Table 2.

Meta-analysis of Mortality Rate in Patients Treated With Clozapine, Including Subgroup and Sensitivity Analyses

	Number of Samples	Total Number of Deaths	Total Number of Patient Years	Number of Deaths per Patient Year	Lower 95% CI	Upper 95% CI	I 2 (%)
Mortality rate in patients treated with clozapine continuously or ever during follow-up (main analysis)	22	1161	196574	0.0067	0.0054	0.0079	84.3
Subgroup analysis
On clozapine ever during follow-up	18	390	59370	0.0071	0.0051	0.0090	78.8
On clozapine continuously during follow-up	4	771	137204	0.0067	0.0046	0.0089	94.4
All studies with a comparator group using other antipsychotics	8	523	75339	0.0066	0.0042	0.0090	93.4
On clozapine ever during follow-up and other antipsychotic comparator group	4	124	14705	0.0077	0.0020	0.0133	92.5
No antipsychotic comparator group	3	207	22286	0.0077	0.0039	0.0115	89.0
>100 patients, >500 patient years	12	1117	192598	0.0069	0.0056	0.0082	89.7
>100 patients, >5 years follow-up	5	477	63834	0.0073	0.0044	0.0102	94.1
Categorical sensitivity analysis (between group P-value)
On clozapine ever or continuously during follow-up (P = .838)
Ever	18	390	59370	0.0071	0.0051	0.0090	78.8
Continuously	4	771	137204	0.0067	0.0046	0.0089	94.4
Continent (P = .227)
Asia	4	21	4630	0.0044	−0.0008	0.0096	60.7
Australia	1	29	4527	0.0064	NA	NA	NA
Europe	10	577	90470	0.0064	0.0047	0.0081	85.4
Multicontinental	1	12	913	0.0131	NA	NA	NA
North-America	6	522	96034	0.0104	0.0051	0.0158	89.0
Treatment-resistant (P = .103)
Treatment-resistant patients only	7	217	41530	0.0052	0.0032	0.0072	60.0
Other	15	944	155044	0.0074	0.0057	0.0091	88.1
Treatment setting (P = .621)
Inpatient only	2	18	3920	0.0191	−0.0181	0.0563	85.6
Outpatient only	3	212	36607	0.0058	0.0050	0.0066	0.0
In- and outpatients	10	654	113036	0.0066	0.0043	0.0090	88.1
Risk of biasa (P = .749)
Low	9	900	149171	0.0078	0.0058	0.0099	91.2
High	13	249	43034	0.0058	0.0039	0.0076	69.2
Diagnosis (P = .087)
Schizophrenia only	7	196	39640	0.0049	0.0027	0.0071	64.5
Schizophrenia and related disorders	15	965	156934	0.0073	0.0057	0.0089	87.4
Start of study conduct (P = .193)
≤1980	1	4	1156	0.0035	NA	NA	NA
1980–1990	4	167	32602	0.0070	0.0015	0.0126	80.4
1991–2000	11	755	138550	0.0064	000048	0.0080	82.7
2001–2010	6	235	24266	0.0054	0.0054	0.0116	76.0
Sample size patient years (P = .463)
0–100	3	5	220	0.0175	0.0000	0.0350	0
>100	4	15	802	0.0202	−0.0005	0.0410	77.0
>500	2	14	1557	0.0076	−0.0021	0.0174	80.9
>1000	9	244	31163	0.0073	0.0049	0.0097	84.4
>10000	4	883	162832	0.0063	0.0046	0.0080	94.5
Years of follow-up (P = .905)
0–5 years	11	463	92286	0.0069	0.0041	0.0098	62.3
>5 years	4	227	25530	0.0077	0.0032	0.0123	94.3
>7.5 years	5	449	76448	0.0063	0.0045	0.0081	86.7
>10 years	2	22	2310	0.0091	−0.0028	0.0210	88.8

^aRisk of bias of the studies was assessed on outcome level with the Cochrane Risk of bias tool for randomized studies or the Newcastle Ottawa scale (NOS, range = 0–9) for observational studies. For observational studies with an ineligible comparison group or convenience samples, we used the NOS (range = 0–6) without the items regarding comparison groups, with a score of ≤5 indicating high risk of bias.