The guarded brain. The role of P-glycoprotein at the blood-brain barrier in major psychiatric disorders and antidepressant treatment

PhD ceremony: Mr. O.L. de Klerk, 16.15 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: The guarded brain. The role of P-glycoprotein at the blood-brain barrier in major psychiatric disorders and antidepressant treatment

Promotor(s): prof. J.A. den Boer, prof. R.A.I.O. Dierckx

Faculty: Medical Sciences

The blood-brain barrier (BBB) is a highly specialized selective barrier that protects the nervous system by limiting the entrance of nearly all substances, while at the same time guaranteeing that the high metabolic needs of the brain are optimally met. To accomplish this task, the capillaries have different transport systems on their surface. In regard to brain protection P-glycoprotein (P-gp) is a major efflux pump located in the capillary wall. It is capable of extruding a wide range of structurally different molecules that have gained access to the endothelial cell. In vitro studies have shown that P-gp has a major impact on the transport of inflammatory proteins and cortisol, substances that are connected to depressive disorders and other major psychiatric illnesses. Moreover, the majority of antidepressants and antipsychotics are influenced by the activity of P-gp. In this thesis we performed PET studies with verapamil and showed changed activity of cerebral P-gp in major psychiatric disorders as well as during chronic antidepressant use. We also demonstrated that variants of the encoding gene (ABCB1) for P-gp influences the occurrence of side effects on SSRIs (that are substrates of P-gp) and may be related to susceptibility for depression. Taken together, P-glycoprotein may play a role (as susceptibility factor) in major depressive disorder and it may be a relevant pharmacokinetic factor in psychiatric drug therapy.