Comparison of the efficacy and safety of 4 and 2 mg/day brexpiprazole for acute schizophrenia: a meta-analysis of double-blind, randomized placebo-controlled trials

Figures & data

Table 1 Study, patient, and treatment characteristics of the included double-blind, randomized, placebo-controlled trials

	Correll et al^Citation4 (Phase III, NCT01396421)	Japan 2018^Citation7 (Phase II/III, NCT01451164)	Kane 2015^Citation5 (Phase III, NCT01393613)
Patients	Experienced an acute exacerbation of psychotic symptoms and marked deterioration of usual function and would benefit from hospitalization or continued hospitalization for treatment. BPRS T score ≥40 and score of ≥4 on two or more BPRS items (hallucinatory behavior, unusual thought content, conceptual disorganization, or suspiciousness)	Experienced an acute exacerbation of psychotic symptoms and marked deterioration of usual function and would benefit from hospitalization or continued hospitalization for treatment. BPRS T score ≥40 and score of ≥4 on two or more BPRS items (hallucinatory behavior, unusual thought content, conceptual disorganization, or suspiciousness)	Experienced an acute exacerbation of psychotic symptoms and marked deterioration of usual function and would benefit from hospitalization or continued hospitalization for treatment. BPRS T score ≥40 and score of ≥4 on two or more BPRS items (hallucinatory behavior, unusual thought content, conceptual disorganization, or suspiciousness)
14 days screening phase	Washout from previous antipsychotics (≥7 days) and prohibited concomitant medications	Washout from previous antipsychotics (≥7 days) and prohibited concomitant medications	Washout from previous antipsychotics (≥7 days) and prohibited concomitant medications
Countries (%)	United States (35.8), Ukraine (18.1), Romania (17.1), Serbia (11.8), Latvia (4.9), Malaysia (3.3), Japan (3.0), Poland (2.5), South Korea (2.4), and Canada (1.1)	Japan (100)	Colombia (NR), Croatia (NR), Mexico (NR), Philippines (NR), Russia (NR), Slovakia (NR), Taiwan (NR), and United States (NR)
Diagnosis	DSM-IV-TR diagnosis of schizophrenia confirmed by MINI	DSM-IV-TR diagnosis of schizophrenia confirmed by MINI	DSM-IV-TR diagnosis of schizophrenia confirmed by MINI
Number of patients (PBO/BRE2/BRE4)	184/182/180	116/115/113	184/186/184
Age (mean age ± SD: PBO/BRE2/BRE4)	18–65 years	18–64 years	18–65 years
	(39.7±10.8/39.6±10.2/40.8±11.0)	(45.0±11.9/43.3±12.0/44.1±11.9)	(39.3±10.8/36.9±10.9/38.6±11.0)
% male (PBO/BRE2/BRE4)	64.1/61.0/61.7	44.0/53.0/48.7	60.3/65.6/61.4
% antipsychotic polypharmacy and high-dose prescription patientsa (PBO/BRE2/BRE4)	1.10/0.00/2.20	6.20/6.20/11.0	0.00/0.00/0.00
Mean PANSS T at baseline ± SD (PBO/BRE2/BRE4)	95.9±11.5/95.9±13.7/94.9±12.2	97.2±19.3/96.6±19.2/96.4±15.7	94.8±13.0/96.3±12.8/95.1±12.5
Result: % discontinuation rate due to all cause (PBO/BRE2/BRE4)	40.2/31.9/32.8	39.7/29.6/39.8	35.9/30.6/29.3
Result: PANSS T scoreb	BRE4 > PBO, BRE2 > PBO	BRE4 = PBO, BRE2 > PBO	BRE4 > PBO, BRE2 = PBO
Result: PANSS P scoreb	BRE4 > PBO, BRE2 > PBO	BRE4 = PBO, BRE2 = PBO	BRE4 > PBO, BRE2 = PBO
Result: PANSS N scoreb	BRE4 > PBO, BRE2 > PBO	BRE4 > PBO, BRE2 > PBO	BRE4 > PBO, BRE2 = PBO
Result: response rateb,c	BRE4 > PBO, BRE2 > PBO	BRE4 = PBO, BRE2 = PBO	BRE4 > PBO, BRE2 = PBO

Notes:

a Criteria of antipsychotic polypharmacy and high-dose prescription patients were administration of >3 antipsychotic agents with a mean total chlorpromazine dose equivalence of >1,000 mg/day or administration of >3 antipsychotic agents with >2 antipsychotics having a chlorpromazine dose equivalence of >600 mg/day, from 30 days prior to informed consent to the day before hospital admission.

b A.B: A was superior to B, A=B: A was similar to B.

c Responder was defined as a ≥30% reduction in the PANSS total score from baseline or CGI-I score of 1 (very much improved) or 2 (much improved) at week 6.

