Iminodibenzyl class antipsychotics for schizophrenia: a systematic review and meta-analysis of carpipramine, clocapramine, and mosapramine

Figures & data

Table 1 Study, patient, and treatment characteristics of the included randomized controlled trials

Study	Comparators	Total n	Patients (%)	Diagnosis	Duration	Age, mean ± SD (range)	Male, %	Ethnicity (%)	AP	n	Dose (mg/day)	Concomitant drugs (%)	Efficacy outcomes
CAR studies
Ito et al^Citation17, double-blinded, industry	CFP	90	Inpatients (100). Inclusion criteria: duration of illness ≥3 years; no obvious positive symptoms; and significant negative symptoms. Exclusion criteria: excitement and/or intellectual disability	NR	8 weeks (no washout phase)	CAR: 36.7±9.0; CFP: 36.7±−8.9	CAR: 66.7; CFP: 62.2	Japanese (100)	CAR CFP	45 45	Mean dose: NR; max dose: 300; flexible Mean dose: NR; max dose: 6; flexible	Anti-C (NR), SP (NR) Anti-C (NR), SP (NR)	Response rate (GIR): CAR=CFP
Tanimukai and Kaneko^Citation16, double-blinded, industry	OXY	58	Inpatients (100). Inclusion criteria: excitement; positive symptoms; and/or negative symptoms	NR	10 weeks (including 2 weeks of PBO and washout phase)	CAR: 35.9±8.1; OXY: 37.0±0.8	CAR: 34.4; OXY: 34.4	Japanese (100)	CAR OXY	29 29	Mean dose: NR; max dose: 300; flexible Mean dose: NR; max dose: 240; flexible	NR NR	Response rate (GIR): CAR=OXY
Kondo et al^Citation15, double-blinded, industry	PEN	86	Inpatients (100). Inclusion criteria: positive symptoms and/or negative symptoms. Exclusion criteria: excitement and/or hebephrenia	NR	8 weeks (including a 3–7-day washout phase)	CAR: 39.0; PEN: 37.7, (15–60)	CAR: 77.3; PEN: 66.7	Japanese (100)	CAR PEN	42 44	Mean dose: NR; max dose: 200; fixed Mean dose: NR; max dose: 80; fixed	PMZ (100) PMZ (100)	Response rate (GCJ): CAR<PEN
Kudo et al^Citation14, double-blinded, industry	PIM	56	Inpatients (100). Inclusion criteria: positive symptoms and/or negative symptoms	NR	8 weeks (preceded by a several-day washout)	(<60)	CAR: 50.0; PIM: 50.0	Japanese (100)	CAR PIM	28 28	Mean dose: NR; range: 75–200; flexible Mean dose: NR; range: 3–8; flexible	Anti-C (NR), SP (NR) Anti-C (NR), SP (NR)	Response rate (GJ): CAR=PIM
CCP studies
Kudo et al^Citation21, double-blinded, industry	BPD	169	Inpatients and outpatients. Exclusion criteria: exacerbation; stupor; and/or hebephrenia	NR	8 weeks (no washout phase)	CCP: 39.4; BPD: 38.9	CCP: 50.6; BPD: 58.0	Japanese (100)	CCP BPD	81 88	Mean dose: 138.8±6.0; range: 25–225; flexible Mean dose: 9.8±0.42; range: 2–18; flexible	AP (2.5), AX (4.9), anti-C (51.9), SP (46.9) AP (3.4), AX (10.2), anti-C (56.8), SP (44.3)	Response rate (FGIR): CCP=BPD
Mukasa et al^Citation22, double-blinded, industry	BPD	136	Inpatients (100). Inclusion criteria: positive symptoms and/or negative symptoms. Exclusion criteria: exacerbation; stupor; and/or hebephrenia	NR	8 weeks (no washout phase)	(20–60)	CCP: 51.4; BPD: 52.3	Japanese (100)	CCP BPD	70 66	Mean dose: NR; range: 25–225; flexible Mean dose: NR; range: 2–18; flexible	AP (NR), AX (NR), anti-C (NR), SP (NR) AP (NR), AX (NR), anti-C (NR), SP (NR)	Response rate (FGIR): CCP=BPD
