Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis

Figures & data

Table 1. Eligibility criteria for assessment of study inclusion.

Criterion	Inclusion	Exclusion
Patient population	Adults (>18 years old) with bipolar depression where at least 50% of the population were diagnosed with bipolar I disorder	• <50% bipolar I disorder  • <18 years old
Interventions	Atypical antipsychotic monotherapy:  • Lurasidone  • Quetiapine  • Olanzapine  • Aripiprazole  • Asenapine  • Risperidone  • Ziprasidone	• Any treatments other than those listed in the inclusion criteria • Any treatments listed in inclusion criteria if administered as adjunctive therapy
Comparators	Any of the above listed interventions and placebo	Comparators other than those listed in the inclusion criteria
Outcomes	Studies reporting at least one of the followingoutcomes:  • Change from baseline in MADRS  • Change from baseline in CGI-BP-S  • Response (defined as ≥50% improvement in MADRS) • Remission (defined as MADRS score ≤12 at endpoint) • Change from baseline in weight • Akathisia^a • Extrapyramidal symptoms • Somnolence • All-cause discontinuation	Studies not reporting at least one of the outcomes included in the inclusion criteria.
Study design	Randomised controlled trials	• Non-randomised controlled trials • Observational studies • Case studies • Pharmacology studies

^a Akathisia was not included in evidence synthesis due to the small number of studies reporting it as a distinct adverse event from extrapyramidal symptoms.

Figure 1. Network of evidence. ARI: aripiprazole; LUR: lurasidone; OLA: olanzapine; PLO: placebo; QUE: quetiapine IR or XR; SLR: systematic literature review; ZIP: ziprasidone.

Table 2. Study design and patient baseline characteristics.

				Baseline characteristics
Study	No. of patients	Treatmentduration (weeks)	Treatment comparisons of interest	Age	Male (%)	Bipolar disorder I (%)	MADRS	CGI-BP-S	Weight (kg)
Calabrese et al. (2005)	511	8	Quetiapine IR 300 mg/day Quetiapine IR 600 mg/day Placebo	37.4	41.9	66.9	30.4	4.4	Not reported
Li et al. (2014)	296	8	Quetiapine XR 300 mg/day Placebo	Not reported	Not reported	50.0	Not reported	Not reported	Not reported
Loebel et al. (2014a)^a	485	6	Lurasidone 20–60 mg/day Lurasidone 80–120 mg/day Placebo	41.5	41.4	100	30.5	4.5	77.2
Lombardo et al. (2012) (Study 1)	504	8	Ziprasidone 40–80 mg/day Ziprasidone 120–160 mg/day Placebo	39.9	43.6	100	28.2	Not reported	Not reported
Lombardo et al. (2012) (Study 2)	381	8	Ziprasidone 20–80 mg/day Placebo	40.2	42.5	100	28.4	Not reported	Not reported
McElroy et al. (2010)	582	8	Quetiapine IR 300 mg/day Quetiapine IR 600 mg/day Placebo	38.5	36.9	64.0	26.9	4.2	80.8
Suppes et al. (2010)	270	8	Quetiapine XR 300 mg/day Placebo	39.5	35.5	80.4	30.0	4.5	88.8
Thase et al. (2006)	467	8	Quetiapine IR 300 mg/day Quetiapine IR 600 mg/day Placebo	37.7	43.1	67.4	30.2	4.5	Not reported
Thase et al. (2008) (Study 1)	374	8	Aripiprazole 5–30 mg/day Placebo	39.0	37.5	100	28.8	4.3	87.2
Thase et al. (2008) (Study 2)	375	8	Aripiprazole 5–30 mg/day Placebo	40.5	40.0	100	29.0	4.5	86.8
Tohen et al. (2003)	747	8	Olanzapine >5 mg/day (mean: 9.7 mg) Placebo	42.0	41.5	100	32.0	4.9	Not reported
Tohen et al. (2012)	514	6	Olanzapine 10–20 mg/day Placebo	35.5	44.3	100	29.0	4.5	Not reported
Young et al. (2010)	647	8	Quetiapine IR 300 mg/day Quetiapine IR 600 mg/day Placebo	42.2	41.6	61.6	28.3	4.3	75.5
Wang et al. (2014)	68	8	Olanzapine10–20 mg/day Placebo	29.2	41.2	100	28.6	4.4	63.9

^a Data not reported in the publication by Loebel et al. (2014) was supplemented by data from the Clinical Study Report for lurasidone (Sunovion Pharmaceuticals, data on file).

