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

Abbas F Almulla; Yanin Thipakorn; Asara Vasupanrajit; Ali Abbas Abo Algon; Chavit Tunvirachaisakul; Ashwan Abdulzahra Hashim Aljanabi; Gregory Oxenkrug; Hussein K Al-Hakeim; Michael Maes

doi:10.1016/j.bbih.2022.100537

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

Brain Behav Immun Health. 2022 Oct 21:26:100537. doi: 10.1016/j.bbih.2022.100537. eCollection 2022 Dec.

Authors

Affiliations

¹ Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
² Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq.
³ Iraqi Education Ministry, Najaf, Iraq.
⁴ Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
⁵ Department of Psychiatry, Faculty of Medicine, University of Kufa, Iraq.
⁶ Department of Psychiatry Al-Hakeem General Hospital, Iraq.
⁷ Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, 02111, USA.
⁸ Department of Chemistry, College of Science, University of Kufa, Kufa, Iraq.
⁹ Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
¹⁰ Department of Psychiatry, IMPACT Strategic Research Centre, Deakin University, Geelong, Victoria, Australia.

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.

Publication types

Review