Abstract

Background: Clinicians need to know the right antipsychotic dose for optimized treatment, and the concept of dose equivalence is important for many clinical and scientific purposes. Methods: We refined a method presented in 2003, which was based on the minimum effective doses found in fixed-dose studies. We operationalized the selection process, updated the original findings, and expanded them by systematically searching more recent literature and by including 13 second-generation antipsychotics. To qualify for the minimum effective dose, a dose had to be significantly more efficacious than placebo in the primary outcome of at least one randomized, double-blind, fixed-dose trial. In a sensitivity analysis, 2 positive trials were required. The minimum effective doses identified were subsequently used to derive olanzapine, risperidone, haloperidol, and chlorpromazine equivalents. Results: We reviewed 73 included studies. The minimum effective daily doses/olanzapine equivalents based on our primary approach were: aripiprazole 10 mg/1.33, asenapine 10 mg/1.33, clozapine 300 mg/40, haloperidol 4 mg/0.53, iloperidone 8 mg/1.07, lurasidone 40 mg/5.33, olanzapine 7.5 mg/1, paliperidone 3 mg/0.4, quetiapine 150 mg/20, risperidone 2 mg/0.27, sertindole 12 mg/1.60, and ziprasidone 40 mg/5.33. For amisulpride and zotepine, reliable estimates could not be derived. Conclusions: This method for determining antipsychotic dose equivalence entails an operationalized and evidence-based approach that can be applied to the various antipsychotic drugs. As a limitation, the results are not applicable to specific populations such as first-episode or refractory patients. We recommend that alternative methods also be updated in order to minimize further differences between the methods and risk of subsequent bias.

Introduction

Dose equivalence estimates of antipsychotics are important for many reasons. Clinicians need such information when they switch from one antipsychotic to another one or when they combine antipsychotic drugs. Trialists and meta-analysts need dose equivalence estimates for the design of fair comparisons of antipsychotic drugs,1,2 and whenever the doses of several antipsychotics have to be converted into 1 unit. Finally, the concept is also important for cost calculations and treatment guidelines.

In a comprehensive review, Patel et al3 listed various approaches to define dose equivalence including: the classical flexible-dose chlorpromazine equivalent method published by Davis in 1974,4 the dose-response curve method to define near-to-maximum doses by Davis and Chen,5 methods based on the maximum licensed doses of the various drugs,6,7 the concept of daily defined doses (DDDs) of the World Health Organization,8 and various (expert) consensus methods (eg, Kane et al9, Gardner et al10, Andreasen et al11). Their review made it clear that a gold standard method does not exist.

In 2003, Woods12 introduced an approach in which he identified the minimum effective doses of the 5 second-generation antipsychotics (SGAs) available at that time based on their placebo-controlled, fixed-dose studies, and he subsequently derived chlorpromazine equivalents. Patel et al3 found that it was the most frequently used method (714 cites found in a Web of Science search on July 25, 2013). Since the original article,12 which made recommendations for 5 SGAs and haloperidol based on 15 studies, several further SGAs have been developed and multiple further placebo-controlled trials have been published. In the current systematic review, we therefore (a) refined the method by operationalizing the decision-making process, (b) updated the material, and (c) included 8 additional SGAs.

Methods

Woods12 identified the lowest fixed dose of each SGA that was consistently more efficacious than placebo in the primary outcome (usually the mean change of the Positive and Negative Syndrome Scale [PANSS13] total score or the Brief Psychiatric Rating Scale [BPRS14] total score from baseline in the intention-to-treat dataset). The identified doses were then used to calculate equivalence ratios. For example, if the minimum effective dose of olanzapine was 7.5 mg/d and that of asenapine was 10 mg/d, the asenapine dose that is equivalent to 1 mg/d olanzapine would be 10/7.5 = 1.33 mg/d. We made several modifications (supplementary webappendix 1 presents Wood’s12 original method):

  1. We primarily calculated olanzapine equivalents, because the minimum effective haloperidol dose is less well understood (see “Results” section). For ease of reference, we also present haloperidol and risperidone equivalents. In keeping with Woods,12 we did not investigate the minimum effective chlorpromazine dose, as the chlorpromazine literature is composed entirely of small, old trials,15 which differ in methodological rigor from more recent SGA trials. However, chlorpromazine equivalents were estimated based on the original finding by Davis that 1.6 mg haloperidol corresponds to 100 mg chlorpromazine.4 Woods assumed that 2 mg haloperidol corresponds to 100 mg chlorpromazine,12 which was based on an APA (American Psychiatric Association) guideline statement16 and not empirical evidence.

  2. Woods12 did not operationalize the criterion “consistently superior” and sometimes only one trial was available (so that “consistency” could not be verified). Our primary criterion was that a dose was statistically significantly superior to placebo for the primary outcome in one double-blind randomized controlled trial (RCT). To explore the possibility that minimum effective doses had been missed due to insufficient power, we meta-analyzed the results of lower doses when available. Standardized mean differences (effect size [ES]) expressed as Hedges’s g were calculated together with their 95% CIs based on a fixed-effects model (the use of a random effects model did not change any result). Due to various problems in trial methodology in recent years, such as increasing placebo response17,18 and high dropout rates,19 it is currently difficult to demonstrate statistical superiority. These developments lead to an increasing number of failed trials (studies in which neither the new drug nor the active comparator was more effective than placebo), so that even well-established compounds such as haloperidol20 or olanzapine21 sometimes do not show separation from placebo or that a lower dose was significantly more efficacious than placebo, whereas higher or intermediate doses were not effective.22,23 In this environment, we feel it is unlikely that superiority to placebo is just a chance finding.

    In order to examine what happens if a more conservative approach is considered, we conducted a sensitivity analysis, which required that a dose was efficacious in a second RCT. In essence, this is in keeping with a rule for the registration of a compound by the Food and Drug Administration (FDA). If a dose was supported by only one trial, the next higher dose that was efficacious in another trial qualified for the secondary criterion.

  3. In contrast to Woods,12 we also included RCTs, which used a dose of the same drug that was presumed to be ineffective by the original authors (eg, olanzapine 1 mg/d).

  4. We included fixed-dose studies and trials that were defined as “fixed-dose range” studies by their authors (eg, iloperidone 4–8 vs 10–16 mg/d vs placebo or olanzapine 5 ± 2.5 vs 10 ± 2.5 mg/d vs placebo). For the latter, we conservatively assumed that the upper limit of the dose range was efficacious (Woods12 used the midpoint of the range).

We examined the following SGAs and haloperidol in adult patients with schizophrenia or schizoaffective disorder: amisulpride, aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, and zotepine. We excluded studies in special populations such as adolescents, elderly, first-episode patients, stable patients (mainly relapse-prevention studies), patients with predominant negative symptoms, or patients with treatment resistance (except for clozapine, which is licensed for treatment resistance), as these populations might require different doses. As a result, the findings will not be applicable to these populations.

Our literature search was mainly based on the exhaustive searches for 4 systematic reviews on SGAs by our group.2,24–26 They included the register of the Cochrane Schizophrenia Group (which is compiled by regular systematic searches in more than 15 databases, clinical trial registers, hand searches, and conference proceedings,27 available up to August 2009) and MEDLINE/PubMed, Embase, Cochrane Central, and clinicaltrials.gov (last search: September 2012). We updated the latter searches in June 2013 (for search terms, see supplementary webappendix 2). We also searched the medical reviews that pharmaceutical companies must submit to the FDA, Cochrane reviews comparing SGAs and haloperidol vs placebo,28–30 and Cochrane reviews on optimum SGA doses.31,32 Finally, we sent the draft results section of each antipsychotic to its manufacturer with a request for additional unpublished trials and the possibility for comments. Most manufacturers replied (see “Acknowledgments” section), which increased our confidence that no study was missed. All data were extracted by S.L. and independently verified by M.S. The analyses were conducted with Excel 2010 and Comprehensive Meta-analysis Version 2.33

Results

Supplementary webappendix 3 shows the PRISMA (Preferred Reporting Items for Systematic Reviews) diagram of the search. A description of the 73 included studies is provided in supplementary webappendix 4. The vast majority of the studies lasted 6 weeks (n = 45) or 8 weeks (n = 14), with a range between 3 and 48 weeks and a mean/median of 6.9/6.0 weeks. Table 1 illustrates which doses separated from placebo and the findings are summarized below. Where we describe a dose as being efficacious, this dose was statistically significantly superior to placebo (or a presumed ineffective dose) in the intention-to-treat analyses of the primary outcome based on the original authors’ tests. Table 2 presents minimum effective doses and dose equivalencies.

Table 1.

