Pathophysiological mechanisms implicated in postpartum depression

Abstract

This review aims to summarize the diverse proposed pathophysiological mechanisms contributing to postpartum depression, highlighting both clinical and basic science research findings. The risk factors for developing postpartum depression are discussed, which may provide insight into potential neurobiological underpinnings. The evidence supporting a role for neuroendocrine changes, neuroinflammation, neurotransmitter alterations, circuit dysfunction, and the involvement of genetics and epigenetics in the pathophysiology of postpartum depression are discussed. This review integrates clinical and preclinical findings and highlights the diversity in the patient population, in which numerous pathophysiological changes may contribute to this disorder. Finally, we attempt to integrate these findings to understand how diverse neurobiological changes may contribute to a common pathological phenotype. This review is meant to serve as a comprehensive resource reviewing the proposed pathophysiological mechanisms underlying postpartum depression.

Keywords: Allopregnanolone; Circuit dysfunction; Epigenetics; GABA; HPA axis; Neuroinflammation; Oscillations; Postpartum depression; Stress.

Figure 1:. Epigenetic regulation of OXTR and hormonal abnormalities associated with postpartum depression.

Variations in DNA methylation of the OXTR gene in women with postpartum depression is negatively correlated with serum estradiol levels (left panel). A significant interaction between estradiol, OXTR DNA methylation, and the ratio of allopregnanolone to progesterone was also observed in women with postpartum depression. Thus, epigenetic changes can influence biochemical pathways associated with postpartum depression.

Figure 2:. Crosstalk between the HPG and HPA axes in postpartum depression.

Reproductive hormones have been shown to impact HPA axis function and vice versa. For example, estrogen signaling is known to impact HPA axis function, another potential biochemical mediator of postpartum depression. Therefore, dysregulation of reproductive hormones could dysregulate the levels of stress hormones thereby contributing to postpartum depression. Similarly, disruption in HPA axis function could influence the levels of reproductive hormones also contributing to postpartum depression.

Figure 3:. Stress hormones and inflammation in postpartum depression.

There are changes in neuroinflammatory markers throughout normal pregnancy. It has been proposed that disruption in these peripartum neuroinflammatory changes may contribute to postpartum depression. One potential culprit negatively impacting neuroinflammation during pregnancy is the HPA axis. Stress hormones are known regulators of immune function. Thus, disruption in HPA axis functioning and altered stress hormone levels can impact immune function. In addition, immune challenges can also activate the HPA axis, leading to altered levels of stress hormones. Thus, disruptions in the crosstalk between stress hormones and neuroinflammation may contribute to postpartum depression.

Figure 4:. Environmental impacts on synaptic transmission and circuit function in postpartum depression.

There is a complex interplay between environmental risk factors for postpartum depression, including stress and neuroinflammation, on synaptic transmission and circuit network function pertinent to mood disorders. Stress hormones (and reproductive hormones not pictured here) exert profound effects on synaptic transmission, altering glutamatergic, GABAergic, and monoaminergic signaling. Similarly, neuroinflammation is associated with changes in neurotransmission. The implications for altered synaptic signaling on circuit function is clear. Thus, it is possible that stress, neuroinflammation, and altered synaptic transmission could lead to circuit dysfunction associated with postpartum depression.

Figure 5:. Complex interplay between the potential pathological mechanisms contributing to postpartum depression.

This review highlights the diverse potential pathological mechanisms associated with postpartum depression, including disruptions in reproductive/lactogenic hormones, stress and HPA axis dysfunction, neuroinflammation, epigenetics, altered synaptic transmission, and circuit-level changes in network communication in brain regions associated with mood and/or the “maternal care network”. This complex interplay between the genetic, environmental, and synaptic/network function highlights the potential diversity in the underlying neurobiology of postpartum depression. We propose that while these diverse mechanisms contribute to heterogeneity in the patient population, it is also likely that there are commonalities in the underlying neurobiological features of postpartum depression.