From non-specific biomarker to targeted action: transdiagnostic and sex-specific drivers of high-CRP status in severe mental illness across the FondaMental Advanced Centers of Expertise (FACE) cohorts
Brain, Behavior, and Immunity. 2026-05-01; 134: 106464
DOI: 10.1016/j.bbi.2026.106464
Rietberg T(1), Barbosa S(2), Meysman P(3), Aouizerate B(4), Bellivier F(5),
Berna F(6), Capdevielle D(7), Chereau I(8), Courtet P(9), Dondé C(10), Dubertret
C(11), Etain B(5), Hage WE(12), Gerentes M(13), Holtzmann J(14), Fakra E(15),
Haffen E(16), Bouaziz N(17), Lefrere A(18), Llorca PM(8), Mallet J(19), Misdrahi
D(20), Olié E(9), Pelletier A(13), Piva G(21), Pignon B(22), Polosan M(23), Rey
R(24), Roux P(25), Samalin L(8), Schürhoff F(22), Schwan R(26), Stephan F(27),
Szekely D(28), Urbach M(25), Vaiva G(29), Very E(30), Yrondi A(31), Leboyer
M(22), Picker L(32), Godin O(22).
Author information:
(1)Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of
Antwerp, Antwerp, Belgium; Scientific Initiative of Neuropsychiatric and
Psychopharmacological Studies (SINAPS), University Psychiatric Centre Campus
Duffel, Duffel, Belgium.
(2)Sorbonne Université, Inserm, Institut Pierre Louis d’Epidémiologie et de
Santé Publique (IPLESP), Epidémiologie Sociale, Santé Mentale et Addictions
(ESSMA), 75012 Paris, France.
(3)Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing
(AUDACIS), University of Antwerp, Antwerp, Belgium; ADReM Data Lab, Department
of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium.
(4)Fondation FondaMental, Créteil, France; Pôle de Psychiatrie Générale et
Universitaire, Centre Hospitalier Charles Perrens, Laboratoire de Nutrition et
Neurobiologie intégrée, NutriNeuro (UMR INRAe 1286), Université de Bordeaux,
Bordeaux, France.
(5)Fondation FondaMental, Créteil, France; Université Paris Cité, INSERM,
Optimisation Thérapeutique en Neuropharmacologie, OPTEN U1144, Département de
Psychiatrie et de Médecine Addictologique, Hôpitaux Lariboisière-Fernand Widal,
GHU APHP.Nord – Université Paris Cité, Paris F-75010, France.
(6)Fondation FondaMental, Créteil, France; Hôpitaux Universitaires de
Strasbourg, Université de Strasbourg, INSERM U1329, Fédération de Médecine
Translationnelle de Strasbourg, Strasbourg, France.
(7)Fondation FondaMental, Créteil, France; Universitary Department of Adult
Psychiatrie, CHU Montpellier, IGF, Univ. Montpellier, CNRS, INSERM, Montpellier,
France.
(8)Fondation FondaMental, Créteil, France; Department of Psychiatry, CHU
Clermont-Ferrand, University of Clermont Auvergne, CNRS, Clermont Auvergne INP,
Institut Pascal (UMR 6602), Clermont-Ferrand, France.
(9)Fondation FondaMental, Créteil, France; Department of Emergency Psychiatry
and Acute Care, Lapeyronie Hospital, Centre Hospitalier Universitaire de
Montpellier, Institute of Functional Genomics, University of Montpellier,
National Centre for Scientific Research, French National Institute of Health and
Medical Research, Montpellier, France.
(10)Fondation FondaMental, Créteil, France; Univ. Grenoble Alpes, F-38000
Grenoble, France; Inserm U1216, F-38000 Grenoble, France; Psychiatry Department,
CH Alpes Isere, F-38000 Grenoble, France; Psychiatry Department, CHU Grenoble
F-38000 Grenoble, France.
(11)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 de Paris
Inserm UMR1266, Sorbonne Paris Cité, Faculté de Médecine, France.
(12)Fondation FondaMental, Créteil, France; Université de Tours, INSERM, Imaging
Brain & Neuropsychiatry iBraiN U1253, 37032 Tours, France.
