pharmacoepidemiology and drug safety 2015; 24: 812–820 Published online 27 May 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3804
ORIGINAL REPORT
Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta-analysis of observational studies Michela Nosè1*, Elisabetta Recla1, Gianluca Trifirò2 and Corrado Barbui1 1 2
Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
ABSTRACT Purpose Pneumonia is one of the major leading causes of morbidity and mortality among persons aged 65 years or older. Recently, several studies suggested an association between antipsychotic (AP) use and risk of pneumonia in elderly patients. The aim of the present systematic review and meta-analysis of observational studies was to investigate if first-generation and second-generation AP drugs increase the risk of pneumonia in the elderly and also in the younger population, and to ascertain the risk associated with exposure to individual drugs. Methods All observational cohort or case–control studies that reported data on pneumonia outcomes in individuals exposed to AP drugs as compared with individuals unexposed or with past exposure to AP drugs were included in the systematic review and meta-analysis. Study participants were of either sex and of any age with no restrictions in terms of diagnostic categories. Results The risk of pneumonia was significantly increased by exposure to first-generation AP drugs (odds ratio (OR) 1.68, 95% confidence interval (95%CI) 1.39–2.04, I2 = 47%) and exposure to second-generation AP drugs (OR 1.98, 95%CI 1.67–2.35, I2 = 36.7%). The risk was similar among different diagnostic categories and age groups, in elderly and young-adult populations; the finding on age was corroborated by a meta-regression analysis, which did not detect any relationship between age and risk of pneumonia. Only few studies provided data on individual drugs. Conclusion Systematic review of current observational evidence suggests that exposure to first-generation and second-generation AP drugs is associated with an increased risk of pneumonia. The present systematic review expands previous knowledge by showing that the increased risk not only applies to elderly individuals but also to younger patients. The information about the risk of pneumonia for individual compounds is still very limited. Copyright © 2015 John Wiley & Sons, Ltd. key words—pneumonia; antipsychotic; side effects; aspiration pneumonia; community-acquired pneumonia; pharmacoepidemiology Received 12 December 2014; Revised 16 March 2015; Accepted 30 April 2015
INTRODUCTION Community-acquired pneumonia (CAP) is one of the major leading causes of morbidity and mortality among persons aged 65 years or older.1 In addition to age, risk factors associated with pneumonia include chronic obstructive pulmonary disease, asthma, diabetes mellitus, congestive heart failure, smoking, malnutrition, and aspiration.2,3 Pneumonia may additionally be associated with use of medicines, including antipsychotic (AP) drugs.4 In 2005, the U.S. Food and Drug Administration warned of increased mortality,
*Correspondence to: M. Nosè, Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, University of Verona, Policlinico GB Rossi, Piazzale Scuro 10, 37134 Verona, Italy. E-mail: michela. [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
mostly due to pneumonia, in elderly patients with dementia who were treated with second-generation APs, and in June 2008, the warning was extended to first-generation AP drugs.5 More recently, the association between AP use and risk of CAP has been explored by epidemiological cohort and case–control studies. Overall, these studies suggest an increase in CAP risk in elderly patients, especially in the early phases of AP treatment. Few data are available about the risk of pneumonia in younger populations exposed to AP drugs.5 In addition, most of these observational studies lacked statistical power to properly investigate the CAP risk for individual APs. We therefore carried out the present systematic review and meta-analysis of observational studies to investigate if first-generation and second-generation
antipsychotic drug and pneumonia
AP drugs increase the risk of pneumonia in elderly and young-adult populations, and to ascertain the risk associated with exposure to individual APs. METHODS Registration of review protocol The protocol for this review was registered in advance with PROSPERO (International Prospective Register of Systematic Reviews). Type of studies Studies were included if they were observational cohort or case–control studies that reported data on pneumonia outcomes, including CAP, fatal and not fatal pneumonia, and aspiration pneumonia, in individuals exposed to AP drugs (anatomical therapeutic chemical classification system: N05A* excluding lithium) as compared with individuals unexposed or exposed in the past to AP drugs. Study participants were of either sex and of any age with no restrictions in terms of diagnostic categories. Included and excluded studies were collected following the Preferred Reporting Items for Systematic
813
Reviews and Meta-analyses flow diagram. Additionally, because the included studies were observational in design, we followed the Meta-analysis of Observational Studies in Epidemiology guidelines published by Stroup and colleagues for the meta-analysis of observational studies in the design, performance, and reporting of this meta-analysis (Figure 1).6 Search strategy and data extraction Relevant studies were located by searching Medline, PubMed, Embase, PsycINFO, CINAHL, and Scopus up to June 2014 using the terms “antipsychotic agents,” “antipsychotic drugs,” “antipsychotics,” and “pneumonia” (full search strategies reported in the Supporting Information 1). Reference lists of relevant papers and previous review articles were hand searched for other relevant studies. Two investigators (M. N. and E. R.) independently examined all titles and abstracts and obtained full texts of potentially relevant papers. Working independently and in duplicate, we read the papers and determined whether they met inclusion criteria. We resolved disagreement by consensus and extracted data independently using an electronic spreadsheet. For all
Figure 1. Included and excluded studies with reasons: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (AP, antipsychotics; PNM, pneumonia; FGA, first-generation AP; SGA, second-generation AP)
Copyright © 2015 John Wiley & Sons, Ltd.