Kurihara et al^Citation23, double-blinded, nonindustry	HAL, PPZ	286	Inpatients (100). Inclusion criteria: positive symptoms and negative symptoms. Exclusion criteria: exacerbation; stupor; and/or hebephrenia	NR	8 weeks (no washout phase)	(NR)	CCP: 56.7, HAL: 57.4, PPZ: 53.7	Japanese (100)	CCP HAL PPZ	97 94 95	Mean max dose: 173.2; range: 75–225; flexible Mean max dose: 7.2; range: 1–9; flexible Mean max dose: 21.6; range: 3–27; flexible	AP (0.0), AX (1.0), anti-C (60.8), SP (46.4) AP (3.2), AX (4.3), anti-C (61.7), SP (50.0) AP (4.2), AX (1.1), anti-C (53.7), SP (49.5)	Response rate (FGIR): CCP= HAL=PPZ
Kato et al^Citation18, double-blinded, industry	MOS	205	Inpatients and outpatients Exclusion criteria: exacerbation; stupor; and/or hebephrenia	ICD-9	8 weeks (no washout phase)	(16–64)	CCP: 61.8; MOS: 57.3	Japanese (100)	CCP MOS	102 103	Max dose: 200; flexible Max dose: 120; flexible	AP (1.0), AX (2.0), anti-C (19.6), SP (10.8) AP (4.9), AX (3.9), anti-C (27.2), SP (13.6)	Response rate (FGIR): CCP=MOS
Kudo et al^Citation19, double-blinded, industry	RIS	200	Exclusion criteria: exacerbation; stupor; and/or hebephrenia	ICD-9 and DSM-III-R	8 weeks (no washout phase)	CCP: 41±14, RIS: 42±14, (19–65)	CCP: 74.0; RIS: 60.6	Japanese (100)	CCP RIS	96 104	Range: 25–300; flexible Range: 1–12; flexible	AP (8.3), AX (25.0), anti-C (53.1), SP (71.9) AP (8.7), AX (23.1), anti-C (40.4), SP (67.3)	Response rate (FGIR): CCP=RIS
Yamagami et al^Citation20, single-blinded, nonindustry	SUL	52	Exclusion criteria: stupor and/or hebephrenia	NR	8 weeks (no washout phase)	(18–59)	CCP: 38.5; SUL: 30.8	Japanese (100)	CCP SUL	26 26	Range: 25–900; flexible Range: 200–1,400; flexible	AX (NR), anti-C (23.1), SP (NR) AX (NR), anti-C (34.6), SP (NR)	Response rate (FGIR): CCP=SUL
MOS studies
031-95-003^Citation5, double-blinded, industry	ARI	238	Schizophrenia	ICD-10	8 weeks	MOS: 45.2±12.7; ARI: 45.5±12.4 (16–65)	MOS: 71; ARI: 63	Japanese (100)	MOS ARI	118 120	(45–180) flexible (6–24) flexible	AP (5.9), AX (28.0), anti-C (57.6), SP (89.0) AP (6.7), AX (18.3), anti-C (26.7), SP (83.3)	Response rate (FGIR): MOS=ARI
Kato et al^Citation18, double-blinded, industry	CCP	205	Inpatients and outpatients. Exclusion criteria: excitement; stupor; and/or hebephrenia	NR	8 weeks (no washout phase)	(16–64)	MOS: 57.3; CCP: 61.8	Japanese (100)	MOS CCP	103 102	Max dose: 120; flexible Max dose: 200; flexible	AP (4.9), AX (3.9), anti-C (27.2), SP (13.6) AP (1.0), AX (2.0), anti-C (19.6), SP (10.8)	Response rate (FGIR): MOS=CCP
Kudo et al^Citation24, double-blinded, industry	HAL	201	Inpatients and outpatients. Exclusion criteria: stupor and/or hebephrenia	NR	12 weeks	(16–64)	MOS: 57.3; HAL: 58.9	Japanese (100)	MOS HAL	98 103	Max dose: 225; flexible Max dose: 13.5; flexible	Anti-C (83.3), SP (71.9) Anti-C (88.2), SP (61.8)	Response rate (FGIR): MOS=HAL
Kudo et al^Citation7, double-blinded, industry	PER	161	Inpatients and outpatients. Exclusion criteria: excitement; stupor; and/or hebephrenia	ICD-10 and DSM-III-R	8 weeks (no washout phase)	MOS: 43.4±13.2; PER: 43.2±13.7; (15–65)	MOS: 65.4; PER: 64.1	Japanese (100)	MOS PER	82 79	Range: 50–300; flexible Range: 8–48; flexible	AP (4.9), anti-C (55.6), SP (64.2) AP (6.4), anti-C (41.0), SP (73.1)	Response rate (FGIR): MOS=PER
Kudo et al^Citation6, double-blinded, industry	QUE	181	Inpatients and outpatients. Exclusion criteria: stupor and/or hebephrenia	ICD-10	8 weeks (no washout phase)	MOS: 45.6±12.1; QUE: 44.0±13.4; (18–64)	MOS: 61.1; QUE: 63.3	Japanese (100)	MOS QUE	90 91	Max dose: 300; flexible Max dose: 600; flexible	AP (11.1), anti-C (62.2), SP (74.4) AP (15.6), anti-C (31.1), SP (65.6)	Response rate (FGIR): MOS=QUE

