UC San Diego

Antipsychotics are among the most prescribed drugs in the US. Although they are effective in treating an array of neurological disorders the drugs share a number of deleterious metabolic side effects. Through a high- throughput screening approach we identified Phenothiazine- based antipsychotics as modulators of insulin promoter activity in the human insulin expression cell line T6PNE. Both typical and atypical antipsychotics were found to modulate the insulin promoter at E-box sequences, with chronic treatment being repressive. Mechanistic work identified the TGF[beta] pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGF[beta] pathway, through a receptor distinct from the TGF[beta] receptor family, and known neurotransmitter receptor targets of antipsychotics responsible for their beneficial CNS effects. In vivo relevance of the findings in T6PNE was demonstrated by analysis of publically available gene expression data from the brains of humans treated with antipsychotics that showed altered expression of SMAD3 responsive genes. Finally, through a comparative cell line approach candidate genes for the direct target of the antipsychotics linking them to SMAD3 were identified. Since the TGF[beta] pathway and SMAD3 in particular are highly associated with obesity, insulin resistance, and type II diabetes this work raises the possibility that antipsychotics could be designed that retain the beneficial neurological effects while lacking the deleterious metabolic side effects that are a major clinical issue with their use