In adults with treatment-resistant depression who had not responded to at least two prior oral antidepressants, esketamine nasal spray taken alone (without an oral antidepressant) reduced depressive symptoms more than a placebo. Over four weeks, both a 56 mg and an 84 mg dose of esketamine produced significantly greater improvements on the Montgomery-Åsberg Depression Rating Scale than placebo, with effects apparent as early as 24 hours after the first dose. Common side effects included nausea, dissociation, dizziness, and headache. The findings suggest that esketamine monotherapy could offer a new treatment option for patients who cannot tolerate or do not respond to oral antidepressants.
In a phase 2b trial, adolescents aged 12 to 17 with major depressive disorder at imminent risk for suicide received either esketamine nasal spray (28, 56, or 84 mg) or a psychoactive placebo (oral midazolam) twice weekly for four weeks, alongside standard care including hospitalization, an antidepressant, and psychotherapy. Pooled esketamine doses (56 and 84 mg) reduced depressive symptoms more than midazolam at 24 hours after the first dose, though individual doses did not reach statistical significance. Suicidality severity improved across all groups. Common side effects included dizziness, nausea, and dissociation.