EDITOR - The meta-analysis and meta-regression analysis of atypical
versus typical antipsychotics by Geddes et al (1)
is an important contribution to the current debate, but as they
acknowledge must be taken as the first, rather than the last, word on the
topic.
Overall they find advantages to the atypicals compared with typicals
as used in current clinical practice. This is important given the repeated
failure to get doctors to increase the dose of tricyclic antidepressants
they prescribed in spite of over years of exhortation (2); it is extremely
optimistic to imagine that typical antipsychotic doses will be reduced in
practice.
With lower typical antipsychotic doses the efficacy advantage for
atypicals diminishes rather than necessarily disappears (the 95%
confidence interval for efficacy encompasses a clinically significant
advantage to atypicals but only a small disadvantage). The tolerability
analysis is problematic. I take issue with the confident equating of
tolerability with drop outs due to all causes. The total number of
patients stopping treatment is a very 'noisy' measure comprising a mixture
of discontinuation due to protocol deviation, withdrawal of consent,
treatment failure or success, as well as adverse events. It is sensible to
analyse discontinuations attributed to adverse events alongside total drop
outs, but even then we are only looking at the 'hard end' of lack of
tolerability - using this measure alone won't detect the patients who
continue in acute treatment spite of significant side effects. This
analysis did find that atypicals do cause fewer extrapyramidal side
effects even than lower dose typicals and the strong clinical impression,
supported by the editorial in the same issue (3), is that patients choose
to avoid them if they can. What is missing from the interpretation of this
analysis is any acknowledgement that the 'user view' may be important. It
is difficult therefore to accept the authors conclusion that atypicals are
no better tolerated than typicals; on the evidence given it just depends
on what you mean.
Finally, and perhaps most importantly, the value judgements used to arrive
at the recommendations based on the evidence are not explicit; this does
us and the subject a disservice. The concluding value judgement that we
should usually use typicals first line appears, in spite of protests, to
be driven by an implicit cost-effectiveness judgement weighing a large
cost difference against a perceived minor clinical benefit. I have argued
here about the certainty of the evidence; how much more shaky and opaque
is the translation to recommendation? My interpretation is that we are
condemned on current best evidence to continue living with the uncertainty
about whether to use typical or atypical antipsychotics first line.
Perhaps this is a situation in which we should listen to our patients?
Reference List
1. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical
antipsychotics in the treatment of schizophrenia: systematic overview and
meta-regression analysis. Br.Med.J. 2000;321:1371-1376.
2. Lawrenson RA, Tyrer F, Newson RB, Farmer RD. The treatment of
depression in UK general practice: selective serotonin reuptake inhibitors
and tricyclic antidepressants compared. J Affect.Disord. 2000;59:149-157.
3. Kapur S, Remington G. Atypical antipsychotics. Patients value the
lower incidence of extrapyramidial side effects. Br.Med.J. 2000;321:1360-
1361.
Rapid Response:
Response to Geddes et al
EDITOR - The meta-analysis and meta-regression analysis of atypical
versus typical antipsychotics by Geddes et al (1)
is an important contribution to the current debate, but as they
acknowledge must be taken as the first, rather than the last, word on the
topic.
Overall they find advantages to the atypicals compared with typicals
as used in current clinical practice. This is important given the repeated
failure to get doctors to increase the dose of tricyclic antidepressants
they prescribed in spite of over years of exhortation (2); it is extremely
optimistic to imagine that typical antipsychotic doses will be reduced in
practice.
With lower typical antipsychotic doses the efficacy advantage for
atypicals diminishes rather than necessarily disappears (the 95%
confidence interval for efficacy encompasses a clinically significant
advantage to atypicals but only a small disadvantage). The tolerability
analysis is problematic. I take issue with the confident equating of
tolerability with drop outs due to all causes. The total number of
patients stopping treatment is a very 'noisy' measure comprising a mixture
of discontinuation due to protocol deviation, withdrawal of consent,
treatment failure or success, as well as adverse events. It is sensible to
analyse discontinuations attributed to adverse events alongside total drop
outs, but even then we are only looking at the 'hard end' of lack of
tolerability - using this measure alone won't detect the patients who
continue in acute treatment spite of significant side effects. This
analysis did find that atypicals do cause fewer extrapyramidal side
effects even than lower dose typicals and the strong clinical impression,
supported by the editorial in the same issue (3), is that patients choose
to avoid them if they can. What is missing from the interpretation of this
analysis is any acknowledgement that the 'user view' may be important. It
is difficult therefore to accept the authors conclusion that atypicals are
no better tolerated than typicals; on the evidence given it just depends
on what you mean.
Finally, and perhaps most importantly, the value judgements used to arrive
at the recommendations based on the evidence are not explicit; this does
us and the subject a disservice. The concluding value judgement that we
should usually use typicals first line appears, in spite of protests, to
be driven by an implicit cost-effectiveness judgement weighing a large
cost difference against a perceived minor clinical benefit. I have argued
here about the certainty of the evidence; how much more shaky and opaque
is the translation to recommendation? My interpretation is that we are
condemned on current best evidence to continue living with the uncertainty
about whether to use typical or atypical antipsychotics first line.
Perhaps this is a situation in which we should listen to our patients?
Reference List
1. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical
antipsychotics in the treatment of schizophrenia: systematic overview and
meta-regression analysis. Br.Med.J. 2000;321:1371-1376.
2. Lawrenson RA, Tyrer F, Newson RB, Farmer RD. The treatment of
depression in UK general practice: selective serotonin reuptake inhibitors
and tricyclic antidepressants compared. J Affect.Disord. 2000;59:149-157.
3. Kapur S, Remington G. Atypical antipsychotics. Patients value the
lower incidence of extrapyramidial side effects. Br.Med.J. 2000;321:1360-
1361.
Competing interests: No competing interests