Abbreviations: n, number of patients; SD, standard deviation; AP, antipsychotic; NR, not reported; CAR, carpipramine; CFP, clofluperol; max, maximum; anti-C, anticholinergic drugs; GIR, Global Improved Rating; SP, sleeping pills; PBO, placebo; OXY, oxypertine; PEN, penfluridol; PMZ, promethazine; GCJ, Global Comprehensive Judgment; PIM, pimozide; GJ, Global Judgment; CCP, clocapramine; FGIR, Final Global Improvement Rating; BPD, bromperidol; AX, anxiolytics; HAL, haloperidol; PPZ, perphenazine; ICD, International Statistical Classification of Diseases and Related Health Problems; MOS, mosapramine; DSM, Diagnostic and Statistical Manual of Mental Disorders; RIS, risperidone; SUL, sulpride; ARI, aripiprazole; PER, perospirone; QUE, quetiapine.

Table 2 The results of the meta-analysis of carpiramine studies

	Number of comparisons (comparators)	Number of patients	I^2	OR*	95% CI	P
Efficacy
Response rate	4 (CFP, OXY, PEN, PIM)	290	14	1.35	0.67–2.74	0.41
Discontinuation because of inefficacy	3 (CFP, OXY, PIM)	204	0	0.97	0.19–4.81	0.97
Tolerability
Discontinuation because of all causes	4 (CFP, OXY, PEN, PIM)	290	0	1.07	0.49–2.35	0.87
Discontinuation because of side effects	3 (CFP, OXY, PIM)	204	0	0.79	0.20–3.09	0.73
Individual side effects
At least one side effect	4 (CFP, OXY, PEN, PIM)	317	0	1.09	0.68–1.74	0.72
Headache	3 (OXY, PEN, PIM)	227	44	0.93	0.16–5.53	0.93
Insomnia	3 (CFP, OXY, PIM)	204	0	1.09	0.62–1.92	0.77
Sleepiness	4 (CFP, OXY, PEN, PIM)	317	0	0.82	0.34–2.02	0.67
Fatiguea	3 (OXY, PEN, PIM)	227	62	0.89	0.23–3.36	0.86
Akathisia	3 (CFP, OXY, PIM)	259	0	0.63	0.33–1.23	0.17
Dyskinesia	3 (CFP, OXY, PEN)	261	0	0.68	0.19–2.35	0.54
Tremor	3 (CFP, OXY, PIM)	259	0	0.54	0.19–1.59	0.27
Rigidity	2 (CFP, PIM)	146	0	0.64	0.19–2.15	0.47
Parkinsonism	4 (CFP, OXY, PEN, PIM)	317	0	0.66	0.36–1.20	0.17
Eye symptoms	2 (OXY, PEN)	171	0	0.19	0.02–1.75	0.14
Dry mouth	3 (OXY, PEN, PIM)	227	0	0.91	0.43–1.96	0.82
Increased salivation	2 (PEN, PIM)	169	30	0.66	0.17–2.62	0.56
Tachycardia	2 (PEN, PIM)	169	0	1.07	0.37–3.08	0.90
Dizziness	3 (OXY, PEN, PIM)	227	0	0.84	0.23–3.06	0.79
Nausea/vomiting	4 (CFP, OXY, PEN, PIM)	317	0	1.16	0.48–2.82	0.74
Constipation	3 (CFP, PEN, PIM)	259	0	0.98	0.35–2.78	0.97
Diarrhea	3 (CFP, PEN, PIM)	259	0	3.02	0.47–19.5	0.25
Rash	2 (CFP, PIM)	146	51	1.73	0.11–26.6	0.69
Sweating	3 (OXY, PEN, PIM)	227	0	1.94	0.33–11.5	0.46
Decreased appetite	4 (CFP, OXY, PEN, PIM)	317	41	1.15	0.55–2.40	0.71

Notes:

* OR<1 favors carpiramine; OR>1 favors other pooled antipsychotics.

a In individual antipsychotic comparisons, carpipramine was associated with less fatigue than was oxypertine (OR=0.11; 95% CI=0.01–0.98; P=0.05; NNH=5, P=0.02; number of patients =58).

