Numerous antidepressants are available for the treatment of the major depressive disorder (MDD). Unfortunately, the disadvantages of these antidepressive medications, including inadequate treatment response, the therapeutic lag between drug administration and the onset of symptoms alleviation, and the safety consideration limit their clinical use and accelerate the exploration of advanced antidepressants with novel action mechanisms/newer targets, with fewer side effects. In this chapter, a series of compounds showing clinical potent in the treatment of MDD has been reviewed based on their reported results from different phase clinical trials. Although the majority of these strategies currently only lead to a systematic approach in the aspects of treatment resistant depression, some of them would be a routine clinical practice which is usable in the treatment of MDD, such as ketamine. Additionally, beyond the mechanism of action for novel therapeutic molecules involving glutamatergic, opiate, cholinergic receptors, and neuroplasticity, some supplemental procedures such as polyunsaturated fatty acids were also included in this chapter due to their solid property against MDD.
Keywords: Anti-inflammation; Ketamine; Neurotransmitters; Novel pharmacological antidepressants.