Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients

Abstract

Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.

Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes

“…Lithium has been shown to increase the expression of the antiapoptotic gene BCL2 [4] and also to increase cAMP-responsive element-/binding protein-mediated gene transcription [5]. More recently, microarray techniques have been applied to study the effects of lithium on mouse brain [6,7], rat brain [8], and in human neuronal or peripheral blood cell lines [9,10,11,12,13]. These studies have reported effects of lithium on the expression of a number of genes involved in ion channel and receptor function, signal transduction (including the phosphatidylinositol system), neuroprotective mechanisms, endothelial growth factor, energy metabolism, and thyroid function.…”

Glutamate-Related Antibodies and Peripheral Insulin-Like Growth Factor in Bipolar Disorder and Lithium Prophylaxis

“…The authors describe altered IGF-binding protein-2 levels as a trait-specific marker for BD, where no differences between patients with major depressive disorder and controls were found. Specific to lithium therapy, Squassina et al [44] demonstrated that IGF-1 expression is related to the response to lithium treatment in BD patients. In genome-wide expression analysis of lymphoblastoid cell lines, the IGF-1 gene was significantly overexpressed in lithium-responsive bipolar patients compared to lithium nonresponders.…”

Current State of Biomarkers in Bipolar Disorder

“…Drug treatment has an important regulatory effect on the expression levels of both trophic factors [41,42]. Peripheral levels of IGF-1 were lower in patients with BD compared to patients with schizophrenia [43].…”