Haloperidol versus chlorpromazine for treatment of schizophrenia

Introduction

Chlorpromazine and haloperidol are benchmark antipsychotic drugs which are frequently used as standards in antipsychotic drug trials.^1,2 For example, in the review on second-generation antipsychotic drugs by Davis et al.³, haloperidol was by far the most frequently used comparator followed by chlorpromazine. To better define the relative efficacy and safety of both compounds is therefore important for the methodology of randomized controlled trials (RCTs) and for clinical practice where both agents are still frequently used.

Objectives

To compare the effects of haloperidol and chlorpromazine for people with schizophrenia and schizophrenia-like psychoses.

Search strategy

We searched the Cochrane Schizophrenia Group's register (August 2006). We searched references of all included studies for further trials. We contacted pharmaceutical companies and authors of relevant trials.

Selection criteria

We included all RCTs that compared haloperidol with chlorpromazine for people with schizophrenia and/or schizophrenia-like psychoses.

Data collection and analysis

Citations and, where possible, abstracts were independently inspected by at least 2 reviewers, and papers ordered, reinspected, and quality assessed. We independently extracted data. For dichotomous data, we calculated the relative risk (RR), 95% confidence interval (CI), and, where appropriate, the number needed to treat (NNT) on an intention-to-treat basis using a random-effects model. For continuous data, we calculated weighted mean differences.

Results

We found 14 relevant studies, mostly of short duration, poorly reported, and conducted in the 1970s (total n = 794 participants). Nine of these compared oral formulations of both compounds and 5 compared intramuscular formulations. Haloperidol was associated with significantly fewer people leaving the studies early (13 RCTs, n = 476, RR = 0.26, CI = 0.08–0.82). The efficacy outcome ‘no significant improvement’ tended to favor haloperidol, but this difference was not statistically significant (9 RCTs, n = 400, RR = 0.81, CI = 0.64–1.04). Movement disorders were more frequent in the haloperidol groups (‘at least one extrapyramidal side-effect’: 6 RCTs, n = 37, RR = 2.2, CI = 1.1–4.4, NNH = 5, CI = 3–33, see figure 1), while chlorpromazine was associated with more frequent hypotension (5 RCTs, n = 175, RR = 0.31, CI = 0.11–0.88, NNH = 7, CI = 4–25, see figure 2). Similar trends were found when studies comparing intramuscular formulations and studies comparing oral formulations were analyzed separately.

Fig. 1.

At least one extrapyramidal side-effect.

Fig. 2.

Hypotension.

Reviewer's conclusion

Given that haloperidol and chlorpromazine are global standard antipsychotic treatments for schizophrenia, it is surprising that less than 800 people have been randomized to a comparison and that incomplete reporting still makes it difficult for anyone to draw clear conclusions on the comparative effects of these drugs. However, it seems that haloperidol causes more movement disorders than chlorpromazine, while chlorpromazine is significantly more likely to lead to hypotonia. We are surprised to have to say that we feel further, large, well-designed, conducted, and reported studies are required.

Implications for practice

Currently available data suggest that haloperidol and chlorpromazine are similarly effective for treatment of schizophrenia. But at least at higher doses, haloperidol seems to be associated with more extrapyramidal side-effects (EPS) while hypotension appears to occur more frequently when chlorpromazine is used. Overall, haloperidol may also be more acceptable for those afflicted by the illness.

Implications for research

High-dose haloperidol was the comparator in most RCTs on second-generation antipsychotics.³ This decision was in part justified because haloperidol was the most frequent antipsychotic in many industrialized countries. Nevertheless, this choice favored the second-generation antipsychotics because they were compared with a very EPS-prone standard. Future studies may take into account that less EPS-associated conventional antipsychotics are also available, and some studies already have.^4,5 The fact that in many countries haloperidol and chlorpromazine are still standard drugs administered in the treatment of schizophrenia justifies further research to compare the properties of these compounds.

Conflict of interest

L.C., M.K., C.L. none known. S.L. has received speaker/consultancy/advisory board honoraria from SanofiAventis, BMS, EliLilly, Janssen/Johnson and Johnson, Lundbeck, and Pfizer. SanofiAventis and EliLilly supported research projects by S.L. J.M.K. has received speaker and/or advisory board/consultancy honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Johnson & Johnson PRD, Otsuka, Pfizer, Inc., Wyeth, Lundbeck, Vanda, Astra-Zeneca, and PGxHealth.