Results of Placebo-Controlled, Fixed-Dose (Fixed-Dose Range) Studies

 Dose Groups in mg/d  
Amisulpride 100 400 800 1200       
    Puech et al 34   a −       
Aripiprazole 10 15 20 30     
    Cutler et al 35  − −        
    McEvoy et al 36         
    Kane et al 37          
    RGH-MD-04 38           
    Potkin et al 39          
    Study 94202 20 (F) −  −   −     
    Study 93202 40       −     
Asenapine 0.4 0.8 1.6 3.2 4.8 10 20    
    Study 041-002 41  − − −        
    Study 041-013 42     − −      
    Kane et al 43       +b    
    Potkin et al 44           
    Hera 041-021 45       − −    
Clozapinec 100 300 600        
    Simpson et al 46          
Haloperidol 4.5 10 12 15 15±5 16 20 
    Zimbroff et al 47         
    Vichaiya et al 48           
    Garry et al 49    −        
    Simpson et al 50    −        
    Kane et al 43           
    Barbato et al 51      −      
    Meltzer et al 52           
    Kane et al 37           
    Study 049 53      −      
    Garcia et al 54           
    Study 94202 20      −      
    Arvanitis et al 55           
    Potkin et al 56           
    Study 115 57           
    Beasley et al 58           
    Zborowski et al 59           
    Study 93202 40           
    Marder et al 60           
    Chouinard et al 61           − 
    Klieser et al 62           − 
Iloperidone 4–8 10–16 12 12–16 20–24 24   
    Study ILPB202 63  −  −        
    Potkin et al (Study 1) 56  −  −       
    Potkin et al (Study 2) 56          
    Potkin et al (Study 3) 56       −    
    Cutler et al 64           
Lurasidone 20 40 80 120 160      
    Study 049 53 (F) − − −        
    Ogasa et al 65          
    Meltzer et al 66          
    Nasrallah et al 22   − −       
    Nakamura et al 67           
    Loebel et al 68          
    Study D1001002 69   d d        
Olanzapine 5±2.5 10 10±2.5 15 15±2.55     
    Beasley et al 70  −         
    Beasley et al 58   −       
    Beasley et al 71 (F)  e  e  e     
    Kane et al 72    +f        
    Marder et al 73    +f        
    Davidson et al 74    +f        
    Hirayasu et al 75    +f        
    Meltzer et al 66           
    Barbato et al 51           
    Corrigan et al 76           
    Patil et al 77           
    AstraZeneca 78           
    Schmidt et al 79           
    Hera 041-021 45           
    Kinon et al 21      −      
Paliperidone 1.5 12 15     
    Coppola et al 80  −  −        
    Canuso et al 81    g  +g      
    Davidson et al 74         
    Kane et al 72         
    Marder et al 73          
    Hirayasu et al 75           
    Canuso et al 82      +h      
Quetiapine 75 150 <250 250 300 400 450 600 750 800 
    Immediate release (IR)          
    Arvanitis et al 55  −      
    Small et al 83    i        
    Fabre et al 84           
    Lindenmayer et al 23      −   −   
    Kahn et al 85           
    King et al 86        +j    
    11915A 87           
    11916A 88           
    Loebel et al 68           
    Canuso et al 82           k 
    Potkin et al 89         l  l 
    Cutler et al 90           − 
    Extended release (XR)          
    Kahn et al 85         
    Lindenmayer et al 23      −    − 
    Cutler et al 90       −  −  − 
Risperidone 10 12 16    
    Study 0204 60,61,91  +m  +m  +m  +m    
    RIS-USA-72 92          
    Peuskens et al 93   +n  +n  n +n    
    Bose et al 94           
    Potkin et al 89    +o        
    Potkin et al 39           
    Barbato et al 51           
    Casey et al 95           
    Study 041-002 41           
    Potkin et al 44    −        
    Potkin et al 56     +p       
    Study D1001002 69   q         
Sertindole 12 16 20 24      
    Zimbroff et al 47         
    Van Kammen et al 96  − −        
    Zborowski et al 59          
    Hale et al 97    +r r +r      
Ziprasidone 10 40 80 120 160 200     
    Daniel et al 98          
    Goff et al 99 (F) − −   s      
    Keck et al 100   −        
    Study 104 101  − − −        
    Study 115 57         
    Cutler et al 64           
Zotepine 75 150 300        
    Cooper et al 102    +t        
    Cooper et al 103    +t        
    Knoll 104  u u u        
 Dose Groups in mg/d  
Amisulpride 100 400 800 1200       
    Puech et al 34   a −       
Aripiprazole 10 15 20 30     
    Cutler et al 35  − −        
    McEvoy et al 36         
    Kane et al 37          
    RGH-MD-04 38           
    Potkin et al 39          
    Study 94202 20 (F) −  −   −     
    Study 93202 40       −     
Asenapine 0.4 0.8 1.6 3.2 4.8 10 20    
    Study 041-002 41  − − −        
    Study 041-013 42     − −      
    Kane et al 43       +b    
    Potkin et al 44           
    Hera 041-021 45       − −    
Clozapinec 100 300 600        
    Simpson et al 46          
Haloperidol 4.5 10 12 15 15±5 16 20 
    Zimbroff et al 47         
    Vichaiya et al 48           
    Garry et al 49    −        
    Simpson et al 50    −        
    Kane et al 43           
    Barbato et al 51      −      
    Meltzer et al 52           
    Kane et al 37           
    Study 049 53      −      
    Garcia et al 54           
    Study 94202 20      −      
    Arvanitis et al 55           
    Potkin et al 56           
    Study 115 57           
    Beasley et al 58           
    Zborowski et al 59           
    Study 93202 40           
    Marder et al 60           
    Chouinard et al 61           − 
    Klieser et al 62           − 
Iloperidone 4–8 10–16 12 12–16 20–24 24   
    Study ILPB202 63  −  −        
    Potkin et al (Study 1) 56  −  −       
    Potkin et al (Study 2) 56          
    Potkin et al (Study 3) 56       −    
    Cutler et al 64           
Lurasidone 20 40 80 120 160      
    Study 049 53 (F) − − −        
    Ogasa et al 65          
    Meltzer et al 66          
    Nasrallah et al 22   − −       
    Nakamura et al 67           
    Loebel et al 68          
    Study D1001002 69   d d        
Olanzapine 5±2.5 10 10±2.5 15 15±2.55     
    Beasley et al 70  −         
    Beasley et al 58   −       
    Beasley et al 71 (F)  e  e  e     
    Kane et al 72    +f        
    Marder et al 73    +f        
    Davidson et al 74    +f        
    Hirayasu et al 75    +f        
    Meltzer et al 66           
    Barbato et al 51           
    Corrigan et al 76           
    Patil et al 77           
    AstraZeneca 78           
    Schmidt et al 79           
    Hera 041-021 45           
    Kinon et al 21      −      
Paliperidone 1.5 12 15     
    Coppola et al 80  −  −        
    Canuso et al 81    g  +g      
    Davidson et al 74         
    Kane et al 72         
    Marder et al 73          
    Hirayasu et al 75           
    Canuso et al 82      +h      
Quetiapine 75 150 <250 250 300 400 450 600 750 800 
    Immediate release (IR)          
    Arvanitis et al 55  −      
    Small et al 83    i        
    Fabre et al 84           
    Lindenmayer et al 23      −   −   
    Kahn et al 85           
    King et al 86        +j    
    11915A 87           
    11916A 88           
    Loebel et al 68           
    Canuso et al 82           k 
    Potkin et al 89         l  l 
    Cutler et al 90           − 
    Extended release (XR)          
    Kahn et al 85         
    Lindenmayer et al 23      −    − 
    Cutler et al 90       −  −  − 
Risperidone 10 12 16    
    Study 0204 60,61,91  +m  +m  +m  +m    
    RIS-USA-72 92          
    Peuskens et al 93   +n  +n  n +n    
    Bose et al 94           
    Potkin et al 89    +o        
    Potkin et al 39           
    Barbato et al 51           
    Casey et al 95           
    Study 041-002 41           
    Potkin et al 44    −        
    Potkin et al 56     +p       
    Study D1001002 69   q         
Sertindole 12 16 20 24      
    Zimbroff et al 47         
    Van Kammen et al 96  − −        
    Zborowski et al 59          
    Hale et al 97    +r r +r      
Ziprasidone 10 40 80 120 160 200     
    Daniel et al 98          
    Goff et al 99 (F) − −   s      
    Keck et al 100   −        
    Study 104 101  − − −        
    Study 115 57         
    Cutler et al 64           
Zotepine 75 150 300        
    Cooper et al 102    +t        
    Cooper et al 103    +t        
    Knoll 104  u u u        

Note: (+) = statistically significantly better than placebo/very low dose in the primary outcome. (−) = not statistically significantly better than placebo/very low dose in the primary outcome. The light grey background illustrates the minimum effective dose based upon our main (primary) criterion (at least 1 trial with a statistically significant difference compared to placebo/low dose). The dark grey background illustrates the minimum effective dose based upon our more conservative secondary criterion (at least 2 positive studies). If a dose met both criteria, only the dark grey background was used. F = failed study, ie, a study in which neither the new drug nor the active comparator was more effective than placebo. A study is only marked as failed in the row for the new drug, not in the row for the active comparator.