Abbreviations: BPRS T, Brief Psychiatric Rating Scale total; BRE, brexpiprazole; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; MINI, Mini International Neuropsychiatric Interview; NR, not reported; PANSS (T, P or N), Positive and Negative Syndrome Scale (T: total, P: positive subscale, N: negative subscale); PBO, placebo.

Table 2 Efficacy outcomes

Outcome	Comparison	n	SMD	95% CI	P-value	I^2 (%)
PANSS total score	BRE 4 mg vs placebo	939	−0.30	−0.43, −0.17	<0.00001	0
	BRE 2 mg vs placebo	943	−0.30	−0.46, −0.13	0.0003	36
	BRE 4 mg vs BRE 2 mg	940	0.00	−0.19, 0.19	0.98	53a
PANSS positive score	BRE 4 mg vs placebo	939	−0.18	−0.42, 0.07	0.16	72b
	BRE 2 mg vs placebo	943	−0.17	−0.32, −0.02	0.03	30
	BRE 4 mg vs BRE 2 mg	940	−0.01	−0.23, 0.20	0.91	63c
PANSS negative score	BRE 4 mg vs placebo	939	−0.30	−0.43, −0.17	<0.00001	0
	BRE 2 mg vs placebo	943	−0.32	−0.51, −0.13	0.001	53d
	BRE 4 mg vs BRE 2 mg	940	0.01	−0.12, 0.14	0.90	0
CGI-S	BRE 4 mg vs placebo	942	−0.25	−0.42, −0.08	0.004	43
	BRE 2 mg vs placebo	947	−0.22	−0.35, −0.10	0.0006	0
	BRE 4 mg vs BRE 2 mg	941	−0.02	−0.22, 0.18	0.83	58
CGI-I	BRE 4 mg vs placebo	942	−0.28	−0.49, −0.07	0.008	61
	BRE 2 mg vs placebo	947	−0.29	−0.42, −0.16	<0.0001	0
	BRE 4 mg vs BRE 2 mg	941	0.01	−0.20, 0.21	0.96	60
Outcome	Comparison	n	RR	95% CI	P-value	I^2 (%)
Response rate	BRE 4 mg vs placebo	939	0.82	0.70, 0.96	0.02e	67f
	BRE 2 mg vs placebo	943	0.86	0.76, 0.98	0.03g	52h
	BRE 4 mg vs BRE 2 mg	940	0.95	0.83, 1.10	0.50	49
Discontinuation rate due to inefficacy	BRE 4 mg vs placebo	961	0.72	0.39, 1.32	0.29	42
	BRE 2 mg vs placebo	967	1.00	0.68, 1.47	0.99	0
	BRE 4 mg vs BRE 2 mg	960	0.72	0.44, 1.15	0.17	13

Notes:

a After excluding Kane study data, considerable heterogeneity disappeared (I² =0%). 4 mg was similar to 2 mg (SMD =−0.09, 95% CI =−0.07, 0.26, P=0.26).

b After excluding Ishigooka study data, considerable heterogeneity disappeared (I² =0%). 4 mg was superior to placebo (SMD =−0.30, 95% CI =−0.44, −0.15, P<0.0001).

c After excluding Ishigooka study data, considerable heterogeneity disappeared (I² =4%). 4 mg was similar to 2 mg (SMD =−0.11, 95% CI =−0.26, 0.04, P=0.16).

d After excluding Kane 2015 study data, considerable heterogeneity disappeared (I² =0%), 2 mg was superior to placebo (SMD =−0.41, 95% CI =−0.57, −0.25, P<0.00001).

e NNT =8.

f After excluding Ishigooka study data, considerable heterogeneity disappeared (I² =0%). 4 mg was superior to placebo (RR =0.76, 95% CI =0.67, 0.85, P<0.00001, NNT =6).

g NNT =10.

h After excluding Correll et al study data, considerable heterogeneity disappeared (I² =0%). 2 mg was not superior to placebo (RR =0.92, 95% CI =0.83, 1.02, P=0.11).