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studies, we extracted information on study design, source of data, population characteristics, outcomes of interests, and matching and confounding factors. Assessment of risk of bias Two authors (M. N. and C. B.) assessed the risk of bias independently. Because all the included studies were nonrandomized and had a cohort or case–control design, the Newcastle–Ottawa Scale (NOS) was used to judge study quality, as recommended by the Cochrane Collaboration.7 This scale uses a star system to assess the quality of a study in three domains: selection, comparability, and outcome (cohort studies) or exposure (case–control studies). The NOS assigns a maximum of four stars for selection, two stars for comparability, and three stars for exposure/outcome. Therefore, nine stars reflect the highest quality. Any discrepancies were addressed by a joint revaluation of the original article with a third author. We recorded the review authors’ judgments about the three NOS domains (selection, comparability, and exposure or outcome) into the risk-of-bias tool of the REVIEW MANAGER software of the Cochrane Collaboration. This tool allowed us to keep a record of the background reasons for each judgment and was additionally used to produce a graphical representation of quality ratings similar to that produced by Cochrane reviews for randomized studies, as suggested by Wells and colleagues.8
The results of the studies were pooled, and an overall estimate of OR was obtained from a random-effects model, as this takes into account any differences between studies even if there is no statistically significant heterogeneity.10 Publication bias was evaluated using funnel plot and Egger’s regression test.11 Primary and secondary analyses and meta-regression The primary analysis included all pneumonia studies meeting the review inclusion criteria. Secondary analyses were carried out to examine effect sizes when grouping studies into the following subgroups: studies with elderly participants only versus studies including adult participants; studies with patients with schizophrenia versus studies with patients with any diagnosis; and studies employing a cohort design versus case–control studies. Additionally, given the limited number of included studies, we tested for possibly excessive influence of individual studies using a metaanalysis influence test that eliminated each of the included studies at a time. Unrestricted maximum likelihood random-effects meta-regression was used to find whether there was a relationship between age and risk of pneumonia. All calculations were carried out with COMPREHENSIVE META-ANALYSIS version 2. RESULTS
Data synthesis
Characteristics of included studies
The outcome measure of this meta-analysis was the occurrence of pneumonia in individuals exposed to AP drugs, in comparison with individuals unexposed or exposed in the past to AP drugs. The summary odds ratios (ORs) for exposure to first-generation and secondgeneration AP drugs, and exposure to individual AP drugs, were calculated. When possible, we pooled adjusted relative risks or OR or hazard ratios, with their 95% confidence interval (CI), with the assumption that these are comparable measures of association given that pneumonia is a relatively rare event; otherwise, we used raw data to compute unadjusted ORs. Visual inspection of graphs was used to investigate the possibility of statistical heterogeneity. This was supplemented using, primarily, the I2 statistic. This provides an estimate of the percentage of variability due to heterogeneity rather than chance alone. According to Higgins and Thompson, a rough guide to interpretation is as follows: I2 of around 25% represents low heterogeneity; I2 of around 50% represents medium heterogeneity; and I2 of around 75% represents high heterogeneity.9
Based on the titles and abstracts of 731 citations and on one study added through other sources, we identified 17 potentially relevant studies. Of these, we excluded nine studies for the reasons reported in the Preferred Reporting Items for Systematic Reviews and Meta-analyses diagram (Figure 1). Thus, eight studies were eligible for inclusion and were assessed for quality. Of the included studies, six were case– control studies,12–17 and two had a cohort design18,19 (with one self-controlled case series18). Six of the studies identified patients from administrative databases,13,14,18,19,15,16 while two used medical records12,17 (Table 1). In five studies, the focus was on elderly subjects only,12,13,18,15,17 two studies included adult participants only,14,16 and one study included both adult and elderly participants.19 In terms of diagnostic categories, one study included patients with schizophrenia,14 one was on patients with bipolar disorder,16 and the others include patients with any diagnosis. Of the eight studies included in the systematic review, only six provided data suitable for metaanalysis.12–14,18,15,16
Copyright © 2015 John Wiley & Sons, Ltd.
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antipsychotic drug and pneumonia Table 1. Characteristics of observational studies assessing the risk of pneumonia associated with exposure to antipsychotic drug Study Gau et al.
Data source 12
Design
Population characteristics
Total population
Medical records of a rural community hospital in Ohio, USA
Case–control study
Knol et al.13
PHARMO database (pharmacy dispensing records) and PRISMANT (hospital discharge records) in the Netherlands
Nested case–control study
Kuo et al.14
Psychiatric Inpatient Medical Claim database in Taiwan
Case–control study
Pratt et al.18
Australian Government Department of Veterans Affairs Health Claims database
Self-controlled case series analysis
Star et al.19
UK Intercontinental Medical Statistics Health Disease Analyzer database, which contains electronic records from the general practitioner Dutch general practice database
Self-controlled cohort analysis
Participants divided into two age groups (aged 18–64 years and aged 65 years or older), who had at least an AP prescription
Pneumonia-related terms: acute chest infection; bronchopneumonia; hypostatic pneumonia
Nested case–control study
Patients aged 65 years or older, who received a first AP prescription between 1996 and 2006 (cases were all patients who had an episode of CAP; up to 20 controls were matched to each case) Patients affected by Alzheimer’s disease, mean age 77 years Bipolar patients aged between 15 and 65 years, (cases were those with a hospitalization for pneumonia after their first psychiatric admission; four controls were matched to each case)
CAP fatal pneumonia
258 cases and 1689 controls
Aspiration pneumonia
104 patients; number of cases and controls is not specified 571 cases and 2277 controls (unavailability of controls for one case)
Trifirò et al.15
Wada et al.17 Yang et al.16
Clinical records from two psychiatric hospitals in Japan National Health Insurance Research database in Taiwan
Case–control study Case–control study
Patients aged 65 years or older, hospitalized during 2004 or 2006 (cases were those with a discharge diagnosis of pneumonia; controls were patients with a discharge diagnosis different from pneumonia) Patients aged >65 years with at least one prescription of AP from 1985 to 2003 (cases: hospital diagnosis of pneumonia; for each case, four controls randomly selected from the same cohort) Schizophrenic patients aged 18–65 years (cases were those who had an episode of pneumonia requiring hospitalization; for each case, four controls were matched) Patients aged 65 years or older with a hospitalization for pneumonia or hip fracture between 2005 and 2008
Outcome CAP
194 cases and 952 controls
Pneumonia (all types)
543 cases and 2163 controls
Pneumonia (all types)
1739 cases and 6949 controls
Hospitalization for pneumonia and hip fracture
13 324 cases hospitalized for pneumonia: 807 cases exposed to FGA, 1107 cases exposed to SGA, 11 410 cases unexposed; 8234 cases hospitalized for hip fracture: 494 cases exposed to FGA, 1091 cases exposed to SGA, 6649 cases unexposed Not stated
Hospitalization for pneumonia
CAP, community-acquired pneumonia; AP, antipsychotic; ICD, International Classification of Diseases; FGA, first-generation antipsychotic; SGA, secondgeneration antipsychotic.
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Table 1. (Continued)
Study
Definition of AP exposure
Case or outcome definition
Controlled variables
High-quality Included in studies meta-analysis
Gau et al.12
Definition of current use is unclear. Duration of exposure is unclear.
