P-953 - Treatment biomarker: blood brain barrier (P-gp) polymorphisms predict antidepressant dose and response - a candidate gene association study

Abstract

Overview Pharmacokinetically important polymorphisms could guide dosing, ensuring adequate CNS bioavailability in a particular individual during a therapeutic trial. Hepatic enzyme (CYP450) polymorphisms have been extensively studied. Less work has been done on the permeability glycoprotein (P-gp) - the key efflux pump at the blood brain barrier (BBB). Methods An eight week prospective multi-centre candidate gene association study of 113 patients with psychiatrist diagnosed DSM-IV MDD was conducted. Subjects were treated with escitalopram (ESCIT) or venlafaxine (VEN) in a naturalistic clinical setting. Treatment outcome was assessed with the 17-item HDRS and Clinical Global Impression (CGI) Scales. Side effects were rated with a comprehensive adverse reactions scale (UKU). All response ratings were blinded to genotype. P-gp, CYP2D6, and CYP2C19 polymorphisms were assayed using microarray methodology. Results BBB (P-gp) polymorphisms associated with less antidepressant CNS entry were associated with need for higher medication dosage and less overall clinical improvement. Patients with higher BBB block polymorphism need 1.45 (p = 0.018) times the dose of escitalopram than those with lower blood brain barrier block polymorphism. Patients with lower BBB block genotype had a 1.602 time greater reduction in depression compared to subjects with higher block polymorphisms (p = 0.043). Subjects with lower BBB block and poorer metaboliser status at cytochrome P450 2D6 and 2C19 genotype were significantly more likely to respond on the HDRS (RR = 1.60, 95%CI 1.095–2.339, p = 0.015). Conclusions This is the first study to demonstrated that P-gp polymorphisms predict antidepressant dose, and that combined P450 and P-gp polymorphisms predict antidepressant response.