Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)
Maggie Fedgchin, Madhukar H. Trivedi, Ella Daly, Rama Melkote, Rosanne Lane, Pilar Lim, Dawn Vitagliano, Pierre Blier, Maurizio Fava, Michael R. Liebowitz, Arun Ravindran, Raphaël Gaillard, Hans van den Ameele, Sheldon H. Preskorn, Husseini Manji, David Hough, Wayne C. Drevets, Jaskaran Singh
The International Journal of Neuropsychopharmacology July 9, 2019 DOI: 10.1093/ijnp/pyz039 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Open-label Peer reviewed |
|---|---|
| Sample size | 346 |
| Population | Adults with moderate-to-severe depression and nonresponse to at least two antidepressants in the current episode |
| Interventions | Esketamine Placebo |
| Dose | 56 or 84 mg |
| Duration | 4-week intervention |
| Topics | Depression Esketamine |
| Citations | 593 |
| Registration | NCT02417064 |
| Key findings | Esketamine nasal spray added to an oral antidepressant did not significantly reduce depression scores compared to placebo plus antidepressant at 4 weeks, though the treatment effect exceeded what is considered clinically meaningful for approved antidepressants. |
Abstract
Background: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.
Methods: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.
Results: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.
Conclusions: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.
Trial Registration: ClinicalTrials.gov identifier: NCT02417064.
In the evidence
This study is part of the evidence base for 3 syntheses in the library. Here is how each one recorded it.
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Esketamine 84 mg plus antidepressant did not significantly reduce MADRS scores versus placebo plus antidepressant at 4 weeks, though the 56 mg comparison showed a nominal difference.
Synthesized
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Esketamine 84 mg plus antidepressant did not significantly reduce MADRS versus placebo plus antidepressant at 4 weeks (difference -3.2, P=.088).
Synthesized
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State of the evidence: Esketamine No effect
Esketamine 84 mg plus an oral antidepressant did not significantly reduce depression scores versus placebo plus antidepressant at 4 weeks, although the 56 mg dose showed a nominal difference.
Synthesized
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.
Citations in the library
Cited by 247
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- 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
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
- Intravenous arketamine for treatment-resistant depression: open-label pilot study European Archives of Psychiatry and Clinical Neuroscience February 20, 2020
and 242 more in the library
Cites 7
- 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
- Measurement of dissociative states with the Clinician‐Administered Dissociative States Scale (CADSS) Journal of Traumatic Stress 1998
- 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
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
and 2 more in the library