{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:44:09Z","timestamp":1790289849815,"version":"4.1.0"},"reference-count":126,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Clozapine is a highly effective antipsychotic used for treating treatment-refractory psychotic and mood disorders. However, clozapine also has a serious risk of side effects leading to mortality, particularly its potentiated risk of leading to pneumonia. This review aims to overview the demographic and health-related risk factors leading to pneumonia to better inform risk assessment for clozapine users and to summarise current theories on the mechanisms for clozapine-associated pneumonia. This paper will highlight the need to prioritise pneumococcal vaccination in this population group. Materials and Method: We conducted a literary search of five online databases conforming to PRISMA. Our review includes all peer-reviewed papers with original data that discuss clozapine and pneumonia and excludes case reports. Baseline information of participants, pneumonia-related information and information regarding risk factors and mechanisms causing pneumonia were also extracted. Results: Clozapine was found to have an increased risk of pneumonia compared to other antipsychotic medications. Factors included comorbidities, higher clozapine dosages, and concurrent use of other antipsychotic medications. Key mechanisms for clozapine-associated pneumonia include clozapine-induced hyper sedation, sialorrhea and neutropoenia. Conclusions: While clozapine improves overall mortality for patients, our review confirms clozapine has the highest risk of pneumonia of all antipsychotics. The review also highlights the prevalent underuse of pneumococcal vaccines among clozapine users and the urgent need to increase uptake.<\/jats:p>","DOI":"10.3390\/medicina60122016","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T10:58:45Z","timestamp":1733482725000},"page":"2016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Clozapine and Pneumonia: Synthesizing the Link by Reviewing Existing Reports\u2014A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8254-1227","authenticated-orcid":false,"given":"Victor","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Melbourne, Parkville 3052, Australia"},{"name":"Department of Psychiatry, Western Health, Footscray 3011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Melbourne, Parkville 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveen","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Western Health, Footscray 3011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7329-8264","authenticated-orcid":false,"given":"Soumitra","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Melbourne, Parkville 3052, Australia"},{"name":"Department of Psychiatry, Western Health, Footscray 3011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41537-019-0090-z","article-title":"The neurobiology of treatment-resistant schizophrenia: Paths to antipsychotic resistance and a roadmap for future research","volume":"6","author":"Potkin","year":"2020","journal-title":"npj Schizophr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1017\/S0033291722002550","article-title":"Psychotic experiences in the general population, a review; definition, risk factors, outcomes and interventions","volume":"52","author":"Staines","year":"2022","journal-title":"Psychol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1093\/schbul\/sbad075","article-title":"A Systematic Review and Meta-Analysis of the Association Between Psychopathology and Social Functioning in Schizophrenia","volume":"49","author":"Handest","year":"2023","journal-title":"Schizophr. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1192\/bjp.bp.115.177261","article-title":"Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: Systematic review and meta-analysis","volume":"209","author":"Siskind","year":"2016","journal-title":"Br. J. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e640","DOI":"10.1097\/JOM.0000000000002930","article-title":"Poor Sleep Quality and Working From Home Influence the Prevalence of Leisure Time Physical Inactivity During the COVID-19 Pandemic: COVID-Inconfidentes Study","volume":"65","author":"Moura","year":"2023","journal-title":"J. Occup. Environ. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0140-6736(19)31135-3","article-title":"Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: A systematic review and network meta-analysis","volume":"394","author":"Huhn","year":"2019","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41398-021-01613-2","article-title":"Efficacy and safety of clozapine in psychotic disorders-a systematic quantitative meta-review","volume":"11","author":"Wagner","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Iqbal, E., Govind, R., Romero, A., Dzahini, O., Broadbent, M., Stewart, R., Smith, T., Kim, C.H., Werbeloff, N., and MacCabe, J.H. (2020). The side effect profile of Clozapine in real world data of three large mental health hospitals. