Breaking Sad: Unleashing the Breakthrough Potential of Ketamine's Rapid Antidepressant Effects

Preclinical Research The surprising results of a small clinical trial on the effects of low dose ketamine, a 65-year old anesthetic drug that is also used off-label for chronic pain and recreationally as a club drug, in eight depressed subjects unleashed the most significant advance in antidepressant drug development in decades. That study and subsequent ones have demonstrated that low dose, infused ketamine is able to induce a remission of depression in patients who have failed conventional medications, within 24 h. The apparent increased efficacy and rapid onset of effect of ketamine distinguish it from all other current antidepressant treatments. However, a single infusion of subanesthetic doses of ketamine produces benefits that typically last <3 weeks. The infusions are associated with a transient "psychedelic" experience and increased blood pressure that requires monitoring. There is also a theoretical potential to induce ketamine addiction. These features limit ketamine's ability to be a widely used treatment for depression and thus limit is ability to have a meaningful impact on the heavy morbidity and mortality associated with this disorder, despite its "breakthrough" rate of efficacy and speed of action. While growing numbers of clinicians are using ketamine to treat treatment resistant depression, many in the depression field believe that the aforementioned limiting aspects need to be separated from its remarkable therapeutic effects in order to unlock the breakthrough potential of this agent. To that end, drug development efforts have focused on various features of ketamine as targets for optimization including its modulation of the NMDA receptor, its pharmacokinetics, its chirality and its active metabolites including HNK (2R, 6R)-hyroxynorketamine. Drug Dev Res 77 : 489-494, 2016. © 2016 Wiley Periodicals, Inc.