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Triple-network model-based graph theory analysis of the effectiveness of low-dose ketamine in patients with treatment-resistant depression: two resting-state functional MRI clinical trials.

Wei-Chen Lin, Li-Kai Cheng, Tung-Ping Su, Li-Fen Chen, Pei-Chi Tu, Cheng-Ta Li, Ya-Mei Bai, Shih-Jen Tsai, Mu-Hong Chen

The British Journal of Psychiatry April 2, 2025 DOI: 10.1192/bjp.2025.14 (opens in new tab)

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AI-extracted from the abstract
Characteristics Secondary analysis of two randomized controlled trials Peer reviewed
Population Patients with treatment-resistant depression; one trial included those with pronounced suicidal symptoms
Interventions ketamine normal saline midazolam
Dose 0.05 mg/kg ketamine, 0.045 mg/kg midazolam
Duration Single infusion, with imaging pre and post infusion at Day 3
Topics Depression Ketamine Esketamine
Keywords Triple-network model Graph theory Resting-state functional connectivity Ketamine therapy Brain connectivity Neuroscience research Mental health treatment
Citations 2
Key findings Low-dose ketamine altered functional connectivity measures in the default mode, salience, and frontoparietal networks in patients with treatment-resistant depression.

Abstract

Evidence suggests the crucial role of dysfunctional default mode (DMN), salience and frontoparietal (FPN) networks, collectively termed the triple network model, in the pathophysiology of treatment-resistant depression (TRD). Using the graph theory- and seed-based functional connectivity analyses, we attempted to elucidate the role of low-dose ketamine in the triple networks, namely the DMN, salience and FPN. Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) data derived from two previous clinical trials of a single, low-dose ketamine infusion were analysed. In clinical trial 1 (Trial 1), patients with TRD were randomised to either a ketamine or normal saline group, while in clinical trial 2 (Trial 2) those patients with TRD and pronounced suicidal symptoms received a single infusion of either 0.05 mg/kg ketamine or 0.045 mg/kg midazolam. All participants underwent rs-fcMRI pre and post infusion at Day 3. Both graph theory- and seed-based functional connectivity analyses were performed independently. Trial 1 demonstrated significant group-by-time effects on the degree centrality and cluster coefficient in the right posterior cingulate cortex (PCC) cortex ventral 23a and b (DMN) and the cluster coefficient in the right supramarginal gyrus perisylvian language (salience). Trial 2 found a significant group-by-time effect on the characteristic path length in the left PCC 7Am (DMN). In addition, both ketamine and normal saline infusions exerted a time effect on the cluster coefficient in the right dorsolateral prefrontal cortex a9-46v (FPN) in Trial 1. These findings may support the utility of the triple-network model in elucidating ketamine's antidepressant effect. Alterations in DMN, salience and FPN function may underlie this effect.

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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