Table 3. Forest plots for base-case analysis of efficacy outcomes.

ΔMADRS score
Comparison	Mean difference	95% CrIs
Lurasidone vs Placebo	–4.70	[–7.20, –2.21]
Lurasidone vs Aripiprazole	–3.62	[–7.04, –0.20]
Lurasidone vs Olanzapine	–0.15	[–3.12, 2.74]
Lurasidone vs Quetiapine	0.10	[–2.68, 2.84]
Lurasidone vs Ziprasidone	–3.38	[–6.68, –0.11]
ΔCGI-BP-S score
Comparison	Mean difference	95% CrIs
Lurasidone vs Placebo	–0.63	[–0.90, –0.37]
Lurasidone vs Aripiprazole	–0.42	[–0.78, –0.07]
Lurasidone vs Olanzapine	–0.31	[–0.65, 0.03]
Lurasidone vs Quetiapine	–0.09	[–0.39, 0.21]
Lurasidone vs Ziprasidone	–0.59	[–0.94, –0.24]
Response (≥50% improvement in MADRS score)
Comparison	Mean OR	95% CrIs
Lurasidone vs Placebo	2.59	[1.65, 3.89]
Lurasidone vs Aripiprazole	2.40	[1.36, 3.96]
Lurasidone vs Olanzapine	1.68	[0.99, 2.69]
Lurasidone vs Quetiapine	1.29	[0.78, 2.01]
Lurasidone vs Ziprasidone	2.45	[1.38, 4.05]
Remission (MADRS score ≤12 at study endpoint)
Comparison	Mean OR	95% CrI
Lurasidone vs Placebo	2.19	[1.36, 3.37]
Lurasidone vs Aripiprazole	2.28	[1.22, 3.90]
Lurasidone vs Olanzapine	1.54	[0.87, 2.53]
Lurasidone vs Quetiapine	1.11	[0.66, 1.77]
Lurasidone vs Ziprasidone	2.18	[1.21, 3.65]

Table 4. Forest plots for base-case analysis of tolerability outcomes.

ΔWeight (kg change from baseline)
Comparison	Mean difference	95% CrIs
Lurasidone vs Placebo	0.34	[–0.33, 1.00]
Lurasidone vs Aripiprazole	0.14	[–0.95, 1.21]
Lurasidone vs Olanzapine	–2.54	[–3.42, –1.67]
Lurasidone vs Quetiapine	–0.83	[–1.59, –0.08]
Somnolence
Comparison	Mean OR	95% CrIs
Lurasidone vs Placebo	1.57	[0.55, 3.77]
Lurasidone vs Aripiprazole	0.87	[0.23, 2.42]
Lurasidone vs Olanzapine	0.56	[0.18, 1.41]
Lurasidone vs Quetiapine	0.33	[0.11, 0.82]
Lurasidone vs Ziprasidone	0.34	[0.09, 0.93]

Appendix Figure 1. Study identification diagram.

Appendix Table 1. Base-case results for the efficacy outcomes of change from baseline in MADRS score, CGI-BP-S score, response and remission.

