Kynurenine pathway dysregulation in peri- and postpartum depression: a systematic review

Background

The kynurenine (KYN) pathway is the primary route of tryptophan (TRP) metabolism, accounting for approximately 95% of its degradation. This pathway produces a range of neuroactive metabolites that play key roles in mood regulation, immune response, and neurophysiological adaptations, particularly during pregnancy. Increasing evidence indicates that alterations in the KYN pathway may contribute to the pathophysiology of peripartum depression (PPD). Specifically, dysregulation of this pathway may reduce serotonin (5-HT) availability by diverting TRP metabolism away from serotonin synthesis toward kynurenine production. In addition, fluctuations in downstream metabolites such as kynurenic acid (KYNA) and quinolinic acid (QUIN) may influence glutamatergic neurotransmission, potentially leading to neurotoxic effects. These metabolic and neurochemical shifts, often associated with inflammatory processes, may contribute to the onset and persistence of depressive symptoms during pregnancy and the postpartum period. This systematic review aims to synthesize current evidence on the relationship between KYN pathway metabolites and depressive symptoms in peripartum women.

Methods

This systematic review was conducted in accordance with PRISMA guidelines and included studies published up to March 2026. A comprehensive literature search was performed across Scopus, Web of Science, and PubMed databases using predefined keywords related to kynurenine metabolites, depressive disorders, and the perinatal period. Search terms included combinations of (kynuren OR KYN OR KYNA OR 3-hydroxykynurenine OR 3-HK OR 3-hydroxyanthranilic acid OR 3-HAA OR quinolinic acid OR QUIN) AND (depression OR affective disorders OR bipolar disorder) AND (perinatal OR postpartum OR pregnancy OR gestation OR postnatal OR prenatal OR antenatal). Eligible studies comprised original research articles, including randomized controlled trials (RCTs), that examined biochemical and inflammatory markers in pregnant or postpartum women. Data extraction focused on TRP metabolism, KYN levels, the KYN/TRP ratio, and associated inflammatory markers, with particular attention to their relationship with depressive symptomatology.

Results

A total of 311 records were initially identified, of which 129 duplicates were removed. Following title and abstract screening and full-text assessment, 19 studies met the inclusion criteria. The findings consistently indicated that women experiencing depressive symptoms during pregnancy or postpartum exhibited increased circulating levels of KYN and QUIN, reduced levels of KYNA, and an elevated KYN/TRP ratio. Some studies reported lower plasma kynurenine levels at term, likely reflecting decreased TRP availability. However, the elevated KYN/TRP ratio observed at term and during the early postpartum period suggests increased enzymatic activity within the KYN pathway, likely driven by inflammatory mechanisms such as activation of indoleamine 2,3-dioxygenase (IDO). Collectively, these alterations indicate a shift toward a neurotoxic profile, characterized by an imbalance between neuroprotective and neurotoxic metabolites, alongside reduced serotonin synthesis.

Conclusions

Dysregulation of the KYN pathway appears to play a significant role in the development and progression of PPD. The observed increase in neurotoxic metabolites, such as QUIN, combined with decreased levels of neuroprotective compounds like KYNA, suggests a biochemical imbalance that may heighten vulnerability to depressive symptoms. These findings underscore the importance of further research to clarify causal relationships and to explore novel therapeutic strategies targeting the KYN pathway.

References

Wang S. et al (2018) Prepartum Depressive Symptoms Correlate Positively with C-Reactive Protein Levels and Negatively with Tryptophan Levels: A Preliminary Report. Int J Child Health Hum Dev. 2008 Aug;1(2):167-174. PMID: 18924606;