Rapid-Acting Antidepressants

Major depressive disorder (MDD) is a highly prevalent and debilitating illness and closely linked to suicide risk. Currently available antidepressants take weeks to work and have low remission rates; indeed, about a third of individuals with MDD fail to fully remit in response to these agents. Novel therapies that target the glutamatergic system, such as ketamine, offer rapid antidepressant effects as well as high remission rates, making them attractive therapeutic options. This chapter reviews the evidence for the antidepressant efficacy of several novel therapeutics (ketamine, esketamine, nitrous oxide, scopolamine, GLYX-13, and buprenorphine) as well as interventional techniques such as sleep deprivation. Notably, ketamine and esketamine also rapidly reduce suicidal thoughts, making them attractive solutions in an emergency setting. Because studying the rapid onset of antidepressant effects associated with these agents has also improved our understanding of the neurocircuitry and neural signaling systems underlying MDD, some pivotal drug trials using rodents, neuroimaging, and electrophysiological studies are also reviewed.