Abbreviations: OR, odds ratio; CI, confidence interval; CFP, clofluperol; OXY, oxypertine; PEN, penfluridol; PIM, pimozide; NNH, number needed to harm.

Table 3 The results of the meta-analysis of clocapramine studies

	Number of comparisons (comparators)	Number of patients	I^2	OR*	95% CI	P
Efficacy
Response rate	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,144	0	1.12	0.86–1.47	0.39
Discontinuation because of inefficacy	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,145	0	0.77	0.44–1.35	0.36
Tolerability
Discontinuation because of all causes	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,145	0	0.77	0.53–1.11	0.16
Discontinuation because of side effects	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,145	0	0.78	0.37–1.64	0.51
Individual side effects
At least one side effect	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	52	1.20	0.83–1.72	0.34
Convulsion	4 (BPD, HAL, MOS, PPZ)	756	2	1.03	0.10–10.3	0.98
Fever	4 (BPD, HAL, MOS, PPZ)	756	0	2.53	0.55–11.6	0.23
Headachea	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	0	0.47	0.25–0.85	0.01**
Agitation/anxiety	3 (BPD, RIS)	503	0	1.07	0.60–1.92	0.83
Insomnia	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	0	0.92	0.70–1.22	0.58
Powerlessness	2 (MOS, RIS)	405	0	2.13	0.78–5.84	0.14
Sleepiness	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	34	1.18	0.64–2.20	0.60
Fatigue	6 (BPD, HAL, PPZ, RIS, SUL)	938	0	0.74	0.47–1.17	0.20
Disturbance of consciousness	4 (BPD, HAL, MOS, PPZ)	756	0	0.34	0.05–2.16	0.25
Ataxia	3 (HAL, MOS, PPZ)	588	0	1.45	0.40–5.32	0.57
Akathisia	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	0	0.86	0.63–1.18	0.35
Akinesia/bradykinesia	3 (BPD, MOS, RIS)	573	0	0.81	0.29–2.22	0.68
Dyskinesia	5 (BPD, HAL, MOS, PPZ)	891	0	0.99	0.55–1.77	0.97
Dystonia	4 (HAL, MOS, PPZ, RIS)	788	0	1.95	0.69–5.49	0.21
Mask-like face	2 (BPD, RIS)	335	0	0.62	0.07–5.06	0.65
Tremorb	5 (BPD, MOS, RIS, SUL)	760	65	0.73	0.36–1.47	0.38
Rigidity	5 (BPD, MOS, RIS, SUL)	760	57	0.81	0.36–1.81	0.61
Parkinsonism	3 (HAL, PPZ, SUL)	435	0	0.81	0.53–1.23	0.32
Paresthesia	3 (HAL, MOS, PPZ)	588	0	0.33	0.09–1.30	0.11
Eye rolling	2 (BPD, SUL)	220	0	0.34	0.03–3.35	0.36
Blurred vision	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	0	0.99	0.50–1.96	0.98
Speech disturbance	4 (BPD, MOS, RIS, SUL)	625	0	0.86	0.35–2.12	0.74
Swallowing disturbance	2 (BPD, RIS)	335	0	3.86	0.63–23.9	0.15
Dry mouth	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	7	0.73	0.42–1.25	0.25
Increased salivation	5 (BPD, MOS, RIS, SUL)	760	0	1.05	0.65–1.69	0.85
Chest pain	4 (BPD, HAL, MOS, PPZ)	756	0	0.88	0.42–1.85	0.74
Tachycardia/palpitation	5 (BPD, HAL, MOS, PPZ, RIS)	956	0	1.33	0.58–3.04	0.50
Dizziness	6 (BPD, HAL, MOS, PPZ, RIS)	1,091	0	0.78	0.47–1.31	0.35
Nausea/vomitingc	6 (BPD, HAL, MOS, PPZ, RIS)	1,091	0	0.76	0.48–1.20	0.24
Constipation	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	44	1.28	0.72–2.29	0.40
Diarrhea	3 (BPD, MOS, RIS)	573	48	0.66	0.03–13.7	0.79
Itching	4 (BPD, HAL, MOS, PPZ)	723	0	0.62	0.19–1.95	0.41
Rash	6 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,008	0	1.48	0.51–4.31	0.47
Sweating	6 (BPD, HAL, MOS, PPZ, RIS)	1,091	29	1.14	0.42–3.11	0.80
Decreased appetited	7 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,143	0	0.57	0.39–0.85	0.005**
Weight gain	5 (BPD, MOS, RIS, SUL)	731	3	1.03	0.41–2.54	0.96
Weight loss	5 (BPD, MOS, RIS, SUL)	731	4	1.32	0.49–3.57	0.58
Dysuria	5 (BPD, HAL, MOS, PPZ, RIS)	956	0	1.20	0.55–2.64	0.64
Use of other additional drugs
Use of sleeping pills	5 (BPD, HAL, MOS, PPZ, RIS)	957	0	0.98	0.74–1.29	0.86
Use of anti-cholinergic drugs	6 (BPD, HAL, MOS, PPZ, RIS, SUL)	1,009	29	1.01	0.74–1.39	0.93
Use of anxiolytics	5 (BPD, HAL, MOS, PPZ, RIS)	957	0	0.80	0.48–1.35	0.41
Use of additional antipsychotics	5 (BPD, HAL, MOS, PPZ, RIS)	957	10	0.52	0.22–1.22	0.13
Laboratory tests of metabolic side effects
Abnormal blood total cholesterol level	3 (BPD, MOS, RIS)	493	0	1.36	0.29–6.26	0.70
Positive urine glucose test	2 (MOS, RIS)	358	NA	NE	NE	NA

