Examining impact of interleukin-1 receptor antagonist on fluoxetine efficacy in a preclinical rodent model of postpartum depression (2021)
Depression is the leading cause of disability worldwide, where women are twice as likely to be diagnosed than men. Pregnancy and early postpartum is an especially vulnerable period, where approximately 15% of birthing individuals are diagnosed with perinatal depression (PND). Approximately 40% of PND cases occur in the postpartum period. Overwhelmingly, most of these cases are the first depressive episode in the birthing individual’s life. Concerningly, selective serotonin reuptake inhibitors (SSRIs), the first line antidepressant treatment for PND, show decreased efficacy in treating postpartum depression symptoms compared to antepartum depression symptoms. Previous research using an animal model of de novo postpartum depression indicates that SSRI inefficacy may be related to increased levels of the proinflammatory cytokine interleukin-1β (IL-1β). This thesis aims to further investigate the relationship between inflammation and the postpartum onset of depression, by targeting the IL-1 receptor using an animal model of postpartum depression. In this model, high corticosterone (primary rat glucocorticoid) is given to the rat dam postpartum. Rat dams received either daily injections of corticosterone, fluoxetine and/or the IL-1 receptor antagonist, anakinra, or their vehicles. Anakinra competitively binds to the IL-1 receptor to block IL-1β activity. Our results indicate anakinra treatment has mixed effects on PND endophenotypes, depending on co-treatment with fluoxetine. With and without fluoxetine co-treatment, anakinra decreases microglia in the hippocampus, indicating an overall dampening of neuroinflammation through IL-1 receptors. Without fluoxetine co-treatment, anakinra decreases maternal care behaviour, whereas anakinra with fluoxetine treatment returned to control levels. Co-treatment of anakinra and fluoxetine resulted in increased active coping behaviours during the Forced Swim Test and increased hippocampal neurogenesis in the ventral dentate gyrus. Notably, fluoxetine with anakinra co-treatment increased ventral hippocampal neurogenesis, while fluoxetine treatment alone was ineffective in these outcome variables. These results suggest a possible therapeutic benefit of anakinra when used as an adjuvant with fluoxetine. Further research is critical to build upon this foundation and continue to explore the connection between neuroinflammation and antidepressant efficacy.