Variation in GNB3 predicts response and adverse reactions to antidepressants.
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.
Keers
Robert
R
MRC SGDP Centre, Institute of Psychiatry, King's College London, UK. Robert.Keers@kcl.ac.uk
Bonvicini
Cristian
C
Scassellati
Catia
C
Uher
Rudolf
R
Placentino
Anna
A
Giovannini
Caterina
C
Rietschel
Marcella
M
Henigsberg
Neven
N
Kozel
Dejan
D
Mors
Ole
O
Maier
Wolfgang
W
Hauser
Joanna
J
Souery
Daniel
D
Mendlewicz
Julien
J
Schmäl
Christine
C
Zobel
Astrid
A
Larsen
Erik R
ER
Szczepankiewicz
Aleksandra
A
Kovacic
Zrnka
Z
Elkin
Amanda
A
Craig
Ian
I
McGuffin
Peter
P
Farmer
Anne E
AE
Aitchison
Katherine J
KJ
Gennarelli
Massimo
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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
D000928:Antidepressive Agents; C454420:G-protein beta3 subunit; D015283:Citalopram; D009661:Nortriptyline; D020962:Heterotrimeric GTP-Binding Proteins