Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: A pilot study

Nikisch, Georg; Eap, Chin B.; Baumann, Pierre

doi:10.1016/j.phrs.2008.09.010

Cited by 87 publications

(63 citation statements)

References 28 publications

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“…Moreover, even if they might not be correlated with antidepressant intra-cerebral concentrations or clinical efficacy [22] , plasma antidepressant levels were not available in this study because of its naturalistic design. However, three recent studies failed to show a significant association between the C3435T polymorphism and antidepressant plasma level [23][24][25] in depressed patients.…”

Section: Discussionmentioning

confidence: 98%

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

Gressier

Verstuyft

et al. 2010

Neuropsychobiology

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Introduction: Pharmacogenetic factors may explain some of the interindividual variability of response to antidepressants in depressed patients. We focused on P-glycoprotein (P-GP), whose expression depends on a functional polymorphism of the ABCB1 gene (C3435T variants: dbSNP: rs1045642), the 3435CC genotype being linked to a high level of P-GP expression. Acting as an efflux pump at the blood-brain barrier, P-GP reduces the intracellular penetration of many drugs. Little is known about the interaction between P-GP and response to antidepressants. The objective of this study is to assess whether the response to antidepressants in depression differs in patients with the 3435CC genotype as compared to patients with the 3435CT and 3435TT genotypes. Methods: 117 in-patients with a major depressive episode requiring a new antidepressant treatment were enrolled in this prospective naturalistic 4-week study. Response to antidepressants was assessed using the Hamilton Depression Rating Scale, the Beck Depression Inventory, the Clinician Global Impression Improvement and Therapeutic Index, and weight change. ABCB1 genotyping was performed using the Taqman method. Clinical assessment was performed blind from genotypes. Results: We failed to show any significant effect of the ABCB1 polymorphism in position 3435 on antidepressant efficacy or tolerance. Discussion: While some in vitro studies showed an influence of P-GP on cerebral concentrations of antidepressants, our results do not support the hypothesis that the C3435T polymorphism is involved in therapeutic response and safety of antidepressants in naturalistic clinical conditions, confirming results of previous studies on efficacy. Nonetheless, some methodological limitations may explain our negative results.

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Section: Discussionmentioning

confidence: 98%

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

Gressier

Verstuyft

et al. 2010

Neuropsychobiology

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“…There is limited information available in relation to antidepressant transport by human P-gp per se. However, in common with escitalopram, pharmacogenetic studies have revealed an association between SNPs in ABCB1 and response to other antidepressants (Gex-Fabry et al, 2008;Kato et al, 2008;Nikisch et al, 2008;Uhr et al, 2008;Sarginson et al, 2010). These antidepressants, including citalopram and paroxetine, are thought to be P-gp substrates based on results from studies in P-gp knockout mice Uhr et al, , 2008Doran et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

O’Brien

O’Connor

Clarke

et al. 2013

Neuropsychopharmacol

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Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysisbased pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.

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“…The rs2032582 (G2677) and rs1045642 (3435C) polymorphisms were associated with altered P-glycoprotein expression and/or function [86], and thus, they appear of particular interest in the field of pharmacogenetics. Some previous studies demonstrated an effect of rs2032582 and rs1045642 [39,40] on antidepressant response. The effect of rs2032582 on antidepressant efficacy was suggested also by a meta-analysis that supported better response in TT genotype carriers, while it did not confirm the effect of rs1045642 [19••].…”

Section: Individual Genes Involved In Antidepressant Responsementioning

confidence: 93%

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

Fabbri

Serretti

2015

Curr Psychiatry Rep

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The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are SLC6A4, HTR2A, BDNF, GNB3, FKBP5, ABCB1, and cytochrome P450 genes (CYP2D6 and CYP2C19). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of SLC6A4, HTR2A, ABCB1, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.

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Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: A pilot study

Cited by 87 publications

References 28 publications

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

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

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

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