Sex-specific exposome components influence vulnerability to Major Depressive Disorder in women.

This mini-narrative review investigates sex-specific exposome components, encompassing environmental and social exposures such as early-life adversity and psychosocial stressors, alongside neuroendocrine signaling and epigenetic regulation. The focus is on women, with comparisons to men made regarding prevalence. The review addresses the primary outcome of vulnerability to Major Depressive Disorder across the lifespan, alongside secondary outcomes including HPA axis responsivity, neuroinflammatory signaling, glutamatergic transmission, synaptic remodeling within corticolimbic circuits, and hippocampal and prefrontal plasticity.

The review indicates that women exhibit nearly twice the lifetime prevalence of depression compared to men. However, the disparity cannot be explained by hormonal or psychosocial factors alone. Mechanistically, fluctuations in ovarian hormones are proposed to modulate HPA axis responsivity, neuroinflammatory signaling, and glutamatergic transmission through the epigenetic regulation of stress-responsive genes, specifically NR3C1, SLC6A4, and BDNF.

Furthermore, environmental and social exposures are described as interacting with microglial activation and chromatin remodeling. This interaction produces long-lasting alterations in hippocampal and prefrontal plasticity. The review does not report specific adverse events, serious adverse events, discontinuations, or tolerability data, nor does it provide absolute numbers or p-values for the reported outcomes. Key limitations regarding the study design and population specifics were not reported in the source material.

The practice relevance identified involves identifying modifiable environmental targets. This approach aims to advance precision, sex-informed preventive, and therapeutic strategies in depression management. Clinicians should interpret these findings as mechanistic hypotheses derived from a narrative review rather than definitive causal evidence from randomized trials.