Rethinking the role of TRKB in the action of antidepressants and psychedelics.
Cecilia Anna Brunello, Cecilia Cannarozzo, Eero Castrén
Trends in Neurosciences November 1, 2024 DOI: 10.1016/j.tins.2024.08.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Depression Ketamine Neuroplasticity |
| Keywords | Bdnf Allosteric modulators Parvalbumin interneurons Psychopharmacology Mental health Depression treatment |
| Citations | 29 |
| Key points | Proposes that some antidepressants may directly bind to TRKB and allosterically potentiate BDNF signaling, and that activating TRKB in parvalbumin-containing interneurons disinhibits cortical networks and reactivates a juvenile-like plasticity window, which may underlie clinical antidepressant effects. |
Abstract
Antidepressant drugs promote neuronal plasticity, and activation of brain-derived neurotrophic factor (BDNF) signaling through its receptor neuronal receptor tyrosine kinase 2 (NTRK2 or TRKB) is among the critical steps in this process. These mechanisms are shared by typical slow-acting antidepressants, fast-acting ketamine, and psychedelic compounds, although the cellular targets of each drug differ. In this opinion article, we propose that some of these antidepressants may directly bind to TRKB and allosterically potentiate BDNF signaling, among other possible effects. TRKB activation in parvalbumin-containing interneurons disinhibits cortical networks and reactivates a juvenile-like plasticity window. Subsequent rewiring of aberrant networks, coupled with environmental stimuli, may underlie its clinical antidepressant effects. The end-to-end hypothesis proposed may stimulate the search for new treatment strategies.
Comparable studies
Other theoretical and historical papers on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper | |
| Arketamine for cognitive impairment in psychiatric disorders | 2023 | Theoretical or philosophical paper | |
| The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression | 2023 | Theoretical or philosophical paper | |
| Ketamine in Bipolar Disorder: A Review | 2020 | Theoretical or philosophical paper | |
| Off-label use of ketamine for treatment-resistant depression in clinical practice: European perspective. | 2019 | Theoretical or philosophical paper |
Citations in the library
Cited by 14
- Trends in research on novel antidepressant treatments. Frontiers in Pharmacology 2025
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- Therapeutic and Structural Dimensions in Psychiatric Prescribing: Bridging Psychedelics and Antidepressants. Harvard Review of Psychiatry
- Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies Biological Psychiatry February 1, 2026
- Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT2A receptor-independent mechanisms Neuropharmacology January 21, 2026
and 9 more in the library
Cites 29
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 24 more in the library