Table 1.

Worldwide increased mortality in patients using antipsychotic agents

Country	Study/Years	Patient No.	Event/duration	Drug Use	Hazard Ratio (HR); [95% CIs]	Reference
United Kingdom	General Practice Research Database (GPRD) 1995–2011	183,392 patients (115,491 typical; 67,901 atypical) versus 544,726 general population controls or 193,920 psychiatric non-users	All-cause mortality	Atypical and typical antipsychotics	Users matched to psychiatric non-users HR = 2.15; [2.10–2.21] and HR = 2.98; [2.93–3.03] matched with general population non-users.	Jones et al., 2013 [37]; Murray-Thomas et al., 2013 [36]
					Sudden cardiac death was greatly increased in psychiatric users versus the psychiatric matched non-users with HR = 5.76; [2.90–11.45]
	UK Clinical Practice Research Datalink 1998–2013	60,121 dementia patients	First-time seizures in Dementia patients over 15-year period	Atypical antipsychotics Olanzapine, quetiapine	*HR = 2.335 [1.35–4.01]	Bloechliger et al., 2015 [38]
				Low-to-medium potency typical antipsychotics	HR = 3.01 [1.34–6.64]	[38]
				Medium-to-high potency typical antipsychotics	HR = 2.21 [1.05–4.62]	[38]
	Welsh Secure Anonymised Information Linkage (SAIL) databank 2003–2011	9,674 newly diagnosed dementia patients aged≥65 years	All-cause Mortality and serious adverse events. 12 months prior compared to 12 months post starting antipychotic	Typical 1513	Prior event rate ratio PERR used as HR = 2.07 [1.732–2.473]. Increased SAEs as Cardiac arrest, venous thromboembolism, stroke or hip fracture. Mainly in first 100 days of use.	Dennis et al., 2017 [40]
				Atypical 1687
France	16 French Memory Centres	534 Alzheimer’s Dementia patients, 102 new users	All-cause Mortality in Alzheimer’s dementia 3.5-year follow-up	Antipsychotics (typical and atypical) new use versus non-user control	HR = 1.93; [1.15–3.25]	Gardette et al., 2012 [41]
Norway	2014 Norwegian Prescription Database	26,940 dementia outpatients	All-cause mortality in Dementia patients short (30 day) or long term use (730–2400 days), Follow up over more than 6 years	Antipsychotic (ATC code N05A) use versus other psychotropics: antidepressants (N06A), benzodiazepine (N03AE01, N05B, N05C), benzodiazepine-like agents (N05C), lithium (N05AN01), and anticonvulsive drugs (N03A).	HR30days = 2.1 [1.6–2.9]	Langballe et al., 2014 [42]
					HR730 - 2,400days = 1.7 [1.6–1.9].
					Haloperidol HR 30 days = 1.7 [1.0–3.0], HR 730–2,400 days = 1.4 [1.0–1.9] compared to risperidone.
Denmark	Danish National Patient Registry 1997–2009	26,821 dementia patients versus 44,286 matched control non-users.	All-cause mortality in dementia patients or non-dementia patients	Psychotropics:	SSRIs HR = 1.355 (SD = 0.023), P = 0.001 in patients versus HR = 1.808 (0.033), p < 0.001 in non-dementia users),	Jennum et al., 2015 [43]
		Also compared use in dementia versus non-dementia users.	4 up to 12-year follow-up	Antidepressants (SSRI) Benzodiazepines, and Typical or Atypical Antipsychotics	Tricyclic antidepressants (HR = 1.004 (0.046), p = 0.925 versus HR = 1.406 (0.061), p < 0.001) in non-dementia users.
				Versus non-user controls	Benzodiazepines HR = 1.131 (SD = 0.039), p = 0.060 patients versus HR = 1.362 (0.028), p < 0.001 in non-dementia users.
					Typical antipsychotics (HR = 1.183 (SD = 0.074), p = 0.022 versus HR = 2.026 (SD = 0.114) in non-dementia users, p < 0.001. Atypical antipsychotics (HR = 1.380 (SD = 0.042) patients, p < 0.001 versus HR = 1.785 (SD = 0.088), p < 0.001) in non-dementia users.
