![]() ![]() The RAAD literature has also expanded with the evaluation of other agents that target NMDAR antagonism, most notably the recent US Food and Drug Administration (FDA) approval of esketamine, the S-enantiomer of ketamine, as an adjunctive treatment for TRD 16 and for adults with major depression with acute suicidal ideation or behavior. ![]() Critically, ketamine has also been linked to the rapid alleviation of suicidal thoughts 14, a particularly important unmet need given that suicide rates continue to rise in the United States and worldwide 15. Although its immediate antidepressant effects were only observed two decades ago 4, the literature has since expanded with evidence of its efficacy in individuals with TRD 2, 5, 6, 7, bipolar depression 8, 9, post-traumatic stress disorder (PTSD) 10, obsessive-compulsive disorder 11, social anxiety disorder 12, and substance dependence 13. Over the last half-century, it has been in widespread, global use as an anesthetic. However, ketamine has less potent psychotomimetic and dissociative effects than PCP, a wider anesthetic safety window, and a shorter half-life 3. Ketamine was originally synthesized as an alternative to phencyclidine (PCP) 3. In contrast, ketamine is associated with rapid improvements in depressive symptoms that occur within minutes to hours (i.e., an immediate-response window), with the largest effect sizes observed within 1 day 2. Traditional antidepressants have a lag of onset that lasts weeks to months (i.e., a slow-response window) and limited efficacy for treatment-resistant depression (TRD) and bipolar depression. In this context, the N-methyl-D-aspartate receptor (NMDAR) antagonist ( R,S)-ketamine (ketamine) and other next-generation rapid-acting antidepressants (RAADs) represent a new frontier for psychiatric research. The onset of antidepressant treatment response has recently been proposed to occur in three time periods: an immediate-response window of 1 to 2 days a rapid-response window of up to 1 week and a slow-response window of more than 1 week 1.
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