Antidepressant therapy: new targets for drug development

Antidepressant drugs have been available for more than 40 years. However, e ssentially all drugs currently available share the common mechanism of modu lating the synaptic transmission of the monoamines serotonin (5-HT), noradr enaline (NE), or dopamine (DA). The mechanisms of action of available drugs include the enhancing the synaptic availability of the monoamines via bloc kade of the high-affinity transporter proteins for these transmitters or al pha -1 receptors, or antagonism of 5-HT receptors. Although the available m edications are often effective, treatment resistance is common and many pat ients discontinue prematurely because of side effect problems. More recentl y, evidence has accumulated suggesting that antidepressants may have effect s beyond the postsynaptic receptors. Enhancement or inhibition of mRNA expr ession for a number of polypeptides have been demonstrated. These proposed ultimate effects of antidepressant agents, such as increasing the expressio n of glucocorticoid receptors and brain derived neurotrophic factor or inhi bition of NMDA receptor subunit and corticotropin releasing hormone (CRH) e xpression, relate to possible new therapeutic targets for antidepressant de velopment. This paper will present data supporting potential new drug targe ts: antagonists for CRH, NMDA, neurokinins and agonists for neuropeptide Y- 1 receptors, as well as reviewing recent relevant patents. The problems wit h establishing new antidepressant agents will also be discussed.