al, 1999;
Watts-Tobin & Horn, 1999). It will be important in future to incorporate into anti-dementia drug trials
and evaluations valid measures of personal functioning that assess those areas
in which carers report worthwhile improvement.
Finally, donepezil was the first drug (apart from clozapine) prescribed by
psychiatrists in Leicestershire to be subjected to a clearly defined protocol
for its use. Overall, we did not encounter any significant problems in
incorporating the protocol into routine clinical practice. The systematic
collection of data on clinical experience with newly introduced drugs usefully
complements the evidence available from clinical trials: our experience
indicates the feasibility of this approach and its acceptability to
prescribers.
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Appendix
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The Leicestershire Mental Health Service NHS Trust Protocol for the
prescribing of cholinesterase inhibitor drugs: 1997
Version1
- Patients should have a diagnosis of probable Alzheimer's disease. Although
this should be a clinical judgement, National Institute of Neurological and
Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders
Association criteria are suggested as guidelines for making the diagnosis.
- Disease should not have progressed to the severe stage. The Cambridge
Examination for Mental Disorders of the Elderly severity classification is
suggested as a model for assessing the disease stage.
- There should be assurance of supervision when administering medication in
the domestic setting.
- Treatment is to be initiated by the specialist but the responsibility of
ongoing prescribing to be that of the patient's general practitioner.
- Treatment should be discontinued if disease progresses to the severe stage
or if there is no benefit from the treatment after an adequate trial.
- The treatment response should be regularly monitored — initially at
2-4 weeks, then at 12 weeks and then at 12-weekly intervals.
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Acknowledgments
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This project was supported in part by an unrestricted grant from Pfizer
Ltd.
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References
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Abstract
Introduction
