Cochrane Schizophrenia Group, Summertown Pavilion, Oxford
Institute of Psychiatry & Guy's, King's and St Thomas' School of Medicine, London
Correspondence: Professor Anthony S. David, Institute of Psychiatry & GKT School of Medicine, Denmark Hill, London SE5 8AF, UK. Tel: 020 7848 0138; Fax: 020 7848 0572; e-mail: a.david{at}iop.kcl.ac.uk
Declaration of interest Funded by the NHS Health Technology Assessment programme. A.S.D. is participating in a trial funded by janssen-Cilag and has been an advisor for them. The Cochrane Schizophrenia Group has received funding from pharmaceutical companies, the NHS and Department of Health.
See pp. 300 307, this
issue.
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ABSTRACT |
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Aims To synthesise relevant systematic Cochrane reviews.
Method The Cochrane Database was searched and summary data were extracted from randomised controlled clinical trials of depots.
Results Standard dose depot v. placebo resulted in significantly less relapse but more movement disorders. Those on depots (v. oral drugs) showed more global change on one outcome measure; relapse and adverse effects showed no difference. Comparisons showed no convincing advantages for one depot over another.
Conclusions Depot antipsychotics are safe and effective. They may confer a small benefit over oral drugs on global outcome. Those for whom depots are most indicated may not be represented. Large studies are required to discern differences in relapse rates and long-term adverse effects, and data on satisfaction, quality of life and economics.
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INTRODUCTION |
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Davis undertook meta-analyses, incorporating several methodologies (Davis et al, 1994) including mirror image and influential discontinuation trials (e.g. Hirsch et al, 1973), and concluded that depots were superior to oral drugs in many respects. Similarly, Glazer & Kane (1992) combined several studies comparing the incidence of tardive dyskinesia for people on depots with those on oral agents. They concluded that depots were no more harmful than oral drugs in this respect. Because non-randomised evaluative studies, including before and after (mirror image) trials, repeatedly have been shown to over-estimate the effect of experimental interventions (Chalmers et al, 1983; Schulz et al, 1995), these have not been included in Cochrane schizophrenia reviews (see Adams & Eisenbruch, 2000; Coutinho et al, 2000; Quraishi & David, 2000a, b, c, d, e; Quraishi et al, 2000).
Objective
The aim of this paper is to provide a synthesis and quantitative summary of
the findings of Cochrane depot reviews.
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METHOD |
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Selection
All reviews of long-acting depot antipsychotics for schizophrenia were
obtained from The Cochrane Library (Issue 1, 2000) by searching using
the term SCHIZOPHRENIA and scanning the titles of completed reviews. The
pre-stated comparisons of interest were of any long-acting depot antipsychotic
medication v. placebo or v. oral medication and, finally,
high-dose depot v. low-dose depot, for people with schizophrenia or
schizophrenia-like illnesses. Outcomes of a priori interest were
intention-to-treat data on death, improvement in global functioning, mental
state, behaviour, social functioning, quality of life, carer burden and
incidence of attrition and adverse effects.
Quality assessment
There was no quality assessment of the primary reviews from which these
data were extracted but the empirical-evidence-based Cochrane reviews have, in
general, been shown to be of higher quality than others
(Jadad et al,
1998).
Data extraction
Data were extracted from reviews by M.K.P.F. and re-extracted by either
C.E.A. or A.S.D. Where disagreement arose, this was resolved through
discussion.
Data analysis
All intention-to-treat data were binary outcomes. Risk ratios (RRs, random)
and their 95% confidence intervals (CI) were extracted from the original
review and entered into RevMan 4.1
(http://www.updatesoftware.com/ccweb/cochrane/revman.htm). These were
calculated in preference to odds ratios because they are robust to
heterogeneity and more intuitive to clinicians
(Boissel et al, 1999).
In turn, where appropriate, summary data from each review were summated and an
overall RR and the summary 95% CI were calculated. Where possible, we
calculated the numbers needed to treat (NNT) or harm (NNH). For a test of
heterogeneity we visually inspected graphs as well as employing the
2 test.
There are some dangers in this overall approach. Because it was not possible to avoid spurious results by counting participants twice in the specific depot v. other depots comparison, totals are not produced. Totalling across different pharmacological classes of antipsychotics is statistically attractive. Power to demonstrate outcomes of interest afforded by summation is increased so that any important effects that the small source trials and reviews would have missed may be highlighted. Clinically and pharmacologically, however, such totalling may not make sense. Clinicians who choose to prescribe a specific depot may not be interested in a summary statistic across all depots. In some circumstances effects could cancel out in an overall summary statistic and causative and protective effects could be masked or cancelled out. Data using summated totals must therefore be interpreted with caution.
