Cardiac and
(Am J Geriatr
Cerebrovascular Morbidity
and Mortality Associated
With Antipsychotic
Medications in Elderly
Psychiatric Inpatients
Yoram Barak, M.D., M.H.A.
Yehuda Baruch, M.D., M.H.A.
Doron Mazeh, M.D.
Diana Paleacu, M.D.
Dov Aizenberg, M.D.
Objective: To evaluate the rate of adverse medical
outcomes for elderly exposed to antipsychotic treat-
ment. Methods: This was a retrospective evaluation
of psychiatric inpatients records. Age, gender, diagno-
sis, treatment with antipsychotics, and duration of
treatment were analyzed. An acute cardiac or cere-
brovascular event necessitating transfer to a general
hospital or resulting in death was the outcome mea-
sure. Results: During 15 years (1990 to 2005), 3,111
elderly were hospitalized. Their mean age was 73.5
6.1 years, 1,220 were male (39%), and 1,891 were
female (61%). Most patients (2,583 [83%]) were ex-
posed to antipsychotics, of which 1,402 (54%) were
exposed to second-generation antipsychotics (SGAs).
Antipsychotic-treated patients did not have a higher
rate of adverse medical outcomes compared with
patients who had not received antipsychotics. No sig-
nificant differences were noted between patients ex-
posed to typical antipsychotics or SGAs. Conclusion:
Treatment of elderly psychiatric inpatients with anti-
psychotics did not increase their risk of adverse med-
ical outcomes. Thus, regulating the use of conven-
tional antipsychotics or SGAs for all elderly patients
Received April 29, 2006; revised November 11, 2006; accepted November 17, 2006. From the Abarbanel Mental Health Center, Bat-Yam, Israel
(YoB, YeB, DM, DP), and the Geha Mental Health Center, Petah-Tiqva, Israel (DA). Send correspondence and reprint requests to Prof. Yoram
Barak, Psychogeriatric Department, Abarbanel Mental Health Center, 15 KKL Street, Bat-Yam, Israel. e-mail: mdybarak@netvision.net.il
2007 American Association for Geriatric Psychiatry
354
in all indications may be premature.
Psychiatry 2007; 15:354356)
Key Words: Antipsychotic, cardiac, cerebrovascular,
morbidity, mortality, elderly
A ntipsychotics are the most studied medications
for treating psychosis and severe agitation in
elderly patients. The advent of the second-generation
antipsychotic medications (SGAs) resulted in wide-
spread use in the elderly, due to their different pro-
le of side effects compared with conventional anti-
psychotics (CAs).1 Recently the U.S. Food and Drug
Administration (FDA) issued a black box warning
stating that the use of SGA nearly doubles the risk of
death in elderly subjects suffering from dementia as
compared with placebo.2
However, only a few studies have focused on the
relative risks associated with exposure of elderly
patients to CA.3 6 Two reports concluded that the
use of CAs does not increase mortality in dementia
patients.3,4 In the general elderly population,5,6 one
observational study found higher rates of death
given haloperidol than those given one of two atyp-
ical drugs5 and another recent publication suggested
that CAs are at least as likely as SGAs to increase this
risk.6
The need for additional data is urgent. We thus
aimed to retrospectively analyze the effects of expo-
sure to both CAs and SGAs in a large group of
elderly patients newly admitted to an acute psychi-
atric ward.
METHODS
The Abarbanel Mental Health Center (Bat-Yam, Is-
rael) is afliated with the Sackler School of Medicine,
Tel-Aviv University. At this center, there are 300
inpatients beds and 60 day-patients, as well as a large
outpatient clinic. The center serves a catchment area
of approximately 850,000 people, of which 13.4% are
Am J Geriatr Psychiatry 15:4, April 2007

65 years or older. In case of acute medical emer-
gency, patients are transferred to a nearby university
hospital that provides all necessary medical treat-
ment.
We conducted a 15-year retrospective analysis of
all records of elderly patients admitted to our center.
For purposes of the present study, an elderly patient
was dened as being 65 years or older. The study
was approved by the centers internal review board.