	Danish National Patient Registries 2000–2011	45,894 Alzheimer’s Dementia patients	All-cause Mortality in Dementia patients:	Antipsychotics: Atypical and Typical	Current antipsychotic users (prior 12 months) HR = 2.31; [2.14–2.49], p < 0.001	Nielsen et al., 2017 [44]
			Cardiovascular, infection, cancer	ATC Code = N05A except Lithium.
			12-month follow-up	Versus non-user control
Finland	Finnish National Prescription Register (FNPR) 2000–2008	332 community dwelling elderly (≥65 years, 0.5% dementia)	All-cause Mortality 9-year follow up	New users of antipsychotics	HR = 2.71; [2.3–3.2]	Gisev et al., 2012 [45]
	MEDALZ 2005–2011	15,806 Alzheimer’s dementia from 57,755 community-dwelling newly diagnosed Alzheimer’s patients 2005–2011	All-cause Mortality.	Antipsychotics	Antipsychotic monotherapy (HR = 1.61; [1.53–1.70]) compared to non-users.	Koponen et al., 2017 [46]
			Median follow-up 2.5 years		(HR1 - 30days = 1.74 to HR30 - 90days = 2.11). At 2 years, HR = 1.30; [1.16–1.46]. Haloperidol HR = 1.52; [1.14–2.02]) relative to risperidone.
					>1mg Haloperidol HR = 2.55; [1.7–3.85] relative to risperidone.
Japan	2014	10,000 dementia patients	All-cause Mortality in Alzheimer patients.	Antipsychotics (typical and atypical) new use versus non-user control	New users	Arai et al., 2016 [47]
			11-24-week follow-up		*HR = 3.7; [1.57–8.3]
Taiwan	Longitudinal Health Insurance Database 2000 (LHID2000)	183,410 patients on antipsychotic monotherapy 1996–2011	All-cause Mortality follow up varied from 2–6 years	Typical Antipsychotics Chlorpromazine (2133)	New users <30 day, 30–90 day and >90 days	Wang et al., 2016 [72]
				Haloperidol (4454)	Haloperidol HR30 = 2.11; [1.87–2.39], risperidone HR30 = 1.79; [1.45–2.22] relative to chlorpromazine as reference.
				Atypical antipsychotics
				Quetiapine (1513)
				Risperidone (1046)
Italy	Milan health information database 2002–2008	4,369 dementia patients≥60 years	All-cause Mortality over 2-year follow up	typical (n = 156) versus atypical (n = 806) antipsychotic drugs	New users antipsychotics.	Musicco et al., [48] - 2011
					Atypical (HR = 2.5; [2.05–3.1])
					Typical (HR = 3.7; [2.6–5.1])
	Teramo Hospital 2007–2009	696 Alzheimer’s dementia patients≥65 years	All-cause Mortality follow up over 3 years; n = 375 users compared to non-user control	Atypical Antipsychotics (quetiapine, risperidone and olanzapine)	HR = 2.354; [1.704–3.279]	Piersanti et al., 2014 [49]
	REPOSI (Registro Politerapie Società Italiana Medicina Interna) database 2010–2012	135 dementia (≥65 years; mean age ∼80 years)	All-cause Mortality over 90 days	Antipsychotics promazine, chlorpromazine, olanzapine, levomepromazine, haloperidol, amisulpride, clotiapine, tiapride, zuclopenthixol, quetiapine, risperidone, periciazine, levosulpiride and clozapine.	New users	Chiesa et al., 2017 [50]
					Hr = 1.57; [0.95–2.61]
Spain	FEDRA Spanish system for Drug Surveillance 1995–2012	N = 5,203 adverse event – exposed; N = 200 related deaths – all users	All-cause Mortality plus adverse events. All users versus users of other drugs	Antipsychotics versus any other drugs as control	Atypical antipsychotics	Martin Arias et al., 2017 [24]
					HR = 2.47; [2.10–2.92]
					Typical antispychotics
					HR = 1.79; [1.47–2.18]
					Particularly: zuclopenthixol (HR = 3.39; [1.75–6.59])
					risperidone HR = 2.07; [1.56–2.75)
					Haloperidol HR = 2.71; 1.98–3.69]. No difference between elderly versus younger groups.
