Targeting the Kynureine Pathways in Pregnancy-Related Depression.

Project: Research project

Project Details

Description

One in seven women experiences an episode of major depressive disorder (MDD) during and after pregnancy with the onset of the majority of these episodes occurring antenatally. Untreated perinatal depression can have devastating consequences including pregnancy-associated suicide, which has remained among the leading contributors to maternal mortality in the United States. In addition, untreated perinatal depression has been associated with adverse consequences in offspring, including fetal growth restriction, preterm birth, and long-term neurobehavioral impairment. As such, perinatal depression has an enormous personal and public health impact. In spite of the high prevalence and potentially catastrophic outcomes of this disorder, there is a major gap in knowledge of its pathophysiology that limits development of treatment options.
In non-pregnant individuals, inflammation is causally linked to subgroups of MDD. Although not yet proven, inflammation may have an important role in perinatal depression, given the profound immunologic changes that occur during pregnancy. Evidence of maternal immune hyperactivation in peripheral blood has been associated with perinatal depressive symptomatology. Our research supports this hypothesis, as we have demonstrated that treatment with psychotropic medications is associated with reduced inflammatory plasma cytokines in women who respond to pharmacotherapy, but not in those who do not respond to treatment. These data suggest that reductions in inflammation improve perinatal depressive symptoms, but the mechanisms underpinning this response remain incompletely understood.
One pathway directly linking inflammatory cytokines with neurotransmission is the kynurenine pathway of tryptophan metabolism. Tryptophan is the precursor to serotonin, a monoamine whose production is critical to mood stability. Th1-cytokines induce expression of indolamine-2,3-dioxygenase (IDO), which degrades tryptophan into its metabolite, kynurenine (KYN). This enhanced degradation of tryptophan yields a state of relative serotonin depletion. Recent data demonstrate an increased KYN/tryptophan ratio in women with perinatal depression. In addition, some downstream metabolites of KYN, such as the NMDA-receptor agonist quinolinic acid (QUIN), may directly induce symptoms of depression whereas metabolites generated from differential enzymatic reactions, kynureninc acid (KYNA) and picolinic acid (PIC), are protective.
A key limitation to most studies on the association between inflammation and perinatal depression is the reliance on peripheral blood markers, which may not reflect the intracerebral environment or be relevant markers of affective disease. A more direct assessment of inflammation associated with perinatal depression requires assessment of the cerebrospinal fluid (CSF). We developed a novel protocol to obtain CSF during routine labor neuraxial anesthesia administration and have the unique ability to collect paired plasma and CSF in a large number of otherwise healthy pregnant women. Our team demonstrated that women with perinatal depression have higher levels of the CSF Th-1 cytokines, interleukin (IL)-1β and IL-33, compared to euthymic women. In this proposal, we aim to elucidate the mechanisms that link overproduction of these inflammatory markers in the CSF with perinatal depression. Our central hypothesis is that the elevated CSF inflammation we detect in women with perinatal depression is mechanistically linked to depressive symptoms via activation of the KYN pathway within the central nervous system. Specificall
StatusActive
Effective start/end date7/1/186/30/20

Funding

  • American Association of Obstetricians and Gynecologists Foundation (Agmt 07/10/18)

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