Do antipsychotics differ in efficacy? Eur Neuropsychopharmacol. 2014 Jul.

The idea that all antipsychotics are of same efficacy ( or comparable efficacy )  is widely accepted.  Chlorpromazine (CPZ)  has been the gold standard to compare antipsychotic effect and It would be interesting to see how all other antipsychotics fare against CPZ.

 Myrto T. Samara, Haoyin Caob, Bartosz Helferb, John M. Davisd & Stefan Leucht report the results of a meta analysis of all  randomised controlled trials that compared oral formulations of chlorpromazine with any other oral antipsychotic for the treatment of schizophrenia or related disorders.

The primary outcome was response to treatment defined  as at least 50% reduction of rating scales.


128 randomized trials published over a period of 55 years from 1956 to 2011 were included.Chlorpromazine was compared with 43 other antipsychotics.  ( risperiodne only 1 study, quetiapine 4 studies , olanzapine 4 studies, Zotepine 2, clozapine 7). The mean/median doses in the chlorpromazine group ranged between 50 and 2000 mg, with a median of 525 mg.

Chlorpromazine was significantly more efficacious than four antipsychotic drugs : butaperazine, mepazine, oxypertine, and reserpine. After Bonferroni correction ( correction for multiple comparisons) only reserpine remained statistically less efficacious than chlorpromazine.

CPZ was significantly less efficacious than four antipsychotic drugs: clomacran, clozapine, olanzapine, zotepine.

The sensitivity analysis  (exclude single blind studies, open label studies,   studies with unclear level of blindness):  confirmed the differences of chlorpromazine compared to butaperazine, clomacran, clozapine and zotepine.

There were no statistically significant differences between chlorpromazine and the remaining 28 antipsychotics.


Small sample sizes in most of the trials ( median :50)  A clinically meaningful responder difference of 10% (which would lead to 100 additional responders among 1000 treated), assuming the average response rate in this meta-analysis (47%), would require a total sample size of 390 which is not met by most comparisons.

The studies varied substantially in design, patient populations ,dosing and other factors. Most of the included studies were carried out more than 30 years ago.

Authors argue that the “equal efficacy statement” regarding antipsychotics is not evidence based.  The observation of some antipsychotics being different support their argument.  A recent Cochrane review that compared haloperidol with all other first-generation antipsychotics yielded similar results (Dold and Leucht, 2012).

One could argue that the present analysis show that CPZ do not differ in efficacy with majority of antipsychotics. Among antipsychotics in use there is difference in efficacy with clozpaine and zotepine only.

‘Equal efficacy argument ‘  has always made exemptions. (mainly for Clozapine).  This analysis also supports that clozapine is superior .

Other recent Meta analysis have shown that some SGAs have small superiority over other FGA s and SGAs.

Comments: This analysis in general support the idea that antipsychotics in general are of comparable efficacy. Clozapine’s  superiority  is supported by other evidence.

Summary of the article:

Chlorpromazine versus every other antipsychotic for schizophrenia: A systematic review and meta-analysischallenging the dogma of equal efficacy of antipsychotic drugs.

Samara MT, Cao H, Helfer B, Davis JM, Leucht S. Eur Neuropsychopharmacol. 2014 Jul;24(7):1046-55.

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