Clozapine and lithium require Caenorhabditis elegans β-arrestin and serum- and glucocorticoid-inducible kinase to affect Daf-16 (FOXO) localization.

Numerous studies have implicated low levels of signaling in the Akt network with psychotic illnesses, and a growing body of literature has shown that all classes of antipsychotic drugs increase Akt signaling. The most clinically effective antipsychotic drug is clozapine. With Caenorhabditis elegans as a model system, this study demonstrates that clozapine is unique among antipsychotic drugs because it requires β-arrestin and serum and glucocorticoid-inducible kinase (SGK) in addition to Akt to suppress the nuclear localization of DAF-16 (Forkhead box O [FOXO]). Lithium, a mood stabilizer often used to treat psychosis, also requires β-arrestin and SGK to suppress the nuclear localization of DAF-16.