Bremer Troy, Diamond Cornelius, McKinney Rebecca, Shehktman Tatyana, Barrett Thomas B, Herold Chris, Kelsoe John R
Prediction Sciences, Inc., San Diego, California, USA.
Mol Diagn Ther. 2007;11(3):161-70. doi: 10.1007/BF03256238.
Based on results from randomized, controlled clinical trials, lithium monotherapy or lithium with the addition of an antipsychotic remains a first-line treatment option for both acute and long-term mood stabilization in bipolar mania. However, response to lithium is poor in bipolar patients who exhibit clinical characteristics such as rapid cycling and mixed manic states, suggesting that they may have a biologically and genetically distinct form of bipolar disorder. A test that could predict response to lithium based upon genetic factors would have significant clinical value.
Eight clinical characteristics were assessed in 92 lithium responders and 92 nonresponders; all probands were from families recruited for linkage studies. Lithium response was rated retrospectively from a standardized interviews and medical records. Eight candidate genes were selected from those reported to be associated with susceptibility to illness, lithium response, or lithium mechanism of action. Sixty-seven single nucleotide polymorphisms (SNPs) were genotyped in these subjects and analyzed for association with the defined clinical characteristics.
Using q-value analysis for multiplicity correction, we found significant interactions between lithium response and SNPs (rs1387923 and rs1565445) in the gene encoding neurotrophic tyrosine kinase receptor type 2 (NTRK2) and suicidal ideation, and between SNP rs2064721 in the gene encoding inositol polyphosphate-1-phosphatase (INPP1) and post-traumatic stress disorder.
These data support the idea that response to lithium has a multi-genetic etiology dependent upon manifestations of other clinical co-diagnoses.
基于随机对照临床试验的结果，锂盐单药治疗或锂盐联合抗精神病药物仍是双相躁狂症急性和长期情绪稳定的一线治疗选择。然而，表现出快速循环和混合躁狂状态等临床特征的双相情感障碍患者对锂盐的反应较差，这表明他们可能患有生物学和遗传学上不同形式的双相情感障碍。一项能够基于遗传因素预测对锂盐反应的测试将具有重要的临床价值。
对92名锂盐反应者和92名无反应者评估了8种临床特征；所有先证者均来自为连锁研究招募的家庭。通过标准化访谈和病历对锂盐反应进行回顾性评分。从报道与疾病易感性、锂盐反应或锂盐作用机制相关的基因中选择了8个候选基因。在这些受试者中对67个单核苷酸多态性（SNP）进行基因分型，并分析其与确定的临床特征的关联。
使用q值分析进行多重校正，我们发现编码神经营养酪氨酸激酶受体2（NTRK2）的基因中的SNP（rs1387923和rs1565445）与自杀观念之间以及编码肌醇多磷酸-1-磷酸酶（INPP1）的基因中的SNP rs2064721与创伤后应激障碍之间，锂盐反应存在显著相互作用。
这些数据支持这样一种观点，即对锂盐的反应具有多基因病因，这取决于其他临床共病的表现。
