The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: A systematic review and meta-analysis

Abstract

Background: There is now evidence that affective disorders including major depressive disorder (MDD) and bipolar disorder (BD) are mediated by immune-inflammatory and nitro-oxidative pathways. Activation of these pathways may be associated with activation of the tryptophan catabolite (TRYCAT) pathway by inducing indoleamine 2,3-dioxygenase (IDO, the rate-limiting enzyme) leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs).

Aims: To systematically review and meta-analyze central and peripheral (free and total) TRP levels, its competing amino-acids (CAAs) and TRYCATs in MDD and BD.

Methods: This review searched PubMed, Google Scholar and SciFinder and included 121 full-text articles and 15470 individuals, including 8024 MDD/BD patients and 7446 healthy controls.

Results: TRP levels (either free and total) and the TRP/CAAs ratio were significantly decreased (p < 0.0001) in MDD/BD as compared with controls with a moderate effect size (standardized mean difference for TRP: SMD = -0.513, 95% confidence interval, CI: -0.611; -0.414; and TRP/CAAs: SMD = -0.558, CI: -0.758; -0.358). Kynurenine (KYN) levels were significantly decreased in patients as compared with controls with a small effect size (p < 0.0001, SMD = -0.213, 95%CI: -0.295; -0.131). These differences were significant in plasma (p < 0.0001, SMD = -0.304, 95%CI: -0.415, -0.194) but not in serum (p = 0.054) or the central nervous system (CNS, p = 0.771). The KYN/TRP ratio, frequently used as an index of IDO activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD.

Conclusions: Our findings suggest that MDD and BD are accompanied by TRP depletion without IDO and TRYCAT pathway activation. Lowered TRP availability is probably the consequence of lowered serum albumin during the inflammatory response in affective disorders.

Keywords: Affective disorders; Inflammation; Neuro-immune; Neurotoxicity; Oxidative and nitrosative stress; Psychiatry.

Fig. 1

A Summary of tryptophan catabolite (TRYCAT) pathway in affective disorders. E.S.: Effect size, TRYCAT: Tryptophan catabolite, IFN-γ: Interferon-Gamma, IL-6: Interleukin 6, IL-1β: Interleukin-1 beta, O&NS: Oxidative and nitrosative stress, NO: Nitric Oxide, 5-HT: 5-Hydroxytryptamine, LPS: Lipopolysaccharides, CNS: Central nervous system, IDO: Indoleamine 2,3 dioxygenase, TDO: Tryptophan 2,3-dioxygenase, KAT: Kynurenine Aminotransferase, KMO: Kynurenine 3-monooxygenase, KYNU: Kynureninase, TRP: Tryptophan, KYN: Kynurenine, KA: Kynurenic Acid, 3HK: 3-Hydroxykynurenine, AA: Anthranilic Acid, XA: Xanthurenic Acid, 3HA: 3-Hydroxyanthranilic Acid, PA: Picolinic Acid, QA: Quinolinic Acid.

Fig. 2

The PRISMA flow chart.