Background: Major depressive disorder (MDD) is one of the most common psychiatric diseases, affecting millions of people worldwide. Evidence confirms that depression is a multifactorial disease. Consequently, the traditionally prescribed antidepressants such as selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors and tricyclic antidepressants, which only depend on modulating the level of monoamines, face many obstacles. These drugs are of moderate efficacy and have a delayed onset of action (4-6 weeks) in addition to an increased rate of resistance against them. These obstacles make it critical to explore novel pathways and therapeutic targets for the treatment of the disease. The literature is flooded with massive numbers of studies investigating many targets with potential antidepressant effect. This review summarizes recent clinical and preclinical studies discussing the most promising therapeutic targets for treatment of MDD, including proinflammatory cytokines, brain-derived neurotrophic factor, gut microbiota, the psychedelic agent (psilocybin) and 5HT-2A receptor.

Conclusion: This review summarizes a large number of recent studies investigating some of the most promising therapeutic targets for MDD and aims to highlight the inconsistent results that impede the approval of these agents for treatment of the disease.