Interactions between antidepressants and P‐glycoprotein at the blood–brain barrier: clinical significance of in vitro and in vivo findings

Abstract

The drug efflux pump P‐glycoprotein (P‐gp) plays an important role in the function of the blood–brain barrier by selectively extruding certain endogenous and exogenous molecules, thus limiting the ability of its substrates to reach the brain. Emerging evidence suggests that P‐gp may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. Despite some inconsistency in the literature, clinical investigations of potential associations between functional single nucleotide polymorphisms in ABCB1, the gene which encodes P‐gp, and antidepressant response have highlighted a potential link between P‐gp function and treatment‐resistant depression (TRD). Therefore, co‐administration of P‐gp inhibitors with antidepressants to patients who are refractory to antidepressant therapy may represent a novel therapeutic approach in the management of TRD. Furthermore, certain antidepressants inhibit P‐gp in vitro, and it has been hypothesized that inhibition of P‐gp by such antidepressant drugs may play a role in their therapeutic action. The present review summarizes the available in vitro, in vivo and clinical data pertaining to interactions between antidepressant drugs and P‐gp, and discusses the potential relevance of these interactions in the treatment of depression.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

“…P-glycoprotein is an important component of the bloodbrain barrier and the intestinal barrier and affects efflux of medications, including psychotropic, cardiac, and cancer agents. 74 However, there is no consistent evidence of clinically relevant P-glycoprotein interactions with antidepressants or antipsychotics. 74,75 Although not a pharmacokinetic drug-drug interaction, serotonin syndrome and/or hypertensive crisis can occur when serotonergic or sympathomimetic drugs are combined with MAO inhibitors, including the reversible MAO-A inhibitor, moclobemide, and the irreversible MAO-B inhibitor, selegiline (Table 9).…”

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

“…It is a drug transport protein with a role in efflux across the blood-brain barrier as it is expressed in the luminal layer of brain capillary endothelial cells. ABCB1 influences the concentration in the brain of antidepressants that are substrates of P-glycoprotein which include citalopram, venlafaxine, desipramine, paroxetine, and amitriptyline [26]. Mirtazapine, bupropion, and fluoxetine are not substrates and may serve as alternative psychotropics [25].…”

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

“…This is one reason that the P-gp substrate specificity of drugs should be considered on individual merit. According to both in vitro and in vivo data P-gp may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies (Ejsing et al, 2007;Linnet and Ejsing, 2008;O'Brien et al, 2012). While there is evidence that venlafaxine and paroxetine are substrates of P-gp (Karlsson et al, 2010;, the results are contradictory for citalopram (Rochat et al, 1999;.…”