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RESULTS |
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Depot antipsychotics v. placebo depots
Understandably, few people have been randomised within this comparison.
Three reviews compared depot medication against placebo (bromperidol,
fluphenazine and haloperidol decanoate). Only one small trial within the
fluphenazine review reported mortality, with no clear differences between
groups (n=54, RR=5, CI=0.25-99). One review reported on relapse
(fluphenazine decanoate v. placebo), with the results favouring the
active drug (n=415, RR=0.3, CI=0.22-0.4; NNT=2, CI=1.8-2.6; see
Fig. 1). Three reviews
presented data for the numbers leaving the studies early. Significantly more
people taking depot medication stayed in the studies than those receiving
placebo (n=152, RR=0.43, CI=0.27-0.71). Two reviews reported on the
adverse effects of blurred vision or dry mouth. Curiously, these symptoms were
more frequent in the placebo group (n=52, RR=0.16, CI=0.03-0.8;
NNT=3, CI=2-9). When data were reported in the review as movement
disorders general, statistical significance was achieved in
favour of those taking placebo (n=51, RR=20.5, CI=1.3-338; NNH=3,
CI=6.5-1.9).
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Depot antipsychotics v. oral antipsychotics
Death is a rare, inconsistently reported outcome. One review presented
limited data and there is no clear effect of either depot or oral
antipsychotic (n=156, RR=2, CI=0.19-21). Three reviews present data
on global change. Significantly fewer numbers of people allocated to depot
preparations had no clinically meaningful change (n=127, RR=0.7,
CI=0.5-0.9; NNT=4, CI=2.4-9; see Fig.
2). For outcomes such as relapse, study attrition, needing
adjunctive anticholinergic medication and incidence of tardive dyskinesia, no
clear differences were demonstrated between those taking depot and people
allocated to oral antipsychotics (relapse, n=844, RR=0.96,
CI=0.8-1.1).
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Specific depot antipsychotic v. another depot
All nine depot reviews contributed to at least one of the outcomes in this
comparison. No data were pooled because it was impossible to avoid counting
data twice: one review's experimental group was another's control. For all
outcomes (see Fig. 3) there
were few convincing data that any real differences exist between depots. All
data from reviews that compared the depot antipsychotic of interest with
another, for the outcome of no important improvement in global
functioning as indexed by Clinical Global Impression (CGI) scores
(Guy, 1976), included the
possibility that there were no differences between depots. This also applies
to the outcome of leaving the study early (25% attrition in the experimental
groups). The outcome of mental state relapse showed that
zuclopenthixol decanoate was statistically superior to the control depots
(largely fluphenazine decanoate) (n=296, RR=0.64, CI=0.4-0.9, NNT=8,
CI=5-53), but this could be a function of publication bias (see
Discussion).
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High-dose depot v. standard dose, and standard dose
v. low dose
There are limited data, but reviews found no differences between high-dose
(250 mg of fluphenazine weekly; 200 mg of flupentixol every 2 weeks)
v. standard-dose (12.5-50 mg of fluphenazine every 2 weeks; 40 mg of
flupentixol biweekly) depot anti-psychotics for global outcome, mental state,
adverse effects or attrition. The estimates of effect all had wide confidence
intervals. Within the standard dose v. low dose comparison, most data
were available for the outcome of relapse (n=638). Pooled data across
three phenothiazine preparations (flupentixol, fluphenazine decanoate and
enanthate) suggest that the standard dose (12.5-50 mg every 2 weeks) is more
effective than the low doses (1.25-25 mg every 2 weeks) (RR=2.5, CI=1.1-5.9;
NNT=7, CI=5-12). Although no clear differences were demonstrated between the
standard dose and low dose on global functioning, attrition and adverse
effects (movement disorders), data are limited.
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DISCUSSION |
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Depot antipsychotics v. placebo depots
Currently, it would be difficult to undertake a trial comparing placebo to
neuroleptic depot in the treatment of schizophrenia, given the availability of
effective treatments. Even with the limited data (n=415),
fluphenazine decanoate clearly reduces relapse between 12 weeks and 2 years
(NNT=2). That significantly more people stayed in the study if allocated to
depot (21% v. 49% over the same time period) can be interpreted as a
positive outcome, assuming that those who left early were unlikely to be well.
