Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors.
Rachael L Sumner, Rebecca McMillan, Meg J Spriggs, Doug Campbell, Gemma Malpas, Elizabeth Maxwell, Carolyn Deng, John Hay, Rhys Ponton, Frederick Sundram, Suresh D Muthukumaraswamy
European Neuropsychopharmacology September 2020 DOI: 10.1016/j.euroneuro.2020.07.009 (opens in new tab)
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, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| 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 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |