Verapamil in treatment resistant depression: A role for the P-glycoprotein transporter?

Introduction: Verapamil is a calcium channel blocker that also inhibits the P-glycoprotein (Pgp) membrane transporter. We have found that administration of verapamil with a recognised antidepressant improves clinical outcome in previously treatment resistant cases despite the fact that verapamil does not possess inherent antidepressant activity. In this study we examined the hypothesis that the antidepressant-like effects of verapamil are mediated through its blockade of the Pgp transporter in the blood brain barrier (BBB). Methods: Following pre-treatment with verapamil (20 mg/kg) or a saline solution male Sprague Dawley rats were injected with imipramine (15 mg/ kg). Two hours later, the animals were sacrificed, trunk blood collected and brain regions dissected out. High performance liquid chromatography (HPLC) was used to quantitate antidepressant drug concentrations in all samples. Results: Verapamil pre-treatment significantly elevated imipramine concentrations in all brain regions studied. The effect was most pronounced in the brainstem and frontal cortex where we observed in excess of a doubling in the brain region: serum ratios. Conclusion: Our results verify inhibition of Pgp as a potential mechanism of action for verapamil during treatment resistant depression. The implications of these findings are discussed in the context of novel treatment strategies in depression.