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Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial.

Tse-Hwei Choo, Hanga C Galfalvy, John G Keilp, Ainsley K Burke, J John Mann, Michael F Grunebaum

Journal of Affective Disorders June 25, 2026 DOI: 10.1016/j.jad.2026.122175 (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 61
Population Suicidal depressed patients
Intervention Ketamine
Dose subanesthetic, intravenous
Duration 24 hours
Topics Depression Ketamine Esketamine
Keywords Cortisol Resilience Stress Suicide
Key findings Ketamine treatment produced a significant increase in waking cortisol 24 hours after infusion, but the correlation between this cortisol increase and reduction in suicidal ideation was small to medium and not statistically significant.

Abstract

Depression and its severe outcomes, suicidal ideation and behavior, are exacerbated by stress. A broad literature links dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) stress response system to depression, suicidal ideation and behavior. Our midazolam-controlled clinical trial of subanesthetic, intravenous ketamine infusion for suicidal depressed patients found rapid reduction in suicidal ideation within 24 h. Here we report on an exploratory aim of the trial to investigate relationships of treatment effect and clinical response to HPA axis function via saliva cortisol analysis. Saliva cortisol awakening response was measured at baseline/pre-infusion and 24 h after with samples obtained upon morning awakening and 30 min later. A significant increase in waking cortisol 24 h after ketamine treatment was observed (t(61) = -3.15, p = 0.0025). Baseline to post-infusion increase in waking cortisol had a small to medium, nonsignificant, correlation with decrease in SI (r = -0.25, p = 0.052). These preliminary results need to be replicated but are consistent with studies suggesting increases in cortisol, if not excessive or prolonged, may enhance stress-resilience.

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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