Lowthert Lori, Leffert Janine, Lin Aiping, Umlauf Sheila, Maloney Kathleen, Muralidharan Anjana, Lorberg Boris, Mane Shrikant, Zhao Hongyu, Sinha Rajita, Bhagwagar Zubin, Beech Robert
Department of Psychiatry, New Haven, CT, 06511, USA.
Biol Mood Anxiety Disord. 2012 Sep 12;2:15. doi: 10.1186/2045-5380-2-15.
Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response.
Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software.
127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point.
These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.
许多人认为锂盐是双相情感障碍（BD）治疗的金标准药物。然而，对锂盐的临床反应存在异质性，且这种反应差异的分子基础尚不清楚。在本研究中，我们试图确定双相情感障碍（BD）患者在开始锂盐治疗后外周血基因表达谱如何随时间变化，以及这些谱随时间的差异是否与临床反应相关。
使用包含超过48,000个转录本探针的Illumina Sentrix Beadchip（Human-6v2）微阵列，测量20名BD抑郁患者在开放标签锂盐治疗8周期间治疗前及每两周外周血中的基因表达水平。比较治疗反应者（定义为汉密尔顿抑郁量表评分降低50%或更多）和无反应者之间的基因表达变化。使用GeneGO Metacore软件进行通路分析。
127个基因在反应者与无反应者中表现出差异反应。通路分析表明，凋亡调节是这些基因中受影响最显著的通路。对BCL2相关基因变化的时间进程进行更仔细检查发现，在锂盐反应者中，开始锂盐治疗一个月后，包括Bcl2和胰岛素受体底物2（IRS2）在内的几个抗凋亡基因上调，而包括BCL2拮抗剂/杀手1（BAK1）和细胞死亡相关的BCL2激动剂（BAD）在内的促凋亡基因下调。相比之下，在锂盐无反应者中，BCL2和IRS2下调，而在一个月时间点BAK1和BAD上调。
这些结果表明，锂盐治疗后促凋亡和抗凋亡基因表达平衡的差异变化可能解释了BD患者临床反应中的一些异质性。
