The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies

Wolfgang Marx*, Amelia J. McGuinness, Tetyana Rocks, Anu Ruusunen, Jasmine Cleminson, Adam J. Walker, Susana Gomes-da-Costa, Melissa Lane, Marsal Sanches, Alexandre P. Diaz, Ping Tao Tseng, Pao Yen Lin, Michael Berk, Gerard Clarke, Adrienne O’Neil, Felice Jacka, Brendon Stubbs, André F. Carvalho, João Quevedo, Jair C. SoaresBrisa S. Fernandes

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

132 Citations (Scopus)


The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges’ g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Original languageEnglish
Pages (from-to)4158-4178
Number of pages21
JournalMolecular Psychiatry
Issue number8
Publication statusPublished - Aug 2021
Externally publishedYes


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