Discharge diagnosis and radiographic findings
Age, serum albumin levels, sex, smoking status, history of congestive heart failure, coronary artery disease, drug use
Yes
Yes
Knol et al.13
Current use: the most recent prescription ended within 7 days of the index data. Duration of exposure: the year before the index date
Hospital admission due to pneumonia Clinical charts
Age, sex, comorbidity, and number of drugs and hospital admissions
Yes
Yes
Kuo et al.14
Current use, defined as the most recent Diagnosis (ICD codes) prescription ended within 30 days of the index data
Charlson Comorbidity Index, physical illnesses, number of psychiatric hospital admissions,
Yes
Yes
Use of antibacterial
Yes
Yes
None
No
No
drug use Pratt et al.18
Pre-exposure risk periods (1; 2–4; 5–8; Diagnosis (ICD codes) 9–12; 13–16; 17–20 weeks) and post-AP initiation periods (1; 2–8; 9–12; >12 weeks)
Duration of exposure: the year before the index date Star et al.19
Definition of current use is unclear. Duration of exposure is unclear.
Diagnosis (ICD codes)
Trifirò et al.15 Current use defined as the most recent prescription ended within 30 days of the index date
Radiographic findings or Comorbidities, housebound specialist diagnosis: lifestyle, indication for use of AP, classified as certain diagnosis; drug use diagnosis by general practitioner was classified as possible diagnosis.
Yes
Yes
Wada et al.17 Definition of current use is unclear.
Radiographic findings and clinical symptoms
None
No
No
Yang et al.16
Discharge diagnosis (ICD codes)
Charlson Comorbidity Index, psychiatric hospital admissions, substance use disorders, physical illnesses, drug use, mood stabilizers, FGA, SGA
Yes
Yes
Current use, defined as the most recent prescription ended within 30 days of the index data
Copyright © 2015 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, 2015; 24: 812–820 DOI: 10.1002/pds
antipsychotic drug and pneumonia
The outcome of interest was defined as aspiration pneumonia in one study,17 CAP in two studies,12,15 and pneumonia with no further specification in the other studies. Six studies employed International Classification of Diseases (ICD) diagnostic criteria (Table 1), while in two studies, in addition to ICD criteria, diagnosis was supported by radiographic findings.15,17 Two studies included adult patients ( 65 years
1 4 1 1 2 4
Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia
1.61 (1.31–2.03) 1.83 (1.52–2.20) 2.18 (1.80–2.65) 1.63 (1.40–1.91) 1.86 (1.53–2.25) 1.86 (1.53–2.20)
— 40 — — 52 40
Study 12
13
Gau et al., Knol et al., Trifirò et al.,15 Yang et al.,16 Kuo et al.14 Pratt et al.18 Gau et al.,12 Knol et al.,13 Trifirò et al.,15 Pratt et al.18 Yang et al.16 Kuo et al.14 Yang et al.,16 Kuo et al.14 Gau et al.,12 Knol et al.,13 Trifirò et al.,15 Pratt et al.18
OR, odds ratio; CI, confidence interval.
2,00 1,80
Log odds ratio
1,60 1,40 1,20 1,00 0,80 0,60 0,40 0,20 0,00 37,50
42,90
48,30
53,70
59,10
64,50
69,90
75,30
80,70
86,10
91,50
Age
Figure 5. Meta-regression on the effect of age on the log odds ratio for the risk of pneumonia associated with exposure to antipsychotic drugs. Each circle represents a comparison. Slope = 0.0129Q, Q = 68.13, df = 11, p < 0.001
Copyright © 2015 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, 2015; 24: 812–820 DOI: 10.1002/pds
antipsychotic drug and pneumonia
small studies that failed to show an excess risk associated with AP exposure (Supporting Information 4). DISCUSSION Interpretation of main results Systematic review of current observational evidence suggests that exposure to first-generation and secondgeneration AP drugs is associated with an increased risk of pneumonia. The magnitude of this increased risk is very difficult to estimate, as the expected absolute event rate in the population may vary considerably in view of socio-demographic and clinical characteristics. However, assuming that AP exposure may be associated with a relative risk of pneumonia of 1.68 (the OR we calculated for first-generation AP drugs), in a population with a baseline absolute event rate of 1/1000, the number of individuals that would need to be exposed to AP drugs to have an extra case would be around 1473, while in a population with a baseline absolute event rate of 1/100, the number of individuals that would need to be exposed to AP drugs to have an extra case would be around 150. Assuming an increased risk of 2.35 (the upper bound of the CI for second-generation AP drugs), in a population with a baseline absolute event rate of 1/100, the number of individuals that would need to be exposed to AP drugs to have an extra case would be as low as 76. Therefore, clinicians should be aware that the clinical relevance of the additional risk attributable to AP exposure is highly influenced by the baseline absolute risk in their target population. The present systematic review expands previous knowledge by showing that the increased risk not only applies to elderly individuals but also to younger patients, although the confidence in this finding is not high. This finding is particularly challenging because adult patients are generally prescribed AP drugs for completely different indications than those in the elderly. Therefore, these data would suggest that factors related to the condition being treated do not contribute to this association. This finding is further reinforced by subgroup analysis, which failed to show significant differences between patients with psychiatric diagnoses (schizophrenia and bipolar disorder) and patients with mainly cognitive impairment or dementia. Clinically, it would be of paramount relevance to understand if individuals’ AP drugs differ in terms of risk of pneumonia, or if there is a dose–response gradient, and if risk is increased during the initial phases of AP exposure only. It should be acknowledged that these issues are hardly addressable by means of a systematic review of aggregate data, and therefore, only tentative suggestions can be drawn. For example, most studies explored Copyright © 2015 John Wiley & Sons, Ltd.
