In a phase 3 trial of 346 adults with moderate-to-severe treatment-resistant depression, adding esketamine nasal spray (56 or 84 mg twice weekly) to a new oral antidepressant for 4 weeks did not significantly reduce depression scores compared to adding placebo nasal spray. The 84 mg dose failed to separate from placebo on the primary outcome, and the 56 mg dose could not be formally tested due to the statistical hierarchy. However, the magnitude of improvement with both esketamine doses exceeded what is typically considered clinically meaningful for approved antidepressants. Common side effects included nausea, dissociation, dizziness, vertigo, and headache. The authors conclude the results provide supportive evidence for esketamine's safety and efficacy in treatment-resistant depression.
This column reviews the development of intranasal esketamine, focusing on the consistency of clinical trial results. It illustrates methodological issues important to the U.S. Food and Drug Administration approval process, including study design, the nature of the comparator, and the prespecified statistical analysis plan. The column discusses what constitutes a positive versus a supportive study, differences between phase 2 and phase 3 studies, and the rationale for including both in development. While especially relevant to intranasal esketamine, it also serves as a general example of drug development and approval.
Intravenous racemic ketamine, which contains both R-ketamine and S-ketamine (esketamine), is not yet FDA-approved for treatment-resistant major depressive disorder. The FDA's typical drug approval process requires three phases: normal volunteer studies, small-scale proof-of-concept trials, and large-scale registration trials that establish efficacy, safety, and tolerability in real-world clinical use. While small academic studies and clinical use abroad supported the unique value of lithium and clozapine for bipolar disorder and treatment-resistant schizophrenia, leading to advocacy and eventual registration trials, comparable registration trials for intravenous racemic ketamine remain to be done. Safety concerns addressed in esketamine's registration trials have not been similarly studied for intravenous racemic ketamine.