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 leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs). Aims To systematically review and meta-analyze TRP, its competing amino-acids (CAAs) and TRYCAT data 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 indoleamine-dioxygenase (IDO) activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD. Conclusions Our findings revealed that MDD/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.