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the effect of first-generation and second-generation AP drugs considered as a whole, with only a minority of studies also providing data on subclasses or individual drugs. Among first-generation AP drugs, for example, in one of the observational studies, a significantly higher risk for pneumonia with phenothiazines as compared with butyrophenones was observed15; similarly, among second-generation AP drugs, the risk for pneumonia was found to be higher with clozapine as compared with other agents.14 In two studies, the highest risk for pneumonia was observed during the first week of treatment with APs,13,15 thus suggesting an acute effect of AP drugs, and in two studies, AP dose was positively associated with the risk of pneumonia.15,16 Potential biases in the review process The main limitations of this review are those of the primary studies included. First, studies based on data from claims databases could capture only pneumonia as the cause of hospitalization. Considering that only a minority of individuals are hospitalized for pneumonia, these studies may not be able to identify most of the pneumonia cases occurring in communitydwelling individuals. Second, although in most studies, statistical analyses were adjusted for several confounding variables, residual confounding by indication cannot be excluded, as the choice of AP prescribing might be associated with the prognosis of a patient, which in itself can be a risk factor for pneumonia. Third, AP prescribing may, in some cases, be the consequence rather than the cause of pneumonia. Severe pneumonia, for example, may induce delirium requiring AP drug use in elderly patients. In such a situation, the occurrence of pneumonia may be mistakenly attributed to the exposure to AP drugs. In order to rule out this possibility, some (but not all) studies excluded 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. Biological plausibility Several potential explanations of the increased risk for pneumonia with the use of AP drugs have been hypothesized, but the possible mechanisms remain speculative. Some authors suggested that extrapyramidal adverse effects could be a risk factor for pneumonia, particularly aspiration pneumonia.20 However, considering that the risk of extrapyramidal adverse effects associated with second-generation AP drugs is substantially lower as compared with first-generation AP drugs, a similarly lower risk of pneumonia would have been expected with newer drugs, while our analysis Pharmacoepidemiology and Drug Safety, 2015; 24: 812–820 DOI: 10.1002/pds
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showed similar overall treatment estimates for both classes of AP drugs.21,22 A second possible mechanism refers to the finding that, in some studies, an increased risk for pneumonia has been observed with AP drugs having the highest affinity to H1 receptor (atypical APs and phenothiazines) as compared with those with the lowest affinity (butyrophenones).5 This generates the hypothesis that excessive sedation as a result of H1 receptor blocking in the central nervous system may play a major role in the occurrence of AP-induced pneumonia. Finally, it has been suggested that AP drugs may lead to pneumonia from direct or indirect effects on the immune system, which has been specifically documented for some compounds.23 Implications for practice Clinicians should consider that the current best evidence shows a significant increased risk of pneumonia in individuals exposed to AP drugs. They should closely monitor patients in treatment with AP drugs if pneumonia-related signs and symptoms are identified, considering the possibility of treatment withdrawal. The risk for pneumonia may vary across different AP drugs, but information about the risk for individual compounds is still very limited. While pneumonia is much more frequent in elderly individuals compared with younger patients, the additional relative risk attributable to AP drug exposure may be the same in different age groups. Future studies are needed to confirm or refute these results and to better quantify the absolute risk and the influence of other potential risk factors. Studies should also better define the mechanisms underlying APinduced pneumonia. CONFLICT OF INTEREST The authors declare no conflict of interest. KEY POINTS Pneumonia is one of the major leading causes of morbidity and mortality among persons aged 65 years or older. • The exposure to first-generation and secondgeneration antipsychotic (AP) drugs is associated with an increased risk of pneumonia. • The increased risk of pneumonia associated with AP drugs is similar among different diagnostic categories and age groups. • More research is needed about the risk of pneumonia for individual AP drugs.
•
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ETHICS STATEMENT The authors state that no ethical approval was needed. REFERENCES 1. Fry A, Shay D, Holman R, et al. Trend in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988–2002. JAMA 2012; 294: 2712–2719. 2. Longo DL. Community-acquired pneumonia. N Eng J Med 2014; 371: 1619–1628. 3. Baik I, Curhan GC, Rimm EB, et al. A prospective study of age and lifestyle factors in community-acquired pneumonia in US men and women. Arch Intern Med 2000; 160: 3082–3088. 4. Jackson J, Schneeweiss S, VanderWeele T, Blacker D. Quantifying the role of adverse events in the mortality difference between first and second generation antipsychotics in older adults: systematic review and meta-synthesis. PLoS One 2014; 9,8: 1–16. 5. Trifirò G. Antipsychotic drug use and community-acquired pneumonia. Curr Infect Dis Resp 2011; 13: 262–268. 6. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008–2012. 7. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane collaboration. Available at: www.cochrane-handbook.org [6 December 2014]. 8. Wells G, Shea B, Higgins J, et al. Checklist of methodological issues for review authors to consider when including non-randomized studies in systematic reviews. JRSM 2013; 4: 63–77. 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558. 10. Furukawa TA, Guyatt GH, Griffith LE. Can we individualize the “number needed to treat?” An empirical study of summary effect measures in metaanalyses. Int J Epidemiol 2002; 31: 72–76. 11. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634. 12. Gau JT, Acharya U, Khan S, et al. Pharmacotherapy and the risk for communityacquired pneumonia. BMC Geriatr 2010; 10: 45. 13. Knol W, van Marum RJ, Jansen PA, et al. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc 2008; 56: 661–666. 14. Kuo CJ, Yang SY, Liao YT, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39: 648–657. 15. Trifirò G, Gambassi G, Sen EF, et al. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study. Ann Intern Med 2010; 152: 418–425. 16. Yang SY, Liao YT, Liu HC, et al. Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case–control study. J Clin Psychiatry 2013; 74: e79. 17. Wada H, Nakajoh K, Satoh-Nakagawa T, et al. Risk factors of aspiration pneumonia in Alzheimer’s disease patients. Gerontology 2001; 47: 271–276. 18. Pratt N, Roughead EE, Ramsay E, et al. Risk of hospitalization for hip fracture and pneumonia associated with antipsychotic prescribing in the elderly: a selfcontrolled case-series analysis in an Australian health care claims database. Drug Saf 2011; 34: 567–575. 19. Star K, Bate A, Meyboom RH, Edwards IR. Pneumonia following antipsychotic prescriptions in electronic health records: a patient safety concern? Br Gen Pract 2010; 60: e385–e394. 20. Marik PE, Kaplan D. Aspiration pneumonia and dysphagia in the elderly. Chest 2003; 124: 328–336. 21. Pierre JM. Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management. Drug Saf 2005; 28: 191–208. 22. Jeste DV, Rockwell E, Harris MJ, et al. Conventional vs newer antipsychotics in elderly patients. Am J Geriatr Psychiatry 1999; 7: 70–76. 23. Pollmacher T, Haack M, Schuld A, et al. Effects of antipsychotic drugs on cytokine networks. J Psychiatr Res 2000; 34: 369–382.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web site.
