From monoamines to genomic targets: a paradigm shift for drug discovery in depression

Depression, a complex psychiatric disorder that affects approximately 15% of the population, has an enormous social cost. Although the disorder is thought to be the outcome of gene-environmental interactions, the causative genes and environmental factors underlying depression remain to be identified. All the antidepressant drugs now in use--the forerunner of which was discovered serendipitously 50 years ago--modulate monoamine neurotransmission, and take six to eight weeks to exert their effects, but each drug is efficacious in only 60-70% of patients. A conceptually novel antidepressant that acted rapidly and safely in a high proportion of patients would almost certainly become the world's bestselling drug. Yet such a drug is not on the horizon. Here, we cover the different phases of antidepressant drug discovery in the past, present and future, and comment on the challenges and opportunities for antidepressant research.