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Postpartum Depression Models

Females are twice as likely as males to be diagnosed with major depressive disorder (MDD). The perinatal period, which encompasses both pregnancy and the postpartum, is a time of heightened susceptibility to depression, affecting up to 20% of females. Natural changes that occur during pregnancy and the postpartum mirror many of the biological markers associated with MDD, suggesting the perinatal period may lead to a perfect storm for those susceptible to MDD (Galea and Frokjaer, 2019; Qiu et al., 2020). According to the DSM-V, perinatal depression (PND) is defined as the onset of depression during pregnancy or anytime up to 4 weeks after parturition. PND can have severe consequences for the mother and long-lasting effects on children. However, PND is a heterogeneous disease; the timing of onset and whether or not depression is de novo (new/first time depression) have implications for disease etiology, symptoms and treatment efficacy. The relative risk for de novo depression is much higher in the postpartum compared to antepartum (during pregnancy). Although 60% of PND cases present with depression during pregnancy, the vast majority of these cases are not de novo, with a previous history of depression being the greatest risk factor for onset during pregnancy. The heterogeneity of PND demands multiple model systems to understand its etiology and treatment and my laboratory has been at the forefront of this research.

We created the first animal models of postpartum depression (PPD) based on the unique physiology of females: ovarian steroid-withdrawal (Galea et al., 2001) or high corticosterone (CORT) postpartum (Brummelte et al., 2006). Adult neurogenesis was suppressed in both models (Green & Galea, 2008; Brummelte & Galea, 2010) and chronic tricyclic antidepressant restored levels of neurogenesis in ‘PPD’ rats (Green & Galea, 2008). Further, CORT-treated dams exhibited more depressive-like behaviour, reduced cell proliferation and dendritic atrophy in the hippocampus (Brummelte et al., 2006; Brummelte & Galea, 2010; Workman et al., 2013). High CORT postpartum, but not during gestation, resulted in depressive-like behaviours in the dam (Brummelte and Galea, 2010). Postpartum SSRIs attenuate CORT effects on maternal care but not on depressive-like behaviour and fail to increase neurogenesis in the hippocampus (Workman et al., 2016; Gobinath et al., 2017; Overgaard et al., 2018). However, maternal exercise with SSRIs does improve both depressive-like behaviour and neurogenesis in the CORT-treated dams (Gobinath et al., 2018). We also examined the effects of SSRI exposure and maternal mood during gestation on neuroplastic markers in infants (Brummelte et al., 2013). Central to this new work we have shown that SSRI inefficacy to reverse long-term deficits due to maternal CORT is coincident with increased inflammation and tryptophan metabolism (Qiu et al., 2020, 2021).  Thus, over the next few years we will target immune and gut health during pregnancy/postpartum to influence depression vulnerability and antidepressant efficacy. Using our model of PPD, we showed that the early postpartum leads to decreased hippocampal neurogenesis and compromised 5-HT signalling coincident with lack of antidepressant efficacy (Gobinath et al., 2017; Qiu et al., 2020; 2021; Workman et al., 2016).

Examining Antidepressant Efficacy in the Perinatal Period 

The perinatal period is a time of the greatest risk to develop de novo depression for women. Untreated perinatal depression (PND) can have severe consequences and, although SSRIs are first line treatment for PND, research shows their limited efficacy. The goal of this project is to determine the mechanisms of SSRI inefficacy in the postpartum to identify novel and adjuvant treatments to improve SSRI efficacy. Our central hypothesis is that antidepressant efficacy in the postpartum is mediated by inflammatory signalling.

Our lab has developed a model of de novo postpartum depression. Administering the stress hormone corticosterone to dams postpartum leads to depressive-like endophenotypes, including reduced maternal care, increased passive-coping, compromised immune signalling and decreased hippocampal plasticity. The integrity of the hippocampus is compromised in MDD and in the postpartum, including the reduction of hippocampal neurogenesis. Neurogenesis is linked to antidepressant efficacy and is an important target in our studies. The immune system is another target to improve antidepressant efficacy, with elevated levels of proinflammatory cytokines, such as IL-1β, associated with increased depression scores in MDD and PND. Antidepressant response is also linked to cytokines as SSRIs reduce inflammation with remission yet increase inflammation in treatment non-responsive MDD individuals. We found that SSRI treatment during the postpartum increased hippocampal IL-1β, which was coincident with a lack of SSRI efficacy in reducing depressive-like endophenotypes. Because IL-1β regulates neurogenesis in the hippocampus, elevated levels in the postpartum may contribute to SSRI inefficacy during this period. 

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