Reaction, polemic

https://doi.org/10.24869/psyd.2022.411

REFLECTIONS ON THE COMPLEX HISTORY OF THE CONCEPT OF CLOZAPINE-INDUCED INFLAMMATION DURING TITRATION

Jose de Leon orcid.org/0000-0002-7756-2314 ; Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain

Abstract

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.

Keywords

clozapine/adverse effects; clozapine/metabolism; mortality/drug effects; myocarditis/chemically induced; myocarditis/etiology

Hrčak ID:

290235

URI

https://hrcak.srce.hr/290235

Publication date:

3.11.2022.

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