Abstract
Lithium is a highly effective medication for bipolar disorder, but its mechanism of action remains unknown. In this study, brain MRI scans and blood samples for gene expression (total of 110 scans and 109 blood samples) were collected from 21 bipolar subjects before and after 2 and 8 weeks of lithium monotherapy and at the same time-points from untreated 16 healthy controls. We used linear mixed-effects models to identify brain structural features and genes with expression changed after lithium treatment, with correction for multiple testing, and correlated their concurrent changes to identify molecular pathways associated with lithium effects. There are significant increases in gray matter fraction, global cortical thickness, and the frontal and parietal cortices after 8 weeks of lithium treatment (corrected p < 0.05). Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures. Several genes showed significant expression changes, and 14 gene pathways were identified for the present integration analysis. Of these, nine pathways had significant correlations with structural changes (FDR < 0.05). Three neurotrophy-related pathways (GDNF family of ligands, NFAT immune-response, and p53-signaling pathway) correlated with structural changes in multiple regions. Mediation analysis showed that the sphingomyelin metabolism pathway is associated with HAM-D change (p < 0.01), and this effect is mediated via the volume of mediodorsal thalamus (p < 0.03). In summary, the integration of lithium effects on brain structural and peripheral gene expression changes revealed effects on several neurotrophic molecular pathways, which provides further insights into the mechanism of lithium action.
Highlights
Lithium is a highly effective and specific medication for bipolar disorder (BD)[1,2,3,4,5]
It has been shown to affect several transcriptional regulators such as cAMP response element-binding protein (CREB), glycogen synthesis kinase 3 (GSK3), protein kinase C involved in signal transduction, and extracellular-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)[8,9,10]
Lithium effects on brain structure features After 2 weeks of treatment, 8 structures had significant changes (Fig. 1 and Table 2), which include the ventricular volume and global, frontal, and parietal cortical thickness
Summary
Lithium is a highly effective and specific medication for bipolar disorder (BD)[1,2,3,4,5]. It is a life-saving medication, as it has consistently been shown to decrease suicides as well as overall mortality in subjects who take it[6]. Though a number of molecular effects of lithium have been reported using in vitro experiments, their significance for clinical treatment and efficacy has been limited due to lack of suitable animal models for BD. Basic science research on lithium has shown it to have a variety of acute effects on membrane function and signal transduction mechanisms[7]. It has been shown to affect several transcriptional regulators such as cAMP response element-binding protein (CREB), glycogen synthesis kinase 3 (GSK3), protein kinase C involved in signal transduction, and extracellular-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)[8,9,10].
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