Bridging Neurobiological Insights and Clinical Biomarkers in Postpartum Depression: A Narrative Review

Abstract

Postpartum depression (PPD) affects 174 million women worldwide and is characterized by profound sadness, anxiety, irritability, and debilitating fatigue, which disrupt maternal caregiving and the mother-infant relationship. Limited pharmacological interventions are currently available. Our understanding of the neurobiological pathophysiology of PPD remains incomplete, potentially hindering the development of novel treatment strategies. Recent hypotheses suggest that PPD is driven by a complex interplay of hormonal changes, neurotransmitter imbalances, inflammation, genetic factors, psychosocial stressors, and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This narrative review examines recent clinical studies on PPD within the past 15 years, emphasizing advancements in neuroimaging findings and blood biomarker detection. Additionally, we summarize recent laboratory work using animal models to mimic PPD, focusing on hormone withdrawal, HPA axis dysfunction, and perinatal stress theories. We also revisit neurobiological results from several brain regions associated with negative emotions, such as the amygdala, prefrontal cortex, hippocampus, and striatum. These insights aim to improve our understanding of PPD's neurobiological mechanisms, guiding future research for better early detection, prevention, and personalized treatment strategies for women affected by PPD and their families.

Keywords: amygdala; animal models; clinical biomarkers; hippocampus; neurobiology; neuroimaging; postpartum depression; striatum; the medial prefrontal cortex.

Figure 1

Tryptophan metabolism in the brain. Tryptophan is mainly metabolized through the kynurenine pathway (95%) and less so through the serotonin pathway (<5%). In the kynurenine pathway, tryptophan is converted to kynurenine by IDO (in the brain) or TDO (in other tissues). This pathway splits into two branches: the KMO branch, where KMO (primarily in microglia) produces 3HK, 3HAA, QUIN, and NAD+, and the KAT branch, where KAT (mainly in astrocytes) converts kynurenine to KYNA. KYNA is neuroprotective, while QUIN is neurotoxic, with distinct effects on brain function.

Figure 2

Laboratory Animal models of PPD: (1) Hormone withdrawal models. Ovariectomized female rats were injected with a low dose of estradiol benzoate and a high dose of progesterone dissolved in sesame oil daily for 16 consecutive days. From day 17 to 23, the dose of estradiol was increased to mimic the levels observed in pregnancy. From day 24 to 27, which is considered the postpartum period, mice only received vehicle (sesame oil) daily. (2) Chronic corticosterone treatment model. Dams were injected with high CORT during the postpartum period (postpartum day 2–24). (3) Gestational stress model. Depression is induced by exposing pregnant female mice to gestational stress from days 10 to 20 during pregnancy. (4) The chronic social stress model. A novel male was placed in their home cage for 1 h each day from days 2 to 16 of lactation, resulting in depressive behaviors. (5) The repeated maternal separation model. Depression is induced by separating the mothers from their pups for periods that last 3–6 h daily during the first 1–3 weeks postpartum.

Figure 3

This review provides a comprehensive examination of postpartum depression (PPD) across four aspects: (1) Basic information, including clinical characteristics, brain imaging, and biomarkers, to offer an initial understanding. (2) Biological mechanisms, detailing PPD pathology with an emphasis on serotonin and kynurenine pathways, where kynurenine branches into neuroprotective KYNA and neurotoxic QUIN. (3) Laboratory animal models focused on hormone manipulation and stress, with model variations. (4) Neuronal mechanisms, involving key brain regions such as the PFC, AMY, HIPP, and striatum. Abbreviations: fMRI: functional magnetic resonance imaging; PET-CT: positron emission tomography-computed tomography; MRS: magnetic resonance spectroscopy; OXT: oxytocin; KYNA: kynurenic acid; QUIN: quinolinic acid; Cort: corticosterone; PFC: prefrontal cortex; AMY: amygdala; HIPP: hippocampus.