Finding what you are not looking for: strategies for developing novel treatments in psychiatry.

SUMMARY: Psychopharmacological treatments in psychiatry are often surprises. Original targets frequently fail, and when successful, may only be the opening volley in a series of ever more important therapeutic applications. Drug development may begin by hypothesis-driven targeting of therapeutic indications with an agent of known and novel mechanism of action. Although this may generate a highly feasible therapeutic indication and can proceed by a well-worn regulatory pathway with known approvable endpoints, it may not only be the least innovative but also the least commercially successful strategy. Because surrogate markers of efficacy are only theoretically attractive but still largely elusive for psychiatric disorders, drug development strategies may need to proceed instead by opportunistic capturing of signals from clinical use of new agents once they enter clinical practice. Outcomes and dosing for clinical trial populations may not match those in clinical practice, so observations from clinical practice must feed back into new clinical trials. In many ways, once efficacy is proven for the originally targeted indication, drug development begins afresh. To get to secondary stages of novel indications for psychiatric drugs and thus to maximize each drug's therapeutic potential, evidence-based prescribing is followed by prescribing-based evidence, namely feedback from clinical practice into clinical proof-of-concept studies followed by large-scale studies and new indications. In many cases, the new indications are the more important therapeutic contributions and the most successful commercial application of a drug. Here we describe this strategy of psychiatric drug development and provide numerous examples.