aOnly significantly better than 100 mg/d in an uncontrolled test.

bSignificantly better in the mixed model for repeated measurements analysis, not in the last-observation-carried-forward analysis.

cAs only one study was available, a minimum effective dose could not be defined based on our secondary criterion.

dThe results of this study comparing lurasidone 40 and 80 mg/d with placebo were not obtained.

eLow-dose olanzapine (1 mg/d) as a comparator, not placebo.

fThe highly significant statistical tests of these 4 paliperidone studies, which used olanzapine 10 mg/d only for “assay sensitivity,” were made post hoc tests by us.

g12 mg/d could be reduced to 9 and 6 mg/d and to 3 mg/d.

hThe initial target dose 9 mg/d could be increased to 12 mg/d. The 2-week monotherapy phase of the study was used for the evaluation.

iQuetiapine was more efficacious than placebo at doses higher than 250 mg/d (average 360 mg/d).

jLow-dose quetiapine 50 mg/d as a control, not placebo.

kThe initial target dose 600 mg/d could be increased to 800 mg/d. The 2-week monotherapy phase of the study was used.

lParticipants with ≤70 kg bodyweight received 400 mg/d, which could be increased to 600 mg/d, and those with >70 kg received 600 mg/d, which could be increased to 800 mg/d. The 2-week monotherapy phase results are presented.

mThe US American and Canadian parts of the same study have been published separately.

nLow-dose 1 mg/d risperidone as a comparator, not placebo.

oParticipants with ≤70 kg bodyweight received 4 mg/d and those with >70 kg received 6 mg/d. The 2-week monotherapy phase results are presented.

pThe fixed-dose range was 6–8 mg/d.

qThe risperidone dose of this unpublished study was 4 mg/d.

rLow-dose sertindole 8 mg/d as the comparator, not placebo.

sThe comparator was ziprasidone 4 mg/d, not placebo. Ziprasidone 160 mg/d and haloperidol were only efficacious in the Clinical Global Impression scale, not in the Brief Psychiatric Rating Scale (BPRS).

tThe dose could be reduced to 150 mg/d.

u75, 150, and 300 mg/d were compared with placebo, the results were not obtained.

Table 2.

Minimum Effective Doses of Second-Generation Antipsychotic Drugs and Dose Equivalents

Drug Minimum Effective Dose OLA
1 mg
Equivalent 
RIS
1 mg
Equivalent 
HAL
1 mg
Equivalent 
CPZ
100 mg
Equivalent 
Amisulpride − − − − − 
Aripiprazole 10 1.33 (1) 5 (2.5) 2.5 (2.2) 4 (3.6) 
Asenapine 10 1.33 (1) 5 (2.5) 2.5 (2.2) 4 (3.6) 
Clozapine 300? 40 (30) 150 (75) 75 (67) 120 (107) 
Haloperidol 4 (4.5) 0.53 (0.45) 2 (1.13) 1.6 
Iloperidone 8a (12) 1.07a (1.2) 4a (3) 2a (2.7) 3.2a (4.3) 
Lurasidone 40 5,33 (4) 20 (10) 10 (8.9) 16 (14.2) 
Olanzapine 7.5 (10) 3.75 (2.5) 1.88 (2.2) 3 (3.6) 
Paliperidone 3 (6) 0.4 (0.6) 1.5 (1.5) 0.75 (1.3) 1.2 (2.1) 
Quetiapine 150 (250) 20 (25) 75 (62.5) 37.5 (55.6) 60 (88.9) 
Risperidone 2 (4) 0.27 (0.4) 0.5 (0.9) 0.8 (1.4) 
Sertindole 12 (16) 1.60 (1.6) 6 (4) 3 (3.6) 4.8 (5.7) 
Ziprasidone 40 (80) 5.33 (8) 20 (20) 10 (17.8) 16 (28.4) 
Zotepine − − − − − 
Drug Minimum Effective Dose OLA
1 mg
Equivalent 
RIS
1 mg
Equivalent 
HAL
1 mg
Equivalent 
CPZ
100 mg
Equivalent 
Amisulpride − − − − − 
Aripiprazole 10 1.33 (1) 5 (2.5) 2.5 (2.2) 4 (3.6) 
Asenapine 10 1.33 (1) 5 (2.5) 2.5 (2.2) 4 (3.6) 
Clozapine 300? 40 (30) 150 (75) 75 (67) 120 (107) 
Haloperidol 4 (4.5) 0.53 (0.45) 2 (1.13) 1.6 
Iloperidone 8a (12) 1.07a (1.2) 4a (3) 2a (2.7) 3.2a (4.3) 
Lurasidone 40 5,33 (4) 20 (10) 10 (8.9) 16 (14.2) 
Olanzapine 7.5 (10) 3.75 (2.5) 1.88 (2.2) 3 (3.6) 
Paliperidone 3 (6) 0.4 (0.6) 1.5 (1.5) 0.75 (1.3) 1.2 (2.1) 
Quetiapine 150 (250) 20 (25) 75 (62.5) 37.5 (55.6) 60 (88.9) 
Risperidone 2 (4) 0.27 (0.4) 0.5 (0.9) 0.8 (1.4) 
Sertindole 12 (16) 1.60 (1.6) 6 (4) 3 (3.6) 4.8 (5.7) 
Ziprasidone 40 (80) 5.33 (8) 20 (20) 10 (17.8) 16 (28.4) 
Zotepine − − − − − 

Note: We present the minimum effective doses and the doses in milligrams that are equivalent to 1 mg/d olanzapine (OLA), 1 mg/d risperidone (RIS), 1 mg/d haloperidol (HAL), and 100 mg/d chlorpromazine (CPZ). Numbers in parentheses are the results of the sensitivity analysis (2 positive trials). The results of the sensitivity analysis are only shown if they deviated from the primary analysis. (−): means that no recommendation could be made. (?): the result is very questionable because it is based on a single small study comparing clozapine 300 mg/d with 100 mg/d, but not with placebo.

aExcluding patients with schizoaffective disorder, the minimum effective iloperidone dose based on the primary criterion is 12 mg/d; the resulting equivalence doses (mg/d) are: olanzapine 1.6, risperidone 6, haloperidol 3, and chlorpromazine 4.8.

Amisulpride

The single dose-finding study in acute schizophrenia compared amisulpride 400, 800, and 1200mg/d with a dose of 100 mg/d,34 which the original authors had presumed to be subtherapeutic. It showed a bell-shaped dose-response curve, where 400 and 800 mg/d were associated with the largest reduction in symptoms, however 400 mg/d was significantly more efficacious than 100 mg/d only in an unadjusted test. Amisulpride 100 mg/d was not actually an ineffective dose as it produced a mean 18.4 BPRS total score reduction from baseline (approximately equivalent to 28 points PANSS total score reduction105). It is therefore impossible to derive a minimum effective dose based on our method (see tables 1 and 2).

Aripiprazole

Seven fixed-dose, placebo-controlled studies20,35–40 examined aripiprazole doses between 2 and 30 mg/d. The dose of 2 mg/d was ineffective in 2 studies.20,35 In a single trial, 5 mg/d was more efficacious than placebo only at a few visits, but not at endpoint (primary outcome).35 Meta-analyses of the single 5 mg/d dose35 and the two 2 mg/d doses20,35 (n = 379, ES: 0.18, 95% CI: −0.03 to 0.39, P = .10) or of the 2 mg/d dose groups20,35 (n = 285, ES: 0.13, 95% CI: −0.10 to 0.36, P = .28) were also not significant. A dose of 10 mg/d was more efficacious than placebo in 3 trials35,36,38 and is the minimum effective dose based on the primary criterion and the sensitivity analysis. This is different from the earlier recommendation by Woods12 (15 mg/d) for whom 2 recent studies35,38 were not yet available (see tables 1 and 2). Higher doses consistently separated from placebo, as well, except for 2 unpublished studies.20,40 Study 94202 failed as no aripiprazole dose and also not the active comparator haloperidol (10 mg/d) was found to be effective.20 Study 93202 was negative, because although the active comparator haloperidol (20 mg/d) showed efficacy for the primary outcome, aripiprazole (30 mg/d) separated from placebo only in secondary outcomes.40

Asenapine

Five placebo-controlled, fixed-dose trials41–45 examined asenapine doses between 0.4 and 20 mg/d. In 2 initial studies, doses up to 4.8 mg/d were not found to be efficacious,41,42 although there was a trend when the 4.8 and 3.2 mg/d doses42 were meta-analytically combined (n = 182, ES: 0.29, CI: −0.02 to 0.59, P = .06). An ongoing study is therefore re-examining 5 mg/d.107 A dose of 10 mg/d is currently the minimum effective dose based on both criteria, because it separated from placebo in 243,44 out of 3 studies.43–45 There is one additional negative study, in which asenapine with a dose of neither 10 nor 20 mg/d was efficacious, while the active comparator olanzapine 15 mg/d was effective,45 and another ongoing study is re-examining 10 and 20 mg/d doses.108

Clozapine

Placebo-controlled, dose-finding studies on clozapine were not available. As clozapine is restricted only for use in patients with treatment resistance, we included a small study in this patient group, which found that clozapine 600 and 300 mg/d were better than 100 mg/d.46 Arguably, 300 mg/d is the minimum effective dose based on our primary criterion. The sensitivity analysis could not be conducted, because only one study was available.

