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

NCT01565759 | Completed Phase 1

• 2 other identifiers: CDHA-RS-2012-317LithiumHV2012
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Drug Mechanism

Keywords

Gene expression; Lithium; Healthy volunteers; Lymphoblastoid cell lines

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  28 days

• 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.

  28 days

Study Arms (1)

Lithium

EXPERIMENTAL

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).

Drug: Lithium Carbonate

Interventions

Lithium Carbonate DRUG

The dose has been selected in order to achieve a therapeutic range of 0.6 - 0.8 mmol/L. Dose titration Day 1: 1 capsule of 300 mg at bedtime Days 2 to 7: 1 capsule of 600 mg at bedtime Day 8: lithium serum levels will be tested and the dose will be adjusted proportionally to a target range of 0.6 - 0.8 mmol/L by increments of 150 mg or 300 mg.

Lithium

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Men, ages 18 to 45 who are physically and mentally healthy.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Nova Scotia Health Authority: lead

Study Sites (1)

Department of Psychiatry, Abbie J Lane Building

Halifax, Nova Scotia, B3H 2E2, Canada

Location

Related Publications (14)

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  PMID: 10665622 BACKGROUND

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  PMID: 17442400 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.

  PMID: 14735134 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.

  PMID: 19949822 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.

  PMID: 19135101 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.

  PMID: 18787660 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.

  PMID: 11849827 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.

  PMID: 17622937 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.

  PMID: 18349697 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.

  PMID: 10037682 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.

  PMID: 17440966 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.

  PMID: 18222042 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.

  PMID: 21167476 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.

  PMID: 21320251 BACKGROUND

MeSH Terms

Interventions

Lithium Carbonate

Intervention Hierarchy (Ancestors)

Carbonates; Alkalies; Inorganic Chemicals; Carbonic Acid; Carbon Compounds, Inorganic; Lithium Compounds

Study Officials

• Martin Alda, MD, FRCPC

  Dalhousie University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 26, 2012
• First Posted: March 29, 2012
• Study Start: May 5, 2012
• Primary Completion: May 11, 2023
• Study Completion: May 11, 2023
• Last Updated: August 21, 2024

Record last verified: 2024-08

Locations

CA (1)