ABCB1 C3435T polymorphism is associated with susceptibility to major depression, but not with a clinical response to citalopram in a Turkish population

doi:10.1016/j.pharep.2013.09.004

Pharmacological Reports

Volume 66, Issue 2, April 2014, Pages 235-238

https://doi.org/10.1016/j.pharep.2013.09.004 Get rights and content

Abstract

Background

The ATP-binding cassette sub-family B member 1 (ABCB1) gene, which encodes the p-glycoprotein at the blood–brain barrier, is investigated for patients’ susceptibility to major depressive disorder (MDD) and their therapeutic response to antidepressants. However, there is an inconsistency between the studies of different ethnic groups. The current study aimed to determine the potential correlations of the ABCB1 gene C3435T polymorphism with the susceptibility to MDD and the therapeutic response to citalopram in a Turkish population.

Methods

Fifty-four patients with MDD who received citalopram and 70 controls from the Turkish population were genotyped for ABCB1 C3435T polymorphism. To assess the therapeutic response to citalopram, all patients were rated baseline, first, second, fourth and sixth weeks according to the 17-item Hamilton Rating Scale for Depression (HAMD-17).

Results

There was a significant correlation between the patient and control groups for ABCB1 C3435T polymorphism. Distribution of CC genotype and C allele frequency were higher in the patients than in the control group (p = 0.006, p = 0.020, respectively). However, no correlation between ABCB1 C3435T polymorphism and a therapeutic response to citalopram was observed.

Conclusion

Our results suggested that C3435T polymorphism in the ABCB1 gene may be an indicator of the susceptibility to major depression, without a likely treatment response to citalopram in a Turkish population. These findings should be replicated in studies on larger patient groups with different ethnicities.

Introduction

Major depressive disorder (MDD) is a prevalent and severe psychiatric disease with a highly variable treatment response and a poorly understood pathogenesis [7]. One-third of MDD patients do not achieve an adequate response to the first-line antidepressant treatment [28], and therefore finding adequate markers for susceptibility to depression and resistance to antidepressants is a major interest of research. Pharmacogenetics and therapeutic drug monitoring could be used as tools for the prediction and improvement of antidepressant responses. In addition, pharmacogenetics research can aid in clarifying the susceptibility to depression [15].

Variations in ABCB1 (ATP-binding cassette, sub-family B member 1) gene, coding for p-glycoprotein (p-gp), also known as multidrug resistance polypeptide 1 (MDR1), is one of the suggested markers for drug resistance [2]. P-gp plays an important role in bioavailability, tissue penetration, and excretion of its substrates including a huge variety of endogenous and exogenous lipophilic compounds. This genetically polymorphic protein serves as an efflux transporter and regulates the entry of drugs into a variety of tissues. P-gp is also expressed in the blood-brain barrier and actively transports its substrates like cortisol and citalopram [30], [32].

It is known that p-gp regulates intracerebral and intracellular levels of glucocorticoids [4], [21]. Although hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been found in patients with MDD, we do not know exactly whether this finding is a reason or a consequence of depression. The mechanisms underlying the HPA axis hyperactivity in major depression are still under investigation. In recent years, over-activity of the HPA axis is thought to be responsible for impaired negative feedback inhibition of HPA axis by glucocorticoids and there has been increasing awareness the importance of p-gp in the pathogenesis and treatment of depression.

Citalopram (R,S-citalopram), a substrate of p-gp, is a widely used antidepressant drug that belongs to the selective serotonin reuptake inhibitor (SSRI) class [1]. Although citalopram is known as a clinically efficient and well-tolerated drug, no therapeutic window defining the relationship between clinical response and serum concentrations exists [9], [37]. We know that serum concentrations of selective serotonin reuptake inhibitors cannot predict the clinical efficacy in routine practice. This is partly due to the difference between SSRI concentrations in serum and cerebrospinal fluid. It may also be important for citalopram to reach the necessary intracerebral drug concentrations as much as serum drug levels as a CNS-acting (central nervous system-acting) drug. As a well-known genetically polymorphic efflux transporter, p-gp could decrease concentrations of drug molecules via active transport through the blood–brain barrier. Among the various single nucleotide polymorphisms (SNPs) of the ABCB1 gene, C3435T polymorphism affects the p-gp expression and/or function [35]. In vivo studies performed with ABCB1 knockout mice show significantly higher cerebrum concentrations of citalopram and cortisol when compared to the wild types [30], [32].

Based on these findings, the present study focused on finding the C3435T polymorphism's influence on susceptibility to depression and clinical response to citalopram.

Section snippets

Subjects

The study was performed between 2006 and 2008 at the Gazi University Medical Faculty Hospital, Ankara, Turkey. Patients (n = 54) who apply to the psychiatric outpatient clinic and met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for major depressive disorder (MDD) were included in the study. Exclusion criteria included clinically significant laboratory abnormalities; major physical and neurological illnesses; psychiatric disorders, except major

Results

The observed and predicted allele frequencies were compared for patient (n = 54) and control groups (n = 70). Patient and control groups were in Hardy–Weinberg equilibrium for ABCB1 3435C/T (patients, χ² = 1.653, p = 0.198; controls, χ² = 3.184, p = 0.074). Of the 54 patients included in the study, eight patients dropped out due to adverse effects (n = 2) or refusal of the visits (n = 6), leaving 46 patients who were screened during the study. Of these 46 patients, 34 were treatment responders at the sixth

Discussion

This study evaluated the ABCB1 gene C3435T polymorphism on efficacy and tolerability of citalopram for the first time in Turkish patients with MDD. Our results indicated that (1) the ABCB1 gene C3435T polymorphism frequency might be different between MDD patients and controls and (2) the ABCB1 gene C3435T polymorphism is not associated with the efficacy of citalopram in patients with MDD.

Because of its location at the blood–brain barrier, p-gp may alter the penetration of its substrates, like

Conflict of interest

All authors declare no conflict of interest that could influence their work.

Funding

This study was supported by grants from the Scientific Research Projects of Gazi University (Project No: 01/2004-44).

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Original research articleABCB1 C3435T polymorphism is associated with susceptibility to major depression, but not with a clinical response to citalopram in a Turkish population

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Subjects

Results

Discussion

Conflict of interest

Funding

Cell

Epilepsy Res

Biol Psychiatry

J Psychiatr Res

Pharmacol Ther

Drug Metab Pharmacokinet

Pharmacol Rep

Pharmacol Res

Drug Metab Pharmacokinet

J Psychiatr Res

Biol Psychiatry

Neuropsychopharmacology

Neuron

Citalopram—a review of pharmacological and clinical effects

J Psychiatry Neurosci

Locally increased P-glycoprotein function in major depression: a PET study with [11C] verapamil as a probe for P-glycoprotein function in the blood–brain barrier

Int J Neuropsychopharmacol

Brain corticosteroid receptor balance in health and disease

Endocr Rev

A high-performance liquid chromatography method with photodiode-array UV detection for therapeutic drug monitoring of the nontricyclic antidepressant drugs

Ther Drug Monit

Identification of polymorphisms on the MDR1 gene among Turkish population and their effects on multidrug resistance in acute leukemia patients

Am J Hematol

Original research article
ABCB1 C3435T polymorphism is associated with susceptibility to major depression, but not with a clinical response to citalopram in a Turkish population

Locally increased P-glycoprotein function in major depression: a PET study with [¹¹C] verapamil as a probe for P-glycoprotein function in the blood–brain barrier