title: Variation in GNB3 predicts response and adverse reactions to antidepressants.
abstract: There is substantial inter-individual variation in response and adverse reactions to antidepressants, and genetic variation may, in part, explain these differences. GNB3 encodes the β3 subunit of the G protein complex, which is involved in the downstream signalling cascade following monoamine receptor activation. A functional polymorphism in this gene (C825T) has been associated with response to antidepressants. Several lines of evidence suggest that GNB3 moderates improvement in the neurovegetative symptoms of depression (such as sleep and appetite) and related adverse reactions independently of change in core mood symptoms. We here report analysis of data from GENDEP, a part-randomized pharmacogenomic trial, on the outcome of 811 subjects with major depression undergoing treatment with either escitalopram or nortriptyline in which the C825T SNP and three further SNPs in GNB3 were genotyped. The TT genotype was significantly associated with a superior response to nortriptyline and these effects were specific to improvements in neurovegetative symptoms. In addition, the same genotype predicted fewer incidents of treatment-emergent insomnia and greater weight gain on the same drug. Our results are consistent with previous associations with GNB3 and emphasize the importance of signalling genes in antidepressant response.
authors.affiliation: MRC SGDP Centre, Institute of Psychiatry, King's College London, UK. Robert.Keers@kcl.ac.uk
authors.forename: Robert
authors.initials: R
authors.lastname: Keers
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.forename: Catia
authors.initials: C
authors.lastname: Scassellati
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Anna
authors.initials: A
authors.lastname: Placentino
authors.forename: Caterina
authors.initials: C
authors.lastname: Giovannini
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Neven
authors.initials: N
authors.lastname: Henigsberg
authors.forename: Dejan
authors.initials: D
authors.lastname: Kozel
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Joanna
authors.initials: J
authors.lastname: Hauser
authors.forename: Daniel
authors.initials: D
authors.lastname: Souery
authors.forename: Julien
authors.initials: J
authors.lastname: Mendlewicz
authors.forename: Christine
authors.initials: C
authors.lastname: Schmäl
authors.forename: Astrid
authors.initials: A
authors.lastname: Zobel
authors.forename: Erik R
authors.initials: ER
authors.lastname: Larsen
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szczepankiewicz
authors.forename: Zrnka
authors.initials: Z
authors.lastname: Kovacic
authors.forename: Amanda
authors.initials: A
authors.lastname: Elkin
authors.forename: Ian
authors.initials: I
authors.lastname: Craig
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015283:Citalopram / Q000009:adverse effects / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005060:Europe; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009661:Nortriptyline / Q000009:adverse effects / Q000627:therapeutic use*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D018570:Risk Assessment; D012307:Risk Factors; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced; D013997:Time Factors; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; C454420:G-protein beta3 subunit; D015283:Citalopram; D009661:Nortriptyline; D020962:Heterotrimeric GTP-Binding Proteins