Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions.

Numerous new agents with rapid onset antidepressant effects are entering clinical trials and clinical practice. Studies focus on either first-line treatment of major depressive disorder or on patients whose major depressive disorder is resistant to prior antidepressant drugs. Novel agents target three very different central nervous system sites: as antagonists of N -methyl-d-aspartate (NMDA) glutamate receptors, as positive allosteric modulators (PAMs) of gamma amino butyric acid (GABA) A neurosteroid and benzodiazepine receptor sites, and as psychedelic agonists of serotonin 2A/2C receptors. Onset of antidepressant action is rapid, sometimes after only one dose whereas traditional agents for depression take several days to weeks to have an antidepressant effect. Although the direct molecular targets of these three classes of agents with rapid antidepressant onset are quite diverse and not clearly related to each other, analysis of the downstream effects of all these agents show that all are "plastogens," namely agents that trigger rapid onset of neuroplasticity that correlates with their rapid onset of antidepressant clinical action. The GABA A PAMs and some of the NMDA antagonists induce neuroplasticity without notable changes in mental status and can be designated "neuroplastogens." Some NMDA antagonists cause mental dissociation, and the psychedelics cause psychotomimetic/hallucinatory experiences and can be designated "psychoplastogens." A great debate exists whether psychoplastogens are effective because of their ability to acutely alter mental state, or whether these acute mental states are unwanted behavioral toxicity. The promise of numerous novel agents with rapid acting antidepressant action and neuroplasticity is set to transform the treatment of major depressive disorder.