Our centers computerized database was queried
for all admissions of elderly patients. Between 1990
and 2005 there were 3,111 admissions fullling the
following inclusion criteria: 1) age 65 years or older,
2) International Classication of Diseases, Ninth Revi-
sion, Clinical Modication (ICD-9-CM) diagnosis, and
3) availability of discharge chart and diagnosis from
the consulting general hospital.
Computerized patient les were reviewed and the
following data extracted: age, gender, diagnosis,
treatment with antipsychotic medications (current
hospitalization), and duration of treatment (days).
Outcome Assessment
The outcome of this study was dened as admis-
sion to the consulting general hospital due to isch-
emic hearth disease, cerebrovascular disease, or
death of a patient that occurred during psychiatric
hospitalization. Assigning a patient to the adverse
medical outcome group was based on a consensus
panel discussion that reviewed all ancillary informa-
tion gathered from both medical and psychiatric
charts. The panel included a board-certied neurol-
ogist (PD), board-certied psychiatrists (MD, AD,
BYo) and a board-certied specialist in health admin-
istration (BYe). The panel was blinded to the type of
antipsychotic treatment subjects had received. We
identied all admissions or deaths in which the dis-
charge diagnosis (ICD-9-CM) was one of the follow-
ing: ischemic heart disease (codes 410 414) or cere-
brovascular disease (codes 430 438).
Statistical Analysis
Data were analyzed using a paired-samples and
independent-samples approach. The two-tailed t-test
and nonparametric test were undertaken to test for
differences between the evaluations for qualitative
parameters. The paired t-test and nonparametric sign
Am J Geriatr Psychiatry 15:4, April 2007
Barak et al.
rank test were applied for testing differences be-
tween baseline assessment and end-of-study assess-
ments for quantitative parameters. Examination of
differences between the categorical parameters was
based on the Fishers exact test. All tests applied
were two-tailed, and p value of 5% or less was con-
sidered statistically signicant. The data were ana-
lyzed using SAS software (SAS Institute).7
RESULTS
During the period of January 1990 to November
2005, 3,111 elderly subjects were hospitalized in the
acute psychogeriatric ward of Abarbanel Mental
Health Center. Mean age for the group was 73.9
5.6 years, 1,220 were male (39%) and 1,891 were
female (61%). The primary psychiatric diagnoses (Di-
agnostic and Statistical Manual of Mental Disorders,
Fourth Edition) were as follows: affective disorders,
1,481 (48%); schizophrenia and schizoaffective disor-
der, 871 (28%); dementia, 534 (17%); and brief psy-
choses, 225 (7%).
The majority of patients (2,583 [83%]) were ex-
posed to antipsychotic medications, whereas a sig-
nicant minority (528 [17%]) did not receive either
CAs or SGAs (group 1). Among patients receiving
antipsychotic treatment, 1,402 (54%) were exposed to
SGAs (group 2), whereas 1,181 (46%) were pre-
scribed a CA (group 3). The mean duration for the
CA group (group 3) was 49.2 50.3, whereas the
mean for the SGA group was 49.5 51.2. These
means are not signicantly different for the CA ver-
sus SGA groups (t 0.17, df2581, p 0.87).
During the study period, 246 patients (7.9%) had
been hospitalized in the consulting general hospital
for any general medical condition. Of these, 74 died
(2.4%). The panel consensus had identied the fol-
lowing rates of cardiac and cerebrovascular adverse
outcomes: group 1, 8 of 528 (1.52%); group 2, 26 of
1,402 (1.85%); group 3, 31 of 1,181 (2.62%).
Using a regular simple 2 test comparing all three
groups yielded p values on the order of 0.29 to 0.39
( 2 1.025, df1, p0.31). Once the overall 2 test
indicated no signicant differences, there was no
justication for performing further multiple con-
trasts.
The mean age of patients not receiving antipsy-
355
Morbidity and Mortality Associated With Antipsychotics
chotic medications was 72.5 5.6 years, whereas the
mean ages for the two treated groups were 73.9 6.6
years (SGA) and 73.4 6.2 years (CA). The differ-
ences among the group ages were signicantly dif-
ferent (F10.38, df2, 3108, p 0.0001).