Change in MADRS from baseline	Mean difference	SD	Median difference	95% CrIs		Change in CGI-BP-S from baseline	Mean difference	SD	Median difference	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	–4.70	1.27	–4.70	–7.20	–2.21	Lurasidone vs Placebo	–0.63	0.13	–0.63	–0.90	–0.37
Aripiprazole vs Placebo	–1.08	1.18	–1.08	–3.40	1.23	Aripiprazole vs Placebo	–0.21	0.12	–0.21	–0.45	0.03
Olanzapine vs Placebo	–4.55	0.77	–4.56	–6.04	–2.97	Olanzapine vs Placebo	–0.32	0.11	–0.32	–0.53	–0.11
Quetiapine vs Placebo	–4.80	0.59	–4.80	–5.96	–3.62	Quetiapine vs Placebo	–0.32	0.11	–0.32	–0.53	–0.11
Ziprasidone vs Placebo	–1.32	1.08	–1.32	–3.44	0.82	Ziprasidone vs Placebo	–0.05	0.12	–0.05	–0.27	0.18
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	–3.62	1.73	–3.62	–7.04	–0.20	Lurasidone vs Aripiprazole	–0.42	0.18	–0.42	–0.78	–0.07
Lurasidone vs Olanzapine	–0.15	1.48	–0.14	–3.12	2.74	Lurasidone vs Olanzapine	–0.31	0.17	–0.31	–0.65	0.03
Lurasidone vs Quetiapine	0.10	1.40	0.11	–2.68	2.84	Lurasidone vs Quetiapine	–0.09	0.15	–0.08	–0.39	0.21
Lurasidone vs Ziprasidone	–3.38	1.66	–3.38	–6.68	–0.11	Lurasidone vs Ziprasidone	–0.59	0.18	–0.59	–0.94	–0.24
SD (between-study heterogeneity)	0.74	0.45	0.70	0.05	1.74	SD (between-study heterogeneity)	0.05	0.04	0.04	0.00	0.15
Total residual deviance	31.16	7.08	30.72	18.54	46.25	Total residual deviance	24.70	6.21	24.05	14.44	38.58
Deviance information criterion	108.08					Deviance information criterion	–32.28
Response^a	Mean odds ratio	SD	Median odds ratio	95% CrIs		Remission^b	Mean odds ratio	SD	Median odds ratio	95% CRIs
versus placebo						versus placebo
Lurasidone vs Placebo	2.59	0.58	2.52	1.65	3.89	Lurasidone vs Placebo	2.19	0.52	2.12	1.36	3.37
Aripiprazole vs Placebo	1.11	0.19	1.09	0.79	1.51	Aripiprazole vs Placebo	0.99	0.18	0.98	0.68	1.40
Olanzapine vs Placebo	1.56	0.21	1.55	1.20	2.02	Olanzapine vs Placebo	1.44	0.21	1.43	1.09	1.90
Quetiapine vs Placebo	2.03	0.20	2.02	1.66	2.45	Quetiapine vs Placebo	1.99	0.20	1.98	1.62	2.41
Ziprasidone vs Placebo	1.09	0.18	1.07	0.77	1.49	Ziprasidone vs Placebo	1.03	0.16	1.01	0.74	1.39
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	2.40	0.67	2.31	1.36	3.96	Lurasidone vs Aripiprazole	2.28	0.69	2.18	1.22	3.90
Lurasidone vs Olanzapine	1.68	0.44	1.63	0.99	2.69	Lurasidone vs Olanzapine	1.54	0.43	1.49	0.87	2.53
Lurasidone vs Quetiapine	1.29	0.31	1.25	0.78	2.01	Lurasidone vs Quetiapine	1.11	0.29	1.07	0.66	1.77
Lurasidone vs Ziprasidone	2.45	0.69	2.36	1.38	4.05	Lurasidone vs Ziprasidone	2.18	0.63	2.10	1.21	3.65
SD (between-study heterogeneity)	0.07	0.06	0.06	0.00	0.21	SD (between-study heterogeneity)	0.08	0.06	0.06	0.00	0.23
Total residual deviance	26.57	6.23	25.93	16.32	40.56	Total residual deviance	2.28	0.69	2.18	1.22	3.90
Deviance information criterion	221.37					Deviance information criterion	229.93

^a Response was defined as ≥50% improvement in MADRS score at endpoint.

^b Remission was defined as a MADRS score ≤12 at endpoint.

Appendix Table 2. Base-case results for the tolerability outcomes of weight change, somnolence, extrapyramidal symptoms and overall discontinuation.

