Antipsychotic Drug Use and Community-Acquired
Published online: 11 March 2011
# The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract Antipsychotics are generally distinguished as
atypical and typical agents, which are indicated in the
treatment of acute and chronic psychoses and other
psychiatric disorders. In April 2005, the US Food and
Drug Administration issued a warning about the increased
risk of all-cause mortality associated with atypical antipsy-
chotic use in elderly patients with dementia. Pneumonia
was one of the most frequently reported causes of death.
The same warning was extended to typical antipsychotics in
June 2008. In recent years, several observational studies
have further explored the association between antipsychotic
use, mainly in elderly patients, and the risk of fatal/nonfatal
community-acquired pneumonia. The aim of this review is
to revise and discuss the scientific evidence and biologic
explanations for the association between atypical and
typical antipsychotic use and pneumonia occurrence. Some
general recommendations to clinicians are proposed to
prevent the risk of pneumonia in patients requiring
Keywords Antipsychotic agents.Butyrophenones.
Aspiration pneumonia.Aged.Drug toxicity
Antipsychotic drugs are generally categorized as typical
antipsychotics (sometimes referred to as first-generation or
conventional antipsychotics, or neuroleptics) and atypical
antipsychotics; both are approved for the treatment of acute
and chronic psychoses (ie, schizophrenia), mania, agitation,
and other psychiatric disorders.
Typical antipsychotics were developed initially in the
1950s. Chlorpromazine was the first typical antipsychotic
to enter clinical use. Atypical antipsychotics have been
marketed since the 1990s, starting with clozapine, followed
by risperidone and olanzapine, and more recently quetia-
pine, aripiprazole, ziprasidone, and paliperidone. The
atypicality of this newer class consists of greater efficacy
in the treatment of negative symptoms (ie, catatonia,
apathy) of schizophrenia and lower risk of extrapyramidal
adverse events, as compared to typical antipsychotics.
Because of a supposed better safety profile, in the past
decade, the use of atypical antipsychotics rapidly expanded
worldwide, even for unlicensed indications of use, such as
the treatment of behavioral and psychological symptoms of
A population-based study found that more than 3% of
community-dwelling patients are currently treated with
antipsychotics in Italy, with a striking increase in the use
of atypical antipsychotics over time [2•]. These findings are
in accord with data from the United Kingdom  and
United States, where olanzapine and risperidone were
already the most commonly prescribed antipsychotic drugs
in 1997 .
The increasing use of atypical antipsychotics has
resulted in a growing number of safety alerts that were
launched in the past few years by international regulatory
agencies, especially regarding off-label use of atypical
G. Trifirò (*)
Department of Medical Informatics, Erasmus University Medical
Dr Molewaterplein 50, 3000 DR,
Rotterdam, The Netherlands
IRCCS Centro Neurolesi Bonino Pulejo,
Curr Infect Dis Rep (2011) 13:262–268
antipsychotics in elderly persons with dementia and related
disorders [5••]. In April 2005, a warning was issued by the
Food and Drug Administration (FDA) to inform health
professionals about the results of a pooled analysis of 17
randomized clinical trials reporting a 1.7 times increased
risk of all-cause mortality associated with atypical antipsy-
chotic use in elderly patients with dementia . Pneumonia
was one of the most frequently reported causes of death.
The FDA stated that at that point, an increased risk could
not be excluded for typical antipsychotic drugs. In June
2008, the FDA extended the warning about the increased
risk for all-cause mortality in elderly patients with dementia
to typical antipsychotic drugs [7••].
The mechanism behind the increase in mortality is not
clear, and the question remains whether it is pneumonia that
increases the risk for mortality in elderly patients receiving
antipsychotic drugs. This question is not easy to assess,
because the baseline risk for fatal pneumonia is already
high in elderly patients with psychiatric diseases .
Nevertheless, several observational studies were recently
conducted to specifically explore the association between
the use of antipsychotics and the risk of fatal/nonfatal
community-acquired pneumonia (CAP), mainly in cohorts
of elderly patients [9••, 10••, 11–14].
The aim of this review is to critically revise the current
scientific evidence concerning the relationship between
antipsychotic use and occurrence of CAP and to discuss
the possible biologic explanations for such an association.
Finally, recommendations are provided for clinicians who
decide to prescribe antipsychotics.
