Haloperidol Dose When Used as Active Comparator in Randomized Controlled Trials With Atypical Antipsychotics in Schizophrenia: Comparison With Officially Recommended Doses
Hugenholtz GW, Heerdink ER, Stolker JJ, Meijer WE, Egberts AC, Nolen WA;
Commented by , 24 Aug 2006
Aim of the study
There is an ongoing debate about the superiority of the new, "atypical" antipsychotics compared to conventional neuroleptics. In most of these studies haloperidol was used as a comparator. This choice is in part justified, because haloperidol was the standard antipsychotic compound at least in the industrialized countries.
Nevertheless, at least two meta-analyses have mentioned an association between the conventional comparator drug and the outcome of such studies. In one meta-analysis by Geddes and colleagues (ref. 1) no efficacy superiority of atypical antipsychotics was found when haloperidol doses higher than 12 mg were used in the studies.
Another meta-analysis found an association between chlorpromazine dose and EPS superiority of atypical antipsychotics (ref. 2). In this context the authors investigated which haloperidol doses were used in randomized controlled trials (RCTs) with atypical antipsychotics in schizophrenia and compared these doses with officially recommended doses for haloperidol in the United Kingdom and in the United States.
Method
The authors searched the reviews of the Cochrane Schizophrenia Group and the Cochrane Central Register of Controlled Trials for RCTs published in English language before 2005 that compared one of the atypical antipsychotics amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, or ziprasidone with haloperidol in schizophrenia or related disorders.
Then they extracted the midpoint required dose (e.g. if the dose range is 5-10, the midpoint required dose is 10, in fixed dose studies it is the fixed dose) and the mean dose used in the haloperidol arms. These doses were compared with the haloperidol doses recommended in the United States by the Food and Drug Administration and in the United Kingdom by the British National Formulary. They also analysed whether there were changes over time in these associations.
Results
The predefined midpoint doses of all the included studies (N = 49) were above the midpoint of the official recommended doses by the US Food and Drug Administration and by the UK British National Formulary for moderately ill patients. 94% of the midpoint doses were above the upper limit of the US recommendations and 80% were above the upper limit of the UK recommendations.
Even when the results were compared with recommendations for severely ill patients in both the United Kingdom and United States (6-15 mg daily), in 35% of the studies the mean actual used dose was above the upper limit of 15mg/day, although the patients in the studies were not refractory by definition.
Dr Leucht's comments
A number of authors have mentioned the possibility that the results of RCTs comparing atypical and typical antipsychotics have possibly been biased by too high haloperidol doses. This study is the first one that compared a representative sample of such studies with recommendations by American and UK agencies. The findings are important and the methodology used was sound.
Nevertheless, I think that there is an important uncertainty about the right haloperidol dose. For example, in Germany – the country where the neuroleptic threshold method was invented - relatively low doses are used. But when I asked US American colleagues about the optimum haloperidol dose they suggested much higher doses.
Indeed, the APA practice guideline for schizophrenia (ref. 3) and the American PORT guidelines suggest 5-20mg haloperidol/day which is higher than the FDA recommendation. More dose finding studies for haloperidol and other typical antipsychotics are still needed. We also need more comparisons of atypical antipsychotics with other typicals such as chlorpromazine, perphenazine or sulpiride that are associated with relatively few EPS, as well.
In the meantime it is an advantage of the atypical antipsychotics that dose finding studies have been conducted for them right from the start.
References
1. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321 (7273); 1371-1376 (Free full text article)
2. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003; 361 (9369); 1581-1589
3. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. American Journal of Psychiatry 2004; (suppl.); 1-114