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0243437"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/schbul\/sbz093","article-title":"Data From the World Health Organization\u2019s Pharmacovigilance Database Supports the Prominent Role of Pneumonia in Mortality Associated With Clozapine Adverse Drug Reactions","volume":"46","author":"Sanz","year":"2020","journal-title":"Schizophr. Bull."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1177\/0269881118795333","article-title":"Antipsychotic drug use and pneumonia: Systematic review and meta-analysis","volume":"32","author":"Dzahini","year":"2018","journal-title":"J. Psychopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/pds.3804","article-title":"Antipsychotic drug exposure and risk of pneumonia: A systematic review and meta-analysis of observational studies","volume":"24","author":"Recla","year":"2015","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1093\/schbul\/sbr202","article-title":"Second-generation antipsychotic medications and risk of pneumonia in schizophrenia","volume":"39","author":"Kuo","year":"2013","journal-title":"Schizophr. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1093\/schbul\/sbaa163","article-title":"Exploring a Safety Signal of Antipsychotic-Associated Pneumonia: A Pharmacovigilance-Pharmacodynamic Study","volume":"47","author":"Cepaityte","year":"2021","journal-title":"Schizophr. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/acps.13142","article-title":"Antipsychotic medication exposure, clozapine, and pneumonia: Results from a self-controlled study","volume":"142","author":"Rohde","year":"2020","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1080\/15622975.2021.2013095","article-title":"Severe mental disorders and vaccinations\u2014A systematic review","volume":"23","author":"Bonkat","year":"2022","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_16","first-page":"32","article-title":"Exploring the Impact of COVID-19 Vaccination on Patients Taking Clozapine","volume":"20","author":"Demler","year":"2023","journal-title":"Innov. Clin. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/acps.12827","article-title":"Adverse cardiac events in out-patients initiating clozapine treatment: A nationwide register-based study","volume":"137","author":"Rohde","year":"2018","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20m02594","DOI":"10.4088\/PCC.20m02594","article-title":"Second-Generation Antipsychotics and Pneumonia-Related Hospitalizations","volume":"22","author":"Milano","year":"2020","journal-title":"Prim. Care Companion CNS Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.schres.2020.05.013","article-title":"Antipsychotic medications and the progression of upper respiratory infection to pneumonia in patients with schizophrenia","volume":"222","author":"Chang","year":"2020","journal-title":"Schizophr. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1097\/JCP.0000000000001090","article-title":"Is Antipsychotic Treatment Associated With Risk of Pneumonia in People With Serious Mental Illness?: The Roles of Severity of Psychiatric Symptoms and Global Functioning","volume":"39","author":"Chan","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1097\/JCP.0000000000001052","article-title":"Estimating the Risk of Pneumonia in Patients With Schizophrenia Newly Receiving Clozapine: A Nationwide Cohort Study","volume":"39","author":"Wu","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"560","DOI":"10.3855\/jidc.17488","article-title":"Risk factors for lower respiratory tract infections in a psychiatric hospital: A retrospective study","volume":"17","author":"Yang","year":"2023","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/npr2.12034","article-title":"Risk factors for pneumonia in patients with schizophrenia","volume":"38","author":"Haga","year":"2018","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.ajic.2022.06.014","article-title":"Risk factors for hospital-acquired pneumonia among inpatients with mental disorders in a large mental health center within a tertiary general hospital","volume":"51","author":"Han","year":"2023","journal-title":"Am. J. Infect. Control"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Han, J., Shen, M., Wan, Q., Lv, Z., Xiao, L., and Wang, G. (2022). Risk factors for community-acquired pneumonia among inpatients with mental disorders in a tertiary general hospital. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.941198"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yang, M., Li, Q., Wang, C., Li, L., Xu, M., Yan, F., Chen, W., and Wan, Y. (2021). Influencing Factors of Hospital-Acquired Pneumonia Infection in the Middle-Aged and Elderly Patients With Schizophrenia. