Article Dans Une Revue Brain, Behavior, and Immunity Année : 2026

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

Tim Rietberg (1) , Susana Barbosa (2, 3) , Pieter Meysman (1) , Bruno Aouizerate (4, 5, 6) , Frank Bellivier (7, 6, 8, 9) , Fabrice Berna (6, 10, 11, 12) , Delphine Capdevielle (6, 13, 14) , Isabelle Chereau-Boudet (6, 15, 16, 17) , Philippe Courtet (13, 14, 6) , Clément Dondé (18, 19, 6, 20) , Caroline Dubertret (21, 6, 22) , Bruno Etain (7, 9, 6, 8) , Wissam El-Hage (23, 6) , Mona Gerentes (6, 24) , Jérôme Holtzmann (6, 20) , Eric Fakra (6, 25, 4) , Emmanuel Haffen (6, 26, 27, 28) , Noomane Bouaziz (6, 29, 30, 31, 32) , Antoine Lefrere (33, 6) , Pierre-Michel Llorca (6, 16, 17) , Jasmina Mallet (34, 35, 6, 36) , David Misdrahi (37, 6, 38, 4) , Émilie Olié (13, 14, 6) , Agnès Pelletier (6, 24) , Giulia Piva (6, 32, 31, 39) , Baptiste Pignon (6, 24, 40, 41) , Mircea Polosan (42, 6, 18, 19) , Romain Rey (6, 4) , Paul Roux (43, 6, 44) , Ludovic Samalin (6, 16, 17) , Franck Schürhoff (6, 45, 24, 46) , Raymund Schwan (6, 47, 48) , Florian Stéphan (49, 6, 50) , David Szekely (51, 6) , Mathieu Urbach (6, 43, 44) , Guillaume Vaiva (52, 53, 6, 54) , Etienne Very (6, 55, 56) , Antoine Yrondi (57, 58, 6) , Marion Leboyer (40, 6, 24, 41) , Livia De Picker (1) , Ophélia Godin (6, 24, 40, 41)
1 Universiteit Antwerpen = University of Antwerp
2 ESSMA - Equipe Sociale Santé Mentale et Addictions [iPLesp]
3 SU - Sorbonne Université
4 Centre hospitalier Charles Perrens [Bordeaux]
5 NutriNeuro - Nutrition et Neurobiologie intégrée
6 Fondation FondaMental [Créteil]
7 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
8 Hôpital Lariboisière-Fernand-Widal [APHP]
9 GHU AP-HP Nord - Université Paris Cité
10 HUS - Hôpitaux Universitaires de Strasbourg
11 FMTS - Fédération de Médecine Translationnelle de Strasbourg
12 STEP - Neuroscience et Psychiatrie Translationnelle de Strasbourg
13 Département de Psychiatrie adulte [Hôpital de la Colombière - CHU Montpellier]
14 IGF - Institut de Génomique Fonctionnelle
15 UCA - Université Clermont Auvergne
16 Service Psychiatrie Adulte [CHU Clermont-Ferrand]
17 IP - Institut Pascal
18 GIN - [GIN] Grenoble Institut des Neurosciences
19 CH Alpes Isere - Centre Hospitalier Alpes Isère [Grenoble, France]
20 Pôle Psychiatrie et Neurologie [Grenoble]
21 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
22 Hôpital Louis Mourier - AP-HP [Colombes]
23 iBraiN - Imaging, Brain & Neuropsychiatry
24 Hôpital Henri Mondor
25 Pôle Psychiatrie [CHU Saint-Etienne]
26 Inserm CIC 1431 - Centre d'Investigation Clinique de Besançon
27 LINC - Laboratoire de recherches Intégratives en Neurosciences et psychologie Cognitive
28 UMLP - Université Marie et Louis Pasteur
29 EPS - Etablissement public de santé de Ville-Evrard [Neuilly-sur-Marne]
30 Université Sorbonne Paris Nord
31 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
32 Centre Hospitalier le Vinatier [Bron]
33 APHM - Assistance Publique - Hôpitaux de Marseille
34 LI2RSO - Laboratoire Interdisciplinaire pour l'Innovation et la Recherche en Santé d’Orléans
35 CHU Orléans - Centre Hospitalier Universitaire d'Orléans
36 EPSM Georges Daumézon - Etablissement public de santé mentale du Loiret Georges Daumézon
37 UB - Université de Bordeaux
38 INCIA - Institut de Neurosciences cognitives et intégratives d'Aquitaine
39 UCBL - Université Claude Bernard Lyon 1
40 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
41 UPEC Médecine - Université Paris-Est Créteil Val-de-Marne - Faculté de médecine
42 CHUGA - CHU de Grenoble-Alpes - Centre Hospitalier Universitaire CHU Grenoble
43 CHV - Centre Hospitalier de Versailles André Mignot
44 CESP - Centre de recherche en épidémiologie et santé des populations
45 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
46 U955 Inserm - UPEC - IMRB - "NeuroPsychologie Interventionnelle" [Créteil]
47 CPN - Centre Psychothérapique de Nancy [Laxou]
48 IADI - Imagerie Adaptative Diagnostique et Interventionnelle
49 EA7479 SPURBO - Soins Primaires, Santé Publique, Registre des cancers de Bretagne Occidentale
50 CHU - Brest- Psychiatrie - CHRU Brest - Psychiatrie Adulte
51 Hôpital Princesse Grace [Monaco]
52 LilNCog - Lille Neurosciences & Cognition - U 1172
53 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
54 Cn2r - Centre National de Ressources et de Résilience [Lille]
55 Service Psychiatrie, Psychothérapies et Art-thérapie [CHU Toulouse]
56 ERRAPHIS - Equipe de Recherche sur les Rationalités Philosophiques et les Savoirs
57 ToNIC - Toulouse NeuroImaging Center
58 Service Psychiatrie et psychologie médicale [CHU Toulouse]

Résumé

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 nonspecific biomarker to targeted treatment strategies and should be validated in prospective studies.

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hal-05494789 , version 1 (05-02-2026)

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Tim Rietberg, Susana Barbosa, Pieter Meysman, Bruno Aouizerate, Frank Bellivier, et al.. 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, 134, pp.106464. ⟨10.1016/j.bbi.2026.106464⟩. ⟨hal-05494789⟩
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