Change in weight from baseline	Mean difference	SD	Median difference	95% CrIs		Somnolence	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	0.34	0.33	0.34	–0.33	1.00	Lurasidone vs Placebo	1.57	0.87	1.37	0.55	3.77
Aripiprazole vs Placebo	0.20	0.43	0.20	–0.65	1.06	Aripiprazole vs Placebo	2.05	0.75	1.92	0.98	3.88
Olanzapine vs Placebo	2.88	0.28	2.88	2.31	3.44	Olanzapine vs Placebo	2.91	0.60	2.84	1.94	4.24
Quetiapine vs Placebo	1.17	0.18	1.17	0.80	1.53	Quetiapine vs Placebo	4.89	0.79	4.82	3.55	6.66
–	–	–	–	–	–	Ziprasidone vs Placebo	5.08	1.78	4.74	2.60	9.49
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	0.14	0.55	0.14	–0.95	1.21	Lurasidone vs Aripiprazole	0.87	0.60	0.71	0.23	2.42
Lurasidone vs Olanzapine	–2.54	0.43	–2.54	–3.42	–1.67	Lurasidone vs Olanzapine	0.56	0.34	0.48	0.18	1.41
Lurasidone vs Quetiapine	–0.83	0.38	–0.83	–1.59	–0.08	Lurasidone vs Quetiapine	0.33	0.19	0.28	0.11	0.82
–	–	–	–	–	–	Lurasidone vs Ziprasidone	0.34	0.23	0.29	0.09	0.93
SD (between-study heterogeneity)	0.28	0.15	0.26	0.03	0.61	SD (between-study heterogeneity)	0.11	0.09	0.09	0.00	0.33
Total residual deviance	26.05	6.90	25.60	14.03	40.83	Total residual deviance	27.63	6.31	26.98	17.18	41.77
Deviance information criterion	23.56					Deviance information criterion	197.02
Extrapyramidal symptoms	Mean odds ratio	SD	Median odds ratio	95% CrIs		All-cause discontinuation	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	4.15	3.51	3.25	1.07	12.50	Lurasidone vs Placebo	1.09	0.28	1.06	0.64	1.75
Aripiprazole vs Placebo	1.97	0.71	1.86	0.98	3.61	Aripiprazole vs Placebo	1.67	0.32	1.64	1.13	2.36
Quetiapine vs Placebo	2.72	0.75	2.61	1.62	4.50	Olanzapine vs Placebo	0.70	0.11	0.69	0.50	0.95
–	–	–	–	–	–	Quetiapine vs Placebo	1.05	0.12	1.04	0.83	1.30
–	–	–	–	–	–	Ziprasidone vs Placebo	1.37	0.24	1.35	0.96	1.92
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	2.36	2.47	1.76	0.48	7.76	Lurasidone vs Aripiprazole	0.68	0.22	0.64	0.35	1.21
Lurasidone vs Quetiapine	1.63	1.52	1.24	0.36	5.18	Lurasidone vs Olanzapine	1.60	0.50	1.54	0.84	2.78
–	–	–	–	–	–	Lurasidone vs Quetiapine	1.05	0.30	1.01	0.59	1.75
–	–	–	–	–	–	Lurasidone vs Ziprasidone	0.82	0.26	0.78	0.42	1.44
SD (between-study heterogeneity)	0.13	0.09	0.12	0.01	0.65	SD (between-study heterogeneity)	0.13	0.09	0.12	0.01	0.33
Total residual deviance	31.43	7.01	31.01	18.82	30.98	Total residual deviance	31.43	7.01	31.01	18.82	46.46
Deviance information criterion	118.60					Deviance information criterion	228.22

Appendix Table 3. Sensitivity analysis results for the efficacy outcomes of change from baseline in MADRS score, CGI-BP-S score, response and remission.

