Postpartum fluoxetine increased maternal hippocampal IL-1β and decreased plasma tryptophan: clues for efficacy

Perinatal depression (PND) affects approximately 15% of women, and de novo postpartum depression affects approximately 40% of PND cases. Selective serotonin reuptake inhibitors (SSRIs) are a common class of antidepressants prescribed to treat PND. However, the safety and efficacy of SSRIs have been questioned in both clinical and preclinical research. Here, using a preclinical rodent model of postpartum depression, we aim to better understand neuroinflammatory cytokines and tryptophan mechanisms that may be related to SSRIs efficacy. Rodent dams were treated with high corticosterone (CORT; 40mg/kg, s.c.) for 21 days in the postpartum period to simulate depressive-like behaviors in the late postpartum period. Concurrently, a subset of dams was treated with the SSRI, fluoxetine (FLX; 10mg/kg, s.c.), in the postpartum period. We showed, consistent with previous studies, that although maternal FLX treatment prevented CORT-induced disturbances in maternal care behavior during the early postpartum, it failed to prevent the expression of CORT-induced depressive-like behavior in the late postpartum. Furthermore, FLX treatment, regardless of CORT treatment, increased maternal hippocampal IL-1{beta} and decreased maternal plasma tryptophan levels, plasma tryptophan, 4-pyridoxic acid, and pyridoxal concentrations. Maternal CORT treatment reduced maternal hippocampal TNF- and IFN-{gamma} levels. Our work suggests that the limited efficacy of FLX in the late postpartum may be associated with elevated levels of the proinflammatory cytokine IL-1{beta} in the maternal hippocampus, decreased plasma tryptophan concentration, and changes in vitamin B6 dependent tryptophan-kynurenine pathway. These findings suggest novel pathways for improving SSRI efficacy in alleviating perinatal depression. HIGHLIGHTSO_LIPostpartum fluoxetine (FLX) increased interleukin-1{beta} levels in hippocampus C_LIO_LIPostpartum corticosterone (CORT) decreased TNF- and IFN-{gamma} in the hippocampus C_LIO_LIPostpartum FLX did not prevent CORT-induced depressive-like behavior C_LIO_LIPostpartum FLX prevented CORT-induced changes in maternal behavior C_LIO_LIPostpartum FLX decreased plasma tryptophan, 4-pyridoxic acid, and pyridoxal levels C_LI