Notes:

* OR<1 favors clocapramine; OR>1 favors other pooled antipsychotics.

** Statistically significant.

a NNH is not significant.

b In individual antipsychotic comparisons, tremors were less strongly associated with clocapramine than with mosapramine (OR=0.34; 95% CI=0.15–0.77; P=0.01; NNH=7, P=0.007; number =205).

c In individual antipsychotic comparisons, nausea and vomiting were less strongly associated with clocapramine than with PPZ (OR=0.38; 95% CI=0.16–0.93; P=0.03; NNH=25, P=0.03; number =192).

d NNH is not significant. In individual antipsychotic comparisons, decreases in appetite were less strongly associated with clocapramine than with HAL (OR=0.35; 95% CI=0.16–0.77; P=0.009; NNH=7, P=0.006; number =191).

Abbreviations: OR, odds ratio; CI, confidence interval; BPD, bromperidol; HAL, haloperidol; MOS, mosapramine; PPZ, perphenazine; RIS, risperidone; SUL, sulpiride; NA, not applicable; NE, not estimable; NNH, number needed to harm.

Table 4 The results of the meta-analysis of mosapramine studies

	Number of comparisons (comparators)	Number of patients	I^2	OR or SMD	95% CI	P
Efficacy
PANSS total scores	3 (ARI, PER, QUE)	555	0	−0.12†	−0.29 to 0.04	0.14
PANSS positive subscale scores	3 (ARI, PER, QUE)	555	9	−0.22†	−0.39 to −0.04	0.02**
PANSS negative subscale scores	3 (ARI, PER, QUE)	555	0	0.07†	−0.09 to 0.24	0.40
PANSS general subscale scores	3 (ARI, PER, QUE)	555	0	−0.12†	−0.29 to 0.05	0.15
Response rate	5 (ARI, CCP, HAL, PER, QUE)	966	0	1.01*	0.77–1.34	0.92
Discontinuation due to inefficacy	5 (ARI, CCP, HAL, PER, QUE)	986	0	0.74*	0.42–1.30	0.30
Tolerability
Discontinuation because of all causes	5 (ARI, CCP, HAL, PER, QUE)	986	9	1.05*	0.76–1.44	0.78
Discontinuation because of side effects	5 (ARI, CCP, HAL, PER, QUE)	986	0	1.33*	0.86–2.05	0.20
Discontinuation because of death	4 (ARI, HAL, PER, QUE)	779	0	1.01*	0.18–5.79	0.99
Discontinuation because of death by suicide	4 (ARI, HAL, PER, QUE)	779	0	0.70*	0.11–4.42	0.71
Individual side effects
At least one side effecta	4 (ARI, CCP, PER, QUE)	782	32	1.72*	1.09–2.70	0.02**
Severe/serious side effects	2 (ARI, PER)	397	42	0.59*	0.09–3.78	0.58
Suicide attempt	3 (ARI, PER, QUE)	577	14	0.73*	0.09–5.59	0.76
Neuroleptic malignant syndrome	3 (ARI, PER, QUE)	577	0	0.56*	0.09–3.44	0.53
Fever	4 (ARI, CCP, PER, QUE)	782	4	0.83*	0.33–2.07	0.69
Headache	5 (ARI, CCP, HAL, PER, QUE)	983	0	0.67*	0.37–1.22	0.19
Anxiety	3 (ARI, PER, QUE)	577	0	0.93*	0.61–1.42	0.74
Depression	3 (ARI, HAL, PER)	598	0	0.69*	0.30–1.59	0.39
Excitement	3 (ARI, PER, QUE)	577	0	0.72*	0.40–1.28	0.26
Insomnia	5 (ARI, CCP, HAL, PER, QUE)	983	0	1.01*	0.74–1.38	0.95
Powerlessnessb	5 (ARI, CCP, HAL, PER, QUE)	983	61	1.10*	0.49–2.51	0.81
Sleepiness/somnolence	5 (ARI, CCP, HAL, PER, QUE)	983	0	1.53*	0.94–2.47	0.09
Fatiguec	3 (ARI, PER, QUE)	577	59	2.21*	0.97–5.02	0.06
Ataxia	2 (CCP, HAL)	406	0	1.65*	0.20–13.5	0.64
Akathisiad	5 (ARI, CCP, HAL, PER, QUE)	983	8	1.81*	1.26–2.62	0.001**