Pharmacoepidemiology and Drug Safety, 2015; 24: 812–820 DOI: 10.1002/pds
ORIGINAL REPORT
Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta-analysis of observational studies Michela Nosè1*, Elisabetta Recla1, Gianluca Trifirò2 and Corrado Barbui1 1 2
Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
ABSTRACT Purpose Pneumonia is one of the major leading causes of morbidity and mortality among persons aged 65 years or older. Recently, several studies suggested an association between antipsychotic (AP) use and risk of pneumonia in elderly patients. The aim of the present systematic review and meta-analysis of observational studies was to investigate if first-generation and second-generation AP drugs increase the risk of pneumonia in the elderly and also in the younger population, and to ascertain the risk associated with exposure to individual drugs. Methods All observational cohort or case–control studies that reported data on pneumonia outcomes in individuals exposed to AP drugs as compared with individuals unexposed or with past exposure to AP drugs were included in the systematic review and meta-analysis. Study participants were of either sex and of any age with no restrictions in terms of diagnostic categories. Results The risk of pneumonia was significantly increased by exposure to first-generation AP drugs (odds ratio (OR) 1.68, 95% confidence interval (95%CI) 1.39–2.04, I2 = 47%) and exposure to second-generation AP drugs (OR 1.98, 95%CI 1.67–2.35, I2 = 36.7%). The risk was similar among different diagnostic categories and age groups, in elderly and young-adult populations; the finding on age was corroborated by a meta-regression analysis, which did not detect any relationship between age and risk of pneumonia. Only few studies provided data on individual drugs. Conclusion Systematic review of current observational evidence suggests that exposure to first-generation and second-generation AP drugs is associated with an increased risk of pneumonia. The present systematic review expands previous knowledge by showing that the increased risk not only applies to elderly individuals but also to younger patients. The information about the risk of pneumonia for individual compounds is still very limited. Copyright © 2015 John Wiley & Sons, Ltd. key words—pneumonia; antipsychotic; side effects; aspiration pneumonia; community-acquired pneumonia; pharmacoepidemiology Received 12 December 2014; Revised 16 March 2015; Accepted 30 April 2015
INTRODUCTION Community-acquired pneumonia (CAP) is one of the major leading causes of morbidity and mortality among persons aged 65 years or older.1 In addition to age, risk factors associated with pneumonia include chronic obstructive pulmonary disease, asthma, diabetes mellitus, congestive heart failure, smoking, malnutrition, and aspiration.2,3 Pneumonia may additionally be associated with use of medicines, including antipsychotic (AP) drugs.4 In 2005, the U.S. Food and Drug Administration warned of increased mortality,
*Correspondence to: M. Nosè, Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology, University of Verona, Policlinico GB Rossi, Piazzale Scuro 10, 37134 Verona, Italy. E-mail: michela. [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
mostly due to pneumonia, in elderly patients with dementia who were treated with second-generation APs, and in June 2008, the warning was extended to first-generation AP drugs.5 More recently, the association between AP use and risk of CAP has been explored by epidemiological cohort and case–control studies. Overall, these studies suggest an increase in CAP risk in elderly patients, especially in the early phases of AP treatment. Few data are available about the risk of pneumonia in younger populations exposed to AP drugs.5 In addition, most of these observational studies lacked statistical power to properly investigate the CAP risk for individual APs. We therefore carried out the present systematic review and meta-analysis of observational studies to investigate if first-generation and second-generation
antipsychotic drug and pneumonia
AP drugs increase the risk of pneumonia in elderly and young-adult populations, and to ascertain the risk associated with exposure to individual APs. METHODS Registration of review protocol The protocol for this review was registered in advance with PROSPERO (International Prospective Register of Systematic Reviews). Type of studies Studies were included if they were observational cohort or case–control studies that reported data on pneumonia outcomes, including CAP, fatal and not fatal pneumonia, and aspiration pneumonia, in individuals exposed to AP drugs (anatomical therapeutic chemical classification system: N05A* excluding lithium) as compared with individuals unexposed or exposed in the past to AP drugs. Study participants were of either sex and of any age with no restrictions in terms of diagnostic categories. Included and excluded studies were collected following the Preferred Reporting Items for Systematic
813
Reviews and Meta-analyses flow diagram. Additionally, because the included studies were observational in design, we followed the Meta-analysis of Observational Studies in Epidemiology guidelines published by Stroup and colleagues for the meta-analysis of observational studies in the design, performance, and reporting of this meta-analysis (Figure 1).6 Search strategy and data extraction Relevant studies were located by searching Medline, PubMed, Embase, PsycINFO, CINAHL, and Scopus up to June 2014 using the terms “antipsychotic agents,” “antipsychotic drugs,” “antipsychotics,” and “pneumonia” (full search strategies reported in the Supporting Information 1). Reference lists of relevant papers and previous review articles were hand searched for other relevant studies. Two investigators (M. N. and E. R.) independently examined all titles and abstracts and obtained full texts of potentially relevant papers. Working independently and in duplicate, we read the papers and determined whether they met inclusion criteria. We resolved disagreement by consensus and extracted data independently using an electronic spreadsheet. For all
Figure 1. Included and excluded studies with reasons: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (AP, antipsychotics; PNM, pneumonia; FGA, first-generation AP; SGA, second-generation AP)
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studies, we extracted information on study design, source of data, population characteristics, outcomes of interests, and matching and confounding factors. Assessment of risk of bias Two authors (M. N. and C. B.) assessed the risk of bias independently. Because all the included studies were nonrandomized and had a cohort or case–control design, the Newcastle–Ottawa Scale (NOS) was used to judge study quality, as recommended by the Cochrane Collaboration.7 This scale uses a star system to assess the quality of a study in three domains: selection, comparability, and outcome (cohort studies) or exposure (case–control studies). The NOS assigns a maximum of four stars for selection, two stars for comparability, and three stars for exposure/outcome. Therefore, nine stars reflect the highest quality. Any discrepancies were addressed by a joint revaluation of the original article with a third author. We recorded the review authors’ judgments about the three NOS domains (selection, comparability, and exposure or outcome) into the risk-of-bias tool of the REVIEW MANAGER software of the Cochrane Collaboration. This tool allowed us to keep a record of the background reasons for each judgment and was additionally used to produce a graphical representation of quality ratings similar to that produced by Cochrane reviews for randomized studies, as suggested by Wells and colleagues.8
