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

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

J Psychiatry Neurosci 2021;46(1):E166-E175 | PDF

Tomasz Pawlowski, MD, PhD; Dariusz Pawlak, PhD; Malgorzata Inglot, MD, PhD; Malgorzata Zalewska, PhD; Dominik Marciniak, PhD; Jolanta Bugajska, PhD; Justyna Janocha-Litwin, MD; Krzysztof Malyszczak, MD, PhD

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-HT1A and 5-HT2A, 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.


Submitted Feb. 7, 2020; Revised Apr. 5, 2020; Revised Jul. 15, 2020; Accepted Jul. 20, 2020

Acknowledgments: We would like to thank Professor Krzysztof Simon, Head of the First Clinical Unit of the Gromkowski Regional Specialist Hospital of Infectious Diseases in Wroclaw, for consenting to the recruitment of patients treated in this unit.

Affiliations: From the Division of Psychotherapy and Psychosomatic Medicine, Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland (Pawlowski, Malyszczak); the Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland (Pawlak); the Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiency, Wroclaw Medical University, Wroclaw, Poland (Inglot, Zalewska); the Department of Drugs Form Technology, Wroclaw Medical University, Wroclaw, Poland (Marciniak); the Clinical Biochemistry Department, Jagiellonian University College of Medicine, Krakow, Poland (Bugajska); and the Department of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland (Janocha-Litwin).

Competing interests: None declared.

Contributors: T. Pawlowski, D. Pawlak and K. Malyszczak designed the study. T. Pawlowski, M. Inglot, M. Zaleska, J. Bugajska and J. Janocha-Litwin acquired the data, which T. Pawlowski and D. Marciniak analyzed T. Pawlowski wrote the article, which all authors reviewed. All authors approved of the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

Funding: This study was supported by research grants NN402366733, NN402586140 from the Polish Ministry of Higher Education.

DOI: 10.1503/jpn.190139

Correspondence to: T. Pawlowski, Department of Psychiatry, Wroclaw Medical University Faculty of Medicine, Pasteura 10 Wroclaw Dolny Slask 50-367, Poland; tomasz.pawlowski@umed.wroc.pl