Association between kynurenine pathway metabolites and psychotropic medications in bipolar disorder: An exploratory study in the FACE-BD cohort
Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2026-08-01; 149: 111891
DOI: 10.1016/j.pnpbp.2026.111891
Etain B(1), Hennion V(2), Autier V(3), Raynal S(3), Godin O(4), Aouizerate B(5),
Belzeaux R(6), Courtet P(7), Dubertret C(8), Lefrere A(9), Olié E(7), Polosan
M(10), Roux P(11), Schwan R(12), Samalin L(13); Fondamental Advanced Centers Of
Expertise In Bipolar Disorders (FACE-BD) Collaborators; Leboyer M(14),
Marie-Claire C(15), Gil S(15).
Author information:
(1)Université Paris Cité, INSERM UMR-S 1144, Optimisation Thérapeutique en
Neuropharmacologie OTeN, Paris, France; AP-HP, Groupe Hospitalo-Universitaire
AP-HP Nord, DMU Neurosciences, Hôpital Fernand Widal, Département de Psychiatrie
et de Médecine Addictologique, Paris, France; Fondation FondaMental, Créteil,
France. Electronic address: .
(2)Université Paris Cité, INSERM UMR-S 1144, Optimisation Thérapeutique en
Neuropharmacologie OTeN, Paris, France; AP-HP, Groupe Hospitalo-Universitaire
AP-HP Nord, DMU Neurosciences, Hôpital Fernand Widal, Département de Psychiatrie
et de Médecine Addictologique, Paris, France; Fondation FondaMental, Créteil,
France.
(3)MetaBrain Research, Les Ulis, France.
(4)Fondation FondaMental, Créteil, France; Université Paris Est Créteil, INSERM
U955, IMRB, Translational NeuroPsychiatry Laboratory, Créteil, France.
(5)Fondation FondaMental, Créteil, France; Centre Expert Trouble Bipolaire, Pôle
de Psychiatrie Générale et Universitaire, Centre Hospitalier Charles Perrens,
Bordeaux, France; Laboratoire de Nutrition et Neurobiologie intégrée, NutriNeuro
(UMR INRAe 1286), Université de Bordeaux, Bordeaux, France.
(6)Fondation FondaMental, Créteil, France; IGF, Univ. Montpellier, CNRS, INSERM,
Montpellier, France; Service de Psychiatrie Adulte CHU Montpellier, Montpellier,
France.
(7)Fondation FondaMental, Créteil, France; Department of Emergency Psychiatry
and Acute Care, CHU Montpellier, IGF, Univ. Montpellier, CNRS, INSERM,
Montpellier, France.
(8)Fondation FondaMental, Créteil, France; AP-HP, Groupe Hospitalo-universitaire
AP-HP Nord, DMU ESPRIT, Service de Psychiatrie et Addictologie, Hôpital Louis
Mourier, Colombes, France; Université Paris Cité, Inserm UMR1266, Sorbonne Paris
Cité, Faculté de Médecine, Paris, France.
(9)Fondation FondaMental, Créteil, France; Pôle de Psychiatrie, Assistance
Publique Hôpitaux de Marseille, Marseille, France.
(10)Fondation FondaMental, Créteil, France; Univ. Grenoble Alpes, Inserm, U1216,
CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France.
(11)Fondation FondaMental, Créteil, France; Centre Hospitalier de Versailles,
Service Universitaire de Psychiatrie d’Adulte et d’Addictologie, Le Chesnay,
France; DisAP, MOODS Team, INSERM 1018, CESP, Université de Versailles
Saint-Quentin-En-Yveline, Université Paris Saclay, France.
(12)Fondation FondaMental, Créteil, France; Université de Lorraine, Nancy
France; Centre d’Etudes et de Recherches sur les SERvices de Santé et qualité de
vie (CEReSS) Aix-Marseille Université, Marseille, France.
(13)Fondation FondaMental, Créteil, France; Centre Hospitalier et Universitaire,
Département de Psychiatrie, Université Clermont Auvergne, CNRS, Clermont
Auvergne INP, Institut Pascal (UMR 6602), Clermont-Ferrand, France.
(14)Fondation FondaMental, Créteil, France; Université Paris Est Créteil, INSERM
U955, IMRB, Translational NeuroPsychiatry Laboratory, Créteil, France; AP-HP,
Hôpitaux Universitaires Henri Mondor, Département Médico-Universitaire de
Psychiatrie et d’Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire
de Médecine de Précision en Psychiatrie (FHU ADAPT), Créteil, France.
(15)Université Paris Cité, INSERM UMR-S 1144, Optimisation Thérapeutique en
Neuropharmacologie OTeN, Paris, France.
BACKGROUND: Abnormalities of the kynurenine pathway (KP) have been described in
bipolar disorder (BD). However, the associations between current psychotropic
treatments and levels of metabolites remain underexplored.
METHODS: Peripheral blood levels of tryptophan (TRP), kynurenine (KYN) and
metabolites were measured using liquid chromatography-tandem mass spectrometry
among 173 individuals with BD. Univariable and multivariable analyses were used
to test associations between each metabolite and current use of lithium,
valproate, lamotrigine, atypical antipsychotics, and antidepressants.
RESULTS: In univariable analyses, valproate current use was associated with
lower levels of TRP (padjusted = 0.00006), KYN (padjusted = 0.000004),
3-hydroxykynurenine (3OHKYN) (padjusted = 0.04), xanthurenic acid (XA)
(padjusted = 0.00004), and quinolinic acid (QUIN) (padjusted = 0.0024). Lithium
current use was associated with higher levels of KYN (padjusted = 0.002),
KYN/TRP ratio (padjusted = 0.003), 3OHKYN (padjusted = 0.008), and XA
(padjusted = 0.024). Lamotrigine current use was associated with higher levels
of KYN (padjusted = 0.03), kynurenic acid (padjusted = 0.003), and QUIN
(padjusted = 0.014). We observed no association between metabolites and current
use of atypical antipsychotics or antidepressants. After covariation by age,
sex, body mass index, tobacco use, manic and depressive symptoms at inclusion,
and BD type, multivariable analyses confirmed most of the associations: lower
levels of TRP, KYN, XA, QUIN among valproate users, higher levels of KYN,
KYN/TRP ratio, 3OHKYN among lithium users, higher levels of QUIN among
lamotrigine users.
CONCLUSIONS: The present study is the first to explore whether current use of
psychotropic drugs is associated with different levels of kynurenine pathway
metabolites in BD. We found that current use of valproate, lithium or
lamotrigine was associated with distinct kynurenine pathway profiles. Future
studies of the kynurenine pathway in psychiatry should consider current
medication exposure as a potential confounder.
Copyright © 2026. Published by Elsevier Inc.
DOI: 10.1016/j.pnpbp.2026.111891
PMID: 42600836
Conflict of interest statement: Declaration of competing interest The authors
declared no potential conflicts of interest with respect to the research,
authorship, and/or publication of this article.