New approaches to rapid onset antidepressants

The challenges for the design of new antidepressant drugs are threefold: rapid onset of antidepressant response, broader efficacy, and fewer adverse effects. While progress has been made to reduce side-effects, the currently available drugs show no convincing evidence for a shorter delay of onset nor for improved efficacy. This review summarizes some of the hypotheses that try to explain the delayed onset and that are currently used for antidepressant drug design. These approaches include combinations of SSRI activity with either NA reuptake inhibition or 5-HT1A-, 5-HT2-, or alpha 2-adrenergic receptor specificity, as well as targeting interactions with specific receptor subtypes (5-HT1A, 5-HT1A/5-HT2, 5-HT1B/D, alpha 2/5-HT2, D2/D3). Structure activity relationship studies to obtain molecular entities with the desired pharmacological profile are discussed. Many structural modifications have exploited successfully the acquired knowledge on structural features that are necessary for monoamine reuptake inhibition as well as for affinities at various receptors. Most of the current drug design efforts are focused on these approaches, which are based on the monoamine theory of depression; however, novel biological concepts of depression involving other receptor systems or intracellular targets are briefly mentioned. Although their impact on the onset of antidepressant response is only a matter of speculation at this moment, they may lead to the identification of targets for truly novel antidepressants.