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.746791"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/gps.5114","article-title":"Clozapine prescribing in older adults","volume":"34","author":"Phaldessai","year":"2019","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/1531-8257(200101)16:1<135::AID-MDS1006>3.0.CO;2-Q","article-title":"Clozapine for the treatment of drug-induced psychosis in Parkinson\u2019s disease: Results of the 12 week open label extension in the PSYCLOPS trial","volume":"16","author":"Factor","year":"2001","journal-title":"Mov. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.psym.2016.11.013","article-title":"Characterization of Admission Types in Medically Hospitalized Patients Prescribed Clozapine","volume":"58","author":"Leung","year":"2017","journal-title":"Psychosomatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/acps.13532","article-title":"A case-control study of antipsychotic use and pneumonia-related mortality in the United Kingdom","volume":"147","author":"Copeland","year":"2023","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.7150\/ijms.63246","article-title":"Risk of Pneumonia is associated with Antipsychotic Drug Use among older patients with Parkinson\u2019s Disease: A Case-control Study","volume":"18","author":"Huang","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/YIC.0000000000000162","article-title":"Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: A retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months","volume":"32","author":"Stoecker","year":"2017","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e79","DOI":"10.4088\/JCP.12m07938","article-title":"Antipsychotic drugs, mood stabilizes, and risk of pneumonia in bipolar disorder: A nationwide case-control study","volume":"74","author":"Yang","year":"2013","journal-title":"J. Clin. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"60","DOI":"10.4088\/JCP.14m09301","article-title":"Antipsychotic reexposure and recurrent pneumonia in schizophrenia: A nested case-control study","volume":"77","author":"Hung","year":"2016","journal-title":"J. Clin. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/pcn.12636","article-title":"Excess incidence and risk factors for recurrent pneumonia in bipolar disorder","volume":"72","author":"Li","year":"2018","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_36","first-page":"39","article-title":"Clozapine increases the incidence of pneumonia compared to risperidone and to no antipsychotic medication in the general hospital population","volume":"14","author":"Stoecker","year":"2018","journal-title":"J. Med. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Higgins, J.P.T., and Altman, D.G. (2008). Assessing Risk of Bias in Included Studies. Cochrane Handbook for Systematic Reviews of Interventions, John Wiley & Sons Ltd.","DOI":"10.1002\/9780470712184.ch8"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1002\/sim.1482","article-title":"Improved tests for a random effects meta-regression with a single covariate","volume":"22","author":"Knapp","year":"2003","journal-title":"Stat Med."},{"key":"ref_42","unstructured":"Team Core, R. (2024, December 02). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/wps.20707","article-title":"Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics","volume":"19","author":"Sanz","year":"2020","journal-title":"World Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/acps.13066","article-title":"Antipsychotic use and risk of life-threatening medical events: Umbrella review of observational studies","volume":"140","author":"Papola","year":"2019","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/j.1532-5415.2007.01625.x","article-title":"Antipsychotic Drug Use and Risk of Pneumonia in Elderly People","volume":"56","author":"Knol","year":"2008","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"de Leon, J., Ruan, C.J., Verdoux, H., and Wang, C. (2020). Clozapine is strongly associated with the risk of pneumonia and inflammation. Gen. Psychiatr., 33.","DOI":"10.1136\/gpsych-2019-100183"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1055\/s-2007-1004591","article-title":"Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model that controls for clozapine doses and confounding variables","volume":"41","author":"Diaz","year":"2008","journal-title":"Pharmacopsychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1177\/0269881120985166","article-title":"Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis","volume":"35","author":"Kuzin","year":"2021","journal-title":"J. Psychopharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1097\/JCP.0000000000001018","article-title":"Clozapine Metabolism in East Asians and Caucasians: A Pilot Exploration of the Prevalence of Poor Metabolizers and a Systematic Review","volume":"39","author":"Ruan","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1159\/000506355","article-title":"Around 3% of 1300 Levels Were Elevated during Infections in a Retrospective Review of 131 Beijing Hospital In-Patients with More than 24,000 Days of Clozapine Treatment","volume":"89","author":"Ruan","year":"2020","journal-title":"Psychother. Psychosom."