First-generation antipsychotics use and reduced risk of pneumonia—Clinical implications in SARS-CoV2 treatment: A systematic review and meta-analysis of observational studies

Abhirami Eby Elsa Jacob P. Samuel Gideon George   

Open Access   

Published:  Jun 22, 2022


The use of antipsychotics (AP) has been linked to nearly 60% increase in the incidence of pneumonia. The study purposes to devise safest treatment regimens for psychiatric patients with underlying respiratory comorbidities. A systematic literature search was conducted. A total of 41 studies were evaluated, which included 33 articles for metaanalysis. The quality of retrieved articles was screened by reviewing independently. The risk of bias in each study was assessed using the Newcastle–Ottawa Scale. Inter-rater agreement calculation was performed using Rayyan QCRI. Statistical analysis was performed using R 4.0.3. The meta-analysis conducted revealed that the risk of pneumonia (OR = 1.66; 95% CI = 1.64–1.68) and respiratory failure (OR = 1.79; 95% CI = 1.61–2.00) were higher in psychotropic users compared to nonusers. Pneumonia risk was higher in second-generation antipsychotic users (OR = 1.12; 95% CI = 1.01–1.25) compared to other antipsychotic users. However, no association was found between firstgeneration antipsychotics and pneumonia compared to other psychotropic exposure (OR = 0.93; 95% CI = 0.86–0.99). Chlorpromazine, sulpiride, and aripiprazole were found to be statistically safer compared to other AP. AP should be of appropriate choice in patients with SARS-CoV-2 infection, recurrent pneumonia history or those with opportunistic infections.

Keyword:     Psychotropics antipsychotics respiratory failure pneumonia COVID-19 PRISMA.


Eby A, Jacob E, George PSG. First-generation antipsychotics use and reduced risk of pneumonia- Clinical implications in SARS-CoV2 treatment: A systematic review and metaanalysis of observational studies. J Appl Pharm Sci, 2022. Online First.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HTML Full Text


Almirall J, Bolíbar I, Balanzó X, González CA. Risk factors for community-acquired pneumonia in adults: a population-based case-control study. Eur Respir J, 1999; 13(2):349-55.

Almirall J, Bolíbar I, Serra-Prat M, Roig J, Hospital I, Carandell E, Agustí M, Ayuso P, Estela A, Torres A; Community-Acquired Pneumonia in Catalan Countries (PACAP) Study Group. New evidence of risk factors for community-acquired pneumonia: a population-based study. Eur Respir J, 2008; 31(6):1274-84.

Aparasu RR, Chatterjee S, Chen H. Risk of pneumonia in elderly nursing home residents using typical versus atypical antipsychotics. Ann Pharmacother, 2013; 47(4):464-74.

Barnett MJ, Perry PJ, Alexander B, Kaboli PJ. Risk of mortality associated with antipsychotic and other neuropsychiatric drugs in pneumonia patients. J Clin Psychopharmacol, 2006; 26(2):182-7.

Bilbul M, Paparone P, Kim AM, Mutalik S, Ernst CL. Psychopharmacology of COVID-19. Psychosomatics, 2020; 61(5):411-27.

Brunnström HR, Englund EM. Cause of death in patients with dementia disorders. Eur J Neurol, 2009; 16(4):488-92.

Cheng SY, Chen WY, Liu HC, Yang TW, Pan CH, Yang SY, Kuo CJ. Benzodiazepines and risk of pneumonia in schizophrenia: a nationwide case-control study. Psychopharmacology (Berl), 2018; 235(11):3329-38.

Chen SJ, Yeh CM, Chao TF, Liu CJ, Wang KL, Chen TJ, Chou P, Wang FD. The use of benzodiazepine receptor agonists and risk of respiratory failure in patients with chronic obstructive pulmonary disease: a nationwide population-based case-control study. Sleep, 2015; 38(7):1045- 50. Published 2015 Jul 1.

Chen TY, Winkelman JW, Mao WC, Liu CL, Hsu CY, Wu CS. The use of benzodiazepine receptor agonists and the risk of hospitalization for pneumonia: a nationwide population-based nested case-control study. Chest, 2018; 153(1):161-71.

