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Rapid Onset of Antidepressant Action: A New Paradigm in the Research and Treatment of Major Depressive Disorder

Rodrigo Machado-Vieira, M.D., Ph.D.; Giacomo Salvadore, M.D.; David A. Luckenbaugh, M.A.; Husseini K. Manji, M.D., F.R.C.P.C.; and Carlos A. Zarate, Jr., M.D.

Objective: Current therapeutics of depression are similar in their time to antidepressant action and often take weeks to months to achieve response and remission, which commonly results in considerable morbidity and disruption in personal, professional, family, and social life, as well as risk for suicidal behavior. Thus, treatment strategies presenting a rapid improvement of depressive symptoms-within hours or even a few days-and whose effects are sustained would have an enormous impact on public health. This article reviews the published data related to different aspects of rapid improvement of depressive symptoms.

Data Sources: Literature for this review was obtained through a search of the MEDLINE database (1966-2007) using the following keywords and phrases: rapid response, antidepressant, time to, glutamate, sleep, therapeutics, latency, and depression. The data obtained were organized according to the following topics: clinical relevance and time course of antidepressant action, interventions showing evidence of rapid response and its potential neurobiological basis, and new technologies for better understanding rapid antidepressant actions.

Data Synthesis: A limited number of prospective studies evaluating rapid antidepressant actions have been conducted. Currently, only a few interventions have been shown to produce antidepressant response in hours or a few days. The neurobiological basis of these rapid antidepressant actions is only now being deciphered.

Conclusions: Certain experimental treatments can produce antidepressant response in a much shorter period of time than existing medications. Understanding the molecular basis of these experimental interventions is likely to lead to the development of improved therapeutics rather than simply furthering our knowledge of current standard antidepressants.


(J Clin Psychiatry 2008;69:946-958. Online Ahead of Print April 22, 2008.)

Received Oct. 30, 2007; accepted Feb. 29, 2008. From the Mood and Anxiety Disorders Program, National Institute of Mental Health, Department of Health and Human Services, Bethesda, Md.

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health and a NARSAD Award (Dr. Zarate).

Drs. Manji and Zarate are listed among the inventors on a patent application submitted for the use of ketamine in depression. They have assigned their rights on the patent to the U.S. government. Drs. Machado-Vieira and Salvadore and Mr. Luckenbaugh report no additional financial or other relationship relevant to the subject of this article.

Corresponding author and reprints: Carlos A. Zarate, Jr., M.D., National Institute of Mental Health, Mark O. Hatfield Clinical Research Center, 10 Center Dr., Unit 7SE, Rm 7-3445, Bethesda, MD 20892-1282 (e-mail: