The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin

Abstract

Background: Tryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-α on the activity of serotonergic receptors 5-HT 1A and 5-HT 2A , and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain. Methods: The study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-α2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery-Åsberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement. Results: Of the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease (β =-0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery-Åsberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively). Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: The present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a.

Peripheral kynurenines as biomarkers and targets for prevention and treatment of psychiatric conditions associated with SARS-CoV-2 infection

“…Authors found that elevation of plasma AA (but not other studied Kyn derivatives) was the best negative prognostic marker for unfavorable course of disease (e.g., transfer to ICU, mechanical ventilation, death) in COVID-19 patients. The discovery of elevated AA plasma levels in prospective study of COVID-19 patients [19] is in line with finding of elevated plasma AA levels in prospective study of hepatitis C patients treated with interferon-alpha [21]. Notably, IFNG activates kynase, the enzyme that catalyzes AA formation from Kyn [22].…”

“…The recent prospective study found elevation of plasma AA as predictor of increased risk of major depressive disorder in interferontreated hepatitis C virus patients [21]. AA plasma levels were associated with severity of depression symptoms in female patients with no clinical and biochemical signs of inflammation [41].…”

Breathomics profiling of metabolic pathways affected by major depression: Possibilities and limitations

“…This finding may suggest that AntA level could mirror the depression severity and should be investigated in a larger population. Increased AntA levels have been reported in different mental disorders such schizophrenia ( 83 ) and MDD ( 55 ) as well as metabolic disorders including chronic hepatitis C, rheumatoid arthritis and osteoarthritis ( 84 ) and type 1 diabetes ( 85 , 86 ). A clinical study reported that blood serum level of AntA may predict the onset and progression of clinical depression ( 55 ).…”

“…Interestingly, an increase in AntA concentration was associated with decreased levels of anti-inflammatory factors in high risk MDD subjects. Pawolwski et al ( 86 ) provided first direct evidence of a role for anthranilic acid in the pathogenesis of inflammation-induced MDD ( 86 ). Generally, downstream metabolites of the kynurenine pathway and availability of tryptophan play critical role for the functioning of efferent nerve system and CNS and thus in the gut-brain communication.…”

The Kynurenine Pathway and Polycystic Ovary Syndrome: Inflammation as a Common Denominator

“…26 The TDO enzyme is under the influence of 4 regulatory mechanisms in the liver: hormonal (glucocorticoids, glucagon, and estrogens); stabilization by tryptophan against degradation; inhibition by intermediate products of tryptophan metabolism; and activation by haem. 27 The first catabolite in tryptophan metabolism governed by the IDO1/2 and TDO enzymes is kynurenine (KYN), which further yields kynurenic acid (KYNA) 28 (via kynurenine aminotransferases [KATs]), anthranilic acid (via kynureninase [KYNU]) 29 or 3-hydroxykynurenine (3-HK) via kynurenine 3-monooxygenase (KMO). 30 In the next stage of Trp metabolism, both anthranilic acid (through non-specific hydroxylation) and 3-HK (via KYNU) serve as sources for the production of 3-hydroxyanthranilic acid (3HAA).…”