Respiratory aspiration during treatment with clozapine and other antipsychotics: a literature search and a pharmacovigilance study in vigibase

ABSTRACT

Introduction

Antipsychotics (APs), during treatment or overdose, may be associated with respiratory aspiration.

Areas covered

A PubMed search on 30 September 2022, provided 3 cases of respiratory aspiration during clozapine therapy and 1 case during an AP overdose. VigiBase records of respiratory aspiration associated with APs from inception until 5 September 2021, were reviewed. VigiBase, the World Health Organization’s global pharmacovigilance database, uses a statistical signal for associations called the information component (IC).

Expert Opinion

The ICs (and IC₀₂₅) were 2.1 (and 2.0) for APs, 3.2 (and 3.0) for clozapine, 2.6 (and 2.4) for quetiapine, and 2.5 (and 2.2) for olanzapine. Cases of respiratory aspiration associated with APs included: 137 overdose/suicide cases (64 fatal) and 609 cases during treatment (385 fatal) including 333 taking clozapine (238 fatal). In logistic regression models of fatal outcomes, the odds ratios, OR, and (95% confidence intervals, CI) of significant independent variables were: a) 2.3–2.6 for clozapine in 3 samples of AP treatment of varying size, b) 1.9 (CI 1.0 to 3.5) for geriatric age in 284 patients on clozapine treatment, and c) 1.8 (CI 1.1–3.2) for antidepressant co-medication in 276 patients on non-clozapine APs. Multiple AP pharmacological mechanisms may explain respiratory aspiration.

KEYWORDS:

• Airway obstruction
• antipsychotic agents/adverse effects
• deglutition disorders
• dementia
• drug overdose
• intellectual disability
• polypharmacy
• respiratory aspiration
• schizophrenia

Article highlights

• In the 746 patients with respiratory aspiration associated with antipsychotics (APs), fatal outcomes, compared with non-fatal outcomes, were associated with a significant decrease in reports of several relevant variables including: suicide/overdose: 14% vs 25% (p<.001, odds ratio, OR=0.51, 95% confidence interval CI, 0.35 to 0.74), pneumonia 18% vs 25% (p=.011, OR=0.63, CI 0.44 to 0.90), and mechanisms associated with respiratory aspiration (absence of mechanisms was present in 51% vs 32% (p<.001, OR=0.54, CI 0.40 to 0.73).

• The limited VigiBase data suggest that 1) clozapine is an AP particularly prone to cause respiratory aspiration through multiple mechanisms, 2) clozapine tends to be strongly associated with fatal respiratory aspiration and 3) most of clozapine respiratory aspiration occurred in non-geriatric patients and during treatment instead of during overdose.

• The limited VigiBase data suggest that regarding respiratory aspirations, APs other than clozapine 1) may be specifically associated to multiple pharmacological mechanisms, 2) may happen in demented patients even with AP monotherapy and 3) may cause more fatal outcomes during treatment with antidepressant co-medication.

• The limited VigiBase data suggest that APs may be different from benzodiazepines, antiepileptic drugs and antidepressants; a drug from these 3 psychiatric classes may contribute to fatal outcomes during respiratory aspiration only as one more drug within the context of polypharmacy.

This box summarizes key points contained in the article.

Acknowledgments

The authors are indebted to the national centers which make up the World Health Organization (WHO) Program for International Drug Monitoring and contribute reports to VigiBase. The information comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. However, the opinions and conclusions of this study are not necessarily those of the various centers nor of the WHO. The authors acknowledge Lorraine Maw, M.A., from the University of Kentucky Mental Health Research Center at Eastern State Hospital, who helped in editing the article.

Declaration of interest

C. De las Cuevas and A. Villasante-Tezanos have never had conflict of interest. E.J. Sanz has never been a consultant for any pharmaceutical industry and his lectures have never been supported by any pharmaceutical company. On several occasions he has been invited to speak at conferences that might have been supported by the industry, but the invitation and reimbursements were given by the scientific society organizing the conference in all cases. He has a signed agreement with the WHO-Uppsala Monitoring Center as member of the external clinical experts Group. J. de Leon personally develops his presentations for lecturing, has never lectured using any pharmaceutical or pharmacogenetic company presentations, and has never been a consultant for pharmacogenetic or pharmaceutical companies. In the past, J. de Leon received researcher-initiated grants from Eli Lilly (one ended in 2003 and the other, as co-investigator, ended in 2007); from Roche Molecular Systems, Inc. (ended in 2007); and, in a collaboration with Genomas, Inc., from the NIH Small Business Innovation Research program (ended in 2010). J. de Leon has been on the advisory boards of Bristol-Myers Squibb (2003/04) and AstraZeneca (2003). Roche Molecular Systems supported one of his educational presentations, which was published in a peer-reviewed journal (2005). His lectures were supported once by Sandoz (1997), twice by Lundbeck (1999 and 1999), twice by Pfizer (2001 and 2001), three times by Eli Lilly (2003, 2006, and 2006), twice by Janssen (2000 and 2006), once by Bristol-Myers Squibb (2006), and seven times by Roche Molecular Systems, Inc. (once in 2005 and six times in 2006). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received manuscript or speaker’s fees from Astellas, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Sumitomo Pharma, Takeda Pharmaceutical, Tsumura, Viatris, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Mochida Pharmaceutical, Meiji Seika Pharma, Shionogi and Sumitomo Pharma. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Data availability

VigiBase does not allow the distribution of their file, but this article’s Supplementary Material includes relevant details from 333 cases of respiratory aspiration associated with clozapine.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2023.2192401

Additional information

Funding

This paper was not funded.