DEVELOPMENT OF NEW ANTIDEPRESSANTS

A large number of novel antidepressants acting on a variety of neurotr ansmitter receptors are currently undergoing clinical evaluation. Most agents have a dual mechanism of action on two or more neurotransmitte r receptors, including two serotonin receptors, two noradrenergic rece ptors, or a combination of serotonin and noradrenergic mechanisms. The most recently approved agent, mirtazapine, is an example of this appr oach of simultaneously targeting both the serotonergic and noradrenerg ic systems. Specifically, mirtazapine's alpha(2) antagonism disinhibit s both serotonin and norepinephrine neurotransmission while its seroto nin-2 and serotonin-3 antagonist properties reduce the side effects no rmally associated with nonselective serotonin receptor activation by s erotonin selective reuptake inhibitors (SSRIs). This approach of ''des igner polypharmacy'' applies principles of rational pharmacologic comb inations to enhance efficacy and improve tolerability of the new and e merging antidepressants.