Association of ABCB1 gene variants, plasma antidepressant concentration, and treatment response: Results from a randomized clinical study

• ABCB1 variants interact with plasma antidepressant levels to predict the antidepressant treatment efficacy.
• For minor allele carriers (rs2032583), plasma drug levels should not exceed recommended range to obtain best treatment outcome.
• Among carriers, the benefit of P-gp substrate treatment in recommended plasma drug range exceeds the benefit of TAU.
• Carriers with high plasma drug levels have more sleep-related side effects than major allele homozygotes with high plasma levels.
• The treatment of MDD can be optimized by ABCB1 genotyping combined with monitoring of plasma drug concentrations.

P-glycoprotein, encoded by the ABCB1 gene, functions as an ATP-driven efflux pump in the blood–brain barrier, extruding its substrates and thereby limiting their passage into the brain. ABCB1 polymorphisms predicted antidepressant drug response: Minor allele carriers of SNPs rs2032583 and rs2235015 had higher remission rates than major allele homozygotes. The aim of the current study was to evaluate an ABCB1 genotype-dependent efficacy of a quick dose escalation strategy.Depressed inpatients (n = 73) treated with antidepressants that are P-glycoprotein substrates were randomly assigned to a standard or high dose condition for 28 days. HAM-D scores, adverse effects and plasma antidepressant concentration were measured weekly and tested among two intronic SNPs rs2032583 and rs2235015. A treatment as usual control sample (n = 128) was retrospectively matched to the study group by gender, age, and diagnosis.There was a significant interaction of genotype x plasma antidepressant concentration: Minor allele carriers of rs2032583 [F(1,65) = 7.221, p = 0.009] and rs2235015 [F(1,65) = 4.939, p = 0.030] whose plasma drug concentration were within recommended range had a greater symptom reduction at study endpoint which exceeded the therapeutic benefit of the treatment as usual group [for rs2032583: F(1,163) = 4.366, p = 0.038]. Minor allele carriers of rs2032583 with high plasma drug levels had more sleep-related side effects than major allele homozygotes with high plasma drug levels.The treatment of MDD can be optimized by ABCB1 genotyping combined with monitoring of plasma drug concentrations: For minor allele carriers of rs2032583 and rs2235015, plasma antidepressant levels should not exceed the recommended range in order to obtain optimal treatment outcome.