Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: comparison with officially recommended doses

Haloperidol Dose When Used as
Active Comparator in Randomized Controlled Trials
With Atypical Antipsychotics in Schizophrenia:
Comparison With Officially Recommended Doses
Gerard W. K. Hugenholtz, Pharm.D., Ph.D.; Eibert R. Heerdink, Ph.D.;
Joost J. Stolker, M.D., Ph.D.; Welmoed E. E. Meijer, Ph.D.;
Antoine C. G. Egberts, Pharm.D., Ph.D.; and Willem A. Nolen, M.D., Ph.D.
Conclusions: Nearly all randomized clinical
trials used haloperidol in doses that were higher Objective: To determine the doses of haloperi-
than the official recommended doses for moder- dol as a comparator drug in randomized con- ately ill or even severely ill patients. Therefore, it trolled trials (RCTs) with atypical antipsychotics is probable that the results of the RCTs were af- in patients with schizophrenia and to compare fected by the high dose of haloperidol, hampering these doses with the officially recommended the interpretation of the effects of atypical anti- doses for haloperidol in the United States and psychotics in their comparison with haloperidol.
(J Clin Psychiatry 2006;67:897–903) Data Sources: We searched for RCTs con-
ducted and published in English in full beforeJanuary 2005 in which atypical antipsychoticswere compared with haloperidol for the treatmentof schizophrenia. We searched for Cochrane Received July 11, 2005; accepted Nov. 29, 2005. From the Reviews in which 1 of the following atypical Altrecht Institute for Mental Health Care, Utrecht, the Netherlands (Drs. antipsychotics was evaluated for the treatment Hugenholtz and Stolker); the Department of Pharmacoepidemiology and of patients with schizophrenia, schizophreniform Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS),Utrecht, the Netherlands (Drs. Hugenholtz, Heerdink, Stolker, Meijer, and psychosis, or other primary psychosis: amisul- Egberts); the Department of Clinical Pharmacy, TweeSteden Hospital pride, aripiprazole, olanzapine, quetiapine, risper- and St. Elisabeth Hospital, Tilburg, the Netherlands (Dr. Egberts); idone, sertindole, and ziprasidone. For the gap and the Department of Psychiatry, University Medical Center between the end point of inclusion of the studies Groningen, Groningen, the Netherlands (Dr. Nolen). in the Cochrane Reviews and January 2005, we The authors report no financial or other relationships relevant to the subject or preparation of this article. electronically searched the Cochrane Central Corresponding author and reprints: Eibert R. Heerdink, Ph.D., Register of Controlled Trials for any further RCTs Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht in which atypical antipsychotics were compared Institute for Pharmaceutical Sciences (UIPS), P.O. Box 80082, 3508 TB with haloperidol for the same indication. Search Utrecht, the Netherlands (e-mail: [email protected]). terms used were haloperidol and schizophren*
and haloperidol and psychotic*, as well as the
names of the selected atypical antipsychotics for
the years that were not covered by the Cochrane
ince the 1970s, haloperidol has been one of the Reviews. For each study, the required dose and most frequently prescribed antipsychotics world- mean dose of haloperidol were compared with wide. Since then, haloperidol has often been used as a officially recommended doses of haloperidol in comparator in randomized controlled trials (RCTs), in- U.S. (Food and Drug Administration) and U.K.
(British National Formulary) guidelines.
cluding those investigating the atypical antipsychotics. In Data Synthesis: In all of the included studies
these RCTs, atypical antipsychotics were found not only (N = 49), the midpoints of the required doses to be equally as effective as haloperidol against positive were above the midpoint of the official recom- symptoms (hallucinations and delusions) but also to have mended doses in the United States and United a more pronounced effect on the negative symptoms asso- Kingdom for moderately ill patients. In 94%(U.S.) and 80% (U.K.) of the studies, they were ciated with schizophrenia and to have a lower incidence of above the upper border of the recommended extrapyramidal side effects than haloperidol.1,2 However, doses. Compared with recommended doses for many of these studies were criticized for the fact that halo- severely ill patients in both the United Kingdom peridol was used in doses higher than necessary to obtain and United States (range, 6–15 mg daily), in 17 an optimal effect, thus accounting for more side effects.3 studies (35%) the mean actual used dose wasabove the upper dose border for severely ill The objective of our study was to determine the re- quired dose ranges and the actual used doses of haloperi- COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Haloperidol Dose in RCTs With Atypical Antipsychotics dol as a comparator drug in RCTs set up to evaluate the In our review, we used the results of the quality assess- efficacy of atypical antipsychotics in schizophrenia and ment used to select RCTs for the Cochrane Reviews. The to compare these doses with the officially recommended methodological quality of the additional RCTs included in doses for haloperidol in the United States and the United this review was assessed by the first and second authors (G.W.K.H., E.R.H.) using the criteria described by Jadadet al.11 This test gives evidence of the strength of the rela- tionship between allocation concealment and direction ofeffect. Studies with a score of 3 or higher were rated as studies with good internal validity.
