Genetic Variants in the ABCB1 Gene Determine Bioavailability of Antidepressants in the Brain

Abstract

Introduction

Antidepressants are the first-line treatment of major depressive disorder, but response rates following the first antidepressant medication are moderate.

Objectives

Clinical efficacy requires to overcome the blood-brain barrier where p-gp molecules are located. If they recognize and bind an antidepressant, they pump it back into the circulation. If the antidepressant is not recognized, the passage is not impaired by p-glycoproteins.

Aims

We studied whether variants in the ABCB1 gene that encodes the p-glycoprotein have an effect on blood-brain passage of antidepressants and as consequence on their clinical benefit.

Methods

ABCB1 gene variants were determined with sequencing (Illumina Bead), substrate property analysis employed mice with deletion of ABCB1-analog genes. Clinical protocols followed those of the MARS-project.

Results

– The SNPs rs2032583 and rs2235015 provide the best clinical information about blood-brain-penetrance, with CC/CT and TT/GT being the favourable gene variants whereas TT and GG are less favourable. This distinction holds only true if antidepressants are p-glycoprotein substrates;

– in the presence of the favourable gene-variant patients treated with an antidepressant that is a p-glycoprotein substrate are more likely to remit in shorter time;

– in the presence of the less favourable gene-variant treatment with a substrate, higher dosages and augmentation strategies, or switch to non-substrates are recommended.

Conclusion

From these data, a treatment algorithm was developed that maximizes treatment benefit and minimizes adverse effects.

Disclosure of interest

The authors have not supplied their declaration of competing interest.