Exploring a Safety Signal of Antipsychotic-Associated Pneumonia: A Pharmacovigilance-Pharmacodynamic Study

Abstract

An association between antipsychotic drugs and pneumonia has been demonstrated in several studies; however, the risk for pneumonia caused by specific antipsychotics has not been extensively studied. The underlying mechanism is still unknown, and several receptor mechanisms have been proposed. Therefore, using a combined pharmacovigilance-pharmacodynamic approach, we aimed to investigate safety signals of US Food and Drug Administration (FDA)-approved antipsychotics for reporting pneumonia and the potential receptor mechanisms involved. A disproportionality analysis was performed to detect a signal for reporting “infective-pneumonia” and “pneumonia-aspiration” and antipsychotics using reports submitted between 2004 and 2019 to the FDA adverse events spontaneous reporting system (FAERS) database. Disproportionality was estimated using the crude and the adjusted reporting odds ratio (aROR) and its 95% confidence interval (CI) in a multivariable logistic regression. Linear regressions investigated the relationship between aROR and receptor occupancy, which was estimated using in vitro receptor-binding profiles. Safety signals for reporting infective-pneumonia were identified for clozapine (LL = 95% 3.4, n = 546 [aROR: 4.8]) as well as olanzapine (LL = 95% 1.5, n = 250 [aROR: 2.1]) compared with haloperidol, while aRORs were associated with higher occupancies of muscarinic receptors (beta = .125, P-value = .016), yet other anti-muscarinic drugs were not included as potential confounders. No safety signals for reporting pneumonia-aspiration were detected for individual antipsychotics. Multiple antipsychotic use was associated with both reporting infective-pneumonia (LL 95%: 1.1, n = 369 [aROR:1.2]) and pneumonia-aspiration (LL 95%: 1.7, n = 194 [aROR: 2.0]). Considering the limitations of disproportionality analysis, further pharmacovigilance data and clinical causality assessment are needed to validate this safety signal.

Exploring the underlying mechanisms of drug‐induced impulse control disorders: a pharmacovigilance‐pharmacodynamic study

“…Among this richness of molecular targets, there is plausibly the key to better management of drug‐related ICDs. Integrating pharmacovigilance and pharmacodynamic data may help in the search for the pathogenetic mechanisms of drug‐induced conditions 26–40 . Therefore, we aim to generate novel hypotheses on the underlying mechanistic basis of drug‐induced ICDs.…”

“…Integrating pharmacovigilance and pharmacodynamic data may help in the search for the pathogenetic mechanisms of drug-induced conditions. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Therefore, we aim to generate novel hypotheses on the underlying mechanistic basis of drug-induced ICDs. A more comprehensive understanding of the role of other molecular targets would drive a more successful drug switching in case of ICDs onset and may support the development and repurposing of pharmacological treatments for ICDs.…”

A case–control study of antipsychotic use and pneumonia‐related mortality in the United Kingdom

“…[37][38][39] Such immune system impairments might be assumed to increase susceptibility to infectious pneumonia. Indeed, it is well recognised that clozapine use increases risk of pneumoniaalthough this is probably because of a reduction in immunoglobulins, [23][24][25][26] and there is emerging evidence for increased risk of pneumonia with olanzapine use. 24 This study supports the evidence for increased risk of infectious pneumonia with olanzapine use.…”

“…Off‐target effects of SGAs at the thromboxane A2 receptor (TBXA2R) and platelet‐activating factor receptor (PTAFR) have been implicated in increased pneumonia prevalence, 20 as TBXA2R and PTAFR mediate capillary permeability at the alveolar level, which if compromised can lead to alveoli oedema–a recognised risk factor as well as symptom of pneumonia 21 . There is also emerging evidence to suggest that clozapine can impede immunoglobulin function 22–26 …”

“…21 There is also emerging evidence to suggest that clozapine can impede immunoglobulin function. [22][23][24][25][26] Few studies have examined risk differences between individual antipsychotics 23,24,27 or association with pneumonia-related death. In this study, we have examined the association of specific antipsychotic exposure to overall pneumonia-related mortality, and performed sub-analysis by pneumonia type-pneumonia can manifest due to pathogenic infection or aspiration of substances, 21 and it is important to understand if there is differential risk with antipsychotic use between pneumonia types.…”