Linking the reversal of gestational insulin resistance to postpartum depression

Abstract

Background: Postpartum depression (PPD) constitutes a significant mental health disorder affecting almost one fifth of pregnancies globally. Despite extensive research, the precise etiological mechanisms underlying PPD remain elusive. However, several risk factors like genetic predisposition, hormonal fluctuations, and stress-related environmental and psychosocial triggers have been found to be implicated in its development. MAIN: Recently, an increased risk of PPD has been reported to be associated with gestational diabetes mellitus (GDM), which is characterized by the disruption of glucose metabolism, primarily attributed to the emergence of insulin resistance (IR). While IR during pregnancy seems to be an evolutionary adaptative mechanism to handle the profound metabolic alterations during pregnancy, its subsequent resolution following delivery necessitates a reconfiguration of the metabolic landscape in both peripheral tissues and the central nervous system (CNS). Considering the pivotal roles of energy metabolism, particularly glucose metabolism, in CNS functions, we propose a novel model that such pronounced changes in IR and the associated glucose metabolism seen postpartum might account for PPD development. This concept is based on the profound influences from insulin and glucose metabolism on brain functions, potentially via modulating neurotransmitter actions of dopamine and serotonin. Their sudden postpartum disruption is likely to be linked to mood changes, as observed in PPD.

Conclusions: The detailed pathogenesis of PPD might be multifactorial and still remains to be fully elucidated. Nevertheless, our hypothesis might account in part for an additional etiological factor to PPD development. If our concept is validated, it can provide guidance for future PPD prevention, diagnosis, and intervention.

Keywords: Gestational diabetes mellitus (GDM); Glucose; Insulin; Insulin resistance (IR); Postpartum depression (PPD); Pregnancy.

Fig. 1

Proposed model linking the development of postpartum depression (PPD) to gestational insulin resistance (IR). During pregnancy, the mother develops IR both in the periphery and the brain, which increases glucose influx into the brain and promotes insulin-mediated glucose metabolism. This supports enhanced serotonin and dopamine signaling, contributing positively to mood control. After delivery, the IR rapidly reverses and glucose influx and metabolism in the brain are reduced, thereby disrupting the serotonin and dopamine signaling of pregnancy. When such changes exceed a critical threshold, as in gestational diabetes mellitus, the significant postpartum alteration of brain glucose metabolism and downstream neural signal pathways may lead to abrupt mood changes, resulting in PPD