Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta -50 T/C SNP.
The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness and with different antidepressant effects of total sleep deprivation. GSK3-beta codes for an enzyme which is a target for the action of lithium and possibly of valproic acid. We studied the effect of this polymorphism on the therapeutic response to lithium salts of 88 bipolar type I patients. Data about recurrence rate of mood episodes were collected for at least 2 years before lithium and 2 years on lithium. Results showed that homozygotes for the wild variant did not change their recurrence index while carriers of the mutant allele improved, thus supporting the hypothesis that GSK is a target for the therapeutic action of lithium. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.
Benedetti
Francesco
F
Istituto Scientifico Universitario Ospedale San Raffaele, Department of Neuropsychiatric Sciences, San Raffaele Turro, 20127 Milano, Italy. benedetti.francesco@hsr.it
Serretti
Alessandro
A
Pontiggia
Adriana
A
Bernasconi
Alessandro
A
Lorenzi
Cristina
C
Colombo
Cristina
C
Smeraldi
Enrico
E
D000328:Adult; D000704:Analysis of Variance; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; 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; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013995:Time; D013997:Time Factors
D012333:RNA, Messenger; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3