Proposed model of clozapine-induced inflammasome activation. Clozapine is bioactivated to a reactive metabolite that irreversibly binds to endogenous proteins, resulting in the generation of neoantigens (ie, haptens). If essential cellular proteins are haptenized, this causes cell stress, damage, or death that, in turn, triggers the release of DAMPs (including drug-modified proteins) and other proinflammatory stimuli from the injured cell. These signals drive the activation of local immune cells such as macrophages that can respond to DAMPs in several ways, including propagation of an inflammatory response via inflammasome activation. Inflammasome-dependent activation of caspase-1 increases the production of mature IL-1β from its inactive form. The released IL-1β induces a proinflammatory state through autocrine and paracrine signaling via the IL-1 receptor (IL-1R), leading to increased release of chemokines and proinflammatory cytokines (ie, CXCL1) and acute phase proteins (ie, α-1-AGP), as well as increased activation and mobilization of peripheral immune cells. VX-765, yVAD-cmk, and zVAD-fmk directly prevent clozapine-induced inflammasome activation through caspase-1 inhibition and anakinra prevents inflammasome signaling through antagonism of IL-1R, ultimately attenuating multiple components of the proinflammatory response to clozapine.