Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation

Abstract

BackgroundLithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response.MethodsIllumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software.Results127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point.ConclusionsThese results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.

Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder

“…42 Also deserving mention was BCL2L13, an apoptosis facilitator 43 (from the Bcl-2 family of apoptosis mediators) upregulated in BD. Interestingly, a shift in expression from pro-to anti-apoptotic Bcl-2 genes has been reported in lithium-responsive BD patients after treatment, 44 supporting a role for apoptosis in BD pathophysiology (although changes in BCL2L13 itself were not significant in that study). The upregulation of immune genes, detected also in the functional pathway analysis and later in the co-expression analysis (via the M7 module), echoes a similar trend from transcriptomic studies of BD (and schizophrenia) investigating other brain regions and blood.…”

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

“…In addition, the role of lithium in the modulation of cell death and apoptosis has been previously suggested by several studies (Bielecka and Obuchowicz, 2008; Breen et al, 2016; Chiu and Chuang, 2010), although the role of specific genes in this mechanism still needs to be unraveled. Top signaling pathways that were suggested to underlie the anti-apoptotic properties of lithium include the modulation of the Wnt pathway (Hu et al, 2011), mitochondrial function and calcium homeostasis (Alda, 2015; Scola et al, 2014), the expression of anti-apoptotic proteins (Dwivedi and Zhang, 2014; Lowthert et al, 2012), neurotrophic factors (Dwivedi and Zhang, 2014; Emamghoreishi et al, 2015a; Hellweg et al, 2002), among others (Alda, 2015; Bielecka and Obuchowicz, 2008). Accordingly, a recent study has shown that lithium upregulates a gene module specific to apoptosis signaling and exert regulatory effects on apoptosis-controlling proteins involved in mitochondrial and endoplasmic reticulum function in LCLs from BD patients (Breen et al, 2016), which corroborates our findings.…”

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

“…Beech et al [16] conducted studies of gene expression changes in peripheral lymphocytes in bipolar subjects on lithium treatment for 1 month as well as bipolar subjects prospectively treated with lithium for 6 months [17]. After 6 months of treatment, responders had a greater upregulation of antiapoptotic genes (BCL2) while proapoptotic genes were downregulated.…”