Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia.
Samuel Kohtala, Tomi Rantamäki
Basic & Clinical Pharmacology & Toxicology August 1, 2021 DOI: 10.1111/bcpt.13598 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Keywords | Electroencephalogram Energy metabolism Protein phosphorylation Rapid-acting antidepressant Sleep |
| Key points | Proposes that rapid-acting antidepressants, including ketamine and nitrous oxide, share the ability to regulate TrkB signaling during homeostatically evoked slow-wave activity, which may be important for sustained antidepressant effects. |
Abstract
Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2 O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.
Comparable studies
Other theoretical and historical papers on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. | 2014 | Historical analysis | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Neuroscience and the Near-Death Experience: Roles for the NMSA-PCP receptor, the sigma receptor and the endopsychosins | 1990 | Theoretical or philosophical paper | |
| A unified model of ketamine's dissociative and psychedelic properties. | 2022 | Theoretical or philosophical paper | |
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper |
Citations in the library
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- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
- Do Psychedelics Change Beliefs? September 15, 2021
- Administration of low dose intranasal ketamine exerts a neuroprotective effect on whole brain irradiation injury model in wistar rats. Radiation and environmental biophysics August 1, 2024
- New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality. Expert Opinion on Pharmacotherapy March 1, 2024
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Cites 20
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- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
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and 15 more in the library