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In a recent editorial, Pierre Blier discussed some of the reasons that new antidepressants have become a rarity.1 The situation is serious enough that GlaxoSmithKline and Astra-Zeneca have decreased work in many areas of psychiatry, and a recent article in Science asks, “Is pharma running out of brainy ideas?”.2 One of the problems is a lack of any clear understanding of the etiology of depression. As Krishnan and Nestler3 have pointed out, “Unlike Parkinson’s or Alzheimer’s disease, depression lacks any clear consensus neuropathology, rare familial genetic causes, or highly penetrant vulnerability genes, providing no obvious starting points for molecular investigations.” The important progress in understanding the etiology of Alzheimer disease has resulted recently in more than a dozen trials of experimental treatments, none of which has shown any therapeutic effect.4 So, what hope is there for progress in treating depression?

Possible directions for the discovery of new antidepressant