Ethyl-EPA and dexamethasone-resistance in therapy-refractory depression

The omega-3 fatty-acid eicosapentaenoic acid (EPA), administered in the form of ethyl-EPA, has a marked clinical effect as an adjunct in therapy-refractory depression (1). Severe depression is characterized by an immunoactivation and by a resistance to dexamethasone (Dex) to suppress the HPA-axis. EPA has an immunosuppressive and HPA-axis suppressing effect, possibly by reversing resistance to dexamethasone and cortisol by acting at an enzyme called p-glycoprotein (p-gp). As both steroids are substrates of p-gp, a high p-gp activity reduces their functional activity, possibly leading to the immun- and endocrine changes in depression. EPA reduces drug resistance and may reverse Dex-resistance. Alternatively by the same mechanism EPA may enhance the action of antidepressants, which are p-gp substrates, by inhibiting their active transport out of the intracerebral space at the level of the blood brain barrier.

1. Peet M, Horrobin DF. Arch Gen Psychiatry 2002;59(10):913–9.