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The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites

Molecular Psychiatry volume 26, pages 3419–3429 (2021)Cite this article

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Abstract

Growing evidence suggests that a dysregulation of the kynurenine pathway (KP) occurs in bipolar disorder (BD). This systematic review and meta-analysis aimed at assessing the possible differences in peripheral blood levels of KP metabolites between individuals with BD and healthy controls. We searched Medline, Embase, and PsycInfo electronic databases for articles indexed up to February 2020. We included any observational study comparing the peripheral blood levels of at least one KP metabolite between adults with BD and healthy controls. Random-effects meta-analyses were carried out generating pooled standardized mean differences (SMDs). Heterogeneity between studies was estimated using the I2 index. Meta-regression and sensitivity analyses were conducted. Sixteen studies met inclusion criteria and were included in our study. Meta-analyses showed that individuals with BD have lower peripheral blood levels of tryptophan (SMD = −0.29), kynurenine (SMD = −0.28), kynurenic acid (SMD = −0.30), and xanthurenic acid (SMD = −0.55), along with lower kynurenic acid to kynurenine (SMD = −0.60) and kynurenic acid to quinolinic acid (SMD = −0.37) ratios, than healthy controls. Individuals with a manic episode showed the greatest reductions in tryptophan levels (SMD = −0.51), whereas kynurenic acid levels were more reduced among subjects in a depressive phase (SMD = −0.70). Meta-regression and sensitivity analyses confirmed our results. The findings of the present meta-analysis support the hypothesis of an abnormality of the KP in BD. Considering the partial inconsistency of the findings and the small-to-medium magnitude of the estimated effect sizes, additional research assessing possible mediators or confounders is needed.

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Fig. 1: Schematic representation of the kynurenine pathway.
Fig. 2: Flow chart of the screening process.
Fig. 3: Effect sizes of the differences in peripheral blood levels of kynurenine pathway metabolites between individuals with bipolar disorder and healthy controls.

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Acknowledgements

We thank all the authors of the studies included into the present systematic review and meta-analysis. A special acknowledgement to Tore I. Aarsland (University of Bergen), Maurizio Pompili (Sapienza University of Rome), Carl M. Sellgren (Karolinska Institutet, Stockholm), and Nils E. Steen (University of Oslo) for having provided additional information. This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

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  1. Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy

    Francesco Bartoli, Tommaso Callovini, Daniele Cavaleri, Riccardo M. Cioni, Cristina Crocamo & Giuseppe Carrà

  2. Department of Genetics, Wrocław Medical University, Wrocław, Poland

    Błażej Misiak

  3. Laureate Institute for Brain Research, Tulsa, OK, USA

    Jonathan B. Savitz

  4. Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA

    Jonathan B. Savitz

  5. Division of Psychiatry, University College London, London, UK

    Giuseppe Carrà

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Bartoli, F., Misiak, B., Callovini, T. et al. The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites. Mol Psychiatry 26, 3419–3429 (2021). https://doi.org/10.1038/s41380-020-00913-1

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