Abstract
Background: Clozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Although the molecule presents with a range of well-known side-effects, its discontinuation/withdrawal syndrome has been only anecdotally described. Aims: the 2005–2018 European Medicines Agency (EMA) dataset of Adverse Drug Reactions (ADRs) was analyzed to identify and describe possible clozapine withdrawal- and misuse-/abuse-/dependence-related issues. Method: A descriptive analysis of clozapine-related ADRs was performed when available, data on ADRs’ outcome, dosage, and possible concomitant drug(s) were considered. Results: Out of 11,847 clozapine-related ADRs, some 599 (5.05%) were related to misuse/abuse/dependence/withdrawal issues, including 258 withdrawal-related (43.1%); 241 abuse-related (40.2%); and 80 intentional product misuse-related (13.3%) ADRs. A small number of overdose- and suicide-related ADRs were reported as well. Clozapine was typically (69.2%) identified alone, and most (84.7%) fatalities/high-dosage intake instances were reported in association with a history of substance abuse. Conclusions: Previous suggestions about the possibility of a clozapine discontinuation/withdrawal occurrence are here supported, but further studies are needed. However, the misuse/abuse cases here identified might be difficult to interpret, given the lack of studies highlighting the possible recreational use of clozapine. The high-dosage intake, fatal outcomes and clozapine/polydrug abuse issues reported here may, however, be a reason for concern.
Highlights
Clozapine was first synthesized in 1959 [1] and made available on the European market in 1971 for the treatment of schizophrenia [2]
In order to investigate the aspects above, EV was requested to provide all Level 2A data [34] comprising case reports of clozapine-related misuse, abuse, dependence, and withdrawal Adverse Drug Reactions (ADRs), which were obtained in the form of line listings, relating to the 2005–June 2018 time-frame
From the publicly available data from the EV website, Level 2A data were presented as Excel sheets divided into information sections reporting in a standardized format according to the Medical Dictionary for Regulatory Activities (MedDRA), which is the internationally agreed list of terms that supports the coding of ADRs [35], which are identified through Preferred Terms (PT)
Summary
Clozapine was first synthesized in 1959 [1] and made available on the European market in 1971 for the treatment of schizophrenia [2]. Food and Drug Administration (FDA) in 1989 for treatment-resistant schizophrenia [2,3]. It was approved in the USA in 2002 for reducing recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Clozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Aims: the 2005–2018 European Medicines Agency (EMA) dataset of Adverse Drug Reactions (ADRs) was analyzed to identify and describe possible clozapine withdrawal- and misuse-/abuse-/dependence-related issues. A small number of overdose- and suicide-related ADRs were reported as well
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