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Oral ketamine for rapid reduction of suicidal ideation in major depressive disorder: A midazolam-controlled randomized clinical trial.

Asif Seraj, Mohammed Reyazuddin, R K Gaur, Chittaranjan Andrade

Asian Journal of Psychiatry April 1, 2025 DOI: 10.1016/j.ajp.2025.104413 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled trial Peer reviewed
Sample size 80
Population Adult patients with major depressive disorder and expressed suicidal ideation
Interventions Oral racemic ketamine Oral midazolam
Dose 3 mg/kg (mean 180 mg) for ketamine; 0.3 mg/kg (mean 1.8 mg) for midazolam
Duration Single session, assessed at 4 hours post-treatment (Day 1) and on Days 3 and 7
Topics Depression Esketamine Ketamine
Keywords Adverse effects Midazolam Oral ketamine Randomized controlled trial Suicidal ideation Depression treatment Suicide prevention Clinical research Psychiatric medication Drug safety
Citations 11
Key findings Oral racemic ketamine produced significantly greater reductions in suicidal ideation and depression than oral midazolam at multiple time points, with no treatment-limiting adverse effects.

Abstract

The simplest, most convenient, and least expensive way to treat depressed and suicidal patients with ketamine is to administer racemic ketamine by the oral route. We describe the first active-controlled randomized clinical trial of oral racemic ketamine for suicidal ideation associated with depression. Adult patients with major depressive disorder and expressed suicidal ideation were randomized to receive a single session of oral racemic ketamine (3 mg/kg; n = 40) or oral midazolam (0.3 mg/kg; n = 40). Suicidal ideation was rated using the Modified Scale for Suicidal Ideation (MSSI) and depression, using the 17-item Hamilton Rating Scale for Depression (HAM-D). Patients were assessed 4 h post-treatment (Day 1) and on Days 3 and 7. Mean doses were 180 mg and 1.8 mg for ketamine and midazolam, respectively. MSSI scores were significantly lower in the ketamine group at all assessment points: 4 h, Day 3, and Day 7. HAM-D scores were significantly lower in the ketamine group at 4 h and on Day 3. The study-defined HAM-D response and remission rates were 25 % vs 0 % and 5 % vs 0 % in ketamine vs midazolam groups on Day 7. Nausea/vomiting, lightness of body, emotional disturbance (anxiety or crying), and depersonalization/derealization were significantly more frequent in the ketamine group; however, no patient considered these to be of treatment-limiting severity. Oral racemic ketamine is a reasonably well-tolerated and rapidly effective intervention for suicidal ideation and depression in adults with major depressive disorder.

Comparable studies

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

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
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

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