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Symptom-level and network analyses of ketamine treatment in treatment-resistant depression: A pooled analysis of two randomized controlled trials.

Kuan-I Liu, Wei-Chen Lin, Cheng-Ta Li, Ya-Mei Bai, Tung-Ping Su, Mu-Hong Chen

Progress in neuro-psychopharmacology & biological psychiatry September 26, 2026 DOI: 10.1016/j.pnpbp.2026.111950 (opens in new tab)

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AI-extracted from the abstract
Characteristics Post hoc analysis of pooled randomized controlled trials Peer reviewed
Sample size 132
Population Adults with treatment-resistant depression
Intervention Ketamine
Dose 0.5 mg/kg
Measures Montgomery-Åsberg Depression Rating Scale (MADRS)
Topics Depression Ketamine Esketamine
Keywords Network intervention analysis Symptom network
Key findings Ketamine produced broad early improvement across depression symptoms, with adjusted control-minus-ketamine differences at 240 minutes of about 1.1 points on apparent sadness, pessimistic thoughts, and suicidal thoughts, and all four symptom domains differing at 240 minutes and day 2. Symptom network global strength increased from 3.38 to 4.47 without a detected structural difference, but the authors state the exploratory network associations were sensitive to reporting thresholds and did not establish symptom-specific mechanisms.

Abstract

We examined symptom-level treatment effects and exploratory symptom networks after ketamine in treatment-resistant depression. This post hoc analysis pooled 132 participants assigned to ketamine 0.5 mg/kg or protocol-specific control (66 each) from saline-controlled 2017 and midazolam-controlled 2023 trials. Baseline- and trial-adjusted models assessed Montgomery-Åsberg Depression Rating Scale (MADRS) items and four literature-derived domains with false discovery rate (FDR) correction. Sensitivity analyses included trial-specific models and mixed models for repeated measures. Ketamine-arm Gaussian graphical models compared baseline with day 2. Treatment-node Network Intervention Analysis (NIA) estimated conditional associations; item-edge reporting required full-sample selection and at least 50% bootstrap selection. At 240 min, 9/10 items met the FDR criterion. Adjusted control-minus-ketamine differences were 1.09 (95% confidence interval 0.65-1.54) for apparent sadness, 1.09 (0.64-1.54) for pessimistic thoughts, and 1.10 (0.68-1.52) for suicidal thoughts. All four domains met the criterion at 240 min and day 2. Global strength increased from 3.38 to 4.47 (median permutation p = 0.024), with no detected structure difference (p = 0.433); baseline edge stability was limited. NIA retained nine edges at 50%, four at 60%, and two at 75%, the latter involving apparent sadness at days 3 and 7. Ketamine showed broad early symptom improvement. Exploratory network associations were sensitive to reporting thresholds and did not establish symptom-specific mechanisms. UMIN000016985, UMIN000033916 and UMIN000033760.

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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