Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead?

Neuropeptide systems have been considered a major opportunity for the development of novel treatment approaches for anxiety disorders based on preclinical evidence and neurochemical alterations seen in anxiety disorders. This excitement was further facilitated by the fact that drugs acting at these systems, such as CRF1 antagonists, NK1 antagonists, NK3 antagonists or CCK2 antagonists, may have unique properties not seen with drugs affecting more classical mechanisms involved in anxiety. Consequently, there have been major efforts to develop such small-molecule, nonpeptide receptor ligands. A number of these molecules have been tested in the clinic, either in trials where levels of anxiety served as a secondary measure, or in a few studies with patients suffering from anxiety disorders. But unfortunately, and despite all the efforts of the field as a whole, we still lack convincing clinical proof-of-concept for any of the neuropeptidergic approaches in patients. It must, therefore, be concluded that neuropeptide targets remain a promising approach for the development of the next generation drugs to treat anxiety disorders, but that they continue to be high-risk targets for drug development.