},{"key":"ref_51","first-page":"100591","article-title":"Epidemiology of pneumonia in hospitalized adults \u226518 years old in four districts of Ulaanbaatar, Mongolia, 2015\u20132019","volume":"30","author":"Fagerli","year":"2023","journal-title":"Lancet Reg. Health\u2013West. Pac."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S2215-0366(19)30132-4","article-title":"The Lancet Psychiatry Commission: A blueprint for protecting physical health in people with mental illness","volume":"6","author":"Firth","year":"2019","journal-title":"Lancet Psychiatry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/17512433.2021.1877135","article-title":"An update on the complex relationship between clozapine and pneumonia","volume":"14","author":"Schoretsanitis","year":"2021","journal-title":"Expert. Rev. Clin. Pharmacol."},{"key":"ref_54","first-page":"100178","article-title":"Factors associated with medication non-adherence among patients with severe mental disorder\u2014A cross sectional study in a tertiary care centre","volume":"7","author":"Ghosh","year":"2022","journal-title":"Explor. Res. Clin. Soc. Pharm."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Wang, X., Zeng, F., Jin, W.S., Zhu, C., Wang, Q.H., Bu, X.L., Luo, H.B., Zou, H.Q., Pu, J., and Zhou, Z.H. (2017). Comorbidity burden of patients with Parkinson\u2019s disease and Parkinsonism between 2003 and 2012: A multicentre, nationwide, retrospective study in China. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-01795-0"},{"key":"ref_56","first-page":"99","article-title":"Interactions between the cytochrome P450 system and the second-generation antipsychotics","volume":"28","author":"Prior","year":"2003","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.schres.2017.03.045","article-title":"Elevated clozapine levels associated with infection: A systematic review","volume":"192","author":"Clark","year":"2018","journal-title":"Schizophr. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1097\/00004714-200112000-00005","article-title":"Individual changes in clozapine levels after smoking cessation: Results and a predictive model","volume":"21","author":"Meyer","year":"2001","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"S42","DOI":"10.1016\/S0140-6736(14)62168-1","article-title":"Systematic reviews and meta-analyses on the effects of active and passive smoking on respiratory health outcomes: The SmokeHaz online resource","volume":"384","author":"Jayes","year":"2014","journal-title":"Lancet"},{"key":"ref_60","first-page":"10","article-title":"Obesity in Schizophrenia","volume":"1","author":"Mary","year":"2016","journal-title":"J. Obes. Manag."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1192\/apt.6.5.327","article-title":"Cigarette smoking and schizophrenia","volume":"6","author":"Kelly","year":"2000","journal-title":"Adv. Psychiatr. Treat."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Adhikary, D., Barman, S., Ranjan, R., and Stone, H. (2022). A Systematic Review of Major Cardiovascular Risk Factors: A Growing Global Health Concern. Cureus, 14.","DOI":"10.7759\/cureus.30119"},{"key":"ref_63","first-page":"6149263","article-title":"A Strong Graded Relationship between Level of Obesity and COPD: Findings from a National Population-Based Study of Lifelong Nonsmokers","volume":"2018","author":"Howden","year":"2018","journal-title":"J. Obes."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.trsl.2017.02.004","article-title":"Smoking and the risk of type 2 diabetes","volume":"184","author":"Maddatu","year":"2017","journal-title":"Transl. Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Yuen, J.W.Y., Kim, D.D., Procyshyn, R.M., White, R.F., Honer, W.G., and Barr, A.M. (2018). Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00203"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/acps.13184","article-title":"Pneumonia risk: Approximately one-third is due to clozapine and two-thirds is due to treatment-resistant schizophrenia","volume":"142","author":"Rohde","year":"2020","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.schres.2023.09.029","article-title":"Association between initial clozapine titration and pneumonia risk among patients with schizophrenia in a Korean tertiary hospital","volume":"268","author":"Kang","year":"2024","journal-title":"Schizophr. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1177\/2042098618756261","article-title":"Safety of antipsychotics for the treatment of schizophrenia: A focus on the adverse effects of clozapine","volume":"9","author":"Rapini","year":"2018","journal-title":"Ther. Adv. Drug Saf."