Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension.
Sanne Y Smith-Apeldoorn, Jolien K E Veraart, Jeanine Kamphuis, Jan Spijker, Annemarie van der Meij, Antoinette D I van Asselt, Marije Aan Het Rot, Robert A Schoevers
Molecular Psychiatry September 1, 2024 DOI: 10.1038/s41380-024-02478-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized placebo-controlled trial with open-label extension Double-blind Peer reviewed |
|---|---|
| Sample size | 111 |
| Population | Patients with treatment-resistant depression |
| Intervention | oral esketamine |
| Dose | 30 mg three times a day (fixed low-dose phase); 0.5 to 3.0 mg/kg two times a week (open-label individually titrated phase) |
| Duration | Six-week fixed low-dose treatment phase, four-week wash-out, and six-week open-label individually titrated treatment phase |
| Topics | Depression Esketamine Ketamine |
| Keywords | Depression treatment Personalized medicine Esketamine therapy Psychiatric research |
| Citations | 23 |
| Key findings | Fixed low-dose oral esketamine (30 mg three times daily) showed no benefit over placebo for depressive symptoms, but individually titrated higher doses (0.5–3.0 mg/kg twice weekly) were associated with a significant reduction in symptom severity. |
Abstract
About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.
Citations in the library
Cited by 20
- Royal Australian and New Zealand College of Psychiatrists professional practice guidelines for the use of ketamine in psychiatric practice. Australian & New Zealand Journal of Psychiatry April 28, 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 April 25, 2025
- Comparative safety and tolerability of ketamine and esketamine for major depressive disorder: a systematic review and meta-analysis. Frontiers in Pharmacology 2025
- Plasma esketamine and noresketamine levels and antidepressant response with oral esketamine treatment. European Journal of Pharmacology July 5, 2025
- Auto-Induction in Oral Esketamine Treatment for Treatment-Resistant Depression: An Exploratory Study. Pharmaceuticals April 25, 2025
and 15 more in the library
Cites 24
- 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
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
- Blinding and expectancy confounds in psychedelic randomized controlled trials Expert Review of Clinical Pharmacology May 26, 2021
- Intravenous arketamine for treatment-resistant depression: open-label pilot study European Archives of Psychiatry and Clinical Neuroscience February 20, 2020
and 19 more in the library