Beyond monoamine-based therapies: clues to new approaches

Advances in antidepressant therapy have resulted in agents with fewer serious side effects than, for example, nonselective monoamine oxidase inhibitors and tricyclic antidepressants. Nonetheless, these newer agents are far from the ideal. Many of the drawbacks associated with these newer agents--slow onset, low rate of response, and low rate of remission--are likely to be mechanism related. In order to overcome these problems, researchers must either improve upon these traditional, biogenic amine-based mechanisms or explore nontraditional mechanisms. Strategies for improving biogenic amine-based antidepressants include the so-called serotonin augmentation strategy and the broad spectrum agent that simultaneously blocks reuptake at the serotonin, norepinephrine, and dopamine transporters. Two nontraditional approaches employ modulation of glutamate receptor function. At face value, these glutamate-based approaches (N-methyl-D-aspartate [NMDA] antagonists and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] receptor potentiators) appear diametrically opposed. However, these 2 mechanisms may ultimately impact similar cellular endpoints.