Comparative Efficacy and Tolerability of Antipsychotic Drugs in Schizophrenia

The Lancet, 27 June 2013 (In Press - DOI: 10.1016/S0140-6736(13)60733-3

Recently available on-line in The Lancet is a paper which describes the comparative efficacy and tolerability of 15 antipsychotics in people with schizophrenia written by a group in Germany with a track record of producing such studies. The difficulty with the evidence when comparing drug treatments is that where you have lots of pharmaceutical options there are rarely any head to head comparisons of the different treatments. One way to get a sense of comparative effectiveness is to do a meta-analysis of different studies.

The authors here combined the results of 212 blinded randomised controlled trials that included 43049 patients who had schizophrenia. They excluded studies where people had mainly negative symptoms, those who were treatment resistant and those done in stable patients (mainly relapse prevention studies).  Of the people in the trials the mean duration of illness was about 12 years and they had an average age of 38 years.

Using a sophisticated form of metal analysis they then produced hierarchies of effect sizes for overall efficacy, discontinuation, weight gain, extrapyramidal side effects, prolactin increase, QTc prolongation and sedation. What they found for overall efficacy is that clozapine (by some margin) was the most effective followed by amisulpiride, olanzapine and risperidone.  Haloperidol came in at seventh in the list. When looking at overall acceptability the top three least likely to be discontinued compared to placebo were amisulpiride, olanzapine and clozapine.

The true interest in this study is that it challenges two ideas. The first is that all antipsychotics have the same effectiveness. Whilst the difference in effectiveness between the drugs was small (and smaller than for the side effects) it was a robust finding that didn’t alter much when tested in the sensitivity analysis. The second challenge is that thinking about antipsychotics as first generation or second generation isn’t very helpful as it obscures differences in adverse effects between all antipsychotics. For example aripiprazole is less sedating than quetiapine but haloperidol is somewhere between; similarly olanzapine causes more weight gain than risperidone but chlorpromazine is in between them.

As the authors state, “Antipsychotic drugs differ in many properties and can therefore not be categorised in first generation and second generation groupings. The suggested hierarchies in seven major domains should help clinicians to adapt choice of antipsychotic drug to the needs of individual patients”.