Change in MADRS from baseline	Mean difference	SD	Median difference	95% CrIs		Change in CGI-BP-S from baseline	Mean difference	SD	Median difference	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	–4.70	1.31	–4.70	–7.31	–2.13	Lurasidone vs Placebo	–0.63	0.14	–0.63	–0.89	–0.36
Aripiprazole vs Placebo	–1.09	1.20	–1.09	–3.45	1.28	Aripiprazole vs Placebo	–0.21	0.12	–0.21	–0.45	0.03
Olanzapine vs Placebo	–4.55	0.80	–4.56	–6.08	–2.92	Olanzapine vs Placebo	–0.32	0.11	–0.32	–0.54	–0.11
Quetiapine IR vs Placebo	–4.85	0.75	–4.85	–6.31	–3.35	Quetiapine IR vs Placebo	–0.53	0.08	–0.53	–0.68	–0.38
Quetiapine XR vs Placebo	–4.68	1.08	–4.67	–6.83	–2.56	Quetiapine XR vs Placebo	–0.60	0.17	–0.60	–0.93	–0.26
Ziprasidone vs Placebo	–1.32	1.10	–1.33	–3.47	0.85	Ziprasidone vs Placebo	–0.04	0.12	–0.04	–0.27	0.19
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	–3.61	1.77	–3.61	–7.14	–0.12	Lurasidone vs Aripiprazole	–0.42	0.18	–0.42	–0.78	–0.06
Lurasidone vs Olanzapine	–0.13	1.35	–0.11	–2.85	2.49	Lurasidone vs Olanzapine	–0.31	0.17	–0.31	–0.65	0.04
Lurasidone vs Quetiapine IR	0.15	1.51	0.16	–2.88	3.09	Lurasidone vs Quetiapine IR	–0.10	0.16	–0.10	–0.41	0.21
Lurasidone vs Quetiapine XR	–0.02	1.69	–0.03	–3.34	3.37	Lurasidone vs Quetiapine XR	–0.03	0.22	–0.03	–0.46	0.40
Lurasidone vs Ziprasidone	–3.38	1.71	–3.37	–6.79	–0.00	Lurasidone vs Ziprasidone	–0.59	0.18	–0.59	–0.94	–0.23
SD (between-study heterogeneity)	0.80	0.49	0.76	0.05	1.87	SD (between-study heterogeneity)	0.05	0.04	0.04	0.00	0.16
Total residual deviance	31.64	7.28	31.21	18.65	47.18	Total residual deviance	25.45	6.37	24.81	14.89	39.66
Deviance information criterion	109.75					Deviance information criterion	–30.47
Response^a	Mean odds ratio	SD	Median odds ratio	95% CrIs		Remission^b	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	2.58	0.57	2.51	1.66	3.88	Lurasidone vs Placebo	2.19	0.53	2.13	1.35	3.41
Aripiprazole vs Placebo	1.11	0.19	1.09	0.79	1.51	Aripiprazole vs Placebo	0.99	0.19	0.98	0.68	1.40
Olanzapine vs Placebo	1.56	0.21	1.54	1.19	2.02	Olanzapine vs Placebo	1.45	0.21	1.43	1.09	1.91
Quetiapine IR vs Placebo	1.96	0.21	1.95	1.58	2.40	Quetiapine IR vs Placebo	2.02	0.23	2.01	1.61	2.50
Quetiapine XR vs Placebo	2.61	0.71	2.52	1.49	4.27	Quetiapine XR vs Placebo	1.89	0.52	1.82	1.07	3.10
Ziprasidone vs Placebo	1.08	0.18	1.07	0.77	1.48	Ziprasidone vs Placebo	1.03	0.17	1.01	0.74	1.39
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	2.40	0.67	2.31	1.35	3.97	Lurasidone vs Aripiprazole	2.28	0.71	2.18	1.22	3.94
Lurasidone vs Olanzapine	1.68	0.44	1.63	0.98	2.71	Lurasidone vs Olanzapine	1.55	0.44	1.49	0.87	2.56
Lurasidone vs Quetiapine IR	1.33	0.33	1.29	0.81	2.10	Lurasidone vs Quetiapine IR	1.10	0.29	1.06	0.64	1.78
Lurasidone vs Quetiapine XR	1.06	0.38	1.00	0.51	1.96	Lurasidone vs Quetiapine XR	1.25	0.47	1.17	0.58	2.38
Lurasidone vs Ziprasidone	2.45	0.69	2.35	1.38	4.03	Lurasidone vs Ziprasidone	2.19	0.65	2.10	1.20	3.70
SD (between-study heterogeneity)	0.07	0.06	0.06	0.00	0.21	SD (between-study heterogeneity)	0.08	0.07	0.07	0.00	0.25
Total residual deviance	26.72	6.35	26.06	16.24	40.95	Total residual deviance	29.42	6.46	28.82	18.56	43.74
Deviance information criterion	222.41					Deviance information criterion	228.85

^a Response was defined as ≥50% improvement in MADRS score at endpoint.

^b Remission was defined as a MADRS score ≤12 at endpoint.

Appendix Table 4. Sensitivity analysis results for the tolerability outcomes of weight change from baseline, somnolence, extrapyramidal symptoms and overall discontinuation.

