Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype - a placebo controlled fMRI study.
Thomas Liebe, Meng Li, Lejla Colic, Matthias H. J. Munk, Catherine M Sweeney-Reed, Marie Woelfer, Moritz Kretzschmar, Johann Steiner, Felicia Von Düring, Gusalija Behnisch, Björn H Schott, Martin Walter
NeuroImage: Clinical 2018 DOI: 10.1016/j.nicl.2018.09.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, randomized, placebo-controlled study Peer reviewed |
|---|---|
| Sample size | 59 |
| Population | Healthy participants (mean age 25.57 ± 4.72) |
| Intervention | Ketamine |
| Dose | 0.5 mg/kg |
| Duration | One hour after injection (single dose) |
| Measures | resting state functional connectivity (rs-fc) |
| Topics | Ketamine Esketamine |
| Keywords | Attention networks Locus coeruleus lc Norepinephrine transporter net Pharmacogenetics |
| Key points | A single subanesthetic dose of ketamine (0.5 mg/kg) decreased resting-state functional connectivity between the locus coeruleus and several thalamic nuclei one hour after administration compared with baseline. The reduction was larger in NET rs28386840 [AA] homozygous participants than in [T] carriers. The authors propose these changes may relate to ketamine's antidepressant effects on arousal regulation networks. |
Abstract
Ketamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI. Fifty-nine healthy participants (mean age 25.57 ± 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840). A significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers. We demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression.
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 |
Citations in the library
Cited by 12
- Rodent ketamine depression-related research: Finding patterns in a literature of variability Behavioural Brain Research August 13, 2019
- Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions International Journal of Molecular Sciences October 26, 2020
- Ketamine induces multiple individually distinct whole-brain functional connectivity signatures. Elife April 17, 2024
- Suicide prevention and ketamine: insights from computational modeling Frontiers in Psychiatry June 30, 2023
- Perspectives in treatment-resistant depression: esketamine and electroconvulsive therapy. Wiener klinische Wochenschrift March 1, 2025
and 7 more in the library
Cites 16
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
and 11 more in the library