A brief history and challenges of clozapine utilization in the Arab world

Abstract

Clozapine synthesis dates back to 1958, when a Swiss pharmaceutical company produced it based on the chemical structure of the tricyclic antidepressant imipramine (Crilly, 2007; Idänpään-Heikkilä et al., 1975). Clinical trials in humans started in the 60's, but it was not until the early 70s when clozapine was first introduced into the European market as Leponex® by Sandoz pharmaceutical company (Crilly, 2007). Initial trials of clozapine in the United States (US) took place in 1975, at around the same time that 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, raised concerns on its safety and led to its withdrawal from the US market, although it remained available in some European countries (Idänpään-Heikkilä et al., 1975). Clozapine was then reintroduced in the US in the early 1990s for the management of treatment resistant schizophrenia (TRS) under a strict mandatory hematological monitoring system which was mostly supported by the manufacturer of clozapine (Bachmann et al., 2017; Nielsen et al., 2016).