Cytokines and tryptophan metabolites can predict depressive symptoms in pregnancy

Abstract

Depression during and after pregnancy affects up to 20% of pregnant women, but the biological underpinnings remain incompletely understood. As pregnancy progresses, the immune system changes to facilitate fetal development, leading to distinct fluctuations in the production of pro-inflammatory factors and neuroactive tryptophan metabolites throughout the peripartum period. Therefore, it is possible that depression in pregnancy could constitute a specific type of inflammation-induced depression. Both inflammatory factors and kynurenine metabolites impact neuroinflammation and glutamatergic neurotransmission and can therefore affect mood and behavior. To determine whether cytokines and kynurenine metabolites can predict the development of depression in pregnancy, we analyzed blood samples and clinical symptoms in 114 women during each trimester and the postpartum. We analyzed plasma IL-1β, IL-2, -6, -8, -10, TNF, kynurenine, tryptophan, serotonin, kynurenic- quinolinic- and picolinic acids and used mixed-effects models to assess the association between biomarkers and depression severity. IL-1β and IL-6 levels associated positively with severity of depressive symptoms across pregnancy and the postpartum, and that the odds of experiencing significant depressive symptoms increased by >30% per median absolute deviation for both IL-1β and IL-6 (both P = 0.01). A combination of cytokines and kynurenine metabolites in the 2nd trimester had a >99% probability of accurately predicting 3rd trimester depression, with an ROC AUC > 0.8. Altogether, our work shows that cytokines and tryptophan metabolites can predict depression during pregnancy and could be useful as clinical markers of risk. Moreover, inflammation and kynurenine pathway enzymes should be considered possible therapeutic targets in peripartum depression.

Relationship between inflammatory biomarkers, vitamin D levels, and depressive symptoms in late pregnancy and during the postpartum period: a prospective, observational study

“…Excessive inflammation induces the tryptophan metabolizing enzyme, Indole Amine Pyrrole 2,3 dioxygenase, causing decreased production of serotonin in the synaptic cleft and at the same time increasing the production of neurotoxic substances through the kynurenine pathway [28]. A recent study proposes a model utilizing inflammatory cytokines and kynurenine metabolites that has > 99% probability of predicting depression in the third trimester [4].…”

“…However, the biological underpinnings of how these factors impact depression outcomes remain largely vague. Genetic vulnerability, sensitivity to changes in estrogen, progesterone, and cortisol levels are among the cited theories [4]. Recently, the inflammatory immune response has received special attention as an etiological mechanism for maternal depression [2][3][4].…”

“…Genetic vulnerability, sensitivity to changes in estrogen, progesterone, and cortisol levels are among the cited theories [4]. Recently, the inflammatory immune response has received special attention as an etiological mechanism for maternal depression [2][3][4]. Several cross-sectional and prospective studies have examined the correlation between various inflammatory markers and depression [2][3][4][5][6][7].…”

“…Recently, the inflammatory immune response has received special attention as an etiological mechanism for maternal depression [2][3][4]. Several cross-sectional and prospective studies have examined the correlation between various inflammatory markers and depression [2][3][4][5][6][7]. Other studies explore differences in vitamin D levels during pregnancy [8].…”

Antidepressant Effects of NSAIDs in Rodent Models of Depression—A Systematic Review

“…Furthermore, depressive symptoms appear in animal models when cytokine levels are experimentally elevated, for example, by injections of the bacterial endotoxin lipopolysaccharide ( Bay-Richter et al, 2011 ) or by poly I:C, which simulates a viral infection ( Gibney et al, 2013 ). Interestingly, depressed patients have, in some studies, been shown to have elevated plasma levels of pro-inflammatory cytokines ( Hestad et al, 2003 ), and it has been suggested that cytokine levels correlate with the severity of depression ( Sha et al, 2022 ). Furthermore, the HPA axis is known to be dysregulated in depression.…”