New approaches to the pharmacological management of major depressive disorder.

Despite effective and safe therapies for major depressive disorder (MDD), the current arsenal of antidepressant therapies does not fully satisfy the needs of patients or physicians. Many patients are only partial responders or are treatment resistant and side effects interfere with compliance. The majority of antidepressants directly affect monoamine neurotransmission within the central nervous system. Moving beyond this mechanism has been a challenge because of the lack of knowledge about the underlying etiology and pathophysiology of MDD. Provided in this report is a review of some of the major new advances in MDD research that suggest the possibility of novel and improved future therapeutic options. Emphasis is placed on studies of unipolar, but not bipolar, depression. New therapies include dual and triple monoamine uptake inhibitors, non-conventional antidepressants such as tianeptine, and a number of augmentation strategies. In addition, studies are underway on a number of mechanisms of action that might yield the next therapeutic advance. These include agents that interact with endocannabiniod systems, examination of natural products, and compounds that influence neuropeptide systems such as galanin and melanin-concentrating hormone, and growth and neurotrophic factors. Epigenetic mechanisms involving histone modification are also being explored. An area of intensive investigation is glutamate neurotransmission. Data support the hypothesis that NMDA receptor antagonists are effective in MDD individuals resistant to conventional therapies. The potential of metabotropic glutamate receptors as novel targets is also discussed. Accumulating evidence supports the idea that amplification of AMPA receptor function is a critical link in the transduction processes involved antidepressant effects.