Haloperidol

Haloperidol has been frequently used as an additional active comparator in placebo-controlled trials of SGAs, usually at fixed doses that are nowadays considered to be relatively high such as 8 mg/d,43 10 mg/d,20,37,51–54 12 mg/d,55 15 mg/d,56,57,99 15 ± 5 mg/d,58 16 mg/d,59 and 20 mg/d.40,60–62 These doses were generally statistically significantly more efficacious than placebo apart from a few studies, which failed as no treatment was better than placebo20,51,53,62,99; 20 mg/d were also not efficacious in Klieser and Lehmann62 and in Chouinard et al.61 However, the evaluation of the low end of the dose range for haloperidol is suboptimal. In a seven-arm sertindole study, 4, 8, and 16 mg/d haloperidol were all more efficacious than placebo.47 This finding is corroborated by a study from 1971 in which haloperidol doses up to 4.5 mg/d were superior to placebo,48 while 2 other small (52 and 24 participants, respectively), old studies found only a trend for superiority of haloperidol up to 6 mg/d compared with placebo.49,50

Thus, 4 mg/d is the minimum effective haloperidol dose according to our primary criterion, while 4.5 mg/d fulfills that of the sensitivity analysis.

Iloperidone

There were 5 placebo-controlled fixed-dose (or fixed-dose range) studies, which examined iloperidone doses between 4 and 24 mg/d. Two 4 mg/d doses56,63 and their meta- analysis were ineffective (n = 293, ES: 0.12, CI: −0.11 to 0.35, P = .30). A dose of 8 mg/d was also ineffective in 2 trials,56,63 and yet the fixed-dose range of 4–8 mg/d was efficacious in another study.56 The upper limit of this dose range, 8 mg/d, therefore, qualifies for the minimum effective dose according to our primary criterion. A dose of 12 mg/d separated from placebo in a further study56 and is thus the minimum effective dose based on the sensitivity analysis. Higher doses were efficacious, as well, except for the fixed-dose range of 12–16 mg/d in Study 3005 (Potkin Study 3).56

We note that if patients with schizoaffective disorder are excluded (as nowadays required by the FDA63), the minimum effective dose would be 12 mg/d for our primary criterion: In Study 3004,56,63 neither 4–8 nor 12–16 mg/day was efficacious, in Study 3000 (Potkin Study 1) 12 mg/day remained effiacious, while in the Study 3 of Potkin et al.,56,63 both 12–16 and 20–24 mg/d were effective.

Lurasidone

There were 7 fixed-dose, placebo-controlled studies, which examined lurasidone doses between 20 and 160 mg/d.22,53,65–69 The dose of 20 mg/d was not efficacious in a single study, which failed as neither any lurasidone dose (20, 40, and 80 mg/d) nor haloperidol 10 mg/d was significantly superior to placebo.53 The dose of 40 mg/d was efficacious in 265,66 out of 422,53,65,66 trials (one of which was a failed study53) and is therefore the minimum effective dose. Higher doses were usually efficacious, except for 80 mg/d in the failed study53 and 120 mg/d in a study reported by Nasrallah et al.22 Data from study NCT00711269/D100100269 (40 and 80 mg/d) are not available. A study that re-examines 20 mg/d is expected to complete in September 2014.109

Olanzapine

We identified 15 relevant studies, which examined olanzapine doses between 1 and 15 ± 2.5 mg/d.21,45,51,58,66,70–79 One olanzapine 1 mg/d70 dose group and 2 fixed-dose range groups of 5 ± 2.5mg/d did not separate neither from placebo58 nor from the presumed ineffective dose of 1 mg/d olanzapine.71 However, their meta-analysis was significant (n = 393, ES: 0.20, CI: 0.005–0.40, P = .04). Therefore, 7.5 mg/d (the upper range of 5 ± 2.5mg/d) is the minimum effective dose. Higher olanzapine doses (10, 10 ± 2.5, 15, and 15 ± 2.5 mg/d) were more efficacious than placebo in 1345,51,58,66,70,74,75,76–79 out of 15 studies. The exceptions were the recent study on a glutamatergic compound21 and the failed study by Beasley et al 199771 in which only the highest olanzapine dose (15 ± 2.5mg/d) was more efficacious than 1 mg/d, but only in secondary outcomes. The authors commented that olanzapine 1 mg/d was not completely ineffective.71 A dose of 10 mg/d olanzapine is the minimum effective dose based on the sensitivity analysis.

Paliperidone

Seven studies were included, which compared paliperidone doses between 1.5 and 15 mg/d72–75,80–82 with placebo. Paliperidone 1.5 mg/d was not effective in the single study that examined this dose,80 whereas 3 mg/d in a single study74 was efficacious and thus is the minimum effective dose based upon the primary criterion.74 The 6 mg/d dose did separate from placebo in 372,73,75 out of 5 studies72,73,75,80,81 and thus meets the criterion of the sensitivity analysis. Doses higher than 6 mg/d were consistently more efficacious than placebo.72–74,81,82

Quetiapine

We included 12 studies on quetiapine immediate release23,55,68,82–90 and 3 on extended release,23,85,90 which examined doses between 75 and 800 mg/d. While 75 mg/d was ineffective,55 150 mg/d separated from placebo in the single study examining it55 and is the minimum effective dose based upon the primary criterion. The dose of 250 mg/d qualifies for the criterion of the sensitivity analysis (Fabre et al84). Overall determining dose response for quetiapine is not straightforward as higher doses did not separate from placebo in several studies, including quetiapine 800 mg/d arms23,90 (see table 1).

Risperidone

Twelve relevant studies compared risperidone doses between 2 and 16 mg/d with placebo39,41,44,51,56,60,61,69,89,92,94,95 or presumed ineffective risperidone 1 mg/d.93 The dose of 2 mg/d was not more efficacious than placebo in the separately published US part60 of the pivotal study 0204, but it was in the Canadian part61 and overall (see FDA report91). Consequently, 2 mg/d qualifies as the primary minimum effective dose. Risperidone 4 mg/d met the criterion of the sensitivity analysis. It was more efficacious than risperidone 1 mg/d (a presumed ineffective dose) in a large international study93 and it was more efficacious than placebo in a recent trial on cariprazine.94 In RIS-USA-72,92 it separated from placebo in the study’s primary outcome (the number of participants with at least 20% PANSS total score reduction), the superiority in the mean PANSS total score change was only of borderline statistical significance (P = .051). The results of a 4 mg/d risperidone group of a lurasidone study have not been published (Study NCT00711269/D100100269). Risperidone doses of 6 mg/d or higher were consistently more efficacious than placebo in all other studies,39,41,51,56,89,95 except for 6 mg/d in one asenapine trial,44 and 12 mg/d did not separate from risperidone 1 mg/d in the large international study.93

Sertindole

Three placebo-controlled studies47,59,96 and 1 with low-dose sertindole (8 mg/d) as a comparator97 examined doses between 8 and 24 mg/d. The dose of 8 mg/d was not efficacious in the single study comparing it with placebo96 and was therefore used as a “presumed ineffective” dose instead of placebo in another study in which it was confirmed as being less efficacious than 16 and 24 mg/d.97 The dose of 12 mg/d was more efficacious than placebo in 147 out of 2 studies47,96 and is therefore the minimum effective dose fulfilling the primary criterion. The dose of 16 mg/d meets the criterion of the sensitivity analysis.97 Higher doses of 20 mg/d47,59,96 and 24 mg/d47,59,97 were efficacious in 3 trials each.

Ziprasidone

We included 6 studies, which compared ziprasidone doses between 10 and 200 mg/d,57,64,98–101 with placebo or ziprasidone 4 mg/d.99 10 mg/d was not efficacious in 2 trials,99,101 and their meta-analysis was also not significant (n = 127, ES: 0.01, CI: −0.34 to 0.35, P = .96). A dose of 40 mg/d separated from placebo in 1 study57 and is therefore the minimum effective dose according to the primary criterion, which is corroborated by a maintenance study, although it was excluded because it was conducted in patients with a stable presentation.110 A dose of 80 mg/d separated from placebo in 198 out of 2 studies98,101 and therefore—taken together with the positive study on 40 mg/d57—meets the criterion of the sensitivity analysis. Higher doses were consistently efficacious in studies that examined them,57,64,98,100 except 1 failed study99 in which only 160 mg/d and haloperidol 15 mg/d separated from the presumed ineffective dose of 4 mg/d ziprasidone, but only for secondary outcomes.

