Two main conclusions can be drawn from this review. Firstly, taking the trial results at face value, atypical antipsychotics are slightly more effective and better tolerated in patients with schizophrenia. Atypical antipsychotics also have a significantly lower risk of causing extrapyramidal side effects. We found no reliable evidence of differential effects between atypical antipsychotics and we have therefore grouped them together in this discussion. Secondly, when we controlled for the higher than recommended dose of conventional antipsychotics used in some trials, a modest advantage in favour of atypical antipsychotics in terms of extrapyramidal side effects remains, but the differences in efficacy and overall tolerability disappear, suggesting that many of the perceived benefits of atypical antipsychotics are really due to excessive doses of the comparator drug used in the trials. Taking these points into account, we think it inappropriate to advocate the first line use of a new drug without clear evidence of overall superior efficacy or tolerability.
However, for patients who do not response adequately to a standard dose of a conventional antipsychotic or experience severe extrapyramidal side effects it is appropriate to use atypical antipsychotics. Because conventional antipsychotics have limited effectiveness and tolerability, a large proportion of patients will, by this criterion, be prescribed atypical antipsychotics, often relatively early on in treatment. One of the most important results of our meta-regression is the confirmation that using conventional drugs at excessive doses reduces efficacy and increases adverse effects.2
Pharmacokinetic variability means that the optimal dose for individual patients will vary, but doses above 12 mg haloperidol a day (or equivalent) do not normally seem appropriate. This point may prove as important to the overall care of patients with schizophrenia as the intrinsic benefits of atypical antipsychotics.
Debate around our conclusion that a conventional antipsychotic should normally be prescribed first is likely to centre on two factors. The first is the negative consequences on patient compliance as a result of extrapyramidal side effects. In other words, if initial treatment produces worse side effects, then the patient may be unwilling to try a second drug. However, our analysis shows that patients taking atypical antipsychotics have no lower dropout rates and no better response than patients taking the optimal dose of conventional antipsychotics. This suggests that the lower risk of extrapyramidal side effects seen with the atypical antipsychotics may be counterbalanced by their greater propensity to cause other side effects and highlights the importance of early detection and treatment of adverse effects. A common side effect of atypical antipsychotic drugs is appreciable weight gain,19
and there are also rarer but serious side effects such as agranulocytosis with clozapine. In addition, concordance with treatment is probably not determined solely, or even primarily, by specific drug side effects, but by many factors, including those related to the disorder and the therapeutic relationship. Secondly, it may be that the lower incidence of extrapyramidal side effects translates into a lower long term risk of tardive dyskinesia.20
However, to date, the evidence on this issue is preliminary and inconclusive.21
Atypical antipsychotics are more expensive than the conventional drugs. Inevitably, therefore, cost has become part of the controversy concerning their prescribing. We believe that cost is not a crucial issue at present because the evidence and analyses described above indicate that the new drugs have no unequivocal advantages for first line use that would need to be set against their greater acquisition costs.
Potential publication bias
As in all systematic overviews, the results are only as good as the studies that contributed to the analyses. Publication is a major source of systematic bias in overviews, where trials with positive results are more likely to be published than those with neutral or negative results, especially if the trials are small. We went to considerable lengths to obtain data on trials that had not been published and trials that were incompletely reported. There is no way of estimating the magnitude of or potential for publication bias, although since the direction of such a bias would normally be in favour of the newer drugs, its existence would not undermine the results presented here.
Beyond the randomised evidence
This review shows that in several key areas, evidence is insufficient or absent. The trials have a median length of six weeks, yet antipsychotic drugs are often used for many years
and the conventional drugs are often used in depot form. The trials exclude a large proportion of patients who are treated with these drugs (including those with comorbid disorders). With the exception of extrapyramidal side effects, there is little consistent reporting of adverse events. There are few data on quality of life or clinically relevant functional outcomes and few reliable data on the cost effectiveness of atypical antipsychotics
none in the United Kingdom.
What is already known on this topic
Antipsychotic drugs have a central role in the treatment of schizophrenia
Newer, atypical antipsychotics are increasingly considered superior to conventional drugs
What this study adds
Atypical antipsychotics have a similar effect on symptoms to conventional antipsychotics at an average dose of
12 mg haloperidol or equivalent
Atypical antipsychotics cause fewer extrapyramidal side effects, but overall tolerability is similar to conventional drugs
Conventional drugs should remain the first treatment, although atypical antipsychotic drugs are a valuable addition to treatment options, especially when extrapyramidal side effects are a problem
Longer term trials that concentrate on prevention of relapses rather than treatment of acute episodes do not yet provide a large or clear body of evidence on which to base recommendations. The case in favour of atypical antipsychotics may be strengthened once good, long term data are available on efficacy (especially in terms of other important outcomes such as reduction in suicide rates or improvement in cognitive functioning), tolerability, and safety. This review will need to be updated regularly as evidence in each of these areas emerges over the next few years.
Evidence and concordance
Implicit in the above considerations, as with all evidence based recommendations, is the importance of an informed relationship between doctor and patient in which treatment decisions can be based on the likely beneficial and adverse effects of atypical and conventional antipsychotics, patient preference, and clinical judgment. Given the equivocal nature of the evidence, deviations from these recommendations may, and should, occur. For example, antipsychotic drugs clearly have different side effect profiles. The broader choice of drugs now available increases the chance of finding a drug for an individual patient that is tolerated as well as effective and thus makes adherence more likely. In the near future it may also be possible to take predictors of treatment response, such as pharmacogenomic considerations, into account when deciding which antipsychotic to prescribe.