Data from within this comparison suggest that the adverse effects of blurred
vision or dry mouth are not good indicators of anti-psychotic activity because
they are more frequent in the placebo group. Unsurprisingly, drugs such as
fluphenazine decanoate are associated with movement disorders. We have
calculated that, on average, between two and seven people have to be given
depot for one person to suffer significant general movement disorders (NNH=3,
CI=2-6.5), which is admittedly a crude index.
Depot antipsychotics v. oral antipsychotics
An underlying assumption in psychiatric therapeutics is that people with
serious mental illnesses may not take oral medication reliably, resulting in
relapse. If this assumption is correct, then the comparison of relapse rates
should demonstrate an advantage for those on depots v. oral drugs.
Although the advantage on one outcome measure in favour of depots was
statistically significant (global improvement: NNT=4, CI=2-9), other important
outcomes such as relapse, attrition and adverse effects were not. Reviews
involving over 800 participants did not demonstrate a statistically
significant difference between depots and oral medications (RR=0.9,
CI=0.8-1.2) in terms of relapse, despite good statistical power. It could be
argued that those participating in trials were reasonably compliant with oral
medications so that the demonstration of any advantages to depot (and
absence of disadvantages) is noteworthy. Trials suggest that adverse effects,
reported as the proxy outcome of needing additional anti-cholinergic
medication, occur in about two-thirds of people on antipsychotics,
whether administered by depot or given orally.
Specific depot antipsychotic v. another depot
Many of these comparisons can be seen as fulfilling the need to market a
new substance rather than answering any relevant clinical question. No
differences were seen on any global measures of change. All nine reviews
reported data on relapse. One found a statistically significant result in
favour of zuclopenthixol decanoate (NNT=8, CI=5-53). Unlike the other depots,
this finding in favour of zuclopenthixol was consistent across the outcomes of
leaving the study early and needing additional anticholinergic drugs. It is
feasible that zuclopenthixol decanoate is indeed a better depot in terms of
the outcomes measured, although relapse rates in the comparator drugs were
high and, pharmacologically, there are no grounds to suspect any superiority.
On the other hand, being one of the newest preparations, it has not been used
as the comparator depot in any other trial
(Gilbody & Song, 2000). By
the same token, this may explain, to some extent, the poor results for
fluphenazine compounds, at least when it comes to adverse effects. These
compounds have been used more than any other as the control drugs and these
data may be the summation of a publication/reporting bias.
High-dose depot v. standard dose, and standard dose
v. low dose
Data from trials support the clinical impression that there is no clear
advantage in the use of high-dose depot preparations introduced for
treatment-resistant cases, and that ultralow doses are little more than
placebo.
Limitations
Many outcomes, stated by trialists to have been recorded, were lost owing
to poor reporting. Modern trialists recommend that all outcome measures should
be reported (Begg et al,
1996). Data from often poorly reported, small trials of limited
generalisability, when taken together with larger trials, support the value of
depot antipsychotic preparations. This complements information from less
methodologically rigorous studies (Davis
et al, 1994). There is little convincing evidence that
one depot is clearly better than another, and none that high or ultra-low
doses have advantages.
Direct data on economic outcomes, quality of life and satisfaction were not found. Such outcomes were scarcely considered in randomised trials from the 1960s to early 1980s. A review of what limited evidence there is relating to satisfaction with depot antipsychotics suggests that patients on depots are, on average, reasonably satisfied (see companion paper Walburn et al, 2001, this issue).
Future studies
Clinicians and recipients of care could still benefit from thorough
evaluation of any one of these widely used compounds within a large, long,
simple and clinically relevant randomised trial
(Hotopf et al, 1999).
Further research should, ideally, focus on those living outside of hospital in
community settings, whose non-adherence to treatment and follow-up is thought
to contribute to relapses in their condition. Such studies are, by their very
nature, difficult to perform. Those designing evaluative studies of depots in
the future, including atypical compounds, should learn from the
limitations and strengths seen in depot trial design over the past three
decades. Such studies would have to be of longer duration than the majority
conducted to date, in order to capture a sufficient number of relapses.
Long-term trials specifically designed to examine outcomes such as tardive
dyskinesia also are required. The definition of relapse requires careful
consideration and would need to be operationalised. Obtaining useful
cost-effectiveness data and data on quality of life, satisfaction, disability,
etc. is a research priority.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication September 6, 2000. Revision received February 5, 2001. Accepted for publication February 8, 2001.
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