Skip to content

Non-inferiority, comparative effectiveness study of intravenous ketamine v. intranasal esketamine for treatment-resistant depression: The EQUIVALENCE trial protocol.

Samuel T. Wilkinson, Sandhya Prashad, Rachel Dalthorp, Lisa Harding, Brandon Kitay, Sagar V Parikh, James Dziura, Ashley Clayton, Geena Fram, Valerie Lepoutre, Julianna Brown, Robert Ostroff, Gerard Sanacora

Contemporary Clinical Trials March 2, 2026 DOI: 10.1016/j.cct.2026.108273 (opens in new tab)

Relevant Not relevant

Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled non-inferiority trial protocol Peer reviewed
Sample size 400
Population Patients with treatment-resistant depression
Interventions Ketamine Esketamine
Duration 8 treatments over a 4-week period
Measures Quick Inventory of Depressive Symptomatology (QIDS)
Topics Ketamine Depression Esketamine
Keywords Humans Antidepressive agents Administration, intranasal Research design Adult Middle aged Female Depressive disorder, treatment-resistant Administration, intravenous
Citations 1
Key findings The EQUIVALENCE trial will test whether intravenous ketamine racemate is non-inferior to intranasal esketamine for treatment-resistant depression, using a 1.6-point QIDS non-inferiority margin in 400 patients. If non-inferiority is shown, a subsequent test will examine superiority. The authors state results will have implications for patient choice, health insurance coverage, and clinical care.

Abstract

Ketamine is a powerful and rapid-acting antidepressant but has no regulatory authorization for any psychiatric illness. The S-enantiomer of ketamine, esketamine, was approved by the FDA in 2019 as adjunctive therapy for treatment-resistant depression. Substantial controversy exists as to whether there is a significant clinical difference between intravenous (IV) ketamine racemate and intranasal esketamine. The EQUIVALENCE protocol will directly compare these therapies for treatment-resistant depression (TRD). Patients with TRD are randomized (1:1) to receive 8 treatments of IV ketamine or IN esketamine over a 4-week period. The primary outcome is change in depression severity as measured by a patient-reported outcome, the Quick Inventory of Depressive Symptomatology (QIDS) after 4 weeks of treatment. The study is designed as a non-inferiority study, with the FDA-approved therapy, esketamine, considered the standard. With a sample size of 400 total (200 per group), the study is powered to declare non-inferiority within a margin of 1.6 on the QIDS. If IV ketamine is found to be non-inferior to esketamine, a subsequent statistical test will examine whether ketamine is superior. Secondary outcomes include response and remission rates, anxiety severity, quality of life, and patient satisfaction, acceptability, and tolerability. We will also examine whether TRD with anxious distress responds differentially to one treatment or the other and the role that patient preference plays in outcomes. Results of the EQUIVALENCE study will have important implications for patient choice, health insurance coverage policies, and clinical care for TRD.

Comparable studies

Other randomized controlled trials on esketamine for depression, most cited first.

Study Year Design Participants
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 Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
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 Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68
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) Adults with moderate-to-severe depression and nonresponse to at least two... 2019 Randomized controlled trial n = 346

Citations in the library

Cited by 2

Cites 22

and 17 more in the library

Related reading

Explore topics

Ketamine Depression Esketamine Anxiety

By condition and practice

Esketamine for depression Ketamine for depression