Pharmacological Research - Modern Chinese Medicine · Published 2026-07-08 · DOI 10.1016/j.prmcm.2026.100846
Seema Sharma, Nishant Tiwari, Sneha Kumari, Sourabh D Jain, Sampat Singh Tanwar
Introduction: Major Depressive Disorder (MDD) is a highly prevalent and disabling neuropsychiatric condition, affecting roughly one in six individuals over their lifetime and imposing substantial clinical, social, and economic costs, including an estimated $210.5 billion annual burden in the United States. Its etiology is multifactorial, involving genetic susceptibility, monoaminergic dysregulation, HPA-axis hyperactivity, impaired neuroplasticity, neuroinflammation, and gut–brain axis disturbances. Conventional antidepressants, while effective for many patients, are limited by delayed onset of action, incomplete remission, and treatment resistance in up to 30% of cases. Traditional Chinese Medicine (TCM) has emerged as a candidate adjunctive approach, offering a holistic, multitarget pharmacological strategy theoretically well-suited to the multifactorial pathophysiology of depression. Despite decades of TCM use for mood disorders, recent advances in network pharmacology and multi-omics technologies now allow, for the first time, systematic mapping of TCM's multi-compound formulas onto specific molecular and circuit-level mechanisms of depression — an integration that has not previously been comprehensively synthesized. Combined with persistent treatment resistance and growing global interest in adjunctive phytotherapeutic strategies, this creates a timely opportunity to critically evaluate TCM's mechanistic and clinical evidence base. This review aims to synthesize current evidence on TCM's pathogenic rationale, therapeutic principles, and mechanistic pathways in MDD. Methods: This is a narrative, systems-based literature review integrating evidence from preclinical (animal model), network pharmacology, metabolomic, and clinical studies on TCM interventions for MDD. The review synthesizes findings across classical TCM theory (e.g., liver qi stagnation, zang-organ dysfunction), bioactive herbal constituents, and 15 classical formulas (including Xiaoyaosan, Chaihu-Shugan-San, and Si Ni San), mapping their reported mechanisms onto established biomedical frameworks of depression pathogenesis, monoaminergic signaling, glutamatergic neurotransmission, BDNF-mediated neuroplasticity, neuroinflammatory and oxidative pathways, and the microbiota–gut–brain axis. Results: TCM formulations and their bioactive constituents (e.g., ginsenoside Rg1, saikosaponin D, baicalin, curcumin, hyperoside) demonstrate antidepressant effects through convergent biological mechanisms: restoration of monoamine balance, suppression of glutamate excitotoxicity via NMDA/AMPA receptor modulation, enhancement of BDNF-driven synaptic plasticity, attenuation of neuroinflammation (e.g., IL-6, TNF-α, NLRP3 inflammasome suppression), antioxidant activity via Nrf2/HO-1 signaling, and normalization of HPA-axis function. At the formula level, several classical prescriptions, including Chaihu-Shugan-San and Xiaoyaosan, showed efficacy comparable or superior to standard antidepressants in meta-analyses and systematic reviews of randomized controlled trials, often with improved tolerability and reduced adverse events, though methodological quality of underlying trials was frequently limited. Classical TCM syndromic categories (liver qi stagnation, spleen deficiency, heart–spleen disharmony) showed plausible correspondence with biomedical constructs such as HPA dysregulation, inflammatory burden, and autonomic imbalance. Discussion: The reviewed evidence indicates that TCM provides a coherent, systems-based therapeutic framework that converges on shared biological endpoints BDNF-centered neuroplasticity, stress-axis normalization, and anti-inflammatory action despite the chemical diversity of its formulations. This positions TCM as a potentially valuable adjunctive, mechanism-based, and phenotype-oriented strategy, particularly for depression subtypes involving inflammatory activation, stress overload, or treatment resistance. However, translational limitations persist, including a predominance of preclinical and small-scale clinical data, inconsistent herbal standardization, unresolved bioavailability and herb–drug interaction concerns, and a scarcity of rigorous, large-scale randomized trials. Future research should prioritize standardized formula characterization, biomarker-guided patient stratification, multi-omics validation, and well-powered multicenter trials to clarify which TCM interventions are most effective for specific depressive phenotypes.
Abstract from DOAJ. Public domain (CC0 1.0).
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Sharma, S., Tiwari, N., Kumari, S., et al. (2026). From Qi to synapse: A systems-based review of Traditional Chinese Medicine in the treatment of major depressive disorder. Pharmacological Research - Modern Chinese Medicine. https://doi.org/10.1016/j.prmcm.2026.100846