Kynurenine pathway abnormalities are state-specific but not diagnosis-specific in schizophrenia and bipolar disorder

Katrien Skorobogatov; Valérie Autier; Marianne Foiselle; Jean-Romain Richard; Wahid Boukouaci; Ching-Lien Wu; Sophie Raynal; Christel Carbonne; Kris Laukens; Pieter Meysman; Violette Coppens; Philippe le Corvoisier; Caroline Barau; Livia De Picker; Manuel Morrens; Ryad Tamouza; Marion Leboyer

doi:10.1016/j.bbih.2022.100584

Kynurenine pathway abnormalities are state-specific but not diagnosis-specific in schizophrenia and bipolar disorder

Brain Behav Immun Health. 2023 Jan 2:27:100584. doi: 10.1016/j.bbih.2022.100584. eCollection 2023 Feb.

Authors

Katrien Skorobogatov^{1

2}, Valérie Autier³, Marianne Foiselle^{4

5

6}, Jean-Romain Richard^{4

5

6}, Wahid Boukouaci^{4

5

6}, Ching-Lien Wu^{4

5

6}, Sophie Raynal³, Christel Carbonne³, Kris Laukens^{7

8}, Pieter Meysman^{7

8}, Violette Coppens^{1

2}, Philippe le Corvoisier⁹, Caroline Barau¹⁰, Livia De Picker^{1

2}, Manuel Morrens^{1

2}, Ryad Tamouza^{4

5

6}, Marion Leboyer^{4

5

6}

Affiliations

¹ Scientific Initiative for Neuropsychiatric and Psychopharmacological Studies (SINAPS), University Psychiatric Hospital Campus Duffel (UPCD), Duffel, Belgium.
² Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium.
³ MetaBrain Research, Chilly-Mazarin, France.
⁴ Université Paris Est Creteil, Inserm U955, IMRB Translational Neuropsychiatry Laboratory, Creteil, France.
⁵ AP-HP, Hôpitaux Universitaires H Mondor, DMU IMPACT, FHU ADAPT, Créteil, France.
⁶ Fondation FondaMental, Creteil, France.
⁷ Biomedical Informatics Research Center Antwerp (BIOMINA), University of Antwerp/Antwerp University Hospital, Antwerp, Belgium.
⁸ Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium.
⁹ Inserm, Centre d'Investigation Clinique 1430, AP-HP, Hôpital Henri Mondor, Université Paris Est Créteil, Créteil, France.
¹⁰ Plateforme de Ressources Biologiques, HU Henri Mondor, F94010, France.

Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) are associated with immunological dysfunctions that have been hypothesized to lead to clinical symptomatology in particular through kynurenine pathway abnormalities. The aim of this study was thus to investigate the impact of serum kynurenine metabolite levels on diagnosis, clinical state, symptom severity and clinical course in a large French transdiagnostic cohort of SCZ and BD patients. Four patient groups (total n = 507) were included in a cross-sectional observational study: 1) hospitalized acute bipolar patients (n = 205); 2) stable bipolar outpatients (n = 116); 3) hospitalized acute schizophrenia patients (n = 111) and 4) stable schizophrenia outpatients (n = 75), in addition to healthy controls (HC) (n = 185). The quantitative determination of serum kynurenine metabolites was performed using liquid chromatography-tandem mass spectrometry. Kynurenine levels were lower in all patients combined compared to HC while ANCOVA analyses did not reveal inter-diagnostic difference between SCZ and BD. Interestingly, hospitalized patients of both diagnostic groups combined displayed significantly lower kynurenine levels than stabilized outpatients. Psychotic symptoms were associated with lower quinaldic acid (F = 9.18, p=<.001), which is KAT-driven, whereas a longer duration of illness contributed to abnormalities in tryptophan (F = 5.41, p = .023), kynurenine (F = 16.93, p=<.001), xanthurenic acid (F = 9.34, p = .002), quinolinic acid (F = 9.18, p = .003) and picolinic acid (F = 4.15, p = .043), metabolized through the KMO-branch. These data confirm illness state rather than diagnosis to drive KP alterations in SCZ and BD. Lower levels of KP metabolites can thus be viewed as a transdiagnostic feature of SCZ and BD, independently associated with acute symptomatology and a longer duration of illness. Quinaldic acid has seldomly been investigated by previous studies and appears an important state marker in SCZ and BD. As serum samples are used in this study, it is not possible to extrapolate these findings to the brain.