All published articles investigating or citing antipsychotic-
related pneumonia were identified through a Medline
search using the key words “antipsychotic agents” or the
name of individual active substances (eg, olanzapine,
risperidone, haloperidol) and “pneumonia.” Among these
articles, only five observational studies specifically inves-
tigated the risk of fatal/nonfatal pneumonia in association
with antipsychotic use, as summarized in Table 1 [9••, 10••,
Trifirò et al. [9••] conducted a population-based, case-
control study nested in a cohort of 2560 Dutch community-
dwelling elderly patients who were newly treated with
antipsychotics from the general practice Integrated Primary
Care Information (IPCI) database. Overall, 258 incident
cases of pneumonia were identified in this cohort and
matched to 1689 control participants on age, sex, and index
date. Sixty-five (25%) of the case patients died in 30 days,
and pneumonia was judged fatal by the authors. Case
patients were more likely to be housebound and to be
affected by chronic obstructive pulmonary disease, diabetes
mellitus, hypertension, heart failure, arrhythmia, or Parkin-
son disease. Current users of either atypical (adjusted odds
ratio [adj. OR]: 2.61; 95% CI: 1.48–4.61) or typical (adj.
OR: 1.76; 95% CI: 1.22–2.53) antipsychotics were associ-
ated with a dose-dependent increase in the risk for
pneumonia as compared to unexposed patients. Analyses
of chemical subgroups of typical antipsychotic drugs
showed some heterogeneity, with butyrophenones being
associated with slightly increased risk for pneumonia,
whereas phenothiazines were associated with a fourfold
increased risk. Analysis of individual drugs was possible
only for a few of the most frequently prescribed anti-
psychotics, and showed that the greatest pneumonia risk
was associated with risperidone (adj. OR: 3.51; 95% CI:
In this study, the highest risk for pneumonia was
observed during the first week of treatment, thus suggesting
an acute effect of antipsychotics. The pneumonia risk was
similarly increased in elderly patients with or without
Concerning fatal pneumonia specifically, only atypical
antipsychotic drugs were associated with an increase in the
risk (adj. OR: 5.97; 95% CI: 1.49–23.98); however, this
analysis was based on only seven exposed cases.
Overall, the conclusions from the study from Trifirò et
al. [9••] are very much in accord with the main findings
from another Dutch population-based, nested case-control
study that was done using data from the PHARMO
database [10••]. This study reported an increased risk for
hospitalization due to pneumonia during the first week after
the initiation of antipsychotic drug therapy, and especially
with atypical agents (adj. OR: 3.1; 95% CI: 1.9–5.1).
Similar findings also were observed in a case-control
study of adults aged 65 years or older at a rural community
hospital in Ohio (USA) during 2004 and 2006. The authors
of this study explored the risk for pneumonia as cause of
hospitalization with the use of atypical antipsychotics and
other non-neuropsychiatric drug classes that were suspected
to be possible risk factors for CAP . As compared to
patients unexposed to study drugs, users of atypical
antipsychotics were associated with a significant increase
in the risk for CAP (adj. OR: 2.26; 95% CI: 1.23–4.15).
Interestingly, the same findings were observed in the
study by Star et al. , which used a completely different
methodology. These authors applied the pattern-discovery
method for longitudinal patient records on the UK IMS
Health Disease Analyzer dataset as of January 1, 2006 .
The method contrasted the observed rate of registration of
pneumonia-related International Classification of Diseases
(ICD)-10 terms in various time periods relative to the
prescription of atypical and typical antipsychotics, to the
overall registration rate of the same medical event, relative
Curr Infect Dis Rep (2011) 13:262–268263
Table 1 List of observational studies that explored specifically the association between onset of fatal/nonfatal pneumonia and use of
Outcome Exposure Main findings
Trifirò et al. [9••],
nested in a
(≥ 65) newly
from the Dutch
Fatal and nonfatal
According to the type of
antipsychotic being prescribed
before the onset of the event:
- others (ie, benzamides)
Fatal/nonfatal pneumonia: a)
current use of atypical vs past
use of any antipsychotics: adj.
OR=2.6 (95% CI: 1.5–4.6);
b) current use of typicals vs
past use of any antipsychotics:
adj. OR=1.8 (95% CI: 1.2–
2.5); c) for both atypical and
typical antipsychotics, dose-
dependent increase in the risk.
Highest increase in risk
during first week of treatment.
Fatal pneumonia: a) current use
of atypical vs past use of any
antipsychotics: adj. OR=6.0
(95% CI: 1.5–24.0).
a) current use of atypical vs no
use of antipsychotics: adj.
OR=3.1 (95% CI: 1.9–5.1);
b) current use of typicals vs
no use of antipsychotics: adj.
