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 via PubMed
Summary
AI-generated from the abstractA randomized placebo-controlled trial tested whether a fixed low dose of oral esketamine (30 mg three times daily) could reduce depression severity in patients with treatment-resistant depression. Over six weeks, the drug showed no benefit compared to placebo on the Hamilton Depression Rating Scale. Dizziness and sleep hallucinations were more common with esketamine. In an open-label extension phase where doses were individually titrated up to 3.0 mg/kg twice weekly, depressive symptoms decreased substantially. The findings suggest that fixed low-dose oral esketamine is ineffective, but individually adjusted higher doses may hold promise for treatment-resistant depression.
Study at a glance
| 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 |
| Keywords | Depression treatment Personalized medicine Esketamine therapy Psychiatric research |
| Citations | 23 |
| Key finding | 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.