Reflections on the Complex History of the Concept of Clozapine-Induced Inflammation during Titration.

Clozapine was synthesized in 1958. The Food and Drug Administration approved it in 1989 when comprehensive pharmacokinetic studies were not required and it was not known that clozapine was metabolized by the cytochrome P450 1A2 (CYP1A2). Currently it is known that clozapine personalized dosing may be influenced by one's DNA ancestry (African, European and/or Asian/Indigenous American), sex/smoking subgroup, and the presence/absence of genetic/non-genetic poor metabolizer (PM) status. The literature does not properly reflect the concept of "clozapine-induced inflammation" during rapid titration. Elaborating upon this concept, this historical review discusses: 1) clozapine-induced fever, 2) the effects of inflammation on clozapine metabolism, 3) clozapine-induced myocarditis, 4) other clozapine-induced inflammations, 4) current support for "clozapine-induced inflammation" as a hypersensitivity reaction, 5) the difficulty in addressing such a concept to a readership with diverse beliefs about it and 6) the limitations of this review in convincing skeptics. Clozapine-induced fever in the absence of any concomitant infection was first described in 1972 and is a mild form of "clozapine-induced inflammation" during rapid titration, which also includes myocarditis and other localized inflammations. They may be part of a hypersensitivity reaction that has 3 phases. In the first phase, the titration is too fast for a specific patient; either the psychiatrist was too aggressive in titrating, and/or the patient is a clozapine PM. This situation leads to a release of cytokines. In the second phase, a positive feedback loop develops; the cytokines inhibit CYP1A2, which further increases plasma clozapine concentrations. In the third phase, if the titration continues, the inflammation becomes complicated by the development of an auto-immune phenomenon leading to localized inflammation. Skeptical readers are challenged to try: 1) 6 titrations proposed for stratified dosing and 2) c-reactive protein (CRP) monitoring for personalized dosing in the absence of genetic testing for clozapine PM status.