OR=1.5 (95% CI: 1.2–1.9); c)
highest increase in risk during
the first week of treatment
with atypical and typical
According to timing relative to event:
- current use
- past use
Knol et al. [10••],
J Am Geriatr
nested in a
(≥ 65) newly
from the Dutch
study of adults
aged 65 years or
older at a rural
hospital in the
state of Ohio
due to pneumonia
According to the type of antipsychotic
being dispensed prior to hospital
According to timing relative to event:
- current use
- recent past use
- past use
- no use
Gau et al. ,
due to community-
According to the drug class
being dispensed prior
to hospital admission:
- atypical antipsychotics
- other drug classes (ie,
narcotics, proton pump
Distribution over time of
atypical and typical
with respect to date of
diagnosis of the study
Use of atypical antipsychotics
vs no use of any study drugs:
adj. OR=2.26 (95% CI: 1.23–
Star et al. , Br
J Gen Pract,
of UK IMS
In elderly patients (≥ 65): a)
higher rate of acute
chest infections following
atypical and much less
prescriptions; b) higher rate
either atypical or typical
patients (< 65): a) no higher
rate of acute chest infections
and much less typical
264Curr Infect Dis Rep (2011) 13:262–268
to prescriptions of other drugs in the same data. In elderly
patients, higher rates of acute chest infections and bron-
chopneumonia following atypical and, to a lesser extent,
typical antipsychotic prescriptions were observed in this
Concerning the risk of pneumonia with antipsychotic
use, two short reports also were recently published [13, 14].
Barnett et al.  presented a brief report on a study
conducted using the US Veterans Administration database.
They found a statistically significant increased risk for in-
hospital mortality only with recent exposure to typical
antipsychotic drugs in patients hospitalized because of
pneumonia. Different setting, aim, and methodology could
explain the difference between this study and previously
described studies. Finally, a small, incompletely reported
study using Medicaid data  found no difference in the
risk for hospitalization for pneumonia between current
users of atypical and typical antipsychotic drugs. No
comparison with unexposed patients was performed in this
US study, which did not assess fatal/nonfatal pneumonia as
In addition to the observational studies, evidence about
fatal pneumonia and pneumonia as a cause of treatment
discontinuation in patients treated with antipsychotics has
also emerged from randomized clinical trials [6, 7••, 15].
To summarize, all epidemiologic studies documented an
increased risk of pneumonia in association with typical and
atypical antipsychotic use exclusively in elderly patients,
but no evidence exists about a similarly high risk in patients
younger than 65 years. Future studies should explore if the
increase in the risk of pneumonia is also observed in young/
adult patients, who are generally prescribed antipsychotics
for completely different indications than the indications in
the elderly. Moreover, most of the studies explored the
effect of the atypical and typical antipsychotics classes as a
whole. Because of relevant differences in the receptor
binding profile across various antipsychotics, heterogeneity
in the risk of pneumonia may be anticipated .
Among typical antipsychotics, a significantly higher risk
for pneumonia with phenothiazines as compared to butyr-
ophenones was observed in one of the observational
studies. Therefore, the observed class effect of antipsy-
chotics with respect to pneumonia risk should be inter-
preted cautiously [9••].
Some epidemiologic issues that have been encountered
in all the observational studies exploring the risk of
pneumonia with antipsychotic use merit further discussion.
Pneumonia Ascertainment in Healthcare Databases
All the observational studies identified newly diagnosed
CAP as the study outcome. The studies that were
carried out using data from claims databases could
capture only pneumonia as cause of hospitalization
[10••, 11, 13, 14], whereas all the potential cases of
CAP could be ascertained in the study conducted though
the Dutch electronic medical record database [9••]. In this
study, pneumonia was ascertained through a two-step
approach. First, a broad search within diagnostic codes
and narrative was undertaken. Subsequently, all the
identified potential cases were independently validated
through manual inspection of medical records by two
researchers, who were blinded to the exposure status. The
two assessors could classify the potential pneumonia
cases as definite (either confirmed by specialist or
diagnosed by chest radiography), possible (diagnosed
by general practitioners on the basis of respiratory signs
and symptoms), or non-cases.
Table 1 (continued)
Outcome ExposureMain findings
a) use of typical
antipsychotics vs no use of
neuropsychiatric drugs: adj.
OR=1.5 (95% CI: 1.0–2.2);
b) use of atypical
antipsychotics vs no use of
neuropsychiatric drugs: adj.
