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 April 25, 2025 DOI: 10.1177/02698811251332831 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Naturalistic study Open-label Peer reviewed |
|---|---|
| Sample size | 185 |
| Population | Adults with severe treatment-resistant depression |
| Intervention | Oral esketamine |
| Dose | 0.5 to 3 mg/kg |
| Duration | 6-week intervention |
| Topics | Depression Esketamine Ketamine |
| Keywords | Oral esketamine Real-world effectiveness Mental health treatment Clinical research |
| Citations | 6 |
| Key points | Oral esketamine treatment improved depressive symptom severity in highly treatment-resistant patients, with outcomes comparable to other routes of ketamine administration. |
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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cited by 5
- Auto-Induction in Oral Esketamine Treatment for Treatment-Resistant Depression: An Exploratory Study. Pharmaceuticals April 25, 2025
- Oral Esketamine as Alternative for Maintenance Electroconvulsive Therapy in Patients With Treatment-Resistant Depression: A Case Series. The Journal of ECT January 21, 2025
- The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine. The pharmacogenomics journal April 24, 2026
- Comparison of average time-to-relapse following ECT versus ketamine - A systematic review. Journal of Psychopharmacology April 16, 2026
- Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial. Journal of Affective Disorders July 16, 2026
Cites 49
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- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
and 44 more in the library