Chen YH, Lin HC, Lin HC. Poor clinical outcomes among pneumonia patients with schizophrenia. Schizophr Bull, 2011; 37(5):1088- 94.

Christodoulou C, Kalaitzi C. Antipsychotic drug-induced acute laryngeal dystonia: two case reports and a mini review. J Psychopharmacol, 2005; 19(3):307-11.

Cicala G, Barbieri MA, Spina E, de Leon J. A comprehensive review of swallowing difficulties and dysphagia associated with antipsychotics in adults. Expert Rev Clin Pharmacol, 2019; 12(3):219-34.

Ciranni MA, Kearney TE, Olson KR. Comparing acute toxicity of first- and second-generation antipsychotic drugs: a 10-year, retrospective cohort study. J Clin Psychiatry, 2009; 70(1):122-9.

Dublin S, Walker RL, Jackson ML, Nelson JC, Weiss NS, Von Korff M, Jackson LA. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study. J Am Geriatr Soc, 2011; 59(10):1899-907.

Dzahini O, Singh N, Taylor D, Haddad PM. Antipsychotic drug use and pneumonia: systematic review and meta-analysis. J Psychopharmacol, 2018; 32(11):1167-81.

Edelman EJ, Gordon KS, Crothers K, Akgün K, Bryant KJ, Becker WC, Gaither JR, Gibert CL, Gordon AJ, Marshall BDL, RodriguezBarradas MC, Samet JH, Justice AC, Tate JP, Fiellin DA. Association of prescribed opioids with increased risk of community-acquired pneumonia among patients with and without HIV. JAMA Intern Med, 2019; 179(3):297- 304.

Farah A. Atypicality of atypical antipsychotics. Prim Care Companion J Clin Psychiatry, 2005; 7(6):268-74.

Gau JT, Acharya U, Khan S, Heh V, Mody L, Kao TC. Pharmacotherapy and the risk for community-acquired pneumonia. BMC Geriatr, 2010; 10:45. Published 2010 Jul 6.

Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol, 2018; 8(11):303-18. Published 2018 Oct 8.

Hals PA, Hall H, Dahl SG. Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. Life Sci, 1988; 43(5):405-12.

Hamina A, Taipale H, Karttunen N, Tanskanen A, Tiihonen J, Tolppanen AM, Hartikainen S. Hospital-treated pneumonia associated with opioid use among community dwellers with Alzheimer's disease. J Alzheimers Dis, 2019; 69(3):807-16.

Hennessy S, Bilker WB, Leonard CE, Chittams J, Palumbo CM, Karlawish JH, Yang YX, Lautenbach E, Baine WB, Metlay JP. Observed association between antidepressant use and pneumonia risk was confounded by comorbidity measures. J Clin Epidemiol, 2007; 60(9):911- 8.

Hossain MM, Tasnim S, Sultana A, Faizah F, Mazumder H, Zou L, McKyer ELJ, Ahmed HU, Ma P. Epidemiology of mental health problems in COVID-19: a review. F1000Res, 2020; 9:636. Published 2020 Jun 23.

Hung GC, Liu HC, Yang SY, Pan CH, Liao YT, Chen CC, Kuo CJ. Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-control study. J Clin Psychiatry, 2016; 77(1):60-6.

Huybrechts KF, Gerhard T, Crystal S, Olfson M, Avorn J, Levin R, Lucas JA, Schneeweiss S. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ, 2012; 344:e977. Published 2012 Feb 23.

Huybrechts KF, Rothman KJ, Silliman RA, Brookhart MA, Schneeweiss S. Risk of death and hospital admission for major medical events after initiation of psychotropic medications in older adults admitted to nursing homes. CMAJ, 2011; 183(7):E411-9.

Huybrechts KF, Schneeweiss S, Gerhard T, Olfson M, Avorn J, Levin R, Lucas JA, Crystal S. Comparative safety of antipsychotic medications in nursing home residents. J Am Geriatr Soc, 2012; 60(3):420- 9.

Jackson JW, VanderWeele TJ, Blacker D, Schneeweiss S. Mediators of first- versus second-generation antipsychotic-related mortality in older adults. Epidemiology, 2015; 26(5):700-9.

