Introduction
overdose, toxicity, hyperactivity, depressive disorder, MDD, depression, depressive disorders
DYSFUNCTION, ADVERSE EFFECT, REMISSION, GENOTOXICITY, PATHOGENESIS
Major depressive disorder (MDD) is one of the most common depressive disorders, with an estimated 12-month prevalence rate of 6.6% and a lifetime prevalence rate of 16.2% [The pathogenesis of MDD is complex, including structure and function alterations of discrete brain regions, especially the hippocampus [Currently, most approved antidepressants for MDD primarily focus on the monoamine neurotransmitters 5-HT and NE. However, there are certain limitations to these antidepressants. For first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAIOs), most of them have a significant adverse effect profile as well as lethality in overdose and are not commonly used. The second generation of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are thought to carry less significant side effects and recommended as first-line treatment for most patients with MDD. The response rate to these drugs is moderate (40–60%), and the remission rate is relatively low [Anhedonia, loss of motivation, energy, and attention, which is one of the core symptoms of MDD, have been linked to the dysfunction of the DA system. DA is produced in small nuclei of tightly clustered neurons-predominantly the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). In animal models of depression, the DA system is downregulated due to hyperactivity of the infralimbic subregion (ilPFC), driving activity in the inhibitory basolateral amygdala (BLA)-ventral pallidum (VP) pathway while attenuating excitation via the Re-ventral subiculum of the hippocampus (vSub)-nucleus accumbens (NAc)-VP pathway [Ansofaxine hydrochlorideis [(±)-4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl) ethyl) phenyl 4-methylbenzoate hydrochloride], a new triple reuptake inhibitor chemical entity, is formulated as an extended-release (ER) oral tablet for the treatment of adults with MDD. Ansofaxine inhibits the function of the transport proteins responsible for clearing dopamine, serotonin, and norepinephrine from the synaptic cleft. A Microdialysis study shows that ansofaxine can increase all three neurotransmitters in the striatum after oral drug administration. Furthermore, in the vitro binding affinities and reuptake inhibition effects trail, ansofaxine exhibits high affinities at SERT, NET, and DAT and differential inhibition potencies at the three transporters. The concentration required to inhibit uptake (IC50) values of ansofaxine on radioligand binding to SERT, NET, and DAT were 1,330 ± 82.5 nM, 2,200 ± 278 nM, and 227 ± 21.7 nM, respectively. The IC50 values for 5-HT, NE, and DA reuptake were 31.4 ± 0.4 nM, 586.7 ± 84 nM, and 733.2 ± 10 nM, respectively. The preclinical safety studies showed that ansofaxine was negative in the genotoxicity combination studies and had acceptable toxicity profiles in the general toxicity studies, fertility and early embryonic development studies, and good safety and tolerance [