Akinesia/bradykinesiae	4 (ARI, CCP, HAL, QUE)	824	0	3.82*	2.16–6.76	<0.00001**
Dyskinesiaf	5 (ARI, CCP, HAL, PER, QUE)	983	33	1.41*	0.63–3.17	0.40
Dystonia	4 (ARI, CCP, PER, QUE)	782	42	2.03*	0.69–5.93	0.20
Tremorg	5 (ARI, CCP, HAL, PER, QUE)	983	0	2.13*	1.53–2.96	<0.00001**
Rigidityh	5 (ARI, CCP, HAL, PER, QUE)	983	27	2.35*	1.47–3.76	0.0004**
Gait disturbancei	3 (ARI, PER, QUE)	577	59	3.04*	1.08–8.59	0.04**
At least one extrapyramidal symptomsj	4 (ARI, HAL, PER, QUE)	778	76	2.17*	1.19–3.98	0.01**
Extrapyramidal symptoms scales scoresk	3 (ARI, PER, QUE)	573	85	0.35†	−0.09 to 0.78	0.12
Paresthesia	2 (CCP, HAL)	406	0	1.63*	0.20–13.4	0.65
Eye rolling	2 (HAL, QUE)	381	0	5.75*	0.66–50.2	0.11
Eye symptoms	2 (CCP, HAL)	406	0	0.53*	0.09–3.07	0.47
Speech disturbancel	4 (CCP, HAL, PER, QUE)	745	47	2.29*	0.73–7.17	0.16
Swallowing disturbancem	3 (HAL, PER, QUE)	540	0	4.58*	1.28–16.4	0.02**
Dry mouth	5 (ARI, CCP, HAL, PER, QUE)	983	0	1.16*	0.68–1.99	0.58
Increased salivationn	5 (ARI, CCP, HAL, PER, QUE)	983	69	2.51*	1.06–5.94	0.04**
Chest pain	2 (CCP, PER)	364	0	1.82*	0.48–6.93	0.38
Palpitation	5 (ARI, CCP, HAL, PER, QUE)	983	0	1.91*	0.76–4.80	0.17
QTc prolongation	2 (ARI, QUE)	377	NA	0.33*	0.01–8.12	0.49
Bradycardia	2 (PER, QUE)	339	0	0.32*	0.03–3.14	0.33
Hypertension	2 (PER, QUE)	339	0	3.92*	0.43–35.8	0.23
Hypotension	2 (PER, QUE)	339	0	0.49*	0.12–2.04	0.33
Dizziness/lightheadedness	5 (ARI, CCP, HAL, PER, QUE)	983	4	1.25*	0.72–2.16	0.42
Nausea/vomiting	5 (ARI, CCP, HAL, PER, QUE)	893	0	1.16*	0.65–2.07	0.61
Constipationo	5 (ARI, CCP, HAL, PER, QUE)	893	26	1.12*	0.65–1.91	0.69
Diarrhea	2 (CCP, QUE)	385	NA	0.33*	0.01–8.20	0.50
Epigastric distress/abdominal pain	3 (ARI, PER, QUE)	577	16	1.38*	0.59–3.20	0.46
Itching	2 (CCP, HAL)	405	0	3.09*	0.32–30.0	0.33
Sweating	5 (ARI, CCP, HAL, PER, QUE)	983	0	1.55*	0.77–3.14	0.22
Increased appetite	3 (CCP, PER, QUE)	544	0	0.98*	0.28–3.44	0.98
Decreased appetite	5 (ARI, CCP, HAL, PER, QUE)	983	10	1.33*	0.81–2.18	0.25
Weight gain	4 (ARI, CCP, PER, QUE)	725	0	1.39*	0.53–3.63	0.50
Weight lossp	5 (ARI, CCP, HAL, PER, QUE)	926	33	0.57*	0.16–2.06	0.39
Change of body weight	3 (ARI, PER, QUE)	524	0	0.15†	−0.02 to 0.33	0.08
Hyperprolactinemiaq	4 (ARI, HAL, PER, QUE)	741	96	10.9*	0.72–164.9	0.08
Change of blood prolactin levelr	3 (ARI, PER, QUE)	388	35	1.19†	0.91–1.47	<0.00001**
Dysuria	5 (ARI, CCP, HAL, PER, QUE)	983	0	2.81*	0.98–8.04	0.05
Use of other additional drugs
Use of sleeping pills	5 (ARI, CCP, HAL, PER, QUE)	980	17	1.28*	0.91–1.80	0.15
Use of anticholinergic drugss	5 (ARI, CCP, HAL, PER, QUE)	980	75	1.98*	1.11–3.53	0.02**
Use of additional antipsychotics	4 (ARI, CCP, PER, QUE)	782	0	0.87*	0.49–1.55	0.63
Laboratory tests of metabolic side effects
Change of blood total cholesterol levelt	3 (ARI, PER, QUE)	541	75	0.07†	−0.27 to 0.41	0.68
Positive glucose urine test	5 (ARI, CCP, HAL, PER, QUE)	890	0	0.56*	0.17–1.86	0.34

