Neuroendocrine and neuroinflammatory mechanisms in postpartum depression: From hormonal withdrawal to central immune dysregulation and emerging therapeutic targets.

Postpartum depression (PPD) affects approximately 10-15% of new mothers worldwide with profound consequences extending to offspring and partners. While the classical "hormonal withdrawal hypothesis" has long emphasized the abrupt decline in estradiol, progesterone, and cortisol following childbirth, emerging evidence demonstrates that these endocrine perturbations converge with dysregulated neuroimmune pathways as central drivers of PPD pathophysiology. This narrative review integrates mechanistic evidence linking reproductive hormone withdrawal, HPA axis dysregulation, neurotransmitter imbalances, and peripheral immune activation to central neuroinflammatory pathways in PPD, with the goal of providing a unified framework for understanding pathophysiology and identifying translational therapeutic opportunities. We synthesize evidence on increased inflammatory cytokines, including IL-6, TNF-α, and IL-1β, blood-brain barrier disruption, microglial activation, and neuroinflammatory signaling pathways. Additionally, we examine structural and functional neuroimaging abnormalities in limbic-prefrontal circuits and metabolic disturbances in monoaminergic, glutamatergic, and GABAergic systems. We evaluate established and emerging therapeutic strategies, including conventional antidepressants, FDA-approved neuroactive steroids (brexanolone, zuranolone), and novel immune-targeted interventions (NLRP3 inhibitors, cytokine antagonists). By integrating biological, genetic, and psychosocial risk factors, this review provides a precision-medicine framework for targeting neuroinflammatory pathways, particularly TLR-mediated immune activation, alongside conventional treatments, while identifying NLRP3 inflammasome signaling as a promising but clinically unvalidated therapeutic target warranting direct investigation in postpartum populations.