Intranasal ketamine and esketamine offer a rapid onset of antidepressant effects within hours for people with major depressive disorder, particularly those with treatment-resistant depression or active suicidal thoughts. A systematic review following PRISMA guidelines found stronger evidence of efficacy for intranasal esketamine than for intranasal ketamine. The safety profile of intranasal esketamine appears acceptable, though further studies are needed; a more accurate delivery device is required for ketamine. These glutamatergic agents bypass the blood–brain barrier, potentially reducing side effects compared with intravenous administration.
Patients with treatment-resistant depression who received esketamine nasal spray experienced 43.2% more weeks with functional remission over 32 weeks compared to those taking quetiapine extended release, a difference of 2.0 weeks. Esketamine also led to an 11.9% reduction in productivity loss due to absenteeism and a 14.2% reduction in overall work productivity loss. Both treatments were taken alongside an ongoing SSRI or SNRI. The findings suggest that esketamine provides greater improvements in daily functioning and workplace productivity for this patient group.
In people with treatment-resistant depression, esketamine nasal spray outperformed quetiapine extended release across multiple measures. Sensitivity analyses using different definitions of remission and relapse consistently favored esketamine, with relative risks for the primary endpoint ranging from 1.462 to 1.737 and for the key secondary endpoint from 1.417 to 1.838. Esketamine also shortened time to first remission by 71% and confirmed remission by 66%. The robustness of the original ESCAPE-TRD trial findings was confirmed.