Notes:

† Negative SMD values favor mosapramine; positive SMD values favor other pooled antipsychotics.

* OR<1 favors mosapramine; OR>1 favors other pooled antipsychotics.

** Statistically significant.

a NNH=13, P=0.05. In individual antipsychotic comparisons, patients on mosapramine were more likely to have at least one side effect than were patients on QUE (OR=2.73; 95% CI=1.09–2.70; P=0.02; NNH=5, P=0.002; number =180).

b In individual antipsychotic comparisons, powerlessness was associated more strongly with mosapramine than with ARI (OR=6.68; 95% CI=1.46–30.5; P=0.01; NNH=11, P=0.005; number =238).

c In individual antipsychotic comparisons, fatigue was more strongly associated with mosapramine than with ARI (OR=5.92; 95% CI=1.96–17.9; P=0.002; NNH=7, P=0.0004; number =238).

d NNH=13, P=0.0004. In individual antipsychotic comparisons, akathisia was more strongly associated with mosapramine than with ARI (OR=2.45; 95% CI=1.28–4.70; P=0.007; NNH=7, P=0.005; number =238) and with QUE (OR=2.41; 95% CI=1.02–5.65; P=0.04; NNH=9, P=0.04; number =180).

e NNH is not significant. In individual antipsychotic comparisons, akinesia/bradykinesia was associated more strongly with mosapramine than with ARI (OR=4.56; 95% CI=1.89–11.0; P=0.0007; NNH=6, P=0.0002; number =238) and QUE (OR=4.26; 95% CI=1.63–11.2; P=0.003; NNH=6, P=0.001; number =180).

f In individual antipsychotic comparisons, dyskinesia was associated more strongly with mosapramine than with ARI (OR=4.42; 95% CI=1.21–16.1; P=0.02; NNH=13, P=0.01; number =238).

