The International Journal of Neuropsychopharmacology


Rapid-acting antidepressant strategies: mechanisms of action

Blynn G. Bunneya1 c1 and William E. Bunneya1

a1 Department of Psychiatry, University of California Irvine, School of Medicine, University of California, Irvine, Irvine, CA, USA


Current antidepressants are ineffective in many depressed patients. Thus there is an urgent need to develop treatment strategies which have significantly faster response, can be sustained and have minimal side-effects. This paper reviews clinical data, potential biomarkers, mechanisms of action and future research directions for two proven strategies that produce marked improvement in severe depressive symptoms within 48 h, ketamine and sleep deprivation therapy (SDT). These treatments provide unequivocal evidence that the depressive process can be rapidly reversed in a subgroup of patients. Seventeen ketamine studies in over 150 patients showed a rapid response. Low-dose intravenous ketamine produced mild psychotomimetic effects but response has not been effectively sustained. SDT has been investigated in over 60 studies with a 40–60% response rate within 48 h. Although SDT is often used in Europe to initiate a rapid response, it is less utilized within the USA, in part, because it has a short duration when administered alone. We review data concerning chronotherapeutic strategies of bright-light therapy (BLT) and sleep-phase advance (SPA) which successfully sustain the antidepressant efficacy of SDT. Evidence is further discussed that a significant group of mood disorders have abnormal circadian rhythms which are known to be controlled by clock genes. It is hypothesized that chronotherapeutic manipulations can reset clock genes and thus, abnormalities in circadian rhythms. Further findings are reviewed that ketamine, in addition to its role as an NMDA antagonist, can also alter circadian rhythms. Thus, ketamine may share a critical mechanism with SDT.

(Received February 21 2011)

(Reviewed March 31 2011)

(Revised April 21 2011)

(Accepted May 16 2011)

(Online publication July 07 2011)


c1 Address for correspondence: Dr B. G. Bunney, Department of Psychiatry, Med Sci I, D438, School of Medicine, University of California Irvine, Irvine, CA 92697. Tel.: 949-824-4242 Fax: 949-824-1787 Email: