Zur klinischen Relevanz der Wirkung von Clozapin auf die Freisetzung von Zytokinen und löslichen Zytokinrezeptoren

Zusammenfassung:

Zytokine sind zentrale Mediatoren der Interaktion immunkompetenter Zellen, aber auch der Kommunikation des Immunsystems mit anderen physiologischen Systemen einschließlich des ZNS. Untersuchungen der letzten Jahre zeigen, dass das Neuroleptikum Clozapin in vivo die Freisetzung von Zytokinen und löslichen Zytokinrezeptoren stimuliert. Diese Wirkung betrifft insbesondere das Tumor-Nekrose-Faktor(TNF)-System, das Interleukin(IL)-2-System, IL-6 und granulocyte colony-stimulating factor (G-CSF). Die vorliegende Arbeit diskutiert die Bedeutung dieser Zytokine für die Pathogenese und Pathophysiologie Clozapin-induzierter Nebenwirkungen. Mit großer Wahrscheinlichkeit spielt TNF-α eine wichtige pathogenetische Rolle für das Clozapin-induzierte Fieber und die hämatopoetischen Nebenwirkungen einschließlich der Agranulozytose. Darüber hinaus gibt es Hinweise darauf, dass TNF-α und andere Zytokine auch in endokrin-metabolische (Gewichtszunahme, Induktion einer diabetischen Stoffwechsellage), kardiale (Myokarditis), zentralnervöse (Sedierung) und einige andere, sehr seltene Nebenwirkungen involviert sind. Die Mechanismen, die den immunmodulatorischen Wirkungen von Clozapin zugrunde liegen, sind nicht bekannt, weshalb in diesem Bereich dringender Forschungsbedarf besteht. Von entsprechenden Untersuchungen sind wesentliche Erkenntnisse hinsichtlich der Pathogenese der erwähnten Nebenwirkungen und Impulse für die Entwicklung prophylaktischer und therapeutischer Strategien zu erwarten.

On the Clinical Relevance of Clozapine-Triggered Release of Cytokines and Soluble Cytokine-Receptors:

Cytokines are pivotal mediators of the interaction between immunocompetent cells. Moreover, they mediate the interaction between the immune system and other physiological systems, including the CNS. It has been shown recently that the antipsychotic drug clozapine stimulates in vivo the release of cytokines and soluble cytokine receptors. This holds true for the tumor necrosis factor(TNF)-system, the interleukin(IL)-2-system, IL-6, and granulocyte colony-stimulating factor (G-CSF). The present paper discusses the clinical relevance of these findings for the pathophysiology of clozapine-induced side-effects. It is very probable that TNF-α plays an important role in clozapin-induced fever and in the hematopoetic side effects, including agranulocytosis. Moreover, it is likely that TNF-α and other cytokines are involved in metabolic (weight gain, diabetes), cardiac (myocarditis), CNS (sedation) and other rare side effects. The mechanisms underlying clozapine-induced immunomodulation are unknown. Hence, further studies are very important to enhance our understanding of clozapins's side effects and to develop strategies for prevention and treatment.

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