Jung S, Spence MM, Escasa NM, Lee EA, Hui RL, Gibbs NE. The risk of pneumonia in older adults using nonbenzodiazepine hypnotics. J Manag Care Spec Pharm, 2016; 22(8):932-8.

Kales HC, Valenstein M, Kim HM, McCarthy JF, Ganoczy D, Cunningham F, Blow FC. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry, 2007; 164(10):1568-623.

Kim DH, Huybrechts KF, Patorno E, Marcantonio ER, Park Y, Levin R, Abdurrob A, Bateman BT. Adverse events associated with antipsychotic use in hospitalized older adults after cardiac surgery. J Am Geriatr Soc, 2017; 65(6):1229-37.

Knol W, van Marum RJ, Jansen PA, Souverein PC, Schobben AF, Egberts AC. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc, 2008; 56(4):661-6.

Kuo CJ, Yang SY, Liao YT, Liao YT, Chen WJ, Lee WC, Shau WY, Chang YT, Tsai SY, Chen CC. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull, 2013; 39(3):648-57.

Lewis K, O'Day CS. Dystonic reactions. In: StatPearls. StatPearls Publishing, Treasure Island, FL, 2021. Maeda T, Babazono A, Nishi T, Yasui M. Quantification of adverse effects of regular use of triazolam on clinical outcomes for older people with insomnia: a retrospective cohort study. Int J Geriatr Psychiatry, 2016; 31(2):186-94.

Marik PE, Kaplan D. Aspiration pneumonia and dysphagia in the elderly. Chest, 2003; 124(1):328-36.

May M, Beauchemin M, Vary C, Barlow D, Houseknecht KL. The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice. PLoS One, 2019; 14(6):e0218937. Published 2019 Jun 26.

Mehta S, Pulungan Z, Jones BT, Teigland C. Comparative safety of atypical antipsychotics and the risk of pneumonia in the elderly. Pharmacoepidemiol Drug Saf, 2015; 24(12):1271-80.

Moreno C, Wykes T, Galderisi S, Nordentoft M, Crossley N, Jones N, Cannon M, Correll CU, Byrne L, Carr S, Chen EYH, Gorwood P, Johnson S, Kärkkäinen H, Krystal JH, Lee J, Lieberman J, López-Jaramillo C, Männikkö M, Phillips MR, Uchida H, Vieta E, Vita A, Arango C. How mental health care should change as a consequence of the COVID-19 pandemic [published correction appears in Lancet Psychiatry. 2021 Jul;8(7):e16]. Lancet Psychiatry, 2020; 7(9):813-24.

Nakafero G, Sanders RD, Nguyen-Van-Tam JS, Myles PR. The association between benzodiazepines and influenza-like illness-related pneumonia and mortality: a survival analysis using UK Primary Care data. Pharmacoepidemiol Drug Saf, 2016; 25(11):1263-73.

Obiora E, Hubbard R, Sanders RD, Myles PR. The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort. Thorax, 2013; 68(2):163-70.

Ostuzzi G, Papola D, Gastaldon C, Schoretsanitis G, Bertolini F, Amaddeo F, Cuomo A, Emsley R, Fagiolini A, Imperadore G, Kishimoto T, Michencigh G, Nosé M, Purgato M, Dursun S, Stubbs B, Taylor D, Thornicroft G, Ward PB, Hiemke C, Correll CU, Barbui C. Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations [published correction appears in BMC Med. 2020 Sep 12;18(1):291]. BMC Med, 2020; 18(1):215. Published 2020 Jul 15.

Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev, 2016; 5(1):210. Published 2016 Dec 5.

Pitts T. Airway protective mechanisms. Lung, 2014; 192(1):27- 31.

Plaze M, Attali D, Petit AC, Blatzer M, Simon-Loriere E, Vinckier F, Cachia A, Chrétien F, Gaillard R. Repurposing chlorpromazine to treat COVID-19: the reCoVery study. Encephale, 2020; 46(3):169-72.

Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: a meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry, 2015; 56(3):345-65.

Pollmächer T, Haack M, Schuld A, Kraus T, Hinze-Selch D. Effects of antipsychotic drugs on cytokine networks. J Psychiatr Res, 2000; 34(6):369-82.

