*3.1. Major Depressive Disorder*

Major depressive disorder is one of the most prevalent and debilitating psychiatric disorders with high impact on the quality of life and negative effects on mood, behavior, and cognition [149]. Over the past few decades, several mechanisms have been investigated in the pathophysiology of MDD, including altered serotonergic, noradrenergic, dopaminergic, and glutamatergic systems, increased inflammation, hypothalamic-pituitary-adrenal axis abnormalities, vascular changes, and decreased neurogenesis and neuroplasticity. In particular, a decrease in serotonergic neurotransmission is regarded as the main etiopathogenetic mechanism occurring in depressed patients. Thus, the most common drugs used to treat MDD are serotonin reuptake inhibitor (SSRI) that block SERT and thus increase serotonin in the raphe nucleus at post-synapse. Therefore, a misbalance in the serotonin production and/or release is believed to play a central role in determining MDD. This led to finding, by means of genetic, proteomic and pharmacological tools, molecules able to increase the expression of serotonin in neurons by modulating neural genes or proteins [150–152]. Among these molecules, TPH2, the rate-limiting enzyme responsible for brain serotonin biosynthesis, plays a crucial role and is amenable of genetic and pharmacological manipulation [153,154]. Nevertheless, in 1997 Duman and Nestler formulated the neurotrophin hypothesis of depression [155]. This theory is now supported by studies demonstrating a decrease in BDNF mRNA and protein levels in postmortem critical regions, such as the hippocampus, prefrontal cortex and amygdala, in patients with MDD compared to controls.
