Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses

Abstract

IntroductionAntipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined.AimThe aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia.MethodsA search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia.ResultsThe literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR.ConclusionInnovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors.

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“…Data from randomized trials including mostly second-generation antipsychotics showed a higher risk of infections [ 78 ] (Table 1 ). Apart from immunity abnormalities [ 82 ], multiple mechanisms may contribute, including reduced clearance of the airways (related to central sedation and inhibition of cough), impaired chest movements and swallowing due to extrapyramidal symptoms, and sialorrea [ 51 ]. This risk might be particularly relevant for clozapine [ 27 ].…”

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“…It is largely recognised with haloperidol presumably reflecting its potency as a dopamine D2 antagonist (Haddad and Dursun, 2008). Sultana et al (2017) used a systematic literature review with computational analyses to investigate possible pharmacological mechanisms to explain antipsychotic-associated pneumonia. Thirty studies included in the review suggested potential mechanisms with the most frequent involving effects on cholinergic, dopaminergic or histaminergic receptors.…”

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“…Les auteurs incitent ainsi à la vigilance chez les patients commenç ant des antipsychotiques et particulièrement chez ceux présentant des facteurs de risque de pneumonie, avec notamment : âge avancé, tabagisme, dysphagie, maladie respiratoire chronique ou cérébrovasculaire [32]. L'origine de cet impact délétère des antipsychotiques demeure très mal connue et si les théorisations autour de l'implication des systèmes cholinergique, histaminergique, sérotoninergique et dopaminergique sont formulées dans la littérature, il existe un biais d'interprétation mettant en exergue les études sur ce qui est « déjà connu » au détriment des pistes alternatives [33] ; cette revue suggère également l'implication de deux nouvelles cibles réceptologiques pouvant être associées à la pneumonie : le récepteur du thromboxane A2 et celui du facteur d'activation plaquettaire. Des données très récentes confirment ces éléments, en objectivant que chez les patients de 65 ans ou plus, hospitalisés pour pneumonie, une association est retrouvée entre l'utilisation d'antipsychotiques de seconde génération et une mortalité accrue, particulièrement chez ceux souffrant antérieurement de troubles psychiques ou cardiaques [34].…”