TY - JOUR
T1 - Gene-gene interaction of glycogen synthase kinase 3-β and serotonin transporter on human antidepressant response to sleep deprivation
AU - Benedetti, Francesco
AU - Dallaspezia, Sara
AU - Lorenzi, Cristina
AU - Pirovano, Adele
AU - Radaelli, Daniele
AU - Locatelli, Clara
AU - Poletti, Sara
AU - Colombo, Cristina
AU - Smeraldi, Enrico
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
KW - Antidepressant
KW - Bipolar disorder
KW - Glycogen synthase kinase 3-β
KW - Serotonin promoter
KW - Sleep deprivation
UR - http://www.scopus.com/inward/record.url?scp=84857357845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857357845&partnerID=8YFLogxK
U2 - 10.1016/j.jad.2011.10.039
DO - 10.1016/j.jad.2011.10.039
M3 - Article
C2 - 22119086
AN - SCOPUS:84857357845
VL - 136
SP - 514
EP - 519
JO - Journal of Affective Disorders
JF - Journal of Affective Disorders
SN - 0165-0327
IS - 3
ER -