Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program
In a naturalistic open‑label study of 185 adults with severe treatment‑resistant depression, twice‑weekly individually titrated oral esketamine for six weeks significantly reduced depressive symptoms (HDRS‑17 mean 21.2→15.8, p<0.001) with MCID 47.1%, response 26.8% and remission 15.6%, and a low dropout rate (7.6%). Treatment was generally well tolerated with frequent but manageable side effects and no significant urinary or cognitive adverse effects, suggesting oral esketamine is a safe, patient‑friendly option with effectiveness comparable to other administration routes.
Authors
- Robert Schoevers
- Jeanine Kamphuis
- Jolien Veraart
Published
Abstract
Background
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.
Aims
Here we present results from a relatively large naturalistic study to evaluate the effectiveness, tolerability, and safety of oral esketamine in patients with TRD.
Methods
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 (HDRS 17 ), Minimal Clinically Important Difference (MCID), response, remission, self-reported symptom improvement, functioning, and side effects.
Results
Oral esketamine treatment improved depressive symptom severity on the HDRS 17 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.
Conclusions
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.
Research Summary of 'Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program'
Introduction
Research on the antidepressant effects of ketamine and its S-enantiomer esketamine has predominantly focused on intravenous and intranasal routes of administration, both of which have demonstrated efficacy in treatment-resistant depression (TRD) but present significant barriers to widespread clinical implementation, including the need for specialist clinical settings, anaesthetic monitoring, and the requirement for supervised administration. Oral esketamine offers a potentially more accessible and cost-effective alternative, but prior studies in this modality have been limited to small samples — ranging from 1 to 80 participants — with relatively low levels of treatment resistance and limited comorbidity. This study aimed to assess the real-world effectiveness, safety, and tolerability of repeated twice-weekly oral esketamine in a large, clinically representative sample of patients with severe TRD treated under a compassionate use protocol across multiple centres.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Veraart, J. K., Smith-Apeldoorn, S. Y., van der Meij, A., Spijker, J., Schoevers, R. A., & Kamphuis, J. (2025). Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program. Journal of Psychopharmacology, 39(6), 559-570. https://doi.org/10.1177/02698811251332831
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