First, we searched the Cochrane Library for published We manually examined potential papers to see if Cochrane Reviews and included the reviews in which they met the inclusion criteria. All potentially relevant 1 of the following atypical antipsychotics was evaluated studies were individually assessed by both the first and for the treatment of patients with schizophrenia, schizo- second authors (G.W.K.H., E.R.H.), and, in case of dis- phreniform psychosis, or other primary psychosis: ami- crepancies, consensus was obtained after discussion. If sulpride,4 aripiprazole,5 olanzapine,6 quetiapine,7 ris- multiple papers were published from the same RCT, the peridone,8 sertindole,9 and ziprasidone.10 Studies on clozapine were not included since this antipsychotic isspecifically indicated for treatment of refractory patients.
Second, for the gap between the end point of inclusion Patients were classified as inpatients or outpatients ac- of the studies in the Cochrane Reviews and January cording to their status at the time of inclusion in the RCT.
2005, we electronically searched the Cochrane Central We also collected information on the number of patients Register of Controlled Trials for any further RCTs in who were included in the haloperidol arm of each RCT.
which atypical antipsychotics were compared withhaloperidol for the same indication. The Cochrane Cen- tral Register of Controlled Trials incorporates results of The first outcome was the required dose or dose range group searches of MEDLINE (1966 onwards), EMBASE of haloperidol according to the RCT protocol. In the case (1980 onwards), CINAHL (1982 onwards), PsycINFO of a dose range, the midpoint required dose was calculated.
(1974 onwards), PSYNDEX (1977 onwards), and The second outcome was the actual used dose, defined as LILACS (1982–1999). We included studies containing the mean dose that was used in the RCT and, if available, the terms haloperidol and schizophren* and studies con-
accompanied by the standard deviation and dose range.
taining the terms haloperidol and psychotic*, as well as
If the mean used dose was not available, the median used the names of the selected atypical antipsychotics for the dose was collected. Finally, the midpoint required dose years that were not covered by the Cochrane Reviews.
and mean actual used dose were weighted for the number Therefore, we searched for studies with amisulpride from of patients included in the haloperidol arm of the studies.
2000 onwards, aripiprazole from 2003 onwards, olanza-pine from 1999 onwards, quetiapine from 2003 onwards, risperidone from 2001 onwards, sertindole from 1999 For recommended doses in the United States, we used onwards, and ziprasidone from 1999 onwards.
the registered U.S. dose ranges of haloperidol for adultsas retrieved from official U.S. Food and Drug Administra- tion (FDA) labeling (latest version, 1998)12: for moderate Studies were eligible for inclusion in this review symptomatology, 1–6 mg daily (midpoint = 3.5 mg); for if they met the following inclusion criteria: amisulpride, severe symptomatology and for chronic or resistant pa- aripiprazole, olanzapine, quetiapine, risperidone, sertin- tients and “to achieve prompt control, higher doses may be dole, or ziprasidone was evaluated; oral formulations required in some cases,” 6–15 mg daily (midpoint = 10.5 of haloperidol were used as comparator drug; dosing mg).12 For recommended doses for schizophrenia and information on the required dose (or dose range) of other psychoses in the United Kingdom, we used dose haloperidol according to the study protocol and/or the ranges provided by the British National Formulary (BNF) mean dose that was used in the RCT was published; the 2005 edition13: for initial treatment, 3–9 mg daily (mid- study population consisted of adult psychiatric patients point = 6 mg); for severely affected or resistant patients, aged 18 to 65 years, treated for schizophrenia, schizo- 6–15 mg daily (midpoint = 10.5 mg); and “for resistant phreniform psychosis, or other primary psychosis; ran- schizophrenia, up to 30 mg daily . . . , adjusted according to dom treatment allocation was mentioned in the study; response to lowest effective maintenance dose.”13 Dose and studies were English-language and were published as recommendations for the United States were collected full reports in peer-reviewed journals before January back until 1971, and, for the United Kingdom, back until 1970. No change of dose recommendation was found in COPYRIGHT 2006 PHYSICIANS P
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Table 1. Randomized Controlled Trials (RCTs) Included in the Review
the United States or the United Kingdom since the intro- Compared with the officially recommended doses in the duction of the atypical antipsychotics.
