Investigation of the Effects of in Vivo Lithium Treatment on Gene Expression Levels Using Lymphoblastoid Cell Lines From Human Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Enzymatic activity of Complex I (known to be altered by lithium) analyzed in lymphoblastoid cell cultures established from lymphocytes sampled in healthy volunteers before and after one month of lithium treatment.
研究概览
简要总结
Psychiatric disorders often result from dysregulation in cellular and molecular mechanisms at the level of the brain. Unable to directly study brain tissues in patients affected by psychiatric conditions, researchers have created alternative experimental models that use different and easy to collect tissues. The underlying assumption is that by studying these "proxy" tissues, it is possible to obtain information on biological mechanisms that is a good approximation of what would be detected in the brain. One of the most established experimental models are lymphoblastoid cell lines derived from B-lymphocytes. Lymphocytes are present in the peripheral blood and can be easily collected and stored virtually forever after undergoing a special laboratory procedure that immortalize them. These cell lines have proved to be very useful in genetic and pharmacogenetic research and, using these, the investigators want to investigate the cellular effects of a mood stabilizing drug called lithium on this specific procedure that makes them virtually immortal. Two main reasons lead us to study this drug: 1) it is the most effective treatment in bipolar disorder, where approximately 30% of patients achieve complete illness remission with prevention of episode recurrence; 2) it has well established regulatory effects on the expression of specific target genes and proteins. The investigators can take advantage of these well-established properties of lithium in regulating the expression of genes, proteins, and enzymes in a stable manner. Conversely, these biological measures could be used as markers for the effects of lithium on the gene expression.
The purpose of this study is to learn more about the changes in the activity of genes in cells sampled from healthy individuals treated with lithium. By studying these cellular changes, the investigators hope to understand if lymphoblastoid cell lines are valid tools in psychiatric genetics research. Specifically, the investigators want to see how specially treated lymphoblastoid cell lines are influenced by external conditions and specifically lithium treatment at the moment of sampling. To do so, the investigators will measure the gene expression (i.e. how much gene is in the cell) of lymphoblastoid cell lines and compare the levels between those sampled before and after one month of lithium treatment.
详细描述
Background
One of the major limitations of psychiatric research is the necessity to use indirect methods to study neuronal functions. Among these, studies of transformed lymphocytes are an invaluable tool. Epstein Barr virus (EBV) transformed lymphoblasts can be used for a variety of purposes including in vitro studies of gene expression and investigations of cellular responses to pharmacological treatment. They can be kept and re-grown as needed and can often serve as a backup supply for DNA for genetic analyses. For these reasons, lymphoblasts cell lines (LCLs) have been collected and used by a number of research groups, including our own.
Most investigators work with the implicit assumption that such transformed cells represent trait characteristics of the person and their illness. In other words, the cell transformation and repeated passages are assumed to reduce the impact of any confounding factors present at the time of blood sampling and lymphocyte isolation. These factors may include, among others, the clinical state, the actual treatment, or time of the day. Surprisingly, we could not find any published data supporting or contradicting this assumption.
Here we propose to investigate the effects of one particular factor that may influence various cellular measures, namely in vivo drug treatment. Specifically, we are interested in assessing the effect of treatment with lithium, an ion that possesses mood-stabilizing properties. Indeed, lithium is the most effective treatment in bipolar disorder, with approximately 30% of patients achieving complete illness remission and prevention of episode recurrence (Baldessarini and Tondo, 2000; Garnham et al., 2007).
Rationale
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Men, ages 18 to 45 who are physically and mentally healthy.
排除标准
- •Personal history of Axis I psychiatric disorders. Subjects with past, but not current (for at least 12 months) history of substance abuse will be eligible.
- •Any medical conditions that represent contraindication to lithium use (for instance kidney or thyroid disease) and/or can potentially affect the gene expression profiles of the subjects.
- •Ongoing treatment with drugs that have the potential of adverse interaction with lithium, for instance chronic use of NSAIDs, or diuretics.
研究组 & 干预措施
Lithium
This will be a short-term longitudinal study of 4 weeks of duration. Twenty (20) healthy male subjects will be recruited and treated with lithium carbonate for 4 weeks. Lithium carbonate (150 mg, 300 mg, 600 mg) will be administered to the recruited subjects. The study will be performed in one centre at Capital District Health Authority - Dalhousie University, Halifax, Nova Scotia, Canada. Lithium serum levels will be tested at day 8, at day 14 and at the end of the treatment. Additional tests may be performed as necessary (as in the case of side effects).
干预措施: Lithium Carbonate (Drug)
结局指标
主要结局
Enzymatic activity of Complex I (known to be altered by lithium) analyzed in lymphoblastoid cell cultures established from lymphocytes sampled in healthy volunteers before and after one month of lithium treatment.
时间窗: 28 days
Expression levels of genes (known to be regulated by lithium) analyzed in lymphoblastoid cell cultures established from lymphocytes sampled in healthy volunteers before and after one month of lithium treatment.
时间窗: 28 days
Expression levels of a protein, BDNF (known to be regulated by lithium) analyzed in lymphoblastoid cell cultures established from lymphocytes sampled in healthy volunteers before and after one month of lithium treatment.
时间窗: 28 days
次要结局
未报告次要终点