ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

Abstract

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

“…Although there is generally no clear correlation between antidepressant plasma levels and therapeutic efficacy (Perry et al, 1987;Spina et al, 1997;Normann et al, 2004), it has been proposed that interindividual variability in BBB transport, due to genetic differences in P-gp functionality, may lead to clinically relevant differences in the brain distribution of certain antidepressants (Kato et al, 2008). These results, in conjunction with previously reported pharmacogenetic associations between ABCB1 genotype and treatment response (Lin et al, 2011;Singh et al, 2012), support this hypothesis in relation to escitalopram, indicating that P-gp may prevent therapeutic brain concentrations from being achieved in certain patients with elevated P-gp activity due to functional SNPs in ABCB1.…”

“…Moreover, we bolster this hypothesis by showing a pharmacodynamic consequence of elevated brain levels of escitalopram by P-gp inhibition in a relevant animal model of antidepressant activity. These novel findings are especially important in light of recent clinical studies, which have found associations between SNPs in ABCB1 and response to escitalopram treatment (Lin et al, 2011) and the dose of escitalopram required to achieve remission in major depression (Singh et al, 2012). Although there is generally no clear correlation between antidepressant plasma levels and therapeutic efficacy (Perry et al, 1987;Spina et al, 1997;Normann et al, 2004), it has been proposed that interindividual variability in BBB transport, due to genetic differences in P-gp functionality, may lead to clinically relevant differences in the brain distribution of certain antidepressants (Kato et al, 2008).…”

“…However, over 30% of escitalopram-treated depressed patients fail to respond to treatment, with a full remission achieved in only 50% of cases (Kennedy et al, 2006). Recent clinical studies have found associations between single-nucleotide polymorphisms (SNPs) in ABCB1, the gene encoding the multidrug efflux transporter P-glycoprotein (P-gp) in humans, and escitalopram response (Lin et al, 2011;Singh et al, 2012). Given that drug efflux by P-gp at the blood-brain barrier (BBB) can prevent therapeutic concentrations of centrallyacting drugs from being achieved in the brain (Loscher and Potschka, 2005), this genetic association may indicate that escitalopram efflux by P-gp at the BBB contributes to the high prevalence of treatment failure (O'Brien et al, 2012b).…”

Pharmacogenetics of Antidepressants, A Review of Significant Genetic Variants in Different Populations

“…The C allele of rs2032583 is more common in Caucasians and African Americans than in Asians or Hispanics and rs2235015 is most common in African Americans. Another study found the SNP rs1045642 T allele of the ABCB1 gene significantly reduces the dose of escitalopram needed for remission of depression [29]. The frequency of this allele is almost equivalent in Caucasians and Asians, but almost twice as common in Hispanics and very rare in African Americans (Table 1).…”

Pharmacogenomic Testing and Personalized Treatment of Depression

“…A common variant was associated with escitalopram dose required for remission in a study of 57 patients, although the greatest dose was required for heterozygous individuals, a result difficult to explain in biological terms (19 ). The same study also suggested that this variant was associated with greater venlafaxine remission rates but not effective dosage, illustrating the challenges inherent in interpreting studies with multiple phenotypic outcomes.…”