A unified model of the biology of peripartum depression

Abstract

Peripartum depression (PPD) is a prevalent and debilitating disorder that adversely affects the development of mothers and infants. Recently, there has been a plea for increased mental health screening during the peripartum period; however, currently, there is no accurate screening tool to identify women at risk of PPD. In addition, some women do not respond to current treatment schemes and develop treatment-resistant depression. The current perspective aims to propose a unified understanding of the biological underpinnings of PPD (UmPPD) that considers the heterogeneity in the onset, symptoms cluster, and severity of PPD. Such a model could promote basic and applied research on PPD and suggest new treatment avenues. The central hub of the model is the kynurenine pathway (KP) and the KP-serotonin ratio. The forces and specific processes at play that cause an imbalance within the KP and between KP and serotonin are inflammation, stress, reproductive hormones (especially estradiol and progesterone), and oxytocin. UmPPD predicts that the most severe PPD would comprise prolonged inflammation, ongoing or multiple stressors, excessive estrogen, progesterone resistance, and avoidance of breastfeeding, skin-to-skin contact, and social proximity. These factors would be associated with a higher likelihood of developing PPD, early onset, and more significant symptom severity. In addition, subtypes of PPD would consist of different compositions and expressions of these components, with one central common factor. UmPPD could aid in directing future research and possibly detecting critical processes that could help discover, develop, and utilize novel treatments for PPD.

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“…These theories include pathways related to endocrine, epigenetic, genetic, synaptic transmission, neural network, neurosteroid, stress, and inflammation 14 . Researchers suggest that a cohesive synthesis of these many theoretical models could lead to a thorough understanding 15 . Numerous studies demonstrate the critical role that reproductive hormones play in determining depressive inclinations, suggesting a neuroendocrine basis for PPD.…”

Staying Up to Date With Evolving Postpartum Depression Pathophysiology and Treatment Research

“…8 Several hypotheses have been developed to explain the pathophysiology of PND, including endocrine, epigenetic, synaptic transmission, neural network, neurosteroid, stress, and inflammatory mechanisms, 9 and researchers believe that the answer lies in a synthesized mechanism of all of these models. 10 Novel and emerging therapeutics are focusing on the neurosteroid mechanism within the integrated hypothesis.…”

Mitochondrial might: powering the peripartum for risk and resilience

“…In addition to influencing parturition, nursing, and maternal behaviors such as maternal-infant attachment (Lévy et al, 1992;Nishimori et al, 1996;Walter et al, 2021), OXT also has suppressive effects on HPA axis reactivity, and in turn may protect against the physical and psychological stress associated with gestation and the peripartum (Bell et al, 2014). Given its roles in peripartum adaptations and stress, OXT has also been implicated in PPD (Post and Leuner, 2019;Thul et al, 2020;Levin and Ein-Dor, 2023). For example, one group assessed genetic and epigenetic variations in the OXT receptor gene in pregnant women who later developed PPD, showing that those with the rs53576_GG polymorphism and high methylation of the OXT receptor gene were three times more likely to develop PPD than those with a different allele (Bell et al, 2015).…”

“…Also considering that OXT regulates the stress response, there may be intricate interactions in which OXT indirectly affects mitochondria through its suppressive modulation of the HPA axis. Finally, OXT affects GABA signaling and the pattern of GABA A R subtype expression (Kaneko et al, 2016), which is related to its inhibitory effects on stress response (Levin and Ein-Dor, 2023). Thus, OXT may impact mitochondrial function through various interconnected mechanisms, which will be crucial to tease apart in the future.…”