Rapid Antidepressant Mechanisms in Mood Disorders
Summary
Mood disorders such as major depressive disorder and bipolar depression impose a substantial global burden and often respond slowly to conventional monoaminergic treatments. In contrast, a growing body of evidence has demonstrated that interventions targeting glutamatergic and cholinergic systems can elicit symptomatic relief within hours to days. These rapid-acting approaches converge on intracellular signalling cascades that drive synaptic protein synthesis and structural remodelling, notably via mammalian target of rapamycin (mTOR) activation and dephosphorylation of elongation factors. At the circuit level, enhanced synaptogenesis in prefrontal cortical and hippocampal networks restores excitatory–inhibitory balance, while modulation of specific interneuronal subtypes refines local inhibition. Key molecular effectors include brain-derived neurotrophic factor (BDNF), postsynaptic density proteins and regulators of translation initiation. Translational studies in stress-exposed rodents and early-phase clinical trials have confirmed that antagonism of N-methyl-D-aspartate (NMDA) receptors or muscarinic acetylcholine receptors accelerates plasticity-dependent processes underlying mood improvement. These discoveries have opened new therapeutic avenues that may reduce morbidity, improve functional recovery and inform precision medicine strategies in depression management.
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Rapid Antidepressant Mechanisms in Mood Disorders publication trend
The graph below shows the total number of articles in rapid antidepressant mechanisms in mood disorders across all publications each year (not limited to Nature Index journals).
Technical terms
eEF2 dephosphorylation: removal of a phosphate group from eukaryotic elongation factor 2, enabling increased protein synthesis at synapses.
mTORC1 signalling: activation of the mammalian target of rapamycin complex 1, a kinase hub that promotes translation of proteins critical for synaptic growth.
M2-AChR: the muscarinic acetylcholine receptor subtype 2, which modulates neuronal excitability and neurotrophic signalling in cortical circuits.
GABAergic interneuron: an inhibitory neuron that releases γ-aminobutyric acid to shape the timing and strength of cortical network activity.
Synaptogenesis: the formation of new synaptic connections, a process essential for structural and functional plasticity underlying sustained mood improvement.
References
- Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation. Pharmacological Reports (2024).
- M2-AChR Mediates Rapid Antidepressant Effects of Scopolamine Through Activating the mTORC1-BDNF Signaling Pathway in the Medial Prefrontal Cortex. Frontiers in Psychiatry (2021).
- Cell-type-specific synaptic modulation of mAChR on SST and PV interneurons. Frontiers in Psychiatry (2023).
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