Treat the brain and treat the periphery: toward a holistic approach to major depressive disorder.

The limited medication for major depressive disorder (MDD) against an ever-rising disease burden presents an urgent need for therapeutic innovations. During recent years, studies looking at the systems regulation of mental health and disease have shown a remarkably powerful control of MDD by systemic signals. Meanwhile, the identification of a host of targets outside the brain opens the way to treat MDD by targeting systemic signals. We examine these emerging findings and consider the implications for current thinking regarding MDD pathogenesis and treatment. We highlight the opportunities and challenges of a periphery-targeting strategy and propose its incorporation into a holistic approach.