OR=1.2 (95% CI: 1.0–1.5)
Barnett et al. ,
cohort study in
due to pneumonia
from US Veterans
In-hospital mortality According to the type of
dispensed within 120 days
prior to hospital admission:
and mood stabilizers was
Adj. OR—adjusted odds ratio; IPCI—Integrated Primary Care Information; NSAID—nonsteroidal anti-inflammatory drug.
Curr Infect Dis Rep (2011) 13:262–268 265
This strategy allowed for a more precise identification of
the start of the disease corresponding to the first manifes-
tation of clinical signs and symptoms that may be related to
pneumonia (ie, fever, dyspnea, and other respiratory signs
Overall, Trifirò et al. [9••] reported that only 56 of 258
case patients (22%) were hospitalized for pneumonia,
thus supporting the idea that studies conducted in
claims databases may not be able to identify most of
the pneumonia cases occurring in community-dwelling
Confounding by Indication
“Confounding by indication” is a commonly used term that
refers to an extraneous determinant of the outcome
parameter that is present if a perceived high risk or poor
prognosis is an indication for intervention. The indication is
a confounder because it correlates with the intervention and
is a risk indicator for the illness . Confounding by
indication is likely in the association between antipsychotic
drugs and new onset of pneumonia, because the choice of
the antipsychotic drug is often associated with the progno-
sis or condition of a patient, which in itself can be a risk
factor for fatal/nonfatal pneumonia. Behavioral and psy-
chotic symptoms requiring antipsychotic treatment may be
predictors of mortality in older demented patients . As a
consequence, confounding by indication should be con-
trolled for, when assessing the risk of fatal pneumonia in
elderly patients treated with antipsychotics as compared to
non-users. For this reason, in the two Dutch investigations,
the study population was restricted to new users of
antipsychotic drugs only [9••, 10]. Yet, atypical antipsy-
chotic drugs seem to be prescribed to less healthier patients
in comparison to typical antipsychotic drugs, because of the
supposed better safety profile . This situation may
partly account for the slightly higher risk of pneumonia
with use of atypical antipsychotic drugs as compared to
typicals, as demonstrated in some studies.
Severe pneumonia may induce delirium requiring antipsy-
chotic drug use in elderly patients . In such a situation,
the occurrence of pneumonia may be mistakenly attributed
to the exposure to antipsychotics (ie, protopathic bias ).
To explore whether the association between antipsychotic
drugs and pneumonia was distorted because of protopathic
bias, Trifirò et al. [9••] performed an analysis excluding all
patients who began the treatment within 7 days before the
index date, which was considered as the first symptom of
pneumonia registered in the medical records (ie, fever,
dyspnea, other respiratory signs and symptoms).
To inspect the presence of the same bias, Knol et al.
[10••] conducted an exploratory analysis removing those
patients with any manifestation of delirium (ie, new
prescription of benzodiazepine, and antibiotic use before
The sensitivity analyses confirmed the main results in
both studies, thus excluding a major role for the protopathic
bias in the observed increased risk of pneumonia in
association with atypical and typical antipsychotics.
Regarding the increase in the risk for pneumonia with the
use of typical and atypical antipsychotics in frail elderly
patients, several potential biologic explanations have been
hypothesized. However, the possible mechanisms of
antipsychotic-induced pneumonia remain speculative.
Aspiration is a well-known pathogenic mechanism for
CAP in elderly people, who are frequently affected by
swallowing disorders and decreased cough reflex [22, 23]. It
has been suggested that the use of typical antipsychotic drugs
may be a risk factor for aspiration pneumonia, as a result of
extrapyramidal effects [9••]. Blocking of dopamine receptors
may result in dyskinesia of the oral pharyngeal musculature,
rigidity, and spasm of the pharyngeal musculature, which can
result in dysphagia and ultimately in aspiration. Several case
reports of antipsychotic-induced dysphagia have been
described for both atypical and typical agents [24–30].
On the other hand, compared to typical agents, the risk for
extrapyramidal adverse events with atypical antipsychotics is
generally much lower, particularly when used at low doses
[31–33], as is often the case in elderly patients [9••]. Thus,
the greater risk for pneumonia with atypical antipsychotics
than typical antipsychotics, which was observed in some
observational studies, suggests that mechanisms other than
extrapyramidal adverse events may play a major role. The
anticholinergic action and histamine-1 (H1)–receptor block-
ing effect of antipsychotic drugs have been proposed as
alternative explanations for the occurrence of pneumonia
[10••]. The anticholinergic effect of antipsychotic drugs
could lead to aspiration pneumonia through dryness of the
mouth and impaired oropharyngeal bolus transport.
