Molecular Mechanisms of Emerging Antidepressant Strategies: From Ketamine to Neuromodulation

Author: mycolabadmin
12/28/2025
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Summary

Depression is a serious mental health condition affecting over 300 million people worldwide, with many patients not responding well to standard antidepressants. This review examines both traditional antidepressants like SSRIs and exciting new treatments including ketamine and psilocybin, as well as brain stimulation techniques. The key finding is that different treatments work through similar mechanisms—all ultimately enhancing brain cell connections and reducing inflammation—suggesting that combining different approaches might work better than single therapies.

Background

Depression affects approximately 322 million individuals globally and represents a major challenge in contemporary medicine. The pathophysiology involves complex dysregulation of multiple systems including HPA axis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity. Current antidepressant therapies have significant limitations including delayed onset, adverse effects, and treatment resistance in a substantial subset of patients.

Objective

To provide a comprehensive, mechanistically integrated review of emerging antidepressant strategies and neuromodulation techniques in the context of current depression pathophysiology. The review synthesizes data on novel pharmacological interventions targeting glutamatergic, GABAergic, and dopaminergic systems alongside non-pharmacological neuromodulatory approaches.

Results

The review identifies convergent molecular mechanisms across diverse therapeutic modalities, including activation of mTOR signaling, enhancement of synaptic plasticity, modulation of BDNF-TrkB pathways, and regulation of inflammatory and oxidative stress responses. Ketamine demonstrates rapid antidepressant effects via NMDAR antagonism and AMPAR activation with remission rates of 30-50% in treatment-resistant populations. Psilocybin shows dose-dependent efficacy through 5-HT2A agonism with clinical improvement in treatment-resistant depression.

Conclusion

Effective antidepressant interventions converge on shared cellular mechanisms regulating synaptic plasticity, stress adaptation, and inflammatory responses. Integration of pharmacological and neuromodulatory strategies within a unified pathophysiological framework enables development of precise, mechanistically targeted, and multimodal treatment approaches for depression heterogeneity. Further long-term randomized studies are needed to establish optimal dosing, safety profiles, and biomarkers of therapeutic response.

Published in:International Journal of Molecular Sciences,
Study Type:Review,
Source: PMID: 41516220