Abbreviations: 95% CI, 95% confidence interval; BRE, brexpiprazole; CGI-I, Clinical Global Impression–Improvement; CGI-S, Clinical Global Impression–Severity; NNT, number needed to treat; PANSS, Positive and Negative Syndrome Scale; RR, risk ratio; SMD, standardized mean difference.

Table 3 A further meta-analysis with respect to PANSS scores, including only the patients who were not on high-dose antipsychotic prescriptions before participating in the study (with at least 6 weeks at a dose equivalent to 1,000 mg/day chlorpromazine)

Outcome	Comparison	n	SMD	95% CI	P-value	I^2 (%)
PANSS total score	BRE 4 mg vs placebo	904	−0.34	−0.47, −0.20	<0.00001	0
	BRE 2 mg vs placebo	913	−0.29	−0.45, −0.12	0.0005	34
	BRE 4 mg vs BRE 2 mg	905	−0.05	−0.19, 0.09	0.51	13
PANSS positive score	BRE 4 mg vs placebo	904	−0.22	−0.40, −0.03	0.02	49
	BRE 2 mg vs placebo	913	−0.15	−0.33, 0.02	0.08	42
	BRE 4 mg vs BRE 2 mg	905	−0.07	−0.20, 0.06	0.27	0
PANSS negative score	BRE 4 mg vs placebo	904	−0.30	−0.43, −0.17	<0.00001	0
	BRE 2 mg vs placebo	913	−0.28	−0.42, −0.13	0.0001	16
	BRE 4 mg vs BRE 2 mg	905	−0.02	−0.15, 0.11	0.71	0

Abbreviations: 95% CI, 95% confidence interval; BRE, brexpiprazole; PANSS, Positive and Negative Syndrome Scale; SMD, standardized mean difference.

