"(Artigas et al. 1994; Blier and Bergeron 1995; P erez et al. 1997). This enhancement would be mediated by blockage of negative feedback inhibition in response to increased serotonin (5-HT) (Bel and Artigas 1993; Rutter et al. 1994; Kreiss and Lucki 1995; Arborelius et al. 1996). Further evidence to support the role of 5-HT 1A receptors in this response comes from the results of combination therapy with SSRIs and WAY-100635, a highly selective 5- HT 1A receptor antagonist (Gartside et al. 1995; Dawson and Nguyen 1998). "
[Show abstract][Hide abstract] ABSTRACT: Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the Ki values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg−1, dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg−1) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg−1) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.
"5-HT 1A receptors were suggested to modulate the SSRIinduced increase of synaptic serotonin levels, as the latter were found to be heightened after administration of fluoxetine in 5-HT 1A receptor knockout mice (Parsons et al., 2001). Similarly, in humans, 5-HT 1A receptor antagonists, for example, pindolol, have been shown to accelerate the therapeutic efficacy of SSRIs in depression by counteracting the 5-HT 1A auto-receptor–induced reduction of cell firing that can be observed early in treatment (Artigas et al., 1994). In vivo neuroimaging findings investigating the role of the 5-HT 1A receptor in anxiety support the assumption of reduced 5-HT 1A receptor densities in anxiety disorders. "
"The greater elevations of extracellular 5-HT evoked by vortioxetine likely result from its multimodal mechanism of action. Indeed, various 5-HT receptors for which vortioxetine shows high affinity have been implicated in the mechanism of action of antidepressant drugs,11 and several of them participate in negative feedback mechanisms that limit the action of SSRI.12,13 In particular, the blockade of 5-HT3 receptors by vortioxetine may be involved in these neurochemical effects, since the 5-HT3 receptor antagonist ondansetron augments the increase in extracellular 5-HT produced by SSRI in mPFC and the hippocampus.8 "
[Show abstract][Hide abstract] ABSTRACT: VORTIOXETINE IS A NEW MULTIMODAL ACTION ANTIDEPRESSANT WITH TWO TYPES OF ACTION: serotonin transporter (SERT) blockade and a strong affinity for several serotoninergic receptors. It is an antagonist of the 5-HT3 and 5-HT7 receptors, a partial agonist of 5-HT1B, and an agonist of 5-HT1A. Its combined action on SERT and four subtypes of serotoninergic receptors increases the extracellular concentration of serotonin, dopamine, and noradrenaline. Twelve clinical trials have been carried out, nine of which had positive results versus placebo. When active comparators were included in the study design, no significant differences were found except in one study in which the efficacy of vortioxetine was superior to the comparator (agomelatine) in depression resistant to selective serotonin reuptake inhibitors (SSRI)/serotonin-norepinephrine reuptake inhibitors (SNRI) treatment. Tolerability studies indicate that the drug does not cause any important problems on blood tests, vital signs, or on electrocardiography. The lack of weight gain and induction of metabolic syndrome and the lack of significant changes in the QTc are especially important. The incidence rate of sexual dysfunction is low and similar to placebo in various trials. Similarly, cognitive function remains intact with vortioxetine.
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