United States,12 in 48 studies (98%) the midpoint requireddoses in the RCT protocol and in 46 studies (94%) the mean actual used doses were above the advised upper dosefor moderate symptomatology (range, 1–6 mg daily) (Fig- From the Cochrane Reviews we identified 89 RCTs in ure 1). Compared with recommended doses in the United which atypical antipsychotics were studied for the treat- Kingdom,13 in 48 studies (98%) the required doses in ment of patients with schizophrenia, schizophreniform the RCT protocol and in 39 studies (80%) the mean actual psychosis, or other primary psychosis. We excluded stud- used doses were above the upper dose border for initial ies in which haloperidol was not the comparator drug dosing (range, 3–9 mg daily). Compared with recom- (N = 40), in which no oral formulation of haloperidol mended doses for severely ill patients in both the United was used (N = 2), for which no dosing information was Kingdom13 and the United States12 (range, 6–15 mg daily), available (N = 2), or that were not published in a peer- in 36 studies (73%) midpoint required dose ranges and in reviewed journal as a full report (N = 8). Eventually, we 26 studies (53%) mean actual used doses were above the included 37 RCTs from the Cochrane Reviews (Table 1).
mean recommended dose (10.5 mg daily). Furthermore, in With our additional literature search, we identified 259 17 studies (35%), the mean actual used dose was above the publications. Subsequently, we excluded studies in which upper dose border for severely ill patients (15 mg daily).
no oral formulation of haloperidol was used (N = 11), that From 1988 to 1994, weighted average required dose and were not published in a peer-reviewed journal as a full re- weighted average actual used dose, respectively, were 17.3 port (N = 105), that were not RCTs (N = 78), that had mg and 18.8 mg; from 1995 to 1999, 12.6 mg and 11.9 mg; been published previously (N = 35), that included pa- and from 2000 to 2004, 11.4 mg and 11.5 mg.
tients not treated for schizophrenia or other psychotic dis-orders (N = 11), that investigated children or the elderly (N = 2), that were not published in English (N = 1), orthat had a Jadad score lower than 3 (N = 2). Eventually, In this review, we found that in more than 90% of all we included 14 additional RCTs, leading to a total of 51 RCTs in which atypical antipsychotics were compared with haloperidol in patients with schizophrenia and other Of these RCTs, 47 provided data on both the required primary psychotic disorders, haloperidol was used in doses dose and the actual used dose of haloperidol in the RCT.
above the upper limit for the officially recommended dose Two studies14,15 did not provide information on the re- range of haloperidol for moderately ill patients (U.S. rec- quired daily dose; 2 other studies16,17 did not provide ommendation) or for initial treatment (U.K. recommen- information on mean actual used dose. Therefore, 49 dations). Compared with the recommended dose for psy- studies provided data on required dose and 49 studies pro- chotic patients “severely affected” (U.K.) or with “severe vided data on actual used dose (Table 2).
symptomatology” (U.S.), we found that in 73% of the Weighted averages of the required daily dose and mean RCTs, the midpoint required doses and, in 53%, the mean actual dose, respectively, of haloperidol were calculated actual used doses were above the mean recommended dose for amisulpride (17.6 and 17.9 mg), aripiprazole (8.9 and of 10.5 mg daily and, in 35% of studies, were even above 10.0 mg), olanzapine (12.4 and 12.0 mg), quetiapine (13.4 the upper border of the recommended dose of 15 mg daily.
and 11.6 mg), sertindole (10.0 and 10.0 mg), ziprasidone High doses of haloperidol are known for not being (10.5 and 9.2 mg), and both risperidone and olanzapine more effective (or for being even less effective) than low doses.18 A meta-analysis found no evidence that high doses COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Haloperidol Dose in RCTs With Atypical Antipsychotics Table 2. Dose and Dose Range of Haloperidol as a Comparator Drug With Atypical Antipsychotics
aValues shown in parentheses are SD except where indicated otherwise.
cValue shown as weighted average.
Symbol: … = unknown.
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Figure 1. Midpoint Required Dose and Mean Actual Used Dose of Haloperidol as a Comparator
Drug Compared With Atypical Antipsychotics
Midpoint Required Dose in the Study ProtocolMean Actual Used Dose in the Study Midpoint Dosing US Moderate (3.5 mg)(range 1–6 mg) affected the efficacy of haloperidol.19 Although one can tant that the dose of the active comparator is optimal. This argue that 1 mg of haloperidol is not an optimal dose, the review suggests that this is not the case and that the results dose response curve of haloperidol begins to flatten out from RCTs should be considered accordingly.
after 3.3 mg. High doses of haloperidol are associatedwith more side effects, particularly extrapyramidal side Drug names: aripiprazole (Abilify), clozapine (Clozaril, FazaClo,and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone effects,19 and may also induce negative symptomatology, explained by an excess of secondary negative symptomsassociated with extrapyramidal side effects.20,21 In a meta-analysis of 52 RCTs that controlled for 1. Meltzer HY. Outcome in schizophrenia: beyond symptom reduction.
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