The results of the studies were pooled, and an overall estimate of OR was obtained from a random-effects model, as this takes into account any differences between studies even if there is no statistically significant heterogeneity.10 Publication bias was evaluated using funnel plot and Egger’s regression test.11 Primary and secondary analyses and meta-regression The primary analysis included all pneumonia studies meeting the review inclusion criteria. Secondary analyses were carried out to examine effect sizes when grouping studies into the following subgroups: studies with elderly participants only versus studies including adult participants; studies with patients with schizophrenia versus studies with patients with any diagnosis; and studies employing a cohort design versus case–control studies. Additionally, given the limited number of included studies, we tested for possibly excessive influence of individual studies using a metaanalysis influence test that eliminated each of the included studies at a time. Unrestricted maximum likelihood random-effects meta-regression was used to find whether there was a relationship between age and risk of pneumonia. All calculations were carried out with COMPREHENSIVE META-ANALYSIS version 2. RESULTS
Data synthesis
Characteristics of included studies
The outcome measure of this meta-analysis was the occurrence of pneumonia in individuals exposed to AP drugs, in comparison with individuals unexposed or exposed in the past to AP drugs. The summary odds ratios (ORs) for exposure to first-generation and secondgeneration AP drugs, and exposure to individual AP drugs, were calculated. When possible, we pooled adjusted relative risks or OR or hazard ratios, with their 95% confidence interval (CI), with the assumption that these are comparable measures of association given that pneumonia is a relatively rare event; otherwise, we used raw data to compute unadjusted ORs. Visual inspection of graphs was used to investigate the possibility of statistical heterogeneity. This was supplemented using, primarily, the I2 statistic. This provides an estimate of the percentage of variability due to heterogeneity rather than chance alone. According to Higgins and Thompson, a rough guide to interpretation is as follows: I2 of around 25% represents low heterogeneity; I2 of around 50% represents medium heterogeneity; and I2 of around 75% represents high heterogeneity.9
Based on the titles and abstracts of 731 citations and on one study added through other sources, we identified 17 potentially relevant studies. Of these, we excluded nine studies for the reasons reported in the Preferred Reporting Items for Systematic Reviews and Meta-analyses diagram (Figure 1). Thus, eight studies were eligible for inclusion and were assessed for quality. Of the included studies, six were case– control studies,12–17 and two had a cohort design18,19 (with one self-controlled case series18). Six of the studies identified patients from administrative databases,13,14,18,19,15,16 while two used medical records12,17 (Table 1). In five studies, the focus was on elderly subjects only,12,13,18,15,17 two studies included adult participants only,14,16 and one study included both adult and elderly participants.19 In terms of diagnostic categories, one study included patients with schizophrenia,14 one was on patients with bipolar disorder,16 and the others include patients with any diagnosis. Of the eight studies included in the systematic review, only six provided data suitable for metaanalysis.12–14,18,15,16
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antipsychotic drug and pneumonia Table 1. Characteristics of observational studies assessing the risk of pneumonia associated with exposure to antipsychotic drug Study Gau et al.
Data source 12
Design
Population characteristics
Total population
Medical records of a rural community hospital in Ohio, USA
Case–control study
Knol et al.13
PHARMO database (pharmacy dispensing records) and PRISMANT (hospital discharge records) in the Netherlands
Nested case–control study
Kuo et al.14
Psychiatric Inpatient Medical Claim database in Taiwan
Case–control study
Pratt et al.18
Australian Government Department of Veterans Affairs Health Claims database
Self-controlled case series analysis
Star et al.19
UK Intercontinental Medical Statistics Health Disease Analyzer database, which contains electronic records from the general practitioner Dutch general practice database
Self-controlled cohort analysis
Participants divided into two age groups (aged 18–64 years and aged 65 years or older), who had at least an AP prescription
Pneumonia-related terms: acute chest infection; bronchopneumonia; hypostatic pneumonia
Nested case–control study
Patients aged 65 years or older, who received a first AP prescription between 1996 and 2006 (cases were all patients who had an episode of CAP; up to 20 controls were matched to each case) Patients affected by Alzheimer’s disease, mean age 77 years Bipolar patients aged between 15 and 65 years, (cases were those with a hospitalization for pneumonia after their first psychiatric admission; four controls were matched to each case)
CAP fatal pneumonia
258 cases and 1689 controls
Aspiration pneumonia
104 patients; number of cases and controls is not specified 571 cases and 2277 controls (unavailability of controls for one case)
Trifirò et al.15
Wada et al.17 Yang et al.16
Clinical records from two psychiatric hospitals in Japan National Health Insurance Research database in Taiwan
Case–control study Case–control study
Patients aged 65 years or older, hospitalized during 2004 or 2006 (cases were those with a discharge diagnosis of pneumonia; controls were patients with a discharge diagnosis different from pneumonia) Patients aged >65 years with at least one prescription of AP from 1985 to 2003 (cases: hospital diagnosis of pneumonia; for each case, four controls randomly selected from the same cohort) Schizophrenic patients aged 18–65 years (cases were those who had an episode of pneumonia requiring hospitalization; for each case, four controls were matched) Patients aged 65 years or older with a hospitalization for pneumonia or hip fracture between 2005 and 2008
Outcome CAP
194 cases and 952 controls
Pneumonia (all types)
543 cases and 2163 controls
Pneumonia (all types)
1739 cases and 6949 controls
Hospitalization for pneumonia and hip fracture
13 324 cases hospitalized for pneumonia: 807 cases exposed to FGA, 1107 cases exposed to SGA, 11 410 cases unexposed; 8234 cases hospitalized for hip fracture: 494 cases exposed to FGA, 1091 cases exposed to SGA, 6649 cases unexposed Not stated
Hospitalization for pneumonia
CAP, community-acquired pneumonia; AP, antipsychotic; ICD, International Classification of Diseases; FGA, first-generation antipsychotic; SGA, secondgeneration antipsychotic.
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Table 1. (Continued)
Study
Definition of AP exposure
Case or outcome definition
Controlled variables
High-quality Included in studies meta-analysis
Gau et al.12
Definition of current use is unclear. Duration of exposure is unclear.
