ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder
Onno L. de Klerk, Ilja Maria Nolte, Pierre M. Bet, Fokko J. Bosker, Harold Snieder, Johan A. den Boer, Richard Bruggeman, Witte J.G. Hoogendijk, Brenda W.J.H. Penninx, et al.
The Pharmacogenomics Journal2013 (epub May 2012)
Summary (paraphrased)
P-glycoprotein, the ABCB1-encoded efflux pump at the blood-brain barrier, controls how much of an SSRI substrate reaches the brain. In 424 patients with major depressive disorder from the Netherlands Study of Depression and Anxiety (NESDA), six ABCB1 variants were tested for association with antidepressant adverse effects. The number of SSRI-related adverse effects was significantly associated with rs2032583 (p=0.001) and rs2235040 (p=0.002) and with a haplotype (p=0.002). Serotonergic effects in particular — sleeplessness, gastrointestinal complaints, and sexual effects — were significantly predicted by these variants and the haplotype. The authors conclude that two common ABCB1 polymorphisms predict adverse drug effects of SSRI treatment, especially serotonergic ones.
Why it’s in the systems review
ABCB1 sits squarely in the causal-pathway logic Powers applies to drug clearance: a transporter variant that changes brain exposure to an SSRI is a mechanistically credible susceptibility factor for who develops severe or persistent serotonergic side effects, sexual effects included. It extends the corpus's pharmacogenomic coverage beyond metabolizing enzymes (CYPs) to the blood-brain-barrier efflux step, and pairs naturally with MECH-035, which tested the same gene in the same phenotype.
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