The brain chemistry that underlies depression is incompletely understood, but research suggests that aberrant signaling by a chemical called brain-derived neurotrophic factor through its receptor TrkB, may contribute to anxiety and depression. Here, researchers describe a screen for stable small molecules that could specifically inhibit TrkB action. They identified one they dubbed ANA-12, which had potent behavioral effects when administered to mice that suggest it will have antidepressant and anti-anxiety activity in humans.