title: Lithium and GSK-3β promoter gene variants influence cortical gray matter volumes in bipolar disorder.
abstract: BACKGROUND
  Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase-3β (GSK-3β). The less active GSK-3β promoter gene variants have been associated with less detrimental clinical features of BD. GSK-3β gene variants and lithium can influence brain gray and white matter structure in psychiatric conditions, so we studied their combined effect in BD.
  
  
  OBJECTIVE
  The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3β promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD.
  
  
  METHODS
  GM volumes were estimated with 3.0 Tesla MRI in 150 patients affected by a major depressive episode in course of BD. Duration of lifetime lithium treatment was retrospectively assessed. Analyses were performed by searching for significant effects of lithium and rs334558 in the whole brain.
  
  
  RESULTS
  The less active GSK-3β rs334558*G gene promoter variant and the long-term administration of lithium were synergistically associated with increased GM volumes in the right frontal lobe, in a large cluster encompassing the boundaries of subgenual and orbitofrontal cortex (including Brodmann areas 25, 11, and 47). Effects of lithium on GM revealed in rs334558*G carriers only, consistent with previously reported clinical effects in these genotype groups, and were proportional to the duration of treatment.
  
  
  CONCLUSIONS
  Lithium and rs334558 influenced GM volumes in areas critical for the generation and control of affect, which have been widely implicated in the process of BD pathophysiology. In the light of the protective effects of lithium on white matter integrity, our results suggest that the clinical effects of lithium associate with a neurotrophic effect on the whole brain, probably mediated by GSK-3β inhibition.
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy, benedetti.francesco@hsr.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedetti
authors.forename: Sara
authors.initials: S
authors.lastname: Poletti
authors.forename: Daniele
authors.initials: D
authors.lastname: Radaelli
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: Benedetta
authors.initials: B
authors.lastname: Vai
authors.forename: Irene
authors.initials: I
authors.lastname: Bollettini
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.forename: Enrico
authors.initials: E
authors.lastname: Smeraldi
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombo
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D066128:Gray Matter / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009929:Organ Size / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D014150:Antipsychotic Agents; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3