Zotepine

Data on the only dose-finding study that compared zotepine 75, 150, and 300 mg/d with placebo could not be obtained.104 The only other 2 placebo-controlled trials102,103 employed fixed doses of 300 mg/d and yet these could be reduced to 150 mg/d. The majority of patients stayed on 300 mg/d in 1 trial, but the proportion doing so in the other trial has not been reported.103 In theory, 300 mg/d would be the minimum effective dose, but this finding is very doubtful.

Discussion

We refined, updated, and expanded the frequently used dose equivalence method first presented by Woods in 200312 by including 8 other SGAs and by expanding the database from 1512 to now 73 RCTs. Some minimum effective doses had to be changed, whereas others were corroborated by new supporting evidence.

Authors agree that ideally large RCTs, which compare multiple fixed doses of multiple drugs, would be needed but, given the high number of antipsychotics, it is unlikely that these will ever be available.3,10,12 The key strength of the method presented by Woods12 is that an operationalized, evidence-based criterion can be applied to each antipsychotic. A critical limitation is the question how well the minimum effective doses of each drug could be identified by the dose-finding trials. Most mean ESs of the minimum effective doses were in a small range and thus, by and large, comparable: asenapine 10 mg/d, n = 561, ES: 0.31, CI: 0.14–0.47; iloperidone 8 mg/d, n = 585, ES: 0.24, CI: 0.08–0.40; lurasidone 40 mg/d, n = 705, ES: 0.13, CI: −0.02 to 0.28 (excluding 1 failed study,53 the result was significant, n = 569, ES: 0.23, CI: 0.06–0.39); olanzapine 7.5 mg/d, ES: 0.20, CI: 0.005–0.40; risperidone 2 mg/d, ES: 0.32, CI: 0.02–0.62; sertindole 12 mg/d, ES: 0.36, CI: 0.09–0.62; ziprasidone 40 mg/d, ES: 0.21, CI: 0.01–0.40 (an ES for clozapine could not be calculated). The mean ESs of haloperidol 4 mg/d (n = 139, ES: 0.49, CI: 0.16–0.83), paliperidone 3 mg/d (n = 243, ES: 0.60, CI: 0.34–0.86, but 1.5 mg/d was not effective and even tended to be less efficacious than placebo80), and possibly also aripiprazole 10 mg/d (n = 497, ES: 0.40, CI: 0.22–0.58) were medium sized, so that future studies might reveal that lower doses are effective, as well. Finally, the minimum effective dose of quetiapine (150 mg/d) appears low, but its ES was high (n = 99, ES: 0.70, CI: 0.29–1.10), and it was numerically higher than all other quetiapine doses including 750 mg/d in the pivotal quetiapine study.55 Several negative results for high doses of quetiapine (see table 1) suggest that the dose-response relationship for this antipsychotic is difficult to understand. But the quetiapine example also shows that including ES in the judgment is problematic, because placebo response17,111 and dropout rates19,112 have increased over the decades, and they have been made responsible for small ESs in recent studies in which even well-established drugs such as haloperidol or olanzapine do not separate from placebo.20,21 Consequently, it is difficult to compare ESs from different periods. Moreover, these in part relatively high ESs also demonstrate that the application of the “FDA two studies rule,” as used in the sensitivity analysis, is particularly subject to the small number of trials available, because the doses identified were often higher.

Other limitations are that we excluded studies in specific populations, which may require different doses. RCTs suggest that 2–3 mg/d haloperidol is effective in first-episode patients. Five placebo-controlled, fixed-dose amisulpride studies113–117 suggest that 50 mg/d is the minimum effective dose for patients with predominant negative symptoms.113,116 Moreover, most included trials are registrational studies with limited follow-up and generalizability, and the approach does not take side-effects into account, which in practice need to be balanced with efficacy. Statistical significance depends in part on the sample size. Theoretically, very high sample sizes could enable even very low doses to show some efficacy over placebo. We included a few “fixed-dose range” studies. However, if we had excluded them all, only the minimum effective dose for iloperidone would need to be increased to 12 mg/d.

The relative value of the minimum effective dose method should also be considered in light of the limitations of other methods to define dose equivalence (see also Patel et al3 for a detailed review). All methods (including Woods12) assume linearity, but the dose relationships between drugs could also be different (eg, quadratic), and the dose-response curves are usually sigmoidal.5 Even when consensus methods were used, experts simply assumed linearity.11 Further, as consensus methods9–11 also depend on the knowledge of experts, we wonder whether the extent of their knowledge is likely to fully include all relevant RCTs as this review included 73 RCTs, some of which were unpublished.

The original method proposed by Davis4 estimated chlorpromazine equivalents by calculating the ratio of the mean doses of each antipsychotic and the mean chlorpromazine dose used in flexible-dose trials. This method is not limited by the robustness of the evidence base from which the minimum effective dose is identified, and a larger evidence base may be available. Its major limitation is that drugs can usually only be given in predefined doses ranges which, in extreme cases, may not even include the optimum dose. Moreover, Davis assumed that all first-generation antipsychotics are equally efficacious, but small efficacy differences between SGAs may exist.2,26

Davis and Chen5 constructed dose-response curves from dose-finding studies for each antipsychotic to identify near-to-maximum effective doses (ED95) and median effective doses (ED50). This approach is extensively used in preclinical research and, while this might seem appropriate, it is again hampered by the paucity of available data and inconsistencies of different dose-finding studies of the same drug.

Cochrane meta-analyses on the doses of a few antipsychotics exist.31,32,118 This is the most comprehensive method, but their aim was not to identify dose equivalence. Rather various efficacy and tolerability outcomes were examined to identify the optimum doses of each drug.

DDDs are the “assumed, average, maintenance doses” of drugs for their main indication in adults.3,8 They have been developed by the World Health Organization as a technical metric to measure drug utilization rather than to define dose equivalence. Finally, “maximum licensed methods”6,7 express doses as a percentage of the maximum licensed dose of a drug. For example, the maximum chlorpromazine dose according to the British National Formulary119 is 1000 mg/d, corresponding to 100%. Obviously, whether this method can be used for dose equivalence depends on the premise that the maximum licensed doses are really the maximally efficacious doses. For example, the summary of product characteristics for risperidone indicates that the effective dose range is from 4 to 16 mg/d, although studies have shown that doses higher than 6–8 mg/d are associated only with more side-effects but not with more efficacy.60,61,93

We conclude that, as with all other methods to define dose equivalence, our update and refinement of the minimum effective dose method has strengths and limitations, but that it will be useful in many situations. We recommend that alternative methods also be updated in order to minimize further differences between the methods and risk of subsequent bias.

Supplementary Material

Supplementary material is available at http:// schizophreniabulletin.oxfordjournals.org.

Funding

Supported in part by a grant from the German Federal Ministry of Education and Research, no FKZ: 01KG 0606, GZ: GFKG01100506.

Acknowledgments

We thank Sanofi-Aventis (amisulpride), Merck (asenapine), Bristol-Myers Squibb (aripiprazole), Novartis (clozapine, iloperidone), Sunovion Pharmaceuticals (lurasidone), Eli Lilly (olanzapine), AstraZeneca (quetiapine), Janssen/Johnson & Johnson (paliperidone and risperidone, information on haloperidol could not be obtained), Lundbeck (sertindole), and Astellas (zotepine) for replying to our letters regarding their respective compounds. In the last 3 years, S.L. has received honoraria for lectures from Abbvie, Astra Zeneca, Bristol-Myers Squibb, ICON, Eli Lilly, Janssen, Johnson & Johnson, Roche, Sanofi-Aventis, Lundbeck, and Pfizer and for consulting/advisory boards from Roche, Eli Lilly, Medavante, Bristol-Myers Squibb, Alkermes, Janssen, Johnson & Johnson, and Lundbeck. Eli Lilly has provided medication for a study with S.L. as the primary investigator. S.H. has received honoraria from Janssen-Cilag, Eli Lilly, Sanofi-Aventis, Lundbeck, and Johnson & Johnson; he has accepted travel or hospitality payment from Janssen-Cilag, Sanofi-Aventis, Johnson & Johnson, Pfizer, Bristol-Myers Squibb, AstraZeneca, Lundbeck, Novartis, and Eli Lilly; he has participated in clinical trials sponsored or supported by Eli Lilly, Janssen Cilag, Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, Otsuka, Lundbeck, Novartis, Servier, Pierre Fabre, Pfizer, Organon, Roche, and Merck; and he has participated in advisory activities and boards for Janssen, Johnson & Johnson, Eli Lilly, Lundbeck, Otsuka, and Roche. M.X.P. holds a Clinician Scientist Award supported by the National Institute for Health Research and has also received consultancy fees, lecturing honoraria, and/or research funding from Janssen, Lilly, Endo, Lundbeck, Otsuka, and Wyeth. M.X.P. has previously worked on clinical drug trials for Janssen and Amgen is currently working on a clinical study supported by Lundbeck. In the past, S.W.W. has received grant funding from Glaxo, Kali-Duphar, Pfizer, Medi-Physics, Hoffman-LaRoche, Sandoz, Janssen, AstraZeneca, Sanofi-Synthelabo, Laxdale, Eli Lilly, UCB Pharma, Bristol-Myers Squibb, and Glytech Pharma. Also in the past, he has received consultancy fees from Otsuka, UCB Pharma, and Merck. He currently holds an investigator-initiated grant from Pfizer. M.S. and J.M.D. have no conflict of interest to declare.