Change in weight from baseline	Mean difference	SD	Median difference	95% CrIs		Somnolence	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	0.34	0.34	0.34	–0.36	1.03	Lurasidone vs Placebo	1.55	0.85	1.36	0.56	3.73
Aripiprazole vs Placebo	0.20	0.44	0.20	–0.66	1.07	Aripiprazole vs Placebo	2.05	0.76	1.92	0.98	3.89
Olanzapine vs Placebo	2.88	0.29	2.88	2.30	3.46	Olanzapine vs Placebo	2.90	0.60	2.84	1.94	4.24
Quetiapine IR vs Placebo	1.12	0.20	1.12	0.72	1.52	Quetiapine IR vs Placebo	4.60	0.80	4.53	3.27	6.37
Quetiapine XR vs Placebo	1.50	0.53	1.50	0.46	2.54	Quetiapine XR vs Placebo	7.97	3.95	7.09	3.14	17.89
	–	–	–	–	–	Ziprasidone vs Placebo	5.08	1.78	4.76	2.59	9.44
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	0.14	0.56	0.14	–0.97	1.24	Lurasidone vs Aripiprazole	0.86	0.59	0.71	0.23	2.37
Lurasidone vs Olanzapine	–2.54	0.45	–2.54	–3.45	–1.64	Lurasidone vs Olanzapine	0.56	0.33	0.48	0.18	1.41
Lurasidone vs Quetiapine IR	–0.78	0.40	–0.78	–1.59	0.02	Lurasidone vs Quetiapine IR	0.35	0.20	0.30	0.12	0.86
Lurasidone vs Quetiapine XR	–1.16	0.63	–1.16	–2.41	0.08	Lurasidone vs Quetiapine XR	0.24	0.18	0.19	0.05	0.69
–	–	–	–	–	–	Lurasidone vs Ziprasidone	0.34	0.23	0.28	0.09	0.93
SD (between-study heterogeneity)	0.29	0.16	0.28	0.03	0.65	SD (between-study heterogeneity)	0.11	0.09	0.09	0.00	0.34
Total residual deviance	26.20	6.97	25.71	14.13	41.21	Total residual deviance	27.72	6.43	27.07	17.05	42.06
Deviance information criterion	24.61					Deviance information criterion	198.02
Extrapyramidal symptoms	Mean odds ratio	SD	Median odds ratio	95% CrIs		All-cause discontinuation	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus placebo						versus placebo
Lurasidone vs Placebo	4.22	3.55	3.30	1.06	12.90	Lurasidone vs Placebo	1.09	0.29	1.06	0.64	1.76
Aripiprazole vs Placebo	1.98	0.71	1.87	0.97	3.62	Aripiprazole vs Placebo	1.67	0.32	1.63	1.13	2.38
Quetiapine IR vs Placebo	2.57	0.72	2.46	1.50	4.27	Olanzapine vs Placebo	0.70	0.11	0.69	0.50	0.95
Quetiapine XR vs Placebo^a	61.81	1265.0	8.72	1.13	266.1	Quetiapine IR vs Placebo	1.01	0.12	1.00	0.78	1.27
–	–	–	–	–	–	Quetiapine XR vs Placebo	1.45	0.45	1.39	0.76	2.52
–	–	–	–	–	–	Ziprasidone vs Placebo	1.37	0.25	1.35	0.95	1.92
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	2.40	2.52	1.78	0.48	8.00	Lurasidone vs Aripiprazole	0.68	0.23	0.65	0.34	1.21
Lurasidone vs Quetiapine IR	1.76	1.60	1.34	0.38	5.68	Lurasidone vs Olanzapine	1.61	0.51	1.54	0.84	2.80
Lurasidone vs Quetiapine XR†	0.84	1.69	0.38	0.01	4.42	Lurasidone vs Quetiapine IR	1.10	0.32	1.06	0.61	1.86
–	–	–	–	–	–	Lurasidone vs Quetiapine XR	0.82	0.35	0.76	0.35	1.67
–	–	–	–	–	–	Lurasidone vs Ziprasidone	0.82	0.27	0.78	0.42	1.45
SD (between-study heterogeneity)	0.22	0.18	0.18	0.01	0.66	SD (between-study heterogeneity)	0.13	0.09	0.12	0.01	0.34
Total residual deviance	19.49	5.42	18.90	10.55	31.75	Total residual deviance	31.28	7.07	30.82	18.65	46.41
Deviance information criterion	119.71					Deviance information criterion	228.85

^a Results for these comparisons should be interpreted with caution due to the low event rates reported for extrapyramidal symptoms in the quetiapine extended release study (Suppes et al., 2014).