Discharge diagnosis and radiographic findings
Age, serum albumin levels, sex, smoking status, history of congestive heart failure, coronary artery disease, drug use
Yes
Yes
Knol et al.13
Current use: the most recent prescription ended within 7 days of the index data. Duration of exposure: the year before the index date
Hospital admission due to pneumonia Clinical charts
Age, sex, comorbidity, and number of drugs and hospital admissions
Yes
Yes
Kuo et al.14
Current use, defined as the most recent Diagnosis (ICD codes) prescription ended within 30 days of the index data
Charlson Comorbidity Index, physical illnesses, number of psychiatric hospital admissions,
Yes
Yes
Use of antibacterial
Yes
Yes
None
No
No
drug use Pratt et al.18
Pre-exposure risk periods (1; 2–4; 5–8; Diagnosis (ICD codes) 9–12; 13–16; 17–20 weeks) and post-AP initiation periods (1; 2–8; 9–12; >12 weeks)
Duration of exposure: the year before the index date Star et al.19
Definition of current use is unclear. Duration of exposure is unclear.
Diagnosis (ICD codes)
Trifirò et al.15 Current use defined as the most recent prescription ended within 30 days of the index date
Radiographic findings or Comorbidities, housebound specialist diagnosis: lifestyle, indication for use of AP, classified as certain diagnosis; drug use diagnosis by general practitioner was classified as possible diagnosis.
Yes
Yes
Wada et al.17 Definition of current use is unclear.
Radiographic findings and clinical symptoms
None
No
No
Yang et al.16
Discharge diagnosis (ICD codes)
Charlson Comorbidity Index, psychiatric hospital admissions, substance use disorders, physical illnesses, drug use, mood stabilizers, FGA, SGA
Yes
Yes
Current use, defined as the most recent prescription ended within 30 days of the index data
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antipsychotic drug and pneumonia
The outcome of interest was defined as aspiration pneumonia in one study,17 CAP in two studies,12,15 and pneumonia with no further specification in the other studies. Six studies employed International Classification of Diseases (ICD) diagnostic criteria (Table 1), while in two studies, in addition to ICD criteria, diagnosis was supported by radiographic findings.15,17 Two studies included adult patients ( 65 years
1 4 1 1 2 4
Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia
1.61 (1.31–2.03) 1.83 (1.52–2.20) 2.18 (1.80–2.65) 1.63 (1.40–1.91) 1.86 (1.53–2.25) 1.86 (1.53–2.20)
— 40 — — 52 40
Study 12
13
Gau et al., Knol et al., Trifirò et al.,15 Yang et al.,16 Kuo et al.14 Pratt et al.18 Gau et al.,12 Knol et al.,13 Trifirò et al.,15 Pratt et al.18 Yang et al.16 Kuo et al.14 Yang et al.,16 Kuo et al.14 Gau et al.,12 Knol et al.,13 Trifirò et al.,15 Pratt et al.18
OR, odds ratio; CI, confidence interval.
2,00 1,80
Log odds ratio
1,60 1,40 1,20 1,00 0,80 0,60 0,40 0,20 0,00 37,50
42,90
48,30
53,70
59,10
64,50
69,90
75,30
80,70
86,10
91,50
Age
Figure 5. Meta-regression on the effect of age on the log odds ratio for the risk of pneumonia associated with exposure to antipsychotic drugs. Each circle represents a comparison. Slope = 0.0129Q, Q = 68.13, df = 11, p < 0.001
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small studies that failed to show an excess risk associated with AP exposure (Supporting Information 4). DISCUSSION Interpretation of main results Systematic review of current observational evidence suggests that exposure to first-generation and secondgeneration AP drugs is associated with an increased risk of pneumonia. The magnitude of this increased risk is very difficult to estimate, as the expected absolute event rate in the population may vary considerably in view of socio-demographic and clinical characteristics. However, assuming that AP exposure may be associated with a relative risk of pneumonia of 1.68 (the OR we calculated for first-generation AP drugs), in a population with a baseline absolute event rate of 1/1000, the number of individuals that would need to be exposed to AP drugs to have an extra case would be around 1473, while in a population with a baseline absolute event rate of 1/100, the number of individuals that would need to be exposed to AP drugs to have an extra case would be around 150. Assuming an increased risk of 2.35 (the upper bound of the CI for second-generation AP drugs), in a population with a baseline absolute event rate of 1/100, the number of individuals that would need to be exposed to AP drugs to have an extra case would be as low as 76. Therefore, clinicians should be aware that the clinical relevance of the additional risk attributable to AP exposure is highly influenced by the baseline absolute risk in their target population. The present systematic review expands previous knowledge by showing that the increased risk not only applies to elderly individuals but also to younger patients, although the confidence in this finding is not high. This finding is particularly challenging because adult patients are generally prescribed AP drugs for completely different indications than those in the elderly. Therefore, these data would suggest that factors related to the condition being treated do not contribute to this association. This finding is further reinforced by subgroup analysis, which failed to show significant differences between patients with psychiatric diagnoses (schizophrenia and bipolar disorder) and patients with mainly cognitive impairment or dementia. Clinically, it would be of paramount relevance to understand if individuals’ AP drugs differ in terms of risk of pneumonia, or if there is a dose–response gradient, and if risk is increased during the initial phases of AP exposure only. It should be acknowledged that these issues are hardly addressable by means of a systematic review of aggregate data, and therefore, only tentative suggestions can be drawn. For example, most studies explored Copyright © 2015 John Wiley & Sons, Ltd.