},{"key":"ref_69","first-page":"275","article-title":"Pathophysiology of clozapine induced sialorrhea and current treatmant choices","volume":"23","author":"Sema","year":"2010","journal-title":"D\u00fc\u015f\u00fcnen Adam J. Psychiatry Neurol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s00213-005-0248-4","article-title":"Clozapine-induced sialorrhea: Pathophysiology and management strategies","volume":"185","author":"Praharaj","year":"2006","journal-title":"Psychopharmacology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1345\/aph.1P761","article-title":"Current treatment strategies for clozapine-induced sialorrhea","volume":"45","author":"Bird","year":"2011","journal-title":"Ann. Pharmacother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"458","DOI":"10.4088\/JCP.09m05527yel","article-title":"Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis","volume":"72","author":"Athanasiou","year":"2011","journal-title":"J. Clin. Psychiatry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0162-3109(97)00037-4","article-title":"Short and long term immunosuppressive effects of clozapine and haloperidol","volume":"37","author":"Leykin","year":"1997","journal-title":"Immunopharmacology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/S0893-133X(98)00006-2","article-title":"Effects of Clozapine on In Vitro Immune Parameters: A Longitudinal Study in Clozapine-Treated Schizophrenic Patients","volume":"19","author":"Becker","year":"1998","journal-title":"Neuropsychopharmacology"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Dar\u00e9, L.O., Bruand, P.E., G\u00e9rard, D., Marin, B., Lameyre, V., Boum\u00e9di\u00e8ne, F., and Preux, P.M. (2019). Co-morbidities of mental disorders and chronic physical diseases in developing and emerging countries: A meta-analysis. BMC Public Health, 19.","DOI":"10.1186\/s12889-019-6623-6"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1001\/archpsyc.64.10.1123","article-title":"A systematic review of mortality in schizophrenia: Is the differential mortality gap worsening over time?","volume":"64","author":"Saha","year":"2007","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Albrich, W.C., Rassouli, F., Waldeck, F., Berger, C., and Baty, F. (2019). Influence of Older Age and Other Risk Factors on Pneumonia Hospitalization in Switzerland in the Pneumococcal Vaccine Era. Front. Med., 6.","DOI":"10.3389\/fmed.2019.00286"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1136\/thoraxjnl-2012-202818","article-title":"Weighing up risk factors for pneumonia: The role of mental illness and benzodiazepine use","volume":"68","author":"Jennifer","year":"2013","journal-title":"Thorax"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/thoraxjnl-2012-202480","article-title":"Risk of pneumonia and pneumococcal disease in people with severe mental illness: English record linkage studies","volume":"68","author":"Olena","year":"2013","journal-title":"Thorax"},{"key":"ref_80","first-page":"1995","article-title":"Rare and very rare adverse effects of clozapine","volume":"11","author":"Gaetano","year":"2015","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00213-004-1940-5","article-title":"The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine","volume":"177","author":"Weiner","year":"2004","journal-title":"Psychopharmacology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"111128","DOI":"10.1016\/j.pscychresns.2020.111128","article-title":"The relationship between plasma levels of clozapine and N-desmethyclozapine as well as M1 receptor polymorphism with cognitive functioning and associated cortical activity in schizophrenia","volume":"303","author":"Baskak","year":"2020","journal-title":"Psychiatry Res. Neuroimaging"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0924-977X(03)00042-7","article-title":"Toxic rise of clozapine plasma concentrations in relation to inflammation","volume":"13","author":"Haack","year":"2003","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/toxsci\/kfab154","article-title":"Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis","volume":"186","author":"Sernoskie","year":"2021","journal-title":"Toxicol. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/MOH.0000000000000391","article-title":"Clozapine-induced agranulocytosis\/granulocytopenia: Mechanisms and monitoring","volume":"25","year":"2018","journal-title":"Curr. Opin. Hematol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/hup.1181","article-title":"Haematological toxicity of clozapine and some other drugs used in psychiatry","volume":"26","author":"Nooijen","year":"2011","journal-title":"Hum. Psychopharmacol. Clin. Exp."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"15535","DOI":"10.1073\/pnas.0607325103","article-title":"Increased susceptibility to bacterial superinfection as a consequence of innate antiviral responses","volume":"103","author":"Navarini","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/ni.3123","article-title":"Control of adaptive immunity by the innate immune system","volume":"16","author":"Iwasaki","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1007\/s00277-020-04215-y","article-title":"Clozapine-induced agranulocytosis","volume":"99","author":"Mijovic","year":"2020","journal-title":"Ann. Hematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1365-2141.1994.tb04786.x","article-title":"N-desmethylclozapine: A clozapine metabolite that suppresses haemopoiesis","volume":"86","author":"Gerson","year":"1994","journal-title":"Br. J. Haematol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1192\/bjp.bp.108.051979","article-title":"Reasons for discontinuing clozapine: Matched, case-control comparison with risperidone long-acting injection","volume":"194","author":"Taylor","year":"2009","journal-title":"Br. J. Psychiatry"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/bmb\/ldaa024","article-title":"Clozapine in the treatment of refractory schizophrenia: A practical guide for healthcare professionals","volume":"135","author":"Flanagan","year":"2020","journal-title":"Br. Med. Bull."