The why, when, where, how, and so what of so-called rapidly acting antidepressants.

Developing antidepressants that are not only more effective but are rapidly acting is the Holy Grail for psychiatry. We review multiple issues that arise in determining rapid responses in antidepressant trials. The current status of purportedly rapid acting agents is first reviewed. Then, a number of key questions/issues are addressed: Is there a unifying definition for rapid response across studies? Should rapid response criteria be based on required measurable effects on overall improvement? On specific symptoms such as psychomotor retardation, depressed mood, or anhedonia? In associated symptoms such as anxiety or insomnia? When should onset be considered rapid-by Day 3? Day7? Day 14? If there is a rapid response, for how long should the effects be maintained? Is maintenance of effect dependent on continuing the medication? Is rapid response associated with specific mechanisms of action? Do the mechanisms of action suggest possible risk for drug abuse? How important is rapid response really in an often chronic or recurrent depressive disorder? In which types of patients could rapid response be particularly important? What are the study design issues that need to be considered for assessing rapid response, including: selection of specific types of depressed patients, multiple doses of drug studied, designation of primary and secondary outcome measures, specific time points at which to determine efficacy, requirements for demonstrating durability, etc. A framework for approaching this complex area is developed for both researchers and clinicians.