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

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood–brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood–brain barrier is changed in patients with major depression. Positron emission tomography was used to measure brain uptake of [11C]verapamil, which is normally expelled from the brain by P-gp. Cerebral volume of distribution (VT) of [11C]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to healthy controls showed a significant decrease of [11C]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [11C]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs. Our results may explain why treatment-resistant depression can develop.