References

1.
Heres
S
Davis
J
Maino
K
Jetzinger
E
Kissling
W
Leucht
S
.
Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics
.
Am J Psychiatry
 
2006
;
163
:
185
194
.
2.
Leucht
S
Cipriani
A
Spineli
L
et al
Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis
.
Lancet
 
2013
;
382
:
951
962
.
3.
Patel
MX
Arista
IA
Taylor
M
Barnes
TR
.
How to compare doses of different antipsychotics: a systematic review of methods
.
Schizophr Res
 .
2013
;
149
:
141
148
.
4.
Davis
JM
.
Dose equivalence of the antipsychotic drugs
.
J Psychiatr Res
 .
1974
;
11
:
65
69
.
5.
Davis
JM
Chen
N
.
Dose response and dose equivalence of antipsychotics
.
J Clin Psychopharmacol
 .
2004
;
24
:
192
208
.
6.
Milton
J
Lawton
J
Buckley
A
.
Neuroleptic prescribing practice
.
Psychiatr Bull
 .
1995
;
19
:
575
576
.
7.
Mace
S
Taylor
D
.
A prescription survey of antipsychotic use in England and Wales following the introduction of NICE guidance
.
Int J Psych Clin Pract
 .
2005
;
9
:
124
126
.
8.
WHO
.
Collaborating Centre for Drug Statistics Methodology
 .
Oslo, Norway
:
ATC Index with DDDs
;
2012
.
9.
Kane
JM
Leucht
S
Carpenter
D
Docherty
JP
.
Optimising pharmacologic treatment of psychotic disorders
.
J Clin Psychiatry
 
2003
;
64
(
suppl 12
):
1
100
.
10.
Gardner
DM
Murphy
AL
O’Donnell
H
Centorrino
F
Baldessarini
RJ
.
International consensus study of antipsychotic dosing
.
Am J Psychiatry
 
2010
;
167
:
686
693
.
11.
Andreasen
NC
Pressler
M
Nopoulos
P
Miller
D
Ho
BC
.
Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs
.
Biol Psychiatry
 
2010
;
67
:
255
262
.
12.
Woods
SW
.
Chlorpromazine equivalent doses for the newer atypical antipsychotics
.
J Clin Psychiatry
 
2003
;
64
:
663
667
.
13.
Kay
SR
Fiszbein
A
Opler
LA
.
The Positive And Negative Syndrome Scale (PANSS) for schizophrenia
.
Schizophr Bull
 .
1987
;
13
:
261
276
.
14.
Overall
JE
Gorham
DR
.
The Brief Psychiatric Rating Scale
.
Psychol Rep
 .
1962
;
10
:
790
812
.
15.
Adams
CE
Awad
G
Rathbone
J
.
Chlorpromazine versus placebo for schizophrenia
.
Cochrane Database Syst Rev
 .
2007
;
2
:
CD000284
.
16.
Lehman
AF
Lieberman
JA
Dixon
LB
et al
;
American Psychiatric Association; Steering Committee on Practice Guidelines
.
Practice guideline for the treatment of patients with schizophrenia, second edition
.
Am J Psychiatry
 
2004
;
161
:
1
56
.
17.
Khin
NA
Chen
YF
Yang
Y
Yang
P
Laughren
TP
.
Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration
.
J Clin Psychiatry
 
2012
;
73
:
856
864
.
18.
Kemp
AS
Schooler
NR
Kalali
AH
et al
What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it?
Schizophr Bull
 .
2010
;
36
:
504
509
.
19.
Spineli
LM
Leucht
S
Cipriani
A
Higgins
JP
Salanti
G
.
The impact of trial characteristics on premature discontinuation of antipsychotics in schizophrenia
.
Eur Neuropsychopharmacol
 .
2013
;
23
:
1010
1016
.
20.
Study 94202
.
Center for Drug Evaluation and Research. Application Number 21-436. Medical Review(s)
;
2002
. http://www.fda.gov/. Accessed January 21, 2014.
21.
Kinon
BJ
Zhang
L
Millen
BA
et al
;
HBBI Study Group
.
A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia
.
J Clin Psychopharmacol
 .
2011
;
31
:
349
355
.
22.
Nasrallah
HA
Silva
R
Phillips
D
et al
Lurasidone for the treatment of acutely psychotic patients with schizophrenia: a 6-week, randomized, placebo-controlled study
.
J Psychiatr Res
 .
2013
;
47
:
670
677
.
23.
Lindenmayer
JP
Brown
D
Liu
S
Brecher
M
Meulien
D
.
The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study
.
Psychopharmacol Bull
 .
2008
;
41
:
11
35
.
24.
Leucht
S
Arbter
D
Engel
RR
Kissling
W
Davis
JM
.
How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials
.
Mol Psychiatry
 
2009
;
14
:
429
447
.
25.
Leucht
S
Komossa
K
Rummel-Kluge
C
et al
A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia
.
Am J Psychiatry
 
2009
;
166
:
152
163
.
26.
Leucht
S
Corves
C
Arbter
D
Engel
RR
Li
C
Davis
JM
.
Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis
.
Lancet
 
2009
;
373
:
31
41
.
27.
Adams
CE
Coutinho
E
Davis
JM
et al
Cochrane Schizophrenia Group in the Cochrane Library
 .
Chichester, UK
:
John Wiley & Sons Ltd
;
2011
.
28.
Belgamwar
RB
El-Sayeh
HG
.
Aripiprazole versus placebo for schizophrenia
.
Cochrane Database Syst Rev
 .
2011
;
8
:
CD006622
.
29.
Rattehalli
RD
Jayaram
MB
Smith
M
.
Risperidone versus placebo for schizophrenia
.
Cochrane Database Syst Rev
 .
2010
;
1
:
CD006918
.
30.
Joy
CB
Adams
CE
Laurie
S
.
Haloperidol versus placebo for schizophrenia
.
Cochrane Database Syst Rev
 .
2007
;
2
:
CD003082
.
31.
Li
C
Xia
J
Wang
J
.
Risperidone dose for schizophrenia
.
Cochrane Database Syst Rev
 .
2009
;
4
:
CD007474
.
32.
Waraich
P
Adams
C
Hammill
K
Marti
J
Roque
M
.
Haloperidol dose for the acutely ill phase of schizophrenia
.
Cochrane Database Syst Rev
 .
2002
;
2
:
CD001951
.
33.
Borenstein
M
Hedges
LV
Higgins
JPT
Rothstein
H
.
Comprehensive Meta-analysis Version 2
;
2006
. www.meta-analysis.com. Accessed January 21, 2014.
34.
Puech
A
Fleurot
O
Rein
W
.
Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group
.
Acta Psychiatr Scand
 .
1998
;
98
:
65
72
.
35.
Cutler
AJ
Marcus
RN
Hardy
SA
O’Donnell
A
Carson
WH
McQuade
RD
.
The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia
.
CNS Spectr
 .
2006
;
11
:
691
702; quiz 719
.
36.
McEvoy
JP
Daniel
DG
Carson
WH
Jr
McQuade
RD
Marcus
RN
.
A randomized, double-blind, placebo-controlled, study of the efficacy and safety of aripiprazole 10, 15 or 20mg/day for the treatment of patients with acute exacerbations of schizophrenia
.
J Psychiatr Res
 .
2007
;
41
:
895
905
.
37.
Kane
JM
Carson
WH
Saha
AR
et al
Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder
.
J Clin Psychiatry
 
2002
;
63
:
763
771
.
38.
Forest Laboratories I. Forest Laboratories, Inc. and Gedeon Richter Plc
.
Announce Results From Two Positive Phase III Trials With the Investigational Antipsychotic Cariprazine for the Treatment of Schizophrenia
;
2012
. http://news.frx.com/press-release/product-news/forest-laboratories-inc-and-gedeon-richter-plc-announce-positive-phase-ii. Accessed
August 9, 2014
.
39.
Potkin
SG
Saha
AR
Kujawa
MJ
et al
Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder
.
Arch Gen Psychiatry
 
