Mechanisms of acupuncture in treating depression: a review

This systematic review represents a comprehensive analysis of the mechanisms by which acupuncture exerts antidepressant effects, based on the analysis of 44 experimental studies published between 2020 and 2024. The work arises from the need to better understand how acupuncture, a millennia-old therapy of traditional Chinese medicine, can be integrated into modern depression treatment, especially considering that only about one-third of patients with major depression achieve meaningful remission with conventional treatments. The researchers conducted a systematic search of PubMed, Web of Science, and Embase, focusing exclusively on basic studies with animal models to eliminate confounding variables of clinical studies. The analysis revealed that the chronic unpredictable mild stress (CUMS) model was the most used (29 studies), followed by the chronic restraint model (5 studies).

The sucrose preference test was the most frequent behavioral indicator (36 studies), followed by the open field test (30 studies). Electroacupuncture (EA) was the predominant modality (29 studies), with the combination of GV-20 (Baihui 百会) and GV-29 (Yintang 印堂) being the most used. The mechanisms identified encompass four main categories: neurotransmitter regulation, synaptic remodeling and neuroprotection, inhibition of neuroinflammation, and neuroendocrine regulation. With regard to neurotransmitters, EA was shown to significantly increase serotonin (5-HT) levels through regulation of the miRNA-16/SERT pathway, in addition to modulating 5-HT1A and 5-HT1B receptors.

Glutamate regulation occurs via excitatory amino acid transporters (EAAT1 and EAAT2), while dopamine is modulated through dopa decarboxylase and regulation of the dopamine transporter. In synaptic remodeling, EA promotes plasticity through modulation of synaptic proteins such as PSD95 and GluA1, in addition to activating important pathways such as BDNF/TrkB/CREB and regulating neurotrophic factors. Mitochondrial protection and reduction of oxidative stress have also been documented, with evidence that EA prevents ferroptosis through activation of the Sirt1/Nrf2 pathway. The anti-inflammatory effects of acupuncture are mediated by inhibition of pathways such as P2X7R/NLRP3 and NF-κB, resulting in reduction of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6.

Microglial and astrocytic modulation also contributes to the neuroprotective effects. Neuroendocrine regulation includes normalization of the hypothalamic-pituitary-adrenal (HPA) axis, with reduction in cortisol and ACTH levels, as well as modulation of tryptophan metabolism through the kynurenine pathway. The clinical implications are significant, because the multiple mechanisms of action identified suggest that acupuncture may be especially useful in cases of treatment-resistant depression or as adjunctive therapy. Evidence that different modalities (EA vs.

manual acupuncture vs. catgut embedding) may have distinct mechanisms opens possibilities for personalization of treatment. However, important limitations exist. The heterogeneity in electroacupuncture parameters (frequency, intensity, duration) across studies makes clinical standardization difficult.

In addition, the predominance of EA studies leaves gaps in knowledge about other modalities. Translation of findings from animal models to humans also requires caution, especially considering the differences in the neuropsychological complexity of human depression. The authors identify important future directions: investigate differences between acupuncture modalities, optimize EA parameters for different depression subtypes, and explore how the multiple mechanisms interact with one another. The connection between inflammation, the gut microbiota, and tryptophan metabolism represents a particularly promising area for future research.