title: Gene-gene interaction of glycogen synthase kinase 3-β and serotonin transporter on human antidepressant response to sleep deprivation.
abstract: BACKGROUND
  Glycogen synthase kinase 3-β (GSK3-β) is involved in the control of cell behavior and in the mechanism of action of lithium and serotonergic antidepressants, and in humans a promoter variant (rs334558*C) was associated with reduced activity and better antidepressant response. The short form of a polymorphism in the promoter in the serotonin transporter (5-HTTLPR) has been consistently associated with worse antidepressant response. In animals the knockout of GSK3-β counteracts the depressive-like behavioral effects of 5-HT inhibition.
  
  
  METHODS
  With a translational approach, we studied the effect of 5-HTTLPR and rs334558 on antidepressant response to sleep deprivation in a unique sample of 122 patients affected by a major depressive episode in course of bipolar disorder. Mood was self rated on Visual Analog Scales, and severity of depression was rated on Montgomery-Asberg rating scale.
  
  
  RESULTS
  We observed a triple interaction of 5-HTTLPR, rs334558 and treatment on severity of depression. While among rs334558 T/T homozygotes the best antidepressant response was associated with 5-HTTLPR l/l homozygosity, among the rs334558 C carriers the 5-HTTLPR s/s showed the best response to treatment.
  
  
  CONCLUSIONS
  A gene promoter polymorphism which reduces the activity of GSK3-β counteracts the detrimental influence of the short form of the 5-HT promoter on antidepressant response. A key component of Wnt pathway, and upstream of the mTOR signaling cascade, GSK3-β influences synaptic plasticity and cell resilience. Gene-gene interactions between components of the monoaminergic signal transduction pathways and of plasticity related pathways can shape the individual antidepressant response.
authors: Department of Clinical Neurosciences, Scientific Institute San Raffaele and University Vita-Salute, Milano, Italy. benedetti.francesco@hsr.it
authors: Francesco
authors: F
authors: Benedetti
authors: Sara
authors: S
authors: Dallaspezia
authors: Cristina
authors: C
authors: Lorenzi
authors: Adele
authors: A
authors: Pirovano
authors: Daniele
authors: D
authors: Radaelli
authors: Clara
authors: C
authors: Locatelli
authors: Sara
authors: S
authors: Poletti
authors: Cristina
authors: C
authors: Colombo
authors: Enrico
authors: E
authors: Smeraldi
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012892:Sleep Deprivation / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000928:Antidepressive Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3