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Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors.

Rachael Sumner, Rebecca McMillan, Meg J. Spriggs, Doug Campbell, Gemma Malpas, Elizabeth A. Maxwell, Carolyn Deng, John Hay, Rhys Ponton, Frederick Sundram, Suresh Muthukumaraswamy

European Neuropsychopharmacology September 2020 DOI: 10.1016/j.euroneuro.2020.07.009 (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 30
Population Patients with major depressive disorder
Interventions Ketamine Remifentanil
Dose 0.44 mg/kg intravenous ketamine; remifentanil infused to a target plasma concentration of 1.7 ng/mL
Duration EEG run 3-4 hours after dosing; antidepressant response assessed at 24 hours
Measures Montgomery-Asberg Depression Rating Scale (MADRS), mismatch negativity (MMN), P3a event-related potentials, dynamic causal modelling
Topics Depression Esketamine Ketamine
Keywords Dynamic causal modelling EEG Mmn Predictive coding
Key findings Ketamine increased MMN and P3a event-related potentials and enhanced forward connectivity between right primary auditory cortex and right inferior temporal cortex, which correlated with antidepressant response at 24 hours. The authors argue this supports the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores prediction-error sensitivity deficits in depression, but the lack of repetition suppression suggests it does not improve adaptive internal model calibration in the short term.

Abstract

Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration.

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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