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"45","DOI":"10.9740\/mhc.2022.01.045","article-title":"Toxic clozapine level as first indication of severe, acute infection","volume":"12","author":"Davis","year":"2022","journal-title":"Ment. Health Clin."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.clinbiochem.2014.09.021","article-title":"Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC\u2013MS\/MS method","volume":"47","author":"Patteet","year":"2014","journal-title":"Clin. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Santos, D.d.A.R., Arcanjo, D.d.P.S., Silva, G.M.B.d.M.e., Mendes, A.L.F., Mendon\u00e7a, S.C.B.d., Lima, T.R.C.d.M., Taguchi, C.K., and Ara\u00fajo, B.C.L. (2020). Factors associated with aspiration pneumonia and preventive measures in hospitalized elderly: A systematic review of observational studies. Rev. CEFAC, 22.","DOI":"10.1590\/1982-0216\/20202262920"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s40263-017-0448-6","article-title":"Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal \u2018Slow Gut\u2019 Reactions, and Comparison with International Drug Safety Advice","volume":"31","author":"Ellis","year":"2017","journal-title":"CNS Drugs"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Sultana, J., Calabr\u00f3, M., Garcia-Serna, R., Ferrajolo, C., Crisafulli, C., Mestres, J., and Trifir\u00f2, G. (2017). Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187034"},{"key":"ref_98","first-page":"279","article-title":"Neuroleptic malignant syndrome presenting as pulmonary edema and severe bronchorrhea","volume":"94","author":"Patel","year":"2002","journal-title":"J. Natl. Med. Assoc."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Lee, C.Y., Cheng, Y.D., Cheng, W.Y., Tsai, T.H., and Huang, K.H. (2020). The Prevalence of Anticholinergic Drugs and Correlation with Pneumonia in Elderly Patients: A Population-Based Study in Taiwan. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17176260"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/jgs.13932","article-title":"Anticholinergic Medication Use and Risk of Pneumonia in Elderly Adults: A Nested Case-Control Study","volume":"64","author":"Chatterjee","year":"2016","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s40263-013-0062-1","article-title":"The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain","volume":"27","author":"He","year":"2013","journal-title":"CNS Drugs"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pnpbp.2009.11.009","article-title":"The role of histaminergic H1 and H3 receptors in food intake: A mechanism for atypical antipsychotic-induced weight gain?","volume":"34","author":"Deng","year":"2010","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/17512433.2019.1577134","article-title":"A comprehensive review of swallowing difficulties and dysphagia associated with antipsychotics in adults","volume":"12","author":"Cicala","year":"2019","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"219","DOI":"10.4103\/0019-5154.110832","article-title":"Pharmacology of antihistamines","volume":"58","author":"Church","year":"2013","journal-title":"Indian J. Dermatol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Lim, R., Kalisch Ellett, L.M., Widagdo, I.S., Pratt, N.L., and Roughead, E.E. (2019). Analysis of anticholinergic and sedative medicine effects on physical function, cognitive function, appetite and frailty: A cross-sectional study in Australia. BMJ Open, 9.","DOI":"10.1136\/bmjopen-2019-029221"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1176\/appi.ajp.161.9.1620","article-title":"Equivalent Occupancy of Dopamine D1 and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics","volume":"161","author":"Tauscher","year":"2004","journal-title":"Am. J. Psychiatry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"35S","DOI":"10.1016\/0893-133X(95)00203-P","article-title":"Extrapyramidal symptoms during long-term treatment with antipsychotics: Special focus on clozapine and D1 and D2 dopamine antagonists","volume":"14","author":"Gerlach","year":"1996","journal-title":"Neuropsychopharmacology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1007\/s11908-011-0175-y","article-title":"Antipsychotic drug use and community-acquired pneumonia","volume":"13","year":"2011","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.schres.2022.08.015","article-title":"Evolution of antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia in the real-life: A 4-year follow-up naturalistic study","volume":"248","author":"Monteleone","year":"2022","journal-title":"Schizophr. