Modification of the association between paroxetine serum concentration and SERT-occupancy by ABCB1 (P-glycoprotein) polymorphisms in major depressive disorder.

Autor:	Simoons M; Department of Clinical Pharmacy, Wilhelmina Hospital Assen, Assen.; Department of Psychiatry, University of Groningen, University Medical Centre Groningen, Groningen.; Unit of PharmacoTherapy, Epidemiology and Economics, Department of Pharmacy, University of Groningen, Groningen., Mulder H; Department of Clinical Pharmacy, Wilhelmina Hospital Assen, Assen.; Psychiatric Hospital GGZ Drenthe, Assen., Appeldoorn JTY; Department of Clinical Pharmacy, Wilhelmina Hospital Assen, Assen., Risselada AJ; Department of Clinical Pharmacy, Wilhelmina Hospital Assen, Assen., Schene AH; Department of Psychiatry, Radboud University and Radboud University Medical Centre Nijmegen, Nijmegen., van Schaik RHN; Department of Clinical Chemistry, Erasmus University Medical Centre Rotterdam, Rotterdam., van Roon EN; Unit of PharmacoTherapy, Epidemiology and Economics, Department of Pharmacy, University of Groningen, Groningen.; Department of Clinical Pharmacy and Clinical Pharmacology, Medical Centre Leeuwarden, The Netherlands., Ruhé EG; Department of Psychiatry, University of Groningen, University Medical Centre Groningen, Groningen.; Department of Psychiatry, Radboud University and Radboud University Medical Centre Nijmegen, Nijmegen.; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	Psychiatric genetics [Psychiatr Genet] 2020 Feb; Vol. 30 (1), pp. 19-29.
DOI:	10.1097/YPG.0000000000000244
Abstrakt:	Background: Selective serotonin reuptake inhibitors (SSRIs) exert substantial variability in effectiveness in patients with major depressive disorder (MDD), with up to 50-60% not achieving adequate response. Elucidating pharmacokinetic factors that explain this variability is important to increase treatment effectiveness. Objectives: To examine potential modification of the relationship between paroxetine serum concentration (PSC) and serotonin transporter (SERT)-occupancy by single nucleotide polymorphisms (SNPs) of the ABCB1 gene, coding for the P-glycoprotein (P-gp) pump, in MDD patients. To investigate the relationship between ABCB1 SNPs and clinical response. Methods: Patients had MDD and received paroxetine 20 mg/day. We measured PSC after 6 weeks. We quantified SERT-occupancy with SPECT imaging (n = 38) and measured 17-item Hamilton Depression Rating Scale (HDRS17)-scores at baseline and after 6 weeks (n = 81). We genotyped ABCB1 at rs1045642 [3435C>T], rs1128503 [1236C>T], rs2032582 [2677G>T/A] and rs2235040 [2505G>A]. For our primary aim, we modeled mean SERT-occupancy in an Emax nonlinear regression model with PSC and assessed whether the model improved by genetic subgrouping. For our secondary aim, we used multivariate linear regression analysis. Results: The rs1128503 and rs2032582 SNPs modified the relationship between PSC and SERT-occupancy in both our intention-to-treat and sensitivity analyses at the carriership level. However, we could not detect significant differences in clinical response between any of the genetic subgroups. Conclusion: Pharmacokinetic influences of the ABCB1 rs1128503 and rs2032582 represent a potentially relevant pharmacogenetic mechanism to consider when evaluating paroxetine efficacy. Future studies are needed to support the role of ABCB1 genotyping for individualizing SSRI pharmacotherapy.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu