BACKGROUND: The World Health Organization (WHO) report has predicted that major depression will become a key cause of illness-induced disability by the year 2020, second only to ischemic heart diseases. OBJECTIVES/METHODS: Although a large number of antidepressant drugs (from monoamine oxidase inhibitors and tricyclic antidepressants to dual reuptake inhibitors) are available for treatment of the disease, approximately 30% of patients failed to respond to this therapy. Therefore, the search for newer or novel drug targets for the treatment of major depression continues. Some of these targets include dopamine, triple reuptake inhibition, L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, sigma-1 receptors, neurosteroids, melatonin, glutamate, 5HT6, 5HT7 serotonin receptor antagonists, beta-3 adrenoceptor antagonist, vasopressin V(Ib) receptor antagonists, NK2 tachykinin receptor antagonists, glucocorticoid receptor antagonists and corticotropin-releasing factor-1 receptor antagonists, as well as herbal antidepressant drugs. The present review attempts to discuss the status of some of these novel approaches and the drugs that are under investigation for the treatment of major depression. An attempt is also made to review the status of three indigenous plant-derived drugs, berberine, curcumin and rutin, as novel and safe future herbal antidepressants. RESULTS/CONCLUSION: There is an exciting future in the discovery of novel targets and target-specific agents for the management of major depression.
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