Antidepressants and Blood-Brain Barrier
Depression is a common and disabling mental disorder. Epidemiological studies estimate that approximately 7% of the adult population in Europe and the United States experience major depressive disorder (MDD) per year. World Health Organization (WHO) projections suggest that by 2030, unipolar depression will be the leading cause of disease burden in high-income countries and will rank second globally.
In addition to the depressive disorder that must be treated, nonresponse to the first prescribed antidepressant is a frequent clinical problem. Although antidepressant resistance is a complex phenomenon involving many factors (e.g., comorbid anxiety disorders, personality features), individual differences in treatment response are assumed to arise in part from variants in genes controlling pharmacokinetic (absorption, distribution, metabolism, excretion of drugs) and pharmacodynamic processes. Numerous single genes have been reported to be associated with antidepressant response since the beginnings of pharmacogenetics in the early 1990s. One important pharmacokinetic candidate gene for antidepressant action is ABCB1 (multidrug resistance gene) encoding the drug transporter P-glycoprotein (P-gp). Due to its function as a transporter in the blood–brain barrier (BBB), it is also an interesting candidate for response to CNS drugs such as antidepressants.
P-gp could affect the uptake of various antidepressants into the brain. ABCB1 genotyping in depression treatment holds promise for helping physicians to make the right treatment decision regarding type, dosage or the augmentation of antidepressants with a P-gp inhibitor at an early treatment stage.
P-glycoprotein (P-gp), the gene product of ABCB1, is a drug transporter at the blood–brain barrier and could be a limiting factor for entrance of antidepressants into the brain, the target site of antidepressant action. Scientific and clinical studies have shown that brain concentrations of many antidepressants depend on P-gp. In humans, ABCB1 genotyping in the treatment of depression rests on the assumption that genetic variations in ABCB1 explain individual differences in antidepressant response via their effects on P-gp expression at the blood–brain barrier. High P-gp expression is hypothesized to lead to lower and often insufficient brain concentrations of P-gp substrate antidepressants. ABCB1 polymorphisms can predict clinical efficacy and/or tolerability of antidepressants in humans and the clinical application of the ABCB1 genotyping status in depression treatment is a breakthrough of the psychiatric pharmacogenetics.
There are numerous clinical studies showing that the genotype of the ABCB1 gene affects the concentration of antidepressants within the brain and the response of those that are substrates of P-gp protein, such as:
- And other ABCB1 sustrates
Gene or region studied