Emerging targets for the treatment of depressive disorder

New agents offering novel mechanisms of action are required in the treatment of depressive disorder. Established agents targeting monoamine systems are unsatisfactory because of full and partial treatment resistance, delay in the onset of their effect and the occurrence of side effects. The monoamine hypothesis of depression is now recognised to provide an incomplete explanation of the pathophysiology of depression. New theories have recently developed and new targets for treatment have emerged. We briefly review some important candidate systems and therapeutic targets in depression: the hypothalamic-pituitary-adrenal axis (HPA) and the glucocorticoid and corticotrophin-releasing factor receptors, synaptic plasticity and neurotrophins and the N-methyl-D-aspartate (NMDA) receptor. The putative role of the neuropeptides substance P and neuropeptide Y, the nicotinic system and the potential therapeutic benefits of cannabinoids are also reviewed. Vagal nerve stimulation (VNS) and transcranial magnetic stimulation, serendipitous advances in treatment, are discussed briefly.