Development of New Antidepressants

A large number of novel antidepressants acting on a variety of neurotransmitter receptors are currentlyundergoing clinical evaluation. Most agents have a dual mechanism of action on two or moreneurotransmitter receptors, including two serotonin receptors, two noradrenergic receptors, or a combinationof serotonin and noradrenergic mechanisms. The most recently approved agent, mirtazapine,is an example of this approach of simultaneously targeting both the serotonergic and noradrenergicsystems. Specifically, mirtazapine’s α2 antagonism disinhibits both serotonin and norepinephrine neurotransmissionwhile its serotonin-2 and serotonin-3 antagonist properties reduce the side effects normallyassociated with nonselective serotonin receptor activation by serotonin selective reuptake inhibitors(SSRIs). This approach of "designer polypharmacy" applies principles of rationalpharmacologic combinations to enhance efficacy and improve tolerability of the new and emergingantidepressants.