Lefrere Antoine, Godin Ophélia, Jamain Stéphane, Dansou Yecodji, Samalin Ludovic, Alda Martin, Aouizerate Bruno, Aubin Valérie, Rey Romain, Contu Martina, Courtet Philippe, Dubertret Caroline, Haffen Emmanuel, Januel Dominique, Leboyer Marion, Llorca Pierre-Michel, Marlinge Emeline, Manchia Mirko, Neilson Samantha, Olié Emilie, Paribello Pasquale, Pinna Marco, Polosan Mircea, Roux Paul, Schwan Raymund, Tondo Leonardo, Walter Michel, Tzavara Eleni, Auzias Guillaume, Deruelle Christine, Etain Bruno, Belzeaux Raoul
Pôle de Psychiatrie, Assistance Publique Hôpitaux de Marseille, Marseille, France; Institut de Neurosciences de la Timone, Aix-Marseille University, Unité mixte de recherche (UMR) Centre National de la Recherche Scientifique, Marseille, France; Fondation Fondamental, Créteil, France.
Fondation Fondamental, Créteil, France; University Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Translational Neuro-Psychiatry, Assistance Publique-Hôpitaux de Paris, Département Médico-Universitaire de Psychiatrie et d'Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision en Psychiatrie (FHU ADAPT).
Biol Psychiatry. 2025 Apr 15;97(8):806-815. doi: 10.1016/j.biopsych.2024.09.025. Epub 2024 Oct 10.
Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. It has been suggested that neurodevelopmental factors contribute to the etiology of BD, but a specific neurodevelopmental phenotype (NDP) of the disorder has not been identified. Our objective was to define and characterize an NDP in BD and validate its associations with clinical outcomes, polygenic risk scores, and treatment responses.
We analyzed the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort of 4468 patients with BD, a validation cohort of 101 patients with BD, and 2 independent replication datasets of 274 and 89 patients with BD. Using factor analyses, we identified a set of criteria for defining NDP. Next, we 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 gender with bootstrap replications.
Our study established an NDP in BD consisting of 9 clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention-deficit/hyperactivity disorder, early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, and 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 NDP load and polygenic risk score for attention-deficit/hyperactivity disorder, suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and attention-deficit/hyperactivity disorder.
The proposed NDP constitutes a promising clinical tool for patient stratification in BD.
双相情感障碍（BD）是一种复杂的异质性精神疾病。有研究表明，神经发育因素与双相情感障碍的病因有关，但尚未确定该疾病的特定神经发育表型（NDP）。我们的目标是定义并描述双相情感障碍中的一种神经发育表型，并验证其与临床结局、多基因风险评分和治疗反应的关联。
我们分析了4468例双相情感障碍患者的双相情感障碍基础高级专业中心队列、101例双相情感障碍患者的验证队列以及2个分别包含274例和89例双相情感障碍患者的独立重复数据集。通过因子分析，我们确定了一组定义神经发育表型的标准。接下来，我们开发了一种神经发育表型负荷评分系统，并使用多元回归评估其与预后、神经软体征、神经发育障碍的多基因风险评分以及治疗反应的关联，同时对年龄和性别进行了自抽样重复调整。
我们的研究确定了双相情感障碍中的一种神经发育表型，该表型由9种临床特征组成：父亲年龄偏大、母亲年龄偏大、童年期受虐待、注意力缺陷多动障碍、双相情感障碍发病早、物质使用障碍发病早、焦虑障碍发病早、饮食障碍发病早以及特定学习障碍。神经发育表型负荷较高的患者预后较差，神经软体征增加。值得注意的是，这些个体对锂盐治疗的反应较差。此外，观察到神经发育表型负荷与注意力缺陷多动障碍的多基因风险评分之间存在显著正相关，这表明双相情感障碍与注意力缺陷多动障碍之间可能存在重叠的遗传因素或病理生理机制。
所提出的神经发育表型是双相情感障碍患者分层的一种有前景的临床工具。