Table 4 Safety outcomes

Outcome	Comparison	n	RR	95% CI	P−value	I^2 (%)
Discontinuation rate due to all	BRE 4 mg vs placebo	961	0.87	0.73, 1.03	0.10	0
cause	BRE 2 mg vs placebo	967	0.80	0.67, 0.96	0.01a	0
	BRE 4 mg vs BRE 2 mg	960	1.08	0.89, 1.30	0.44	5
Discontinuation rate due to	BRE 4 mg vs placebo	961	0.66	0.47, 0.92	0.02b	0
adverse events	BRE 2 mg vs placebo	967	0.51	0.35, 0.74	0.0003c	0
	BRE 4 mg vs BRE 2 mg	960	1.28	0.85, 1.92	0.23	0
Serious adverse event	BRE 4 mg vs placebo	961	0.47	0.22, 1.00	0.05	0
	BRE 2 mg vs placebo	966	0.60	0.30, 1.20	0.15	0
	BRE 4 mg vs BRE 2 mg	959	0.78	0.34, 1.78	0.56	0
Death	BRE 4 mg vs placebo	961	3.08	0.13, 74.80	0.49	NA
	BRE 2 mg vs placebo	No death was reported in both the groups
	BRE 4 mg vs BRE 2 mg	960	3.05	0.13, 74.15	0.49	NA
At least one adverse event	BRE 4 mg vs placebo	961	0.96	0.81, 1.14	0.64	67
	BRE 2 mg vs placebo	966	0.95	0.86, 1.05	0.31	1
	BRE 4 mg vs BRE 2 mg	959	1.01	0.91, 1.12	0.84	0
Schizophrenia	BRE 4 mg vs placebo	961	0.71	0.51, 0.99	0.04d	0
	BRE 2 mg vs placebo	966	0.50	0.35, 0.73	0.0003e	0
	BRE 4 mg vs BRE 2 mg	959	1.39	0.93, 2.09	0.11	0
Agitation	BRE 4 mg vs placebo	961	0.82	0.50, 1.35	0.44	0
	BRE 2 mg vs placebo	966	0.85	0.41, 1.74	0.65	51
	BRE 4 mg vs BRE 2 mg	959	0.97	0.58, 1.64	0.92	0
Headache	BRE 4 mg vs placebo	961	0.94	0.53, 1.68	0.83	44
	BRE 2 mg vs placebo	966	1.00	0.63, 1.60	0.99	25
	BRE 4 mg vs BRE 2 mg	959	0.92	0.52, 1.65	0.79	44
Insomnia	BRE 4 mg vs placebo	961	0.97	0.66, 1.42	0.87	0
	BRE 2 mg vs placebo	966	0.88	0.60, 1.30	0.53	0
	BRE 4 mg vs BRE 2 mg	959	1.10	0.74, 1.63	0.64	0
Somnolence	BRE 4 mg vs placebo	961	1.12	0.50, 2.50	0.78	0
	BRE 2 mg vs placebo	966	0.79	0.31, 1.96	0.61	0
	BRE 4 mg vs BRE 2 mg	959	1.38	0.42, 4.58	0.60	33
Suicidal thought/suicidal behavior	BRE 4 mg vs placebo	961	0.73	0.14, 3.78	0.71	0
and serious active suicidal ideation	BRE 2 mg vs placebo	966	0.78	0.08, 7.27	0.82	28
	BRE 4 mg vs BRE 2 mg	959	1.15	0.19, 7.04	0.88	0
Akathisia	BRE 4 mg vs placebo	961	1.26	0.55, 2.89	0.58	56
	BRE 2 mg vs placebo	966	0.85	0.40, 1.79	0.67	35
	BRE 4 mg vs BRE 2 mg	959	1.49	0.87, 2.56	0.15	0
Weight gain (≥7%)	BRE 4 mg vs placebo	961	2.51	1.42, 4.42	0.001f	0
	BRE 2 mg vs placebo	966	2.73	1.56, 4.78	0.0004g	0
	BRE 4 mg vs BRE 2 mg	959	0.91	0.60, 1.36	0.63	0
Outcome	Comparison	n	RR	95% CI	P−value	I^2 (%)
BARS score	BRE 4 mg vs placebo	950	0.06	−0.07, 0.18	0.38	0
	BRE 2 mg vs placebo	952	−0.07	−0.19, 0.06	0.31	0
	BRE 4 mg vs BRE 2 mg	948	0.12	−0.00, 0.25	0.06	0
SAS/DIEPSS score	BRE 4 mg vs placebo	927	0.08	−0.05, 0.21	0.20	0
	BRE 2 mg vs placebo	926	−0.13	−0.25, 0.00	0.06	0
	BRE 4 mg vs BRE 2 mg	925	0.20	0.07, 0.33	0.002	0
AIMS score	BRE 4 mg vs placebo	949	−0.04	−0.17, 0.09	0.54	0
	BRE 2 mg vs placebo	951	−0.07	−0.19, 0.06	0.30	0
	BRE 4 mg vs BRE 2 mg	948	0.02	−0.10, 0.15	0.71	0
QTcF	BRE 4 mg vs placebo	906	−0.10	−0.29, 0.09	0.32	54
	BRE 2 mg vs placebo	920	−0.05	−0.18, 0.08	0.48	0
	BRE 4 mg vs BRE 2 mg	920	−0.04	−0.31, 0.23	0.79	76

Notes:

a NNH =13.

b NNH =20.

c NNH =14.

d NNH =20.

e NNH =17.

f NNH =25.

g NNH =17.

Abbreviations: 95% CI, 95% confidence interval; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; BRE, brexpiprazole; DIEPSS, Drug Induced Extra-Pyramidal Symptoms Scale; NA, not applicable; NNH, number needed to harm; QTcF, Fridericia’s corrected QT; RR, risk ratio; SAS, Simpson-Angus Scale; SMD, standardized mean difference.

Figure S1 PRISMA flow diagram.

Notes: From Moher et al.¹ For more information, visit www.prisma-statment.org.

Figure S2 Risk of bias.

CorrellCUSkubanAOuyangJEfficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled TrialAm J Psychiatry2015172987088025882325

 PubMed Web of Science ®Google Scholar

IshigookaJIwashitaSTadoriYEfficacy and safety of brexpiprazole for the treatment of acute schizophrenia in Japan: A 6-week, randomized, double-blind, placebo-controlled studyPsychiatry Clin Neurosci2018

 Web of Science ®Google Scholar

KaneJMSkubanAOuyangJA multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophreniaSchizophr Res20151641–312713525682550

 PubMed Web of Science ®Google Scholar

MoherDLiberatiATetzlaffJAltmanDGPRISMA GroupPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statementBMJ2009339b253519622551

 PubMed Web of Science ®Google Scholar