Development of new antidepressants.

A large number of novel antidepressants acting on a variety of neurotransmitter receptors are currently undergoing clinical evaluation. Most agents have a dual mechanism of action on two or more neurotransmitter receptors, including two serotonin receptors, two noradrenergic receptors, or a combination of serotonin and noradrenergic mechanisms. The most recently approved agent, mirtazapine, is an example of this approach of simultaneously targeting both the serotonergic and noradrenergic systems. Specifically, mirtazapine's alpha 2 antagonism disinhibits both serotonin and norepinephrine neurotransmission while its serotonin-2 and serotonin-3 antagonist properties reduce the side effects normally associated with nonselective serotonin receptor activation by serotonin selective reuptake inhibitors (SSRIs). This approach of "designer polypharmacy" applies principles of rational pharmacologic combinations to enhance efficacy and improve tolerability of the new and emerging antidepressants.