Neurobiological Mechanisms in Treatment-Resistant Depression

Treatment-resistant depression (TRD) poses a significant challenge to global mental health, characterised by persistent symptoms despite multiple therapeutic trials. Neurobiological investigations have uncovered convergent mechanisms underlying this refractoriness. Abnormal glutamatergic neurotransmission, notably dysregulation of N-methyl-D-aspartate receptors, disrupts synaptic plasticity in the prefrontal cortex and hippocampus. Concurrent deficits in brain-derived neurotrophic factor signalling compromise dendritic spine density and structural connectivity. Neuroinflammatory cascades, driven by activated microglia and elevated cytokine levels, further impair synaptic function and may attenuate treatment effects. Alterations in GABAergic interneuron activity lead to cortical disinhibition, exacerbating circuit dysfunction. Emerging evidence implicates the gut–microbiota–brain axis in modulating neurotrophic and inflammatory pathways, adding a peripheral dimension to central pathology. Plasticity-related signalling networks, including mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase pathways, have been linked to rapid antidepressant responses, suggesting pharmacological strategies that restore these cascades may overcome traditional resistance. Together, these interrelated mechanisms form a multi-layered framework that informs novel therapeutic targets, from molecular receptors to systemic microbial interactions, offering hope for more effective interventions in TRD.

Research from Nature Portfolio

A comparative study in rodent models demonstrated that the R-enantiomer of ketamine, but not a structurally related NMDA receptor antagonist, reversed chronic stress–induced dysbiosis of gut microbial communities and produced rapid, sustained antidepressant-like effects. These findings spotlight the gut–brain microbiota axis as a crucial modulator of treatment response in resistant depression.

Neurobiological Mechanisms in Treatment-Resistant Depression publication trend

The graph below shows the total number of articles in neurobiological mechanisms in treatment-resistant depression across all publications each year (not limited to Nature Index journals).

Technical terms

N-methyl-D-aspartate receptor (NMDAR): A glutamate-gated ion channel central to excitatory synaptic transmission and plasticity.

Brain-derived neurotrophic factor (BDNF): A neurotrophin that supports neuron survival, synaptic growth and adaptive plasticity.

Synaptogenesis: The process of forming new synapses between neurons, critical for network remodelling.

Neuroinflammation: Activation of immune pathways within the central nervous system, often via microglia, that can impair synaptic function.

Microbiota–brain axis: The bidirectional communication network linking gut microbial ecosystems to central nervous system processes.

References

1. S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2. Advanced Science (2025).
2. Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota–brain axis. Gut Microbes (2024).
3. GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents. Neuropsychopharmacology (2024).
4. Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model. Scientific Reports (2017).