Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

预测双相情感障碍（BD）中的锂反应（LiR）可能会为治疗计划提供依据，但表型异质性会使基因组标记物的发现复杂化。我们假设具有“典型表型”的患者（其临床特征与LiR和无应答（LiNR）可靠相关）的患者比具有较少典型表型的患者在基因上更具可分离性。使用从BD患者（ 7个中心的n = 1266； 34.7％应答者）收集的临床数据，我们计算出“临床样本评分”，该评分衡量受试者的临床表型可可靠预测LiR / LiNR的程度。对于患者的基因型可用（ñ = 321），我们评估了根据遗传数据，与临床样本得分最高的25％（“最佳临床样本”）相比，应答者/非应答者的亚组是否更准确地进行了分类；临床范例评分（“不良临床范例”）。平均而言，LiR的最佳临床表现是发病较晚，临床完全发作，无快速骑车和精神病以及精神病合并症。LiR和LiNR的最佳临床示例在基因上是可分离的，接受者工作特征曲线下的面积为0.88（IQR [0.83，0.98]），而接受者的工作特性曲线为0.66 [0.61，0.80]（p = 0.0032）。阿尔茨海默氏症的淀粉样蛋白-分泌酶途径以及G蛋白偶联受体，毒蕈碱型乙酰胆碱和组胺H1R信号传导途径的变异是信息丰富的预测因子。这项研究必须在较大的样本上重复进行，并扩展到预测对其他情绪稳定剂的反应。