Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study
Antoine Lefrere
(1, 2, 3)
,
Ophélia Godin
(4, 1)
,
Stéphane Jamain
(5, 1)
,
Yecodji Dansou
(1)
,
Ludovic Samalin
(1, 6, 7, 8)
,
Martin Alda
(9, 10)
,
Bruno Aouizerate
(11, 12, 1)
,
Valérie Aubin
(1, 13)
,
Romain Rey
(14, 15, 1)
,
Martina Contu
(16)
,
Philippe Courtet
(17, 18, 1)
,
Caroline Dubertret
(19, 20, 1)
,
Emmanuel Haffen
(21, 1, 22)
,
Dominique Januel
(23, 1)
,
Marion Leboyer
(24, 1)
,
Pierre Michel Llorca
(8, 7, 6, 1)
,
Emeline Marlinge
(25, 26, 1)
,
Mirko Manchia
(16)
,
Samantha Neilson
(3)
,
Emilie Olié
(17, 18, 1)
,
Pasquale Paribello
(27)
,
Marco Pinna
(16, 27)
,
Mircea Polosan
(28, 29, 1)
,
Paul Roux
(30, 31, 1)
,
Raymund Schwan
(32, 33, 1)
,
Leonardo Tondo
(27, 34, 35)
,
Michel Walter
(36, 1)
,
Eleni Tzavara
(37, 2)
,
Guillaume Auzias
(3)
,
Christine Deruelle
(3)
,
Bruno Etain
(24, 1)
,
Raoul Belzeaux
(17, 18, 1)
1
Fondation FondaMental [Créteil]
2 APHM - Assistance Publique - Hôpitaux de Marseille
3 INT - Institut de Neurosciences de la Timone
4 U955 Inserm - UPEC - IMRB - "Biologie du système neuromusculaire" [Créteil]
5 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
6 IP - Institut Pascal
7 UCA - Université Clermont Auvergne
8 Service Psychiatrie Adulte [CHU Clermont-Ferrand]
9 Dalhousie University [Halifax]
10 National Institute of Mental Health, Klecany, Czech Republic
11 Centre hospitalier Charles Perrens [Bordeaux]
12 NutriNeuro - Nutrition et Neurobiologie intégrée
13 Centre Hospitalier Princesse Grace
14 Centre Hospitalier le Vinatier [Bron]
15 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
16 University of Cagliari
17 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
18 IGF - Institut de Génomique Fonctionnelle
19 Hôpital Louis Mourier - AP-HP [Colombes]
20 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
21 NEURO - Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481)
22 Inserm CIC 1431 - Centre d'Investigation Clinique de Besançon
23 EPS - Etablissement public de santé de Ville-Evrard [Neuilly-sur-Marne]
24 IMRB - Institut Mondor de Recherche Biomédicale
25 Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
26 GHU AP-HP Nord - Université Paris Cité
27 Centro Lucio Bini [Cagliari, Italy]
28 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
29 GIN - [GIN] Grenoble Institut des Neurosciences
30 CHV - Centre Hospitalier de Versailles André Mignot
31 CESP - Centre de recherche en épidémiologie et santé des populations
32 CPN - Centre Psychothérapique de Nancy [Laxou]
33 UL - Université de Lorraine
34 McLean Hospital [Belmont, Ma.]
35 HMS - Harvard Medical School [Boston]
36 CHU - BREST - Hopital de Bohars - CHRU Brest
37 INCC - UMR 8002 - Centre Neurosciences intégratives et Cognition / Integrative Neuroscience and Cognition Center
2 APHM - Assistance Publique - Hôpitaux de Marseille
3 INT - Institut de Neurosciences de la Timone
4 U955 Inserm - UPEC - IMRB - "Biologie du système neuromusculaire" [Créteil]
5 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
6 IP - Institut Pascal
7 UCA - Université Clermont Auvergne
8 Service Psychiatrie Adulte [CHU Clermont-Ferrand]
9 Dalhousie University [Halifax]
10 National Institute of Mental Health, Klecany, Czech Republic
11 Centre hospitalier Charles Perrens [Bordeaux]
12 NutriNeuro - Nutrition et Neurobiologie intégrée
13 Centre Hospitalier Princesse Grace
14 Centre Hospitalier le Vinatier [Bron]
15 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
16 University of Cagliari
17 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
18 IGF - Institut de Génomique Fonctionnelle
19 Hôpital Louis Mourier - AP-HP [Colombes]
20 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
21 NEURO - Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481)
22 Inserm CIC 1431 - Centre d'Investigation Clinique de Besançon
23 EPS - Etablissement public de santé de Ville-Evrard [Neuilly-sur-Marne]
24 IMRB - Institut Mondor de Recherche Biomédicale
25 Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
26 GHU AP-HP Nord - Université Paris Cité
27 Centro Lucio Bini [Cagliari, Italy]
28 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
29 GIN - [GIN] Grenoble Institut des Neurosciences
30 CHV - Centre Hospitalier de Versailles André Mignot
31 CESP - Centre de recherche en épidémiologie et santé des populations
32 CPN - Centre Psychothérapique de Nancy [Laxou]
33 UL - Université de Lorraine
34 McLean Hospital [Belmont, Ma.]
35 HMS - Harvard Medical School [Boston]
36 CHU - BREST - Hopital de Bohars - CHRU Brest
37 INCC - UMR 8002 - Centre Neurosciences intégratives et Cognition / Integrative Neuroscience and Cognition Center
Guillaume Auzias
- Fonction : Auteur
- PersonId : 19274
- IdHAL : guillaume-auzias
- ORCID : 0000-0002-0414-5691
- IdRef : 142544736
Bruno Etain
- Fonction : Auteur
- PersonId : 757741
- IdHAL : bruno-etain
- ORCID : 0000-0002-5377-1488
- IdRef : 074181106
Raoul Belzeaux
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- Fonction : Auteur correspondant
- PersonId : 1429400
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Résumé
Background: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses.
Method: We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications.
Results: Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD.
Conclusions: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.