(13)Fondation FondaMental, Créteil, France; Assistance Publique Hôpitaux de
Paris, Hôpitaux Universitaires Henri Mondor, Département Médico-Universitaire de
Psychiatrie et d’Addictologie, France.
(14)Fondation FondaMental, Créteil, France; Psychiatry Department, CHU Grenoble
F-38000 Grenoble, France.
(15)Fondation FondaMental, Créteil, France; Department of Psychiatry, University
Hospital of Saint-Etienne, Saint-Etienne, France; Department of Adult
Psychiatry, Charles Perrens Hospital, Bordeaux, France.
(16)Fondation FondaMental, Créteil, France; Université Marie et Louis Pasteur,
UMR INSERM LINC 1322, Besançon, Service de Psychiatrie de l’Adulte, CIC-1431
INSERM, CHU de Besançon, France.
(17)Fondation FondaMental, Créteil, France; Université Sorbonne Paris Nord
93017, Bobigny Cedex, France; Département de recherche clinique, Pole
universitaire93G03, EPS Ville Evrard Neuilly sur Marne, 93330, France; INSERM
U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Université
Claude Bernard Lyon 1, Equipe PSYR2, Centre Hospitalier Le Vinatier, Pole Est,
95 bd Pinel, BP 30039, 69678 Bron Cedex, France.
(18)Fondation FondaMental, Créteil, France; Pôle de Psychiatrie, Assistance
Publique Hôpitaux de Marseille, Marseille, France.
(19)Fondation FondaMental, Créteil, France; Service de Psychiatrie, Centre
Hospitalier Universitaire d’Orléans, EPSM du Loiret, B-CLINE, Laboratoire
Interdisciplinaire pour l’Innovation et la Recherche en Santé d’Orléans
(LI2RSO), Université d’Orléans, Orléans, France.
(20)Fondation FondaMental, Créteil, France; University of Bordeaux, Aquitaine
Institute for Cognitive and Integrative Neuroscience (CNRS UMR 5287-INCIA),
Bordeaux, France; Department of Adult Psychiatry, Charles Perrens Hospital,
Bordeaux, France.
(21)Fondation FondaMental, Créteil, France; INSERM U1028, CNRS UMR5292, Centre
de Recherche en Neurosciences de Lyon, Université Claude Bernard Lyon 1, Equipe
PSYR2, Centre Hospitalier Le Vinatier, Pole Est, 95 bd Pinel, BP 30039, 69678
Bron Cedex, France.
(22)Fondation FondaMental, Créteil, France; Assistance Publique Hôpitaux de
Paris, Hôpitaux Universitaires Henri Mondor, Département Médico-Universitaire de
Psychiatrie et d’Addictologie, France; Université Paris Est Créteil (UPEC),
INSERM, Institut Henri Mondor de Recherche Biomédicale, Laboratoire
Neuro-Psychiatrie Translationnelle, Créteil, France.
(23)Fondation FondaMental, Créteil, France; Université Grenoble Alpes, Inserm,
U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France.
(24)Fondation FondaMental, Créteil, France; Department of Adult Psychiatry,
Charles Perrens Hospital, Bordeaux, France.
(25)Fondation FondaMental, Créteil, France; Versailles Hospital, Department of
Adult Psychiatry and Addictology, Centre Hospitalier de Versailles, 177 rue de
Versailles, 78157 Le Chesnay, France; MOODS Team, INSERM UMR1018, CESP, Faculté
de Médecine Paris-Saclay, Université de Versailles Saint-Quentin-En-Yvelines,
Université Paris-Saclay, Villejuif, France.
(26)Fondation FondaMental, Créteil, France; Université de Lorraine, Centre
Psychothérapique de Nancy, Inserm U1254, Nancy, France.
(27)Fondation FondaMental, Créteil, France; Service Hospitalo-Universitaire de
Psychiatrie Générale et de Réhabilitation Psycho Sociale, 29G01 Et 29G02,
Fondation FondaMental, EA 7479 CHU Brest, France.
(28)Fondation FondaMental, Créteil, France; Service de Psychiatrie, Centre
Hospitalier Princesse Grace, 9800, Monaco.