g NNH=8, P<0.00001. In individual antipsychotic comparisons, tremors were more strongly associated with mosapramine than with ARI (OR=2.15; 95% CI=1.14–4.05; P=0.02; NNH=8, P=0.02; number =238), CCP (OR=2.97, 95% CI=1.30–6.79; P=0.01; NNH=7, P=0.007; number =205), and QUE (OR=3.25; 95% CI=1.46–7.23; P=0.004; NNH=6, P=0.002; number =180).

h NNH=10, P<0.0001. In individual antipsychotic comparisons, rigidity was associated more strongly with mosapramine than with ARI (OR=2.56; 95% CI=1.25–5.23; P=0.01; NNH=8, P=0.008; number =238) and QUE (OR=7.75; 95% CI=2.21–27.3; P=0.001; NNH=6, P=0.0002; number =180).

i NNH=11, P<0.0001. In individual antipsychotic comparisons, disturbance of gait was more strongly associated with mosapramine than with ARI (OR=4.55; 95% CI=1.47–14.1; P=0.008; NNH=10, P=0.004; number =238) and QUE (OR=6.77; 95% CI=1.47–31.2; P=0.01; NNH=9, P=0.004; number =180).

j NNH=5, P=0.01. In individual antipsychotic comparisons, mosapramine was more strongly associated with at least one extrapyramidal symptom than were ARI (OR=3.63; 95% CI=2.12–6.20; P<0.00001; NNH=3, P<0.00001; number =238) and QUE (OR=3.67; 95% CI=1.97–6.81; P<0.0001; NNH=3, P<0.0001; number =180).

k In individual antipsychotic comparisons, higher extrapyramidal symptom scale scores were more likley to be associated with mosapramine than with ARI (SMD=0.73; 95% CI=0.47–0.90; P<0.00001; number =234) and QUE (SMD=0.33; 95% CI=0.04–0.62; P=0.03; number =180).

l For individual antipsychotic comparisons, disturbance of speech was associated more strongly with mosapramine than with QUE (OR=6.27; 95% CI=1.76–22.4; P=0.005; NNH=7, P=0.001; number =180).

m NNH is not significant. In individual antipsychotic comparisons, disturbance of swallowing was associated more strongly with mosapramine than with QUE (OR=4.89; 95% CI=1.03–23.3; P=0.05; NNH=13, P=0.03; number =180).

n NNH=10, P=0.04. In individual antipsychotic comparisons, increased salivation was associated more strongly with mosapramine than were ARI (OR=3.35; 95% CI=1.63–6.89; P=0.001; NNH=6, P=0.0005; number =238) and QUE (OR=30.6; 95% CI=4.02–231.9; P=0.0009; NNH=4, P<0.00001; number =180).

o In individual antipsychotic comparisons, constipation was associated more strongly with mosapramine than with HAL (OR=3.79; 95% CI=1.01–14.2; P=0.05; NNH=14, P=0.04; number =201).

p In individual antipsychotic comparisons, weight loss was associated less strongly with mosapramine than with ARI (OR=0.35; 95% CI=0.16–0.77; P=0.009; NNH=8, P=0.006; number =238).

q In individual antipsychotic comparisons, hyperprolactinemia was associated more strongly with mosapramine than with ARI (OR=569.9; 95% CI=117.9–2,753.6; P<0.00001; NNH=1, P<0.00001; number =201).

r In individual antipsychotic comparisons, a change in blood prolactin level was more highly associated with mosapramine than with ARI (SMD=1.27; 95% CI=0.97–1.58; P<0.00001; number =201), PER (SMD=0.72; 95% CI=0.11–1.32; P=0.02; number =45), and QUE (SMD=1.32; 95% CI=0.96–1.68; P<0.00001; number =142).

s NNH=6, P=0.04. In individual antipsychotic comparisons, the use of anticholinergic drugs was associated more strongly with mosapramine than with ARI (OR=3.74; 95% CI=2.17–6.45; P<0.00001; NNH=3, P<0.00001; number =238) and QUE (OR=3.65; 95% CI=1.97–6.76; P<0.0001; NNH=3, P<0.0001; number =180).

t In individual antipsychotic comparisons, a higher change of total blood cholesterol level was associated with mosapramine than with ARI (SMD=0.38; 95% CI=0.11–0.64; P=0.005; number =226).

Abbreviations: OR, odds ratio; SMD, standardized mean difference; CI, confidence interval; PANSS, Positive and Negative Syndrome Scale; ARI, aripiprazole; PER, perospirone; QUE, quetiapine; CCP, clocapramine; HAL, haloperidol; NA, not applicable; NNH, number needed to harm.

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