2003
;
60
:
681
690
.
40.
93202 S.
Center for Drug Evaluation and Research. Application Number 21-436. Medical Review(s)
;
2002
. http://www.fda.gov/. Accessed January 21, 2014.
41.
Study 041-002
.
Center for Drug Evaluation and Research. Application Number 22-117. Medical Review(s)
;
2009
. http://www.fda.gov/. Accessed January 21, 2014.
42.
Study 041-013
.
Center for Drug Evaluation and Research. Application Number 200603. Medical Review(s)
;
2009
. http://www.fda.gov/. Accessed January 21, 2014.
43.
Kane
JM
Cohen
M
Zhao
J
Alphs
L
Panagides
J
.
Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia
.
J Clin Psychopharmacol
 .
2010
;
30
:
106
115
.
44.
Potkin
SG
Cohen
M
Panagides
J
.
Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial
.
J Clin Psychiatry
 
2007
;
68
:
1492
1500
.
45.
041-021 SH
.
A multicenter, randomized, double-blind, fixed-dose, 6-week trial of the efficacy and safety of asenapine compared with placebo using olanzapinepositive control in subjects with an acute exacerbation of schizophrenia. Center for Drug Evaluation and Research. Application Number 22–117. Medical Review(s)
;
2009
. http://www.fda.gov/. Accessed January 21, 2014.
46.
Simpson
GM
Josiassen
RC
Stanilla
JK
et al
Double-blind study of clozapine dose response in chronic schizophrenia
.
Am J Psychiatry
 
1999
;
156
:
1744
1750
.
47.
Zimbroff
DL
Kane
JM
Tamminga
CA
et al
Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group
.
Am J Psychiatry
 
1997
;
154
:
782
791
.
48.
Vichaiya
V
.
Clinical trial of haloperidol in schizophrenia
.
J Psychiatric Ass Thailand
 
1971
;
16
:
31
43
.
49.
Garry
JW
Leonard
TJ
.
Haloperidol: a controlled trial in chronic schizophrenia
.
J Ment Sci
 .
1962
;
108
:
105
107
.
50.
Simpson
GM
Angus
JW
Edwards
JG
.
A controlled study of haloperidol in chronic schizophrenia
.
Curr Ther Res Clin Exp
 .
1967
;
9
:
407
412
.
51.
Barbato
L
Newcomer
J
Heisterberg
J
Yeung
P
Shapira
N
.
Efficacy and metabolic profile of bifeprunox in patients with schizophrenia
.
11th International Congress on Schizophrenia Research
;
March 28 to April 1, 2007
;
Colorado Springs,
CO
.
52.
Meltzer
HY
Arvanitis
L
Bauer
D
Rein
W
;
Meta-Trial Study Group
.
Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder
.
Am J Psychiatry
 
2004
;
161
:
975
984
.
53.
Study 049
.
A 6-week, double-blind, randomized, fixed dose, parallel-group study of the efficacy and safety of three dose levels of SM-13496 (lurasidone) compared to placebo and haloperidol in patients with schizophrenia who are experiencing an acute exacerbation of symptoms. Center for Drug Evaluation and Research. Application Number 200603. Medical Review(s)
;
2010
. http://www.fda.gov/. Accessed January 21, 2014.
54.
Garcia
E
Robert
M
Peris
F
Nakamura
H
Sato
N
Terazawa
Y
.
The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia: a randomized, double-blind, placebo-controlled, multicentre study
.
CNS Drugs
 
2009
;
23
:
615
625
.
55.
Arvanitis
LA
Miller
BG
.
Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group
.
Biol Psychiatry
 
1997
;
42
:
233
246
.
56.
Potkin
SG
Litman
RE
Torres
R
Wolfgang
CD
.
Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies
.
J Clin Psychopharmacol
 .
2008
;
28
:
S4
11
.
57.
Study 2000
.
Center for Drug Evaluation and Research Approval Package for Application Number 20-825. Medical Review
;
2000
. http://www.fda.gov/. Accessed January 21, 2014.
58.
Beasley
CM
Jr
Tollefson
G
Tran
P
Satterlee
W
Sanger
T
Hamilton
S
.
Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial
.
Neuropsychopharmacology
 
1996
;
14
:
111
123
.
59.
Zborowski
J
Schmitz
P
Staser
J
et al
Efficacy and safety of sertindole in a trial of schizophrenic patients
.
Biol Psychiatry
 
1995
;
37
:
661
662
.
60.
Marder
SR
Meibach
RC
.
Risperidone in the treatment of schizophrenia
.
Am J Psychiatry
 
1994
;
151
:
825
835
.
61.
Chouinard
G
Jones
B
Remington
G
et al
A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients
.
J Clin Psychopharmacol
 .
1993
;
13
:
25
40
.
62.
Klieser
E
Lehmann
E
.
Experimental examination of trazodone
.
Clin Neuropharmacol
 .
1989
;
12
(
suppl 1
):
S18
S24
.
63.
FDA
.
Drug Approval Package. Fanapt (Iloperidone) Tablets
;
2009
. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022192s000TOC.cfm. Accessed
June 12, 2009
.
64.
Cutler
AJ
Kalali
AH
Weiden
PJ
Hamilton
J
Wolfgang
CD
.
Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia
.
J Clin Psychopharmacol
 .
2008
;
28
:
S20
S28
.
65.
Ogasa
M
Kimura
T
Nakamura
M
Guarino
J
.
Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study
.
Psychopharmacology (Berl)
 .
2013
;
225
:
519
530
.
66.
Meltzer
HY
Cucchiaro
J
Silva
R
et al
Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study
.
Am J Psychiatry
 
2011
;
168
:
957
967
.
67.
Nakamura
M
Ogasa
M
Guarino
J
et al
Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial
.
J Clin Psychiatry
 
2009
;
70
:
829
836
.
68.
Loebel
A
Cucchiaro
J
Sarma
K
et al
Efficacy and safety of lurasidone 80mg/day and 160mg/day in the treatment of schizophrenia: a randomized, double-blind, placebo- and active-controlled trial
.
Schizophr Res
 .
2013
;
145
:
101
109
.
69.
Dainippon Sumitomo Pharma
.
Study of SM-13496 (Lurasidone HCl) in Patients With Schizophrenia
. http://clinicaltrials.gov/show/ NCT00711269. Accessed
July 22, 2013
.
70.
Beasley
CM
Jr
Sanger
T
Satterlee
W
Tollefson
G
Tran
P
Hamilton
S
.
Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial
.
Psychopharmacology (Berl)
 .
1996
;
124
:
159
167
.
71.
Beasley
CM
Jr
Hamilton
SH
Crawford
AM
et al
Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial
.
Eur Neuropsychopharmacol
 .
1997
;
7
:
125
137
.
72.
Kane
J
Canas
F
Kramer
M
et al
Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial
.
Schizophr Res
 .
2007
;
90
:
147
161
.
73.
Marder
SR
Kramer
M
Ford
L
et al
Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study
.
Biol Psychiatry
 
2007
;
62
:
1363
1370
.
74.
Davidson
M
Emsley
R
Kramer
M
et al
Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study
.
Schizophr Res
 .
2007
;
93
:
117
130
.
75.
Hirayasu
Y
Tomioka
M
Iizumi
M
Kikuchi
H
.
A double-blind, placebo-controlled, comparative study of paliperidone extended release (ER) tablets in patients with schizophrenia
.
Jpn J Clin Psychopharmacol
 .
2010
;
13
:
2077
2103
.
76.
Corrigan
MH
Gallen
CC
Bonura
ML
Merchant
KM
;
Sonepiprazole Study Group
.
Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial
.
Biol Psychiatry
 
2004
;
55
:
445
451
.
77.
Patil
ST
Zhang
L
Martenyi
F
et al
Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial
.
Nat Med
 .
2007
;
13
:
1102
1107
.
78.
AstraZeneca
.
Phase IIA Study in Patients With Schizophrenia
;
2012
. http://clinicaltrials.gov/show/NCT00686998. Accessed January 21, 2014.
79.
Schmidt
ME
Kent
JM
Daly
E
et al
A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D(2) receptor antagonist in the treatment of acute exacerbation of schizophrenia
.
Eur Neuropsychopharmacol
 .
2012
;
22
:
721
733
.
80.
Coppola
D
Melkote
R
Lannie
C
et al
Efficacy and safety of paliperidone extended release 1.5mg/day - a double-blind, placebo- and active-controlled, study in the treatment of patients with schizophrenia
.
Psychopharmacol Bull
 .
2011
;
44
:
1
19
.
81.
Canuso
CM
Lindenmayer
JP
Kosik-Gonzalez
C
et al
A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder
.
J Clin Psychiatry
 
