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.