(29)Fondation FondaMental, Créteil, France; Inserm-U1172-LilNCog-Lille
Neuroscience & Cognition, Centre National de Ressources & Résilience pour les
Psychotraumatismes (Cn2r Lille Paris), Université de Lille (CHU Lille), 59000
Lille, France.
(30)Fondation FondaMental, Créteil, France; Department of Psychiatry,
Psychotherapies, Art-therapy, Toulouse University Hospital, France; Equipe de
Recherche sur les Rationalités Philosophiques et les Savoirs – EA3051,
Université de Toulouse – Jean Jaurès, Toulouse, France.
(31)Fondation FondaMental, Créteil, France; Service de Psychiatrie et de
Psychologie Médicale, Centre Expert Dépression Résistante FondaMental, CHU de
Toulouse, Hôpital Purpan, ToNIC Toulouse, NeuroImaging Centre, Toulouse, France;
Université de Toulouse, INSERM, UPS, Toulouse, France.
(32)Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of
Antwerp, Antwerp, Belgium; Scientific Initiative of Neuropsychiatric and
Psychopharmacological Studies (SINAPS), University Psychiatric Centre Campus
Duffel, Duffel, Belgium. Electronic address: .
BACKGROUND AND OBJECTIVES: Low-grade systemic inflammation contributes to the
pathophysiology of severe mental illness (SMI) in a substantial subset of
patients, who often experience greater disease burden and poorer treatment
response. Elevated C-reactive protein (CRP), defined as CRP ≥ 3 mg/L, has been
proposed to identify this group, but its non-specificity limits the biomarker’s
ability to guide targeted intervention. We aimed to determine the most
consistent drivers of high CRP across bipolar disorder (BD), schizophrenia (SZ)
and major depressive disorder (MDD), and to translate these into clinically
actionable intervention targets using robust data-driven methods.
METHODS: We pooled and harmonised data from three large French national SMI
cohorts (n = 7149: 4797 bipolar disorder, 1958 schizophrenia and 394 resistant
major depression) and classified participants by CRP ≥ 3 mg/L, as well as an
alternative cut-off of 5 mg/L. We applied penalised logistic regression (PLR),
random forests (RF) and unsupervised clustering, using 28 biopsychosocial
variables to identify robust drivers of high-CRP status. We then grouped these
into actionable targets and assessed relative dominance.
RESULTS: In total, 30.16% of participants had CRP ≥ 3 mg/L. PLR identified
female sex (OR [95% CI]: 1.60 [1.27, 1.93]), higher BMI (OR: 1.09 [1.07, 1.13]),
current nicotine dependence (OR: 1.05 [1.02, 1.09]), lower HDL cholesterol (OR:
0.57 [0.44, 0.73]) and smoking (ex-smoker status OR: 0.84 [0.66, 0.98]) as
consistent drivers. RF highlighted a similar set of key drivers, also including
waist circumference, triglycerides and cardiovascular comorbidities. Clustering
of the high-CRP group was almost entirely driven by smoking status and nicotine
dependence. When grouped into actionable targets, the identified drivers
accounted for 16% of variance in CRP status, with obesity emerging as most
dominant contributor. This pattern was most pronounced in females; in males it
was more diffuse, with a more prominent role for smoking.
CONCLUSIONS: We propose a decision tree framework where CRP can serve as a
first-line screening marker for inflammation in SMI, with subsequent steps
focusing on the main contributing factors to guide targeted interventions.
Priority should be given to targeting obesity and metabolic dysregulation. Among
females, hyperuricemia represents the next most appropriate target, whereas in
males, smoking warrants greater attention. This stepwise approach provides a
route from a non-specific biomarker to targeted treatment strategies and should
be validated in prospective studies.
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbi.2026.106464
PMID: 41621630
Conflict of interest statement: Declaration of competing interest The authors
declare the following financial interests/personal relationships which may be
considered as potential competing interests: Unrelated to the submitted work,
LDP reports honoraria for consultancy and presentations from
Boehringer-Ingelheim and Janssen R&D. LDP and ML are members of the ECNP
Immuno-NeuroPsychiatry Network.