Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder.
ABSTRACT 1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.
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ABSTRACT: Vortioxetine lengthens circadian period and produces a phase delay.•5-HT7 receptor activation abolishes vortioxetine's effects on circadian activity.•Vortioxetine and 5-HT7 receptor activation modulate recognition memory in rodents.Neuropharmacology 10/2014; · 4.82 Impact Factor
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ABSTRACT: Background Vortioxetine is a novel multimodal compound that has recently been approved by the FDA for the treatment of major depressive disorder (MDD). It is a selective serotonin (5-HT) 3A and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of serotonin transporters. The objective of this meta-analysis was to evaluate the efficacy and safety of vortioxetine in adults with MDD.MethodsA literature search was conducted in the databases of PubMed, EMBASE, Cochrane library and HINARI. The meta-analysis was conducted by including randomized controlled trials that assessed the efficacy and safety of vortioxetine in adult patients with MDD. Using the random effects model, which assumes individual studies are estimating different treatment effects, the efficacy and safety of vortioxetine was determined by weighted mean differences (WMDs) and odds ratios (ORs). The findings were considered as statistically significant when the 95% CI of WMDs and ORs did not include 0 and 1, respectively. Heterogeneity testing, meta-regression and sensitivity analysis were also performed.ResultsDuring the initial literature search about 151 publications were identified. Based on the predetermined inclusion criteria, 7 randomized controlled trials were included. The pooled analysis demonstrated a statistically significant reduction in the Montgomery¿Åsberg Depression Rating Scale (MADRS) total score from baseline among patients who were on vortioxetine (WMD¿=¿¿3.92; 95% CI, ¿5.258 to ¿2.581). Furthermore, a statistically significant number of patients with MDD who were on vortioxetine have achieved a greater than or equal to 50% reduction in depression symptoms from baseline. However, a significant number of patients who were on vortioxetine therapy reported more adverse events than patients who were on placebo (overall OR¿=¿1.21; 95% CI, 1.06 to 1.38).Conclusions Therapy with vortioxetine was significantly associated with reduction in depression symptoms from baseline compared to placebo. Nevertheless, a significant number of patients who were on vortioxetine therapy have reported more adverse events.BMC Psychiatry 09/2014; 14(1):276. · 2.24 Impact Factor
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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.Neuropsychiatric Disease and Treatment 01/2014; 10:1297-307. · 2.00 Impact Factor