2010
;
71
:
587
598
.
82.
Canuso
CM
Dirks
B
Carothers
J
et al
Randomized, double-blind, placebo-controlled study of paliperidone extended-release and quetiapine in inpatients with recently exacerbated schizophrenia
.
Am J Psychiatry
 
2009
;
166
:
691
701
.
83.
Small
JG
Hirsch
SR
Arvanitis
LA
Miller
BG
Link
CG
.
Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group
.
Arch Gen Psychiatry
 
1997
;
54
:
549
557
.
84.
Fabre
LF
Jr
Arvanitis
L
Pultz
J
Jones
VM
Malick
JB
Slotnick
VB
.
ICI 204,636, a novel, atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia
.
Clin Ther
 .
1995
;
17
:
366
378
.
85.
Kahn
RS
Schulz
SC
Palazov
VD
et al
;
Study 132 Investigators
.
Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study
.
J Clin Psychiatry
 
2007
;
68
:
832
842
.
86.
King
DJ
Link
CG
Kowalcyk
B
.
A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia
.
Psychopharmacology (Berl)
 .
1998
;
137
:
139
146
.
87.
Lundbeck
.
Study 11915A: a one-year multi-national, multi-centre, randomised, double-blind, parallel-group, fixed-dose bifeprunox study combining a 12-week placebo-controlled, quetiapine referenced phase with a 12-month quetiapine-controlled phase in patients with schizophrenia
. http://clinicaltrials.gov/show/NCT00704509. Assessed
July 22, 2013
.
88.
Lundbeck
.
Study 11916A: a one-year multi-national, multi-centre, randomised, double-blind, parallel-group, fixed-dose bifeprunox study combining a 12-week placebo-controlled, quetiapine referenced phase with a 12-month quetiapine-controlled phase in patients with schizophrenia
. http://clinicaltrials.gov/show/NCT00658645. Assessed
July 22, 2013
.
89.
Potkin
SG
Gharabawi
GM
Greenspan
AJ
et al
A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization
.
Schizophr Res
 .
2006
;
85
:
254
265
.
90.
Cutler
AJ
Tran-Johnson
T
Kalali
A
Aström
M
Brecher
M
Meulien
D
.
A failed 6-week, randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned
.
Psychopharmacol Bull
 .
2010
;
43
:
37
69
.
91.
Administration FaD
.
Risperdal (Risperidone) NDA 20-272 Review and Evaluation of Clinical Data. Available on request from FDA via Freedom of Information Act
;
1993
. http://www.fda.gov/. Accessed January 21, 2014.
92.
1996 SR-U-
.
Office of Clinical Pharmacology and Biopharmacy Review. NDA Number: 20272. Janssen-Cilag, data on file
;
1996
.
93.
Peuskens
J
.
Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Risperidone Study Group
.
Br J Psychiatry
 
1995
;
166
:
712
26; discussion 727
.
94.
Bose
A
Li
D
Migliore
R
.
The efficacy and safety of the novel antipsychotic cariprazine in acute exacerbation of schizophrenia
.
Poster Presentation 1-73, NCDEU 50th Annual Meeting
;
June 14–17, 2010
;
Boca Raton, FL
.
95.
Casey
DE
Sands
EE
Heisterberg
J
Yang
HM
.
Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study
.
Psychopharmacology (Berl)
 .
2008
;
200
:
317
331
.
96.
van Kammen
DP
McEvoy
JP
Targum
SD
Kardatzke
D
Sebree
TB
.
A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia
.
Psychopharmacology (Berl)
 .
1996
;
124
:
168
175
.
97.
Hale
A
Azorin
JM
Kasper
S
et al
Sertindole improves both the positive and negative symptoms of schizophrenia: results of a phase III trial
.
Int J Psych Clin Pract
 .
2000
;
4
:
55
62
.
98.
Daniel
DG
Zimbroff
DL
Potkin
SG
Reeves
KR
Harrigan
EP
Lakshminarayanan
M
.
Ziprasidone 80mg/day and 160mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group
.
Neuropsychopharmacology
 
1999
;
20
:
491
505
.
99.
Goff
DC
Posever
T
Herz
L
et al
An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder
.
J Clin Psychopharmacol
 .
1998
;
18
:
296
304
.
100.
Keck
P
Jr
Buffenstein
A
Ferguson
J
et al
Ziprasidone 40 and 120mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial
.
Psychopharmacology (Berl)
 .
1998
;
140
:
173
184
.
101.
Study 104
.
Center for Drug Evaluation and Research Approval Package for Application Number 20-825. Medical Review
;
1998
. http://www.fda.gov/. Accessed January 21, 2014.
102.
Cooper
SJ
Tweed
J
Raniwalla
J
Butler
A
Welch
C
.
A placebo-controlled comparison of zotepine versus chlorpromazine in patients with acute exacerbation of schizophrenia
.
Acta Psychiatr Scand
 .
2000
;
101
:
218
225
.
103.
Cooper
SJ
Butler
A
Tweed
J
Welch
C
Raniwalla
J
.
Zotepine in the prevention of recurrence: a randomised, double-blind, placebo-controlled study for chronic schizophrenia
.
Psychopharmacology (Berl)
 .
2000
;
150
:
237
243
.
104.
Pharmaceuticals K
.
A multicentre, double-blind, placebo-controlled, parallel-group, dose-ranging study to evaluate the efficacy, safety and tolerability of zotepine 75, 150 and 300 mg daily doses in the treatment of acute schizophrenia. Study Reference No BPI 1201
;
1996
.
105.
Leucht
S
Rothe
P
Davis
JM
Engel
RR
.
Equipercentile linking of the BPRS and the PANSS
.
Eur Neuropsychopharmacol
 .
2013
;
23
:
956
959
.
106.
041-022 SH
.
A multicenter, randomized, double-blind, flexible-dose, 6-week trial of the efficacy and safety of asenapine compared with placebo using olanzapinepositive control in subjects with an acute exacerbation of schizophrenia. Center for Drug Evaluation and Research. Application Number 22-117. Medical Review(s)
;
2009
. http://www.fda.gov/. Accessed January 21, 2014.
107.
NCT01617187
.
A Study of the Efficacy and Safety of Asenapine in Participants With an Acute Exacerbation of Schizophrenia (P05688 AM2)
;
2012
. http://clinicaltrials.gov/ct2/show/NCT01617187. Accessed January 21, 2014.
108.
NCT01098110
.
6-Week Trial of the Efficacy and Safety of Asenapine Compared to Placebo in Subjects With an Acute Exacerbation of Schizophrenia (Study P06124 AM3)
;
2012
. http://clinicaltrials.gov/show/NCT01098110. Accessed January 21, 2014.
109.
NCT01821378
.
Lurasidone Low-Dose - High-Dose Study Study
;
2013
. http://clinicaltrials.gov/show/NCT01821378. Accessed January 21, 2014.
110.
Arato
M
O′Connor
R
Meltzer
HY
.
A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study
.
Int Clin Psychopharmacol
 .
2002
;
17
:
207
215
.
111.
Alphs
L
Benedetti
F
Fleischhacker
WW
Kane
JM
.
Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it?
Int J Neuropsychopharmacol
 .
2012
;
15
:
1003
1014
.
112.
Kemmler
G
Hummer
M
Widschwendter
C
Fleischhacker
WW
.
Dropout rates in placebo-controlled and active-control clinical trials of antipsychotic drugs: a meta-analysis
.
Arch Gen Psychiatry
 
2005
;
62
:
1305
1312
.
113.
Oosthuizen
P
Emsley
R
Jadri Turner
H
Keyter
N
.
A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis
.
The international journal of neuropsychopharmacology
 .
2004
;
7
:
125
131
.
114.
Kapur
S
Zipursky
R
Jones
C
Remington
G
Houle
S
.
Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia
.
Am J Psychiatry. Apr
 
2000
;
157
(
4
):
514
520
.
115.
Boyer
P
Lecrubier
Y
Puech
AJ
Dewailly
J
Aubin
F
.
Treatment of negative symptoms in schizophrenia with amisulpride
.
Br J Psychiatry
 
1995
;
166
:
68
72
.
116.
Danion
JM
Rein
W
Fleurot
O
.
Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride.
.
Am J Psychiatry
 
1999
;
156
:
610
616
.
117.
Loo
H
Poirier-Littre
MF
Theron
M
Rein
W
Fleurot
O
.
Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia
.
Br J Psychiatry
 
1997
;
170
:
18
22
.
118.
Liu
X
De Haan
S
.
Chlorpromazine dose for people with schizophrenia
.
Cochrane Database Syst Rev
 .
2009
;
2
:
CD007778
.
119.
Committee
JF
.
British National Formulary
 .
64
ed.
London, UK
:
Royal Pharmaceutical Society and BMJ Publishing Group Ltd
;
2012
.

Supplementary data