Failed drug discovery in psychiatry: time for human genome-guided solutions

•Ill-suited models and diagnostic constructs jeopardize drug discovery in psychiatry.•Deconstruction of diagnoses into biologically informed domains is urgently needed.•Human genome information will be key to the identification of novel drug targets.

Our knowledge about the molecular and neural mechanisms of emotional and cognitive processes has increased exponentially in the past decades. Unfortunately, there has been no translation of this knowledge into the development of novel and improved pharmacological treatments for psychiatric disorders. We comment on some of the reasons for failed drug discovery in psychiatry, particularly on the use of ill-suited disease models and on the use of diagnostic constructs unrelated to the underlying biological mechanisms. Furthermore, we argue that the use of human genetic findings together with biologically informed phenotypes and advanced data-mining methodology will catalyze the identification of promising drug targets and, finally, will lead to improved therapeutic outcomes.