Background:

Lithium continues to be a very important medication for major depression and bipolar disorder. Approximately 1% of Canadians use lithium and in 30-40% of people with bipolar disorder, lithium is more effective than other medications¹. Many people with bipolar disorder are getting older, so doctors are concerned about potential medical risks of lithium, including renal disease: chronic kidney disease (CKD) and nephrogenic diabetes insipidus (NDI). People with bipolar disorder often have risk factors such as natural aging, diabetes mellitus, and hypertension¹, so it is unclear whether lithium independently increases the risk of renal disease in older adults. There is little human data examining the genetic underpinnings of renal disease in this population. Mice studies suggest that underactive Inositol Monophosphate/GSK3Beta and overactive TGF-Beta molecular pathways² may be contributory.

Project Summary

Main Hypothesis: Genetic polymorphisms associated with hypofunctioning of the Inositol Monophosphate/GSK3Beta pathway and hyperfunctioning of the TGF-Beta pathway are associated with increased risk of renal disease.

Methods: From the Douglas hospital, we will recruit 200 patients with bipolar disorder (100 aged ≥60, 100 aged 18-59), with half of these using lithium and half using other medications. Patients will undergo one blood and urine tests.

Outcome: CKD (estimated glomerular filtration rate) and NDI (urine osmolality).

Exposure: Single nucleotide polymorphisms (SNPs) in TGF-Beta and Inositol Monophosphate/GSK3Beta pathways3.

Analyses: We will conduct chi-squared, t-tests, and logistic regression analyses between genetic SNPs/pathways with both CKD and NDI, controlling for covariates (e.g. age, diabetes mellitus).

Sample Size: With 100 lithium users and 200 subjects total at two-tailed alpha=0.05 and 1-Beta=0.80, ANCOVA will be able to detect effect sizes of 0.27 and 0.20 (G*Power 3.1.3, Universitat Kiel, Germany), which will be adequate³.

Significance: This will be the first human study to 1) examine genetic predictors of renal disease in older lithium users and 2) rigorously examine multiple possible predictors of renal disease in a broad age range of lithium users using a bipolar disorder control group.

A better understanding of molecular mechanisms underlying renal disease will help us:

• Identify genetic profiles associated with higher risk of developing renal disease, which could eventually be used in clinical practice to better weigh the risks of lithium in those patients. This personalized medicine could allow more patients with mood disorders to be appropriately treated psychiatrically, while lowering medical risks, thereby potentially lowering future psychiatric and medical health resource utilization in Canada.
• Confirm potential biological mechanisms underlying kidney disease in human lithium users, thereby identifying potential treatment and prevention targets
• Better understand molecular mechanisms potentially involved in the neurobiology of lithium and bipolar disorder, helping researchers develop new strategies to treat bipolar disorder, which remains difficult-to-treat and poorly understood.

1. Rej et al 2014. Prevalence and Correlates of Renal Disease in Older Lithium Users: A Population-Based Study. Am J Geriatric Psychiatry
2. Walker et al 2013. Chronic interstitial fibrosis in the rat kidney induced by long-term exposure to lithium. Am J Physiology.
3. Rybakowski, J. K. 2013. Genetic influences on response to mood stabilizers in bipolar disorder: current status of knowledge. CNS drugs