Objectives: The kynurenine (KYN) pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of studies examining KYN pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD. Methods: The PubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies published until April 2022 that assessed KYN metabolites, namely, tryptophan (TRP), KYN, kynurenic acid (KA), quinolinic acid (QA), and 3-hydroxykynurenine (3-HK), in subjects with SZ, BD, or MDD compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected for comparison of standardized mean differences (SMD) between two groups. Results: Twenty-three articles met the inclusion criteria (k = 8, k = 8, k = 11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased (SMD = 2.64, confidence interval [CI] = 1.16 to 4.13, p = 0.0005, I2 = 96%, k = 6, n=384). TRP (k = 5) and KYN (k = 4) did not differ significantly. In BD, TRP levels (k = 7) did not differ significantly. The level of KA was increased in MDD (k = 2), but the small number of studies precluded evaluation of statistical significance. Finally, in MDD, although some studies tended to show an increased level of KYN in those with remission vs. decreased levels in those with current depression, no significant difference was found in any KYN metabolite levels. Similarly, an increased level of QA was found, but the number of studies (k = 2) was small. Conclusion: KA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. Alterations in the KYN pathway may occur based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.

Objective: Changes in the kynurenine pathway are recognized in psychiatric disorders, but their role in Alzheimer’s disease (AD) is less clear. We aimed to conduct a systematic review and meta-analysis to determine whether tryptophan and kynurenine pathway metabolites are altered in AD. Methods: We performed a systematic review and random-effects meta-analyses. Inclusion criteria were studies that compared AD and cognitively normal (CN) groups and assessed tryptophan or kynurenine pathway metabolites in cerebrospinal fluid or peripheral blood. Results: Twenty-two studies with a total of 1,356 participants (664 with AD and 692 CN individuals) were included. Tryptophan was decreased only in peripheral blood. The kynurenine-to-tryptophan ratio was only increased in peripheral blood of the AD group. 3-Hydroxykynurenine was decreased only in cerebrospinal fluid and showed higher variability in the CN group than the AD group. Kynurenic acid was increased in cerebrospinal fluid and decreased in peripheral blood. Finally, there were no changes in kynurenine and quinolinic acid between the groups. Conclusions: Our results suggested a shift toward the kynurenine pathway in both the brain and in the periphery, as well as a shift towards increased kynurenic acid production in the brain but decreased production in peripheral blood. In addition, our analysis indicated dissociation between the central and peripheral levels, as well as between plasma and serum for some of these metabolites. Finally, changes in the kynurenine pathway are suggested to be a core component of AD. More studies are warranted to verify and consolidate our results.

Treatment-resistant bipolar depression (TRBD) has been reported in about one-quarter of patients with bipolar disorders, and few interventions have shown clear and established effectiveness. We conducted a narrative review of the published medical literature to identify papers discussing treatment-resistant depression concepts and novel interventions for bipolar depression that focus on TRBD. We searched for potentially relevant English-language articles published in the last decade. Selected articles (based on the title and abstract) were retrieved for a more detailed evaluation. A number of promising new interventions, both pharmacological and non-pharmacological, are being investigated for TRBD treatment, including ketamine, lurasidone, D-cycloserine, pioglitazone, N-acetylcysteine, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cyclooxygenase 2 inhibitors, magnetic seizure therapy, intermittent theta-burst stimulation, deep transcranial magnetic stimulation, vagus nerve stimulation therapy, and deep brain stimulation. Although there is no consensus about the concept of TRBD, better clarification of the neurobiology associated with treatment non-response could help identify novel strategies. More research is warranted, mainly focusing on personalizing current treatments to optimize response and remission rates.