Association between changes in estradiol, serotonin, and BDNF and antidepressant response in perimenopausal
Jian Peng1, Xiaoli Gan1, Xiong Li2
1Department of Traditional Chinese Medicine, Pingxiang Maternity and Child Health Care Hospital, Pingxiang, Jiangxi, China.
Background:
Perimenopausal depression (PMD) involves complex neuroendocrine interactions among estradiol (E2), serotonin (5-HT), and brain-derived neurotrophic factor (BDNF). Integrated traditional Chinese medicine and acupuncture (TCM-Acu) is widely used clinically, but its biological mechanisms relative to selective serotonin reuptake inhibitors (SSRIs) remain poorly characterized.
Methods:
We conducted a single-center retrospective cohort study in 240 perimenopausal women (TCM-Acu, n = 120; SSRIs, n = 120) treated for a minimum of eight weeks. Treatment effects were estimated using multivariable-adjusted regression (ANCOVA) accounting for baseline imbalances in age, disease duration, HAMD-17 score, and other covariates. Biomarker associations were examined via treatment × ΔBiomarker interaction terms.
Results:
In multivariable-adjusted analyses, TCM-Acu was associated with significantly greater HAMD-17 improvement relative to SSRIs (adjusted β = 3.79 points, 95% CI 2.79-4.79; P < 0.001; unadjusted mean change: 7.07 vs. 3.24 points). However, absolute treatment response rates (≥50% HAMD-17 reduction) were low in both groups (14.2% vs. 5.0%), indicating the observed difference reflects a relative rather than absolute clinical advantage. TCM-Acu was also associated with greater increases in 5-HT (adjusted β = 9.24 ng/mL, 95% CI 6.92-11.56; P < 0.001) and BDNF (adjusted β = 1.60 ng/mL, 95% CI 0.95-2.25; P < 0.001). Unadjusted estradiol levels did not differ significantly between groups (P = 0.592). Across the full cohort, changes in 5-HT and BDNF were positively associated with HAMD-17 improvement (Spearman ρ = 0.31 and 0.37, respectively), with the BDNF-HAMD-17 association being more pronounced in the TCM-Acu group on interaction testing.
Conclusion:
In multivariable-adjusted analyses, TCM-Acu was associated with greater HAMD-17 improvement and more pronounced increases in 5-HT and BDNF compared to SSRIs, while both treatments showed minimal differential effects on estradiol. However, absolute response rates were low in both groups, and the between-group difference reflects a relative rather than absolute clinical advantage. These observational findings are consistent with-but do not establish-the hypothesis that TCM-Acu's antidepressant associations may be mediated primarily through serotonergic and neurotrophic pathways; this requires prospective confirmation. Key limitations include the retrospective single-center design, baseline imbalances, absence of a sham acupuncture control, and differential treatment durations, which collectively preclude causal inference.