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the effect of first-generation and second-generation AP drugs considered as a whole, with only a minority of studies also providing data on subclasses or individual drugs. Among first-generation AP drugs, for example, in one of the observational studies, a significantly higher risk for pneumonia with phenothiazines as compared with butyrophenones was observed15; similarly, among second-generation AP drugs, the risk for pneumonia was found to be higher with clozapine as compared with other agents.14 In two studies, the highest risk for pneumonia was observed during the first week of treatment with APs,13,15 thus suggesting an acute effect of AP drugs, and in two studies, AP dose was positively associated with the risk of pneumonia.15,16 Potential biases in the review process The main limitations of this review are those of the primary studies included. First, studies based on data from claims databases could capture only pneumonia as the cause of hospitalization. Considering that only a minority of individuals are hospitalized for pneumonia, these studies may not be able to identify most of the pneumonia cases occurring in communitydwelling individuals. Second, although in most studies, statistical analyses were adjusted for several confounding variables, residual confounding by indication cannot be excluded, as the choice of AP prescribing might be associated with the prognosis of a patient, which in itself can be a risk factor for pneumonia. Third, AP prescribing may, in some cases, be the consequence rather than the cause of pneumonia. Severe pneumonia, for example, may induce delirium requiring AP drug use in elderly patients. In such a situation, the occurrence of pneumonia may be mistakenly attributed to the exposure to AP drugs. In order to rule out this possibility, some (but not all) studies excluded 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. Biological plausibility Several potential explanations of the increased risk for pneumonia with the use of AP drugs have been hypothesized, but the possible mechanisms remain speculative. Some authors suggested that extrapyramidal adverse effects could be a risk factor for pneumonia, particularly aspiration pneumonia.20 However, considering that the risk of extrapyramidal adverse effects associated with second-generation AP drugs is substantially lower as compared with first-generation AP drugs, a similarly lower risk of pneumonia would have been expected with newer drugs, while our analysis Pharmacoepidemiology and Drug Safety, 2015; 24: 812–820 DOI: 10.1002/pds
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showed similar overall treatment estimates for both classes of AP drugs.21,22 A second possible mechanism refers to the finding that, in some studies, an increased risk for pneumonia has been observed with AP drugs having the highest affinity to H1 receptor (atypical APs and phenothiazines) as compared with those with the lowest affinity (butyrophenones).5 This generates the hypothesis that excessive sedation as a result of H1 receptor blocking in the central nervous system may play a major role in the occurrence of AP-induced pneumonia. Finally, it has been suggested that AP drugs may lead to pneumonia from direct or indirect effects on the immune system, which has been specifically documented for some compounds.23 Implications for practice Clinicians should consider that the current best evidence shows a significant increased risk of pneumonia in individuals exposed to AP drugs. They should closely monitor patients in treatment with AP drugs if pneumonia-related signs and symptoms are identified, considering the possibility of treatment withdrawal. The risk for pneumonia may vary across different AP drugs, but information about the risk for individual compounds is still very limited. While pneumonia is much more frequent in elderly individuals compared with younger patients, the additional relative risk attributable to AP drug exposure may be the same in different age groups. Future studies are needed to confirm or refute these results and to better quantify the absolute risk and the influence of other potential risk factors. Studies should also better define the mechanisms underlying APinduced pneumonia. CONFLICT OF INTEREST The authors declare no conflict of interest. KEY POINTS Pneumonia is one of the major leading causes of morbidity and mortality among persons aged 65 years or older. • The exposure to first-generation and secondgeneration antipsychotic (AP) drugs is associated with an increased risk of pneumonia. • The increased risk of pneumonia associated with AP drugs is similar among different diagnostic categories and age groups. • More research is needed about the risk of pneumonia for individual AP drugs.
•
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ETHICS STATEMENT The authors state that no ethical approval was needed. REFERENCES 1. Fry A, Shay D, Holman R, et al. Trend in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988–2002. JAMA 2012; 294: 2712–2719. 2. Longo DL. Community-acquired pneumonia. N Eng J Med 2014; 371: 1619–1628. 3. Baik I, Curhan GC, Rimm EB, et al. A prospective study of age and lifestyle factors in community-acquired pneumonia in US men and women. Arch Intern Med 2000; 160: 3082–3088. 4. Jackson J, Schneeweiss S, VanderWeele T, Blacker D. Quantifying the role of adverse events in the mortality difference between first and second generation antipsychotics in older adults: systematic review and meta-synthesis. PLoS One 2014; 9,8: 1–16. 5. Trifirò G. Antipsychotic drug use and community-acquired pneumonia. Curr Infect Dis Resp 2011; 13: 262–268. 6. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008–2012. 7. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane collaboration. Available at: www.cochrane-handbook.org [6 December 2014]. 8. Wells G, Shea B, Higgins J, et al. Checklist of methodological issues for review authors to consider when including non-randomized studies in systematic reviews. JRSM 2013; 4: 63–77. 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558. 10. Furukawa TA, Guyatt GH, Griffith LE. Can we individualize the “number needed to treat?” An empirical study of summary effect measures in metaanalyses. Int J Epidemiol 2002; 31: 72–76. 11. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634. 12. Gau JT, Acharya U, Khan S, et al. Pharmacotherapy and the risk for communityacquired pneumonia. BMC Geriatr 2010; 10: 45. 13. Knol W, van Marum RJ, Jansen PA, et al. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc 2008; 56: 661–666. 14. Kuo CJ, Yang SY, Liao YT, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39: 648–657. 15. Trifirò G, Gambassi G, Sen EF, et al. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study. Ann Intern Med 2010; 152: 418–425. 16. Yang SY, Liao YT, Liu HC, et al. Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case–control study. J Clin Psychiatry 2013; 74: e79. 17. Wada H, Nakajoh K, Satoh-Nakagawa T, et al. Risk factors of aspiration pneumonia in Alzheimer’s disease patients. Gerontology 2001; 47: 271–276. 18. Pratt N, Roughead EE, Ramsay E, et al. Risk of hospitalization for hip fracture and pneumonia associated with antipsychotic prescribing in the elderly: a selfcontrolled case-series analysis in an Australian health care claims database. Drug Saf 2011; 34: 567–575. 19. Star K, Bate A, Meyboom RH, Edwards IR. Pneumonia following antipsychotic prescriptions in electronic health records: a patient safety concern? Br Gen Pract 2010; 60: e385–e394. 20. Marik PE, Kaplan D. Aspiration pneumonia and dysphagia in the elderly. Chest 2003; 124: 328–336. 21. Pierre JM. Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management. Drug Saf 2005; 28: 191–208. 22. Jeste DV, Rockwell E, Harris MJ, et al. Conventional vs newer antipsychotics in elderly patients. Am J Geriatr Psychiatry 1999; 7: 70–76. 23. Pollmacher T, Haack M, Schuld A, et al. Effects of antipsychotic drugs on cytokine networks. J Psychiatr Res 2000; 34: 369–382.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web site.
Pharmacoepidemiology and Drug Safety, 2015; 24: 812–820 DOI: 10.1002/pds
