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 | 2 | 5 | 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 | 4.5 | 6 | 8 | 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 | 4–8 | 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 | 1 | 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 | 3 | 6 | 9 | 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 | 2 | 4 | 6 | 8 | 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 | 8 | 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.