Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 12/2011; 340(3):666-75. DOI: 10.1124/jpet.111.189068
Source: PubMed


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-HT7 receptor antagonist (K-i = 19 nM), h5-HT1B receptor partial agonist (K-i = 33 nM), h5-HT1A 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-HT1B receptor agonist [EC50 = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT7 receptor antagonist (K-i = 200 nM and IC50 = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT1B receptor and rSERT (ED50 = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT3 receptor antagonist in the Bezold-Jarisch reflex assay (ED50 = 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-HT3 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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    • "This result was reproducible in experiments in which both higher and lower concentrations were used. The fact that vortioxetine acts through multiple 5-HT receptors, in addition to inhibiting the SERT (Mork et al., 2012; Westrich et al., 2012), supports our results, which reflect a gradual engagement of receptors as vortioxetine concentration increases. Vortioxetine's regulation of circadian rhythms likely involves a complex interplay between 5-HT tone and inhibition/activation of 5-HT receptor subtypes, i.e., 5-HT 1A , 5- HT 1B , 5-HT 3 , and 5-HT 7 receptors (Graff et al., 2007; Lovenberg et al., 1993; Pickard et al., 1999; Roca et al., 1993). "
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    ABSTRACT: Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 mu M vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/ kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (
    Full-text · Article · Oct 2014 · Neuropharmacology
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    • "Vortioxetine is a novel multimodal compound that has recently been approved by the Food and Drug Administration (FDA) of the United States of America for the treatment of MDD. This drug is a 5-HT 3A, 5-HