Postpartum fluoxetine increased maternal inflammatory signalling and decreased tryptophan metabolism: Clues for efficacy

Qiu, Wansu; Duarte‐Guterman, Paula; Eid, Rand S.; Go, Kimberly A.; Lamers, Yvonne; Galea, Liisa A.M.

doi:10.1016/j.neuropharm.2020.108174

Cited by 15 publications

(23 citation statements)

References 102 publications

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“…Although this finding is partially inconsistent with a study in MDD individuals where TNF was positively associated with plasma TKP (Haroon et al, 2020), this other study used sex as covariate and did not consider treatment effects in their analyses. The present findings coupled with the results of higher IL-1β and reduced TRP concentrations with maternal postpartum FLX (Qiu et al, 2020a) may have contributed towards the limited efficacy of FLX previously reported in this model of de novo PPD.…”

Section: Discussionsupporting

confidence: 52%

“…Curiously, PND is associated with higher kynurenic acid (KYNA) (Teshigawara et al, 2019), but MDD is associated with reduced KYNA (reviewed by Maes et al, 2011). Previously, we found reduced cytokine (TNF-α and IFN-γ) expression and elevated concentrations of a TKP enzyme cofactor (vitamin B6) due to postpartum CORT (Qiu et al, 2020a), indicating an altered immune system and TKP in this model of de novo PPD.…”

Section: Introductionmentioning

confidence: 59%

“…Data for 5 samples were not collected due to human error. We also examined inflammation in the periphery, hippocampus and frontal cortex and these results have been published elsewhere (Qiu et al, 2020a). Briefly, we found that postpartum FLX elevated hippocampal IL-1β and circulating CXCL1 and postpartum CORT reduced IFN-γ and TNF-α.…”

Section: Methodsmentioning

confidence: 99%

“…This model mimics elevated cortisol levels seen in those women with depression symptoms postpartum (Iliadis et al, 2015). Maternal postpartum CORT consistently induces various depressive-like endophenotypes, such as reduced maternal care behaviour, increased passive-coping behaviour, and reduced hippocampal integrity (Workman et al, 2016; Gobinath et al, 2018; Qiu et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

“…Selective serotonin reuptake inhibitors (SSRIs) are the first line treatment for PND although efficacy of SSRIs varies with timing of depression onset as those with postpartum onset have lower efficacy than those with antenatal onset (Cox et al,2016). Both inflammation and TKP are implicated in antidepressant efficacy both in humans (Syed et al, 2018; Sun et al, 2020) and in rodents (Qiu et al, 2020a). Individuals with MDD who are non-responsive to SSRI treatment show either no change or an elevation of circulating cytokine levels (Syed et al, 2018) and display higher baseline tryptophan metabolism defined by kynurenine to tryptophan ratio (Sun et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

Qiu

Lamers

et al. 2021

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Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND, but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1B levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

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Section: Discussionsupporting

confidence: 52%