Distribution of psychiatric diagnoses among the
different groups who had suffered an adverse med-
ical outcome were as follows: group 1, 5 affective
disorders and 3 schizophrenia; group 2, 20 schizo-
phrenia and 11 dementia; group 3, 13 dementia, 7
affective disorders, and 6 schizophrenia.
DISCUSSION
A recent expert consensus panel for using antipsy-
chotic drugs in the elderly favored SGAs as rst-line
choice in several disorders as follows: agitated de-
mentia with delusions, late-life schizophrenia, delu-
sional disorder, geriatric psychotic major depression,
and psychotic mania. The growing number of SGAs
available expands clinical options but complicates
decision making.8
In April 2005, following publication of several
alarming reports, the FDA warned that the use of
SGAs increases risk of death compared with placebo
in elderly persons suffering from dementia.2 If SGAs
are banned for treating agitated demented patients,
then there is the possibility that clinicians will switch
to using CAs. The association of CAs with cardiac
and cerebrovascular morbidity and mortality has not
References
1. Barak Y, Aizenberg D: Effects of olanzapine on lipid abnormalities
in elderly psychotic patients. Drugs Aging 2003; 20:893896
2. Food and Drug Administration. FDA public health advisory:
deaths with antipsychotics in elderly patients with behavioral
disturbances. Available at: http://www.fda.gov/cder/drug/advisory/
antipsychotics.htm. Accessed November 3, 2005.
3. Finkel S, Kozma C, Long S, et al: Risperidone treatment in elderly
patients with dementia: relative risk of cerebrovascular events
versus other antipsychotics. Int Psychogeriatr 2005; 17:617629
4. Suh GH, Shah A: Effect of antipsychotics on mortality in elderly
patients with dementia: a 1-year prospective study in a nursing
home. Int Psychogeriatr 2005; 17:429441
5. Nasrallah HA, White T, Nasrallah AT: Lower mortality in geriatric
patients receiving risperidone and olanzapine versus haloperidol:
preliminary analysis of retrospective data. Am J Geriatr Psychiatry
2004; 12:437439
356
been critically examined. Moreover, haloperidol was
reported to have a higher risk of cerebrovascular
adverse outcome compared to placebo.9
The results of the present study do not support
the hypothesis that antipsychotics, either CAs or
SGAs, are associated with higher cardiac and cere-
brovascular morbidity and mortality. The strengths
of this study are its naturalistic design, long dura-
tion, and comparison of two drug classes within the
same therapeutic setting. Other studies published to
date have all focused mainly on patients suffering
from dementia,35 whereas the present analysis ex-
amined the use of antipsychotics in a wider range of
psychiatric indications for this treatment in the el-
derly.
The limitations of this analysis are: retrospective
nature, short duration of treatment, large variance of
age between treated groups, and the relatively low
number of adverse outcomes. It is important to note
that further analysis of outcomes broken down into
four categories (either death or hospitalization for
either cardiac or cerebrovascular reason) proved to
be of no statistical signicance, in part due to the
small number of events.
In conclusion, prospective studies and individual
patient analysis modeling are needed to establish
safety of SGA use in the elderly.10 However, this
naturalistic study provides data supported by sev-
eral other investigations that regulating the use of
CAs or SGAs for all elderly patients in all indications
may be premature.
6. Wang PS, Schneeweiss S, Avorn J et al: Risk of death in elderly
users of conventional vs. atypical antipsychotic medications.
N Eng J Med 2005; 353:23352341
7. SAS/STAT Users Guide, Version 6, 4th Ed. Cary, NC, SAS Insti-
tute, 1990
8. Alexopoulos GS, Streim J, Carpenter D, Docherty JP: Expert
Consensus Panel for Using Antipsychotic Drugs in Older Patients.
Using antipsychotic agents in older patients. J Clin Psychiatry
2004; 65(suppl 2):599
9. Shah A, Suh GH: A case for judicious use of risperidone and
olanzapine in behavioral and psychological symptoms of demen-
tia (BPSD). Int Psychogeriatr 2005; 17:1222
10. Schneider LS, Dagerman KS, Insel P: Risk of death with atypical
antipsychotic drug treatment for dementia: meta-analysis of
randomized placebo-controlled trials. JAMA 2005; 294:1934
1943
Am J Geriatr Psychiatry 15:4, April 2007