title: Association of ABCB1 gene variants, plasma antidepressant concentration, and treatment response: Results from a randomized clinical study.
abstract: 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.
authors.affiliation: HMNC GmbH, Maximilianstr. 34, 80539 Munich, Germany; Max Planck Institute of Psychiatry, Kraepelinstr. 2 - 10, 80804 Munich, Germany; Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany. Electronic address: barbara.breitenstein@hmnc.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Breitenstein
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2 - 10, 80804 Munich, Germany. Electronic address: sandra_scheuer@psych.mpg.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Scheuer
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2 - 10, 80804 Munich, Germany. Electronic address: brueckl@psych.mpg.de.
authors.forename: Tanja Maria
authors.initials: TM
authors.lastname: Brückl
authors.affiliation: Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany. Electronic address: meyerjo@uni-trier.de.
authors.forename: Jobst
authors.initials: J
authors.lastname: Meyer
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2 - 10, 80804 Munich, Germany. Electronic address: ising@psych.mpg.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2 - 10, 80804 Munich, Germany. Electronic address: uhr@psych.mpg.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: HMNC GmbH, Maximilianstr. 34, 80539 Munich, Germany; Max Planck Institute of Psychiatry, Kraepelinstr. 2 - 10, 80804 Munich, Germany. Electronic address: florian.holsboer@hmnc.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000483:Alleles; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000097:blood* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003863:Depression / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000928:Antidepressive Agents
keywords: ABCB1; Antidepressant treatment; MDR1; Major depressive disorder; P-glycoprotein; Side effects