Pratt N, Roughead EE, Ramsay E, Salter A, Ryan P. Risk of hospitalization for hip fracture and pneumonia associated with antipsychotic prescribing in the elderly: a self-controlled case-series analysis in an Australian health care claims database. Drug Saf, 2011; 34(7):567-75.

Rafaniello C, Lombardo F, Ferrajolo C, Sportiello L, Parretta E, Formica R, Potenza S, Rinaldi B, Irpino A, Raschetti R, Vanacore N, Rossi F, Capuano A. Predictors of mortality in atypical antipsychotic-treated community-dwelling elderly patients with behavioural and psychological symptoms of dementia: a prospective population-based cohort study from Italy. Eur J Clin Pharmacol, 2014; 70(2):187-95.

Rajamaki B, Hartikainen S, Tolppanen AM. Psychotropic drugassociated pneumonia in older adults. Drugs Aging, 2020; 37(4):241-61.

Rohde C, Siskind D, de Leon J, Nielsen J. Antipsychotic medication exposure, clozapine, and pneumonia: results from a self-controlled study. Acta Psychiatr Scand, 2020; 142(2):78-86.

Setoguchi S, Wang PS, Alan Brookhart M, Canning CF, Kaci L, Schneeweiss S. Potential causes of higher mortality in elderly users of conventional and atypical antipsychotic medications. J Am Geriatr Soc, 2008; 56(9):1644-50.

Star K, Bate A, Meyboom RH, Edwards IR. Pneumonia following antipsychotic prescriptions in electronic health records: a patient safety concern? Br J Gen Pract, 2010; 60(579):e385-94.

Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry, 2018; 17(3):341-56.

Taipale H, Tolppanen AM, Koponen M, Tanskanen A, Lavikainen P, Sund R, Tiihonen J, Hartikainen S. Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease. CMAJ, 2017; 189(14):E519-29.

Tolppanen AM, Koponen M, Tanskanen A, Lavikainen P, Sund R, Tiihonen J, Hartikainen S, Taipale H. Antipsychotic use and risk of hospitalization or death due to pneumonia in persons with and those without Alzheimer disease. Chest, 2016; 150(6):1233-41.

Trifirò G, Gambassi G, Sen EF, Stephenson AL, O'Donnell DE, Gershon AS, Gill SS, Rochon PA. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested casecontrol study. Ann Intern Med, 2010; 152(7):418-W140.

Vozoris NT, Wang X, Austin PC, et al. Serotonergic antidepressant use and morbidity and mortality among older adults with COPD. Eur Respir J, 2018; 52(1):1800475. Published 2018 Jul 27.

Wang MT, Lin CW, Tsai CL, Wang YH, Lai JH, Yeh CB, Huang YL, Hsu YJ. Use of antipsychotics and the risk of acute respiratory failure among adults: a disease risk score-matched nested case-control study. Br J Clin Pharmacol, 2020; 86(11):2204-16.

Wang MT, Tsai CL, Lin CW, Yeh CB, Wang YH, Lin HL. Association between antipsychotic agents and risk of acute respiratory failure in patients with chronic obstructive pulmonary disease. JAMA Psychiatry, 2017; 74(3):252-60.

Wang MT, Wang YH, Chang HA, Tsai CL, Yang YS, Lin CW, Kuo CC, Hsu YJ. Benzodiazepine and Z-drug use and risk of pneumonia in patients with chronic kidney disease: a population-based nested casecontrol study. PLoS One, 2017; 12(7):e0179472. Published 2017 Jul 10.

Wilson H, Ridley S. Antipsychotic drugs and the acute respiratory distress syndrome. Br J Anaesth, 2007; 99(2):301-2

Yang SY, Liao YT, Liu HC, Chen WJ, Chen CC, Kuo CJ. Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study. J Clin Psychiatry, 2013; 74(1):e79-86.

Article Metrics

0 Absract views 0 PDF Downloads 0 Total views

   Abstract      Pdf Download

Related Search

By author names

Citiaion Alert By Google Scholar

Name Required
Email Required Invalid Email Address

Comment required