Excessive sedation as a result of H1-receptor blocking in
the central nervous system is a well-known cause of
swallowing problems, which could facilitate aspiration
pneumonia in frail elderly patients, as a result of impaired
laryngeal reflexes . In accord with this hypothesis,
Trifirò et al. [9••] documented a significantly increased risk
for pneumonia with antipsychotics having the highest
affinity to H1-receptor (atypical antipsychotics and pheno-
thiazines) as compared to those with the lowest affinity
(butyrophenones). This finding would support the hypothesis
266 Curr Infect Dis Rep (2011) 13:262–268
that the antihistaminergic effect of antipsychotics may play a
major role in the occurrence of antipsychotic-induced
Finally, some authors suggested that antipsychotics may
lead to pneumonia from direct or indirect effects on the
immune system, which has been specifically documented for
somecompounds. Agranulocytosis, a severe neutropenia
that may increase the risk of infections, is a well-known
adverse drug reaction of clozapine, even though it occurs in
less than 1% of treated patients. Recent evidence suggests
that all the other atypical antipsychotics and some typical
antipsychotics can induce neutropenia but, in contrast to
clozapine, this neutropenia very rarely progresses to agran-
ulocytosis . In a US cohort of 11,555 clozapine users in
whom a weekly white-cell count was required to receive a
supply of the drug, most of the cases of agranulocytosis
occurred within the first 3 months of the treatment . This
finding seems to contrast with the very high risk for
pneumonia during the first week of antipsychotic treatment,
as observed in two studies [9••, 10].
To summarize, it is likely that antipsychotics induce
aspiration pneumonia in frail elderly patients through
multiple possible mechanisms. Extrapyramidal adverse
events, dysphagia, and sedation as a result of dopamine,
cholinergic receptors, and H1 receptors may all play a role
in antipsychotic-induced pneumonia.
Recommendations for Clinicians
Appropriate and judicious use of antipsychotic drugs may
dramatically improve the quality of life and functional status
of many psychiatric patients . However, antipsychotic
drugs are often misused and overused, especially in the
elderly population, and in recent years, this inappropriate use
of antipsychotics has resulted in several safety concerns.
Current scientific evidence supports an association between
use of antipsychotics in community-dwelling elderly and
development of CAP in a dose-dependent manner soon after
the beginning of treatment. For this reason, clinicians who
start treatment with antipsychotic drugs should closely
monitor elderly patients, particularly at the early phases of
therapy and with high doses. If pneumonia-related signs and
symptoms are identified, the withdrawal of antipsychotic
treatment should be considered. In general, the lowest
possible dose of antipsychotics should be prescribed.
Whenever possible, concomitant administration of antipsy-
chotics with other neuropsychiatric drugs having a sedative
effect (ie, opioids, benzodiazepines) or anticholinergic
properties (ie, antidepressant tricyclics) should be discour-
aged or limited to short periods with careful observation,
because these drugs are additional risk factors for aspiration
pneumonia in frail elderly patients.
Because pneumonia seems to be a frequent cause of
death in elderly demented patients who are treated with
antipsychotics, clinicians should very cautiously prescribe
antipsychotics in these patients.
The risk for pneumonia may vary across different
antipsychotics, but information about the risk for individual
compounds is very limited. Hence, at this time, the risk for
pneumonia in elderly patients should be considered when
prescribing any antipsychotic medication.
Antipsychotic-associated CAP (probably aspiration pneumo-
nia) seems to be a clinically relevant issue in frail elderly
patients, as consistently documented in several epidemiologic
investigations. No clear evidence exists for an increased risk
of pneumonia in younger patients treated with antipsychotics.
In elderly populations, the increase in risk is dose-dependent,
and is more pronounced in the early phases of treatment with
either typical or atypical antipsychotics.
On the basis of significant differences in the receptor
binding profile of individual antipsychotics, heterogeneity in
the risk for pneumonia among various compounds is
suggested. Extrapyramidal adverse events, sedation, and
dysphagia as a result of the antipsychotic action at dopamine,
H1 receptors, and cholinergic receptors, are risk factors that
may all play a role in antipsychotic-induced pneumonia.
Future studies should better define the mechanism underlying
antipsychotic-induced pneumonia and identify subgroups of
antipsychotic users at higher risk of developing pneumonia.
Conflict of interest: G. Trifirò—none.
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