title: Lithium and GSK3-β promoter gene variants influence white matter microstructure in bipolar disorder.
abstract: Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.
authors.affiliation: Istituto Scientifico Ospedale San Raffaele, Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute, San Raffaele Turro, Milan, Italy. benedetti.francesco@hsr.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedetti
authors.forename: Irene
authors.initials: I
authors.lastname: Bollettini
authors.forename: Ignazio
authors.initials: I
authors.lastname: Barberi
authors.forename: Daniele
authors.initials: D
authors.lastname: Radaelli
authors.forename: Sara
authors.initials: S
authors.lastname: Poletti
authors.forename: Clara
authors.initials: C
authors.lastname: Locatelli
authors.forename: Adele
authors.initials: A
authors.lastname: Pirovano
authors.forename: Cristina
authors.initials: C
authors.lastname: Lorenzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombo
authors.forename: Enrico
authors.initials: E
authors.lastname: Smeraldi
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000201:enzymology / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3