Major depression: emerging therapeutics.

The first effective antidepressants, monoamine oxidase inhibitors and tricyclic antidepressants, were identified 50 years ago, largely through serendipity. These medications were found to improve mood in a little more than half of depressed patients after a few weeks of chronic use. Almost all antidepressants prescribed today were developed through minor modifications of these original antidepressants and, like monoamine oxidase inhibitors and tricyclic antidepressants, act primarily through monoaminergic mechanisms. Although there have been improvements in side-effect profiles and overdose toxicity, these newer medications have not provided substantial advances in the efficacy and speed of the antidepressant effect for patients. Over the last 2 decades, our understanding of the neurobiology underlying depression has expanded exponentially. Given this expansion, we may be nearing an inflection point in antidepressant drug development, at which useful medicines will be designed through a rational understanding of the biological systems. In this review, we discuss the biological basis and preclinical and clinical evidence for a series of promising classes of antidepressants developed primarily out of a pathophysiologically informed approach.