Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program.
Jolien Ke Veraart, Sanne Y Smith-Apeldoorn, Annemarie van der Meij, Jan Spijker, Robert A Schoevers, Jeanine Kamphuis
Journal of psychopharmacology (Oxford, England) April 25, 2025 DOI: 10.1177/02698811251332831
Summary
New hope emerges for people with severe treatment-resistant depression: Oral esketamine shows promising results in improving symptoms for nearly half of patients who hadn't responded to multiple previous treatments. In a breakthrough study of 185 adults, twice-weekly oral doses significantly reduced depression scores, with 47% showing meaningful improvement. The treatment proved safe and well-tolerated, with few dropouts.
Abstract
Oral esketamine for patients with treatment-resistant depression (TRD) could offer certain advantages over other routes, such as intravenous or intranasal, but it has not been systematically studied in a real-world setting. Here we present results from a relatively large naturalistic study to evaluate the effectiveness, tolerability, and safety of oral esketamine in patients with TRD. One hundred eighty-five adults with severe TRD (average of 8.1 antidepressant trials plus electroconvulsive therapy in 63% without beneficial outcome) received oral esketamine treatment twice-weekly for 6 weeks with individually titrated doses ranging from 0.5 to 3 mg/kg. Outcome measures included change from baseline to week 6 on the Hamilton Depression Rating Scale (HDRS17), Minimal Clinically Important Difference (MCID), response, remission, self-reported symptom improvement, functioning, and side effects. Oral esketamine treatment improved depressive symptom severity on the HDRS17 from 21.2 to 15.8 (p < 0.001). MCID, response, and remission rates were 47.1%, 26.8% and 15.6% respectively. In 45.9% of participants, treatment was continued after 6 weeks to maintain initial positive effects. Side effects were reported frequently but were overall well tolerated. The drop-out rate was 7.6%. We found no significant adverse effects associated with urinary tract or cognition. Repeated treatment with oral esketamine is effective in improving depressive symptom severity in highly treatment-resistant depressive patients. It is safe, well tolerated, and patient-friendly. Considering the level of treatment resistance, outcomes were in the range of studies investigating other routes of (es)ketamine administration.