Menstrual cycle-related neurotrophic and inflammatory variation differs between adult females with and without Major Depressive Disorder

Abstract

Abstract Background The pathophysiology of Major Depressive Disorder (MDD), which disproportionately affects females, has been linked to neuroimmune mechanisms. However, many canonical biomarkers of MDD may be influenced by physiological changes across the menstrual cycle. Despite evidence for sex differences and alterations in neurotrophic and inflammatory pathways in MDD, mechanisms underlying elevated risk in reproductive-aged females remain unclear. Methods Here, we examined whether peripheral levels of brain-derived neurotrophic factor (BDNF) and inflammatory markers (IL-6, CRP, TNF-α) vary according to menstrual cycle timing (days since last period; DSLP) in regularly menstruating adult females (aged 21–54) with and without MDD ( n = 35 MDDs, n = 25 psychiatrically healthy controls), as well as whether these findings are dependent on age and associated with depressive symptom severity. Results Average levels of each biomarker did not differ between the MDD and control group. However, higher DSLP was associated with higher BDNF in the MDD group only ( β = 0.23, p =.02), and age moderation revealed that this association was significant specifically among MDD females under 36 years of age. In contrast, within-diagnostic group analyses showed that DSLP was negatively associated with TNF-α ( β =-0.03, p =.03) and CRP ( β =-0.04, p =.06) in the MDD group only, and age moderation likewise revealed that the TNF-α association was significant among MDDs under 35 years of age. Neither DSLP nor the biomarkers were associated with depressive symptom severity. Conclusions Overall, peripheral neurotrophic and inflammatory factors showed menstrual cycle-related variation in females with MDD (higher DSLP-higher BDNF; higher DSLP-lower TNF-α and CRP), but this variability was not associated with depressive symptoms. These findings suggest that cycle-sensitive peripheral neuroimmune processes are partially dissociable from concurrent depressive state in regularly menstruating adult females and highlight the importance of accounting for menstrual cycle timing when examining MDD peripheral biomarkers.

The authors' abstract, as published at the source. Biology of Sex Differences, 2026 · DOI ↗