In Vivo Lithium Treatment Effects on Gene Expression Levels in Lymphoblastoid Cell Lines From Human Healthy Subjects

Summary

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.

Timeline

Start

2012-05-05

Primary completion

2023-05-11

Completion

2023-05-11

Publications

• Background Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch Gen Psychiatry. 2000 Feb;57(2):187-90. doi: 10.1001/archpsyc.57.2.187.
• Background Garnham J, Munro A, Slaney C, Macdougall M, Passmore M, Duffy A, O'Donovan C, Teehan A, Alda M. Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. J Affect Disord. 2007 Dec;104(1-3):185-90. doi: 10.1016/j.jad.2007.03.003. Epub 2007 Apr 17.
• Background Sun X, Young LT, Wang JF, Grof P, Turecki G, Rouleau GA, Alda M. Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder. Neuropsychopharmacology. 2004 Apr;29(4):799-804. doi: 10.1038/sj.npp.1300383.
• Background Sugawara H, Iwamoto K, Bundo M, Ishiwata M, Ueda J, Kakiuchi C, Ishigooka J, Kato T. Effect of mood stabilizers on gene expression in lymphoblastoid cells. J Neural Transm (Vienna). 2010 Feb;117(2):155-64. doi: 10.1007/s00702-009-0340-8. Epub 2009 Dec 1.
• Background Washizuka S, Iwamoto K, Kakiuchi C, Bundo M, Kato T. Expression of mitochondrial complex I subunit gene NDUFV2 in the lymphoblastoid cells derived from patients with bipolar disorder and schizophrenia. Neurosci Res. 2009 Mar;63(3):199-204. doi: 10.1016/j.neures.2008.12.004. Epub 2008 Dec 24.
• Background Tseng M, Alda M, Xu L, Sun X, Wang JF, Grof P, Turecki G, Rouleau G, Young LT. BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder. J Psychiatry Neurosci. 2008 Sep;33(5):449-53.
• Background Bosetti F, Seemann R, Bell JM, Zahorchak R, Friedman E, Rapoport SI, Manickam P. Analysis of gene expression with cDNA microarrays in rat brain after 7 and 42 days of oral lithium administration. Brain Res Bull. 2002 Jan 15;57(2):205-9. doi: 10.1016/s0361-9230(01)00744-4.
• Background McQuillin A, Rizig M, Gurling HM. A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet Genomics. 2007 Aug;17(8):605-17. doi: 10.1097/FPC.0b013e328011b5b2.
• Background Chetcuti A, Adams LJ, Mitchell PB, Schofield PR. Microarray gene expression profiling of mouse brain mRNA in a model of lithium treatment. Psychiatr Genet. 2008 Apr;18(2):64-72. doi: 10.1097/YPG.0b013e3282fb0051.
• Background Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem. 1999 Mar 5;274(10):6039-42. doi: 10.1074/jbc.274.10.6039.
• Background Sun A, Shanmugam I, Song J, Terranova PF, Thrasher JB, Li B. Lithium suppresses cell proliferation by interrupting E2F-DNA interaction and subsequently reducing S-phase gene expression in prostate cancer. Prostate. 2007 Jun 15;67(9):976-88. doi: 10.1002/pros.20586.
• Background Seelan RS, Khalyfa A, Lakshmanan J, Casanova MF, Parthasarathy RN. Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells. Neuroscience. 2008 Feb 19;151(4):1184-97. doi: 10.1016/j.neuroscience.2007.10.045. Epub 2007 Nov 13.
• Background Machado-Vieira R, Pivovarova NB, Stanika RI, Yuan P, Wang Y, Zhou R, Zarate CA Jr, Drevets WC, Brantner CA, Baum A, Laje G, McMahon FJ, Chen G, Du J, Manji HK, Andrews SB. The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry. 2011 Feb 15;69(4):344-52. doi: 10.1016/j.biopsych.2010.10.019. Epub 2010 Dec 16.
• Background Uemura T, Green M, Corson TW, Perova T, Li PP, Warsh JJ. Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder. Bipolar Disord. 2011 Feb;13(1):41-51. doi: 10.1111/j.1399-5618.2011.00897.x.

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