Clozapine and noradrenergic function: support for a novel hypothesis for superior efficacy.

Because of its superior clinical efficacy, clozapine is considered the new "reference" antipsychotic agent. Currently, there is an intensive investigational effort attempting to delineate which of clozapine's many biochemical effects are important for its impressive clinical profile. In this paper, the effects of clozapine on noradrenergic function are examined. Preclinical and clinical studies indicate that clozapine selectively increases noradrenergic activity and norepinephrine outflow. Moreover, data are presented demonstrating that clozapine causes fivefold increases in plasma norepinephrine in schizophrenic patients and that these increases are related to its superior clinical efficacy. A novel hypothesis for its superior efficacy is proposed that involves complex actions on noradrenergic systems that result in robust norepinephrine outflow. Implications of heightened norepinephrine outflow are discussed.