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1093\/schbul\/sbq019","article-title":"Poor clinical outcomes among pneumonia patients with schizophrenia","volume":"37","author":"Chen","year":"2011","journal-title":"Schizophr. Bull."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1097\/JCP.0000000000000458","article-title":"Aspiration Pneumonia: An Underappreciated Risk of Clozapine Treatment","volume":"36","author":"Gurrera","year":"2016","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/S0140-6736(09)60742-X","article-title":"11-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study)","volume":"374","author":"Tiihonen","year":"2009","journal-title":"Lancet"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.schres.2023.07.014","article-title":"Clozapine and its protective effect on all-cause, natural, and suicide mortality in patients with schizophrenia: A nationwide cohort study in Taiwan","volume":"268","author":"Chen","year":"2024","journal-title":"Schizophr. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/acps.12989","article-title":"Clozapine and all-cause mortality in treatment-resistant schizophrenia: A historical cohort study","volume":"139","author":"Cho","year":"2019","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/acps.13267","article-title":"Clozapine and mortality: A comparison with other antipsychotics in a nationwide Danish cohort study","volume":"143","author":"Foldager","year":"2021","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1176\/appi.ajp.2017.16091097","article-title":"Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia","volume":"174","author":"Wimberley","year":"2017","journal-title":"Am. J. Psychiatry"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/schbul\/sby052","article-title":"Clozapine and Long-Term Mortality Risk in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years","volume":"45","author":"Vermeulen","year":"2019","journal-title":"Schizophr. Bull."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1055\/s-0043-116492","article-title":"Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017","volume":"51","author":"Hiemke","year":"2018","journal-title":"Pharmacopsychiatry"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s40262-021-01021-1","article-title":"Comment on: \u201cElevated Clozapine Concentrations in Clozapine-Treated Patients with Hypersalivation\u201d","volume":"60","author":"Suhas","year":"2021","journal-title":"Clin. Pharmacokinet."},{"key":"ref_120","first-page":"26838","article-title":"Selective Immunoglobulin M Deficiency Among Clozapine-Treated Patients: A Nested Case-Control Study","volume":"17","author":"Lozano","year":"2015","journal-title":"Prim. Care Companion CNS Disord."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"20451253211072341","DOI":"10.1177\/20451253211072341","article-title":"Clozapine- and non-clozapine-associated neutropenia in patients with schizophrenia: A retrospective cohort study","volume":"12","author":"Johannsen","year":"2022","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/schbul\/sbac148","article-title":"Clozapine Therapy and COVID-19: A Systematic Review of the Prevalence Rates, Health Outcomes, Hematological Markers, and Patient Perspectives","volume":"49","author":"Giles","year":"2023","journal-title":"Schizophr. Bull."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Suffel, A.M., Ojo-Aromokudu, O., Carreira, H., Mounier-Jack, S., Osborn, D., Warren-Gash, C., and McDonald, H.I. (2023). Exploring the impact of mental health conditions on vaccine uptake in high-income countries: A systematic review. BMC Psychiatry, 23.","DOI":"10.1186\/s12888-022-04512-y"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1176\/appi.ps.202100702","article-title":"Increasing COVID-19 Vaccination Rates Among Patients With Serious Mental Illness: A Pilot Intervention Study","volume":"73","author":"Lim","year":"2022","journal-title":"Psychiatr. Serv."},{"key":"ref_125","unstructured":"Department of Health and Aged Care, A.G. (2023). Pneumococcal disease. The Australian Immunisation Handbook, Department of Health and Aged Care, A.G."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"231","DOI":"10.18773\/austprescr.2017.067","article-title":"Clozapine in primary care","volume":"40","author":"Winckel","year":"2017","journal-title":"Aust. Prescr."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/12\/2016\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:49:02Z","timestamp":1760114942000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/12\/2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,6]]},"references-count":126,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["medicina60122016"],"URL":"https:\/\/doi.org\/10.3390\/medicina60122016","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,6]]}}}