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Chemically reactive drugs and drugs that form reactive metabolites often cause idiosyncratic drug reactions (IDRs); however, not all such drugs are associated with IDRs. Most IDRs appear to be immune mediated; therefore, the ability of a drug to induce an immune response may be the determinant of which drugs will cause IDRs. Inflammasome activation plays an important role in the initiation of an immune response. In this study, we studied two pairs of similar chemically reactive drugs, telaprevir/boceprevir and dimethyl fumarate/ethacrynic acid. In both pairs, the drug associated with skin reactions activated inflammasomes in THP-1 cells, and the drug not associated with skin reactions did not.

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Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and non-differentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1β release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague-Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1β, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1β production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of idiosyncratic drug-induced agranulocytosis, enabling safer, more frequent use of clozapine in patients.

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