Neurotrophic Factors and Antidepressant Mechanisms in Mood Disorders

Neurotrophic factors are a family of proteins that regulate neuronal survival, growth and synaptic plasticity across the lifespan. Among these, brain-derived neurotrophic factor (BDNF) has emerged as a central mediator of mood regulation, acting through its high-affinity receptor tropomyosin receptor kinase B (TrkB) to modulate dendritic spine formation, long-term potentiation and network connectivity in the hippocampus, prefrontal cortex and other limbic structures. In major depressive disorder and related conditions, BDNF expression and TrkB signalling are consistently reduced, correlating with structural atrophy and impaired synaptic function. Traditional monoaminergic antidepressants require weeks of administration to upregulate BDNF and restore plasticity, whereas novel fast-acting agents such as ketamine and certain psychedelics trigger rapid TrkB-dependent synaptic remodelling. Converging evidence indicates that neurotrophic enhancement underlies both symptom relief and resilience, reinstating a juvenile-like window of cortical flexibility. Ongoing research seeks to delineate how distinct drugs allosterically modulate TrkB, influence interneuron subtypes and interact with perineuronal nets to promote enduring rewiring of mood-related circuits. A clearer understanding of neurotrophin-based mechanisms promises new targets for precision therapies and may explain individual differences in treatment response.

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Neurotrophic Factors and Antidepressant Mechanisms in Mood Disorders publication trend

The graph below shows the total number of articles in neurotrophic factors and antidepressant mechanisms in mood disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Brain-derived neurotrophic factor (BDNF): A neurotrophin essential for neuronal survival, differentiation and synaptic plasticity in mood-regulating circuits.

Tropomyosin receptor kinase B (TrkB): The high-affinity receptor for BDNF that activates intracellular cascades governing plasticity and resilience.

Neuroplasticity: The capacity of neural circuits to change structurally and functionally in response to experience, injury or pharmacological agents.

Critical period-like plasticity (iPlasticity): A reinstated developmental-stage window in adult brain allowing heightened synaptic remodelling upon neurotrophic stimulation.

Perineuronal net (PNN): A specialised extracellular matrix that modulates synaptic stability around certain interneurons and is dynamically regulated during plasticity.

References

1. Rethinking the role of TRKB in the action of antidepressants and psychedelics. Trends in Neurosciences (2024).
2. Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. International Journal of Molecular Sciences (2024).
3. Mutation in the TRKB Cholesterol Recognition Site that blocks Antidepressant Binding does not Influence the Basal or BDNF-Stimulated Activation of TRKB. Cellular and Molecular Neurobiology (2023).
4. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell (2021).
5. Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action. Biological Psychiatry (2021).