7 European Union countries; including Israel	59 Nursing homes 2009–2011	Dementia patients n = 604≥65 years old	All-cause mortality in dementia patients	Antipsychotic users n = 278 versus other drugs as control.	HR = 1.71; [1.15–2.54]	Liperoti et al., 2017 [23]
Australia	Nationwide memory clinics	Community based dementia patients 779. Mostly >65 years	follow-up 3 years with mortality determined at 8 years	Atypical antipsychotic drugs versus non-users	Atypical HR = 1.61; [1.29–2.02] (p < 0.01)	Connors et al., 2016 [51]
U.S.A.	Tennessee Medicaid records 1990–2005	Antipsychotic drug users 30–74 years old (mean age 46)	Sudden cardiac death from baseline. Median follow-up 2.5 years	Antipsychotic users (Typical 44218, atypical 44089) versus 186,600 non-users (sub-group to matched psychiatric non-users)	Typical HR = 1.99; [1.69–2.35]	Ray et al., 2009 [52]
					Atypical HR = 2.26; [1.88–2.72]. Dose-related with high dose HR = 2.7
	1998–2005 National VHA database Texas	Antipsychotics dementia users versus non-user control N = 8,867–32,996	All-cause mortality, 5-year follow-up	Antipsychotics	30 day first use:	Rossom et al., 2010 [53]
		≥65 years old		Haloperidol, 2,217	HR = 3.2; [2.2–4.5], p < 0.001
				Quetiapine, 4,277	HR = 1.2; [0.7–1.8], p = 0.5
				Olanzapine, 3,384	HR = 1.5; [1.1–2.0], p = 0.01
				Risperidone, 8,249	HR = 1.5; [1.1–2.2], p = 0.01
	1998–2000 Across 5 states. Nursing homes	6,524 new users atypical and 3205 typical antipsychotics≥65 years old	All-cause mortality in dementia patients.	Typical Antipsychotics cf’d atypicals.	HR = 1.26; [1.13–1.42]	Liperoti et al., 2009 [6]
			6-month follow-up	Except quetiapine or olanzapine cf’d risperdone.	HR = 1.06; [0.80–1.39]
				Haloperidol compared to risperidone.	HR = 0.95; [0.8–1.12]
				risperidone (n = 4,406); haloperidol (n = 1,413)	HR = 1.31; [1.13–1.53]
	2001–2005 Nursing homes	75,445≥65 years	All-cause mortality elderly in nursing homes.	Antipsychotic	HR = 2.07; [1.89–2.26]	Huybrechts et al., 2012 [7]
			6-month follow-up	Haloperidol compared to risperidone
	Dept. Veteran Affairs 1999–2008	33,604≥65 years	All-cause mortality in dementia patients.	Antipsychotic	Haloperidol HR = 1.54; [1.38–1.73] compared to valproate	Kales et al., [8]- 2012
			6-month follow-up	(risperidone, olanzapine, quetiapine, or haloperidol)
	Dept. Veteran Affairs 1998–2009	90,786≥65 years	All-cause mortality in dementia patients.	New users of atypical antipsychotics (olanzapine, quetiapine, and risperidone, haloperidol). Dose-related increase in mortality compared to matched non-user controls or alternatively, antidepressants as reference group;	Haloperidol HR = 1.123; [1.086–1.16]; p < 0.01 cf’d antidepressant group.	Maust et al., 2015 [54, 55]
			6-month follow-up		Atypical antipsychotics (olanzapine, quetiapine, and risperidone) dose-response increase in mortality risk, HR = 1.035; [1.005–1.065]; p = 0.02 in the high-dose subgroup relative to the low-dose group.

*Relative risk (RR) calculated from adjusted Odds Ratio (OR) given incidence in controls using online convertor (http://clincalc.com/stats/convertor.aspx).