Appendix Table 5. Sensitivity analysis results for the efficacy and safety outcomes (excluding Wang et al. (2014) from the base-case analysis).

Change in MADRS from baseline	Mean difference	SD	Median difference	95% CrIs		Change in CGI-BP-S from baseline	Mean difference	SD	Median difference	95% CrIs
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	–4.69	1.17	–4.70	–6.99	–2.40	Lurasidone vs Aripiprazole	–0.63	0.14	–0.63	–0.90	–0.37
Lurasidone vs Quetiapine Pooled	0.11	1.29	0.12	–2.43	2.63	Lurasidone vs Quetiapine pooled	–0.08	0.15	–0.08	–0.38	0.21
Lurasidone vs Olanzapine	–1.28	1.46	–1.28	–4.17	1.59	Lurasidone vs Olanzapine	–0.31	0.17	–0.31	–0.65	0.03
Lurasidone vs Ziprasidone	–3.38	1.55	–3.38	–6.42	–0.34	Lurasidone vs Ziprasidone	–0.42	0.18	–0.42	–0.78	–0.06
SD (between-study heterogeneity)	0.53	0.39	0.46	0.02	1.46	SD (between-study heterogeneity)	–0.59	0.18	–0.59	–0.93	–0.24
Total residual deviance	26.73	6.26	26.15	16.12	40.62	Total residual deviance	0.056	0.035	0.06	0.002	0.137
Deviance information criterion	98.82					Deviance information criterion	–35.67
Response^a	Mean odds ratio	SD	Median odds ratio	95% CrIs		Remission^b	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	2.59	0.58	2.53	1.65	3.92	Lurasidone vs Aripiprazole	2.19	0.52	2.12	1.35	3.37
Lurasidone vs Quetiapine Pooled	1.29	0.32	1.25	0.79	2.02	Lurasidone vs Quetiapine Pooled	1.11	0.29	1.07	0.66	1.77
Lurasidone vs Olanzapine	1.80	0.48	1.73	1.05	2.90	Lurasidone vs Olanzapine	1.63	0.45	1.57	0.93	2.68
Lurasidone vs Ziprasidone	2.46	0.69	2.37	1.38	4.07	Lurasidone vs Ziprasidone	2.28	0.69	2.18	1.22	3.91
SD (between-study heterogeneity)	0.07	0.05	0.06	0.00	0.20	SD (between-study heterogeneity)	2.19	0.63	2.10	1.22	3.66
Total residual deviance	22.51	6.04	21.86	12.65	36.12	Total residual deviance	0.08	0.06	0.06	0.00	0.22
Deviance information criterion	198.02					Deviance information criterion	210.67

^a Response was defined as ≥50% improvement in MADRS score at endpoint.

^b Remission was defined as a MADRS score ≤12 at endpoint.

Appendix Table 7. Sensitivity analysis results for the tolerability outcomes (excluding Wang et al. (2014) from the base-case analysis).

Change in weight from baseline	Mean difference	SD	Median difference	95% CrIs		All-cause discontinuation	Mean odds ratio	SD	Median odds ratio	95% CrIs
versus other atypical antipsychotics						versus other atypical antipsychotics
Lurasidone vs Aripiprazole	0.34	0.33	0.34	–0.33	1.00	Lurasidone vs Aripiprazole	1.09	0.29	1.06	0.64	1.75
Lurasidone vs Quetiapine Pooled	–0.83	0.38	–0.83	–1.59	–0.08	Lurasidone vs Quetiapine Pooled	1.05	0.30	1.01	0.58	1.76
Lurasidone vs Olanzapine	–2.53	0.44	–2.53	–3.39	–1.64	Lurasidone vs Olanzapine	1.62	0.52	1.55	0.84	2.83
Lurasidone vs Ziprasidone	0.14	0.55	0.14	–0.95	1.21	Lurasidone vs Ziprasidone	0.68	0.22	0.65	0.34	1.21
SD (between-study heterogeneity)	0.28	0.15	0.26	0.03	0.62	SD (between-study heterogeneity)	0.82	0.27	0.78	0.42	1.44
Total residual deviance	24.86	6.78	24.40	13.10	39.39	Total residual deviance	0.13	0.09	0.12	0.01	0.33
Deviance information criterion	15.93					Deviance information criterion	219.29

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