ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder.
P-glycoprotein (P-gp), an ATP-driven efflux pump in the blood-brain barrier, has a major impact on the delivery of antidepressant drugs in the brain. Genetic variants in the gene ABCB1 encoding for P-gp have inconsistently been associated with adverse effects. In order to resolve these inconsistencies, we conducted a study in a large cohort of patients with major depressive disorder with the aim to unravel the association of ABCB1 variants with adverse effects of antidepressants and in particular with selective serotonin reuptake inhibitors (SSRIs), which display affinity as substrate for P-gp. The Netherlands Study of Depression and Anxiety (NESDA) study was used as a clinical sample. For 424 patients data were available on drug use, side effects. We selected six ABCB1 gene variants (1236T>C, 2677G>T/A, 3435T>C, rs2032583, rs2235040 and rs2235015) and analyzed them for association with adverse drug effects using multinomial regression analysis for both single variants and haplotypes. We found a significant association between the number of SSRI-related adverse drug effects and rs2032583 (P=0.001), rs2235040 (P=0.002) and a haplotype (P=0.002). Moreover, serotonergic effects (sleeplessness, gastrointestinal complaints and sexual effects) were significantly predicted by these variants and haplotype (P=0.002/0.003). We conclude that adverse drug effects with SSRI treatment, in particular serotonergic effects, are predicted by two common polymorphisms of the ABCB1 gene.
University Center of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands. o.l.klerk@ngmb.umcg.nl
O L
OL
de Klerk
I M
IM
Nolte
P M
PM
Bet
F J
FJ
Bosker
H
H
Snieder
J A
JA
den Boer
R
R
Bruggeman
W J
WJ
Hoogendijk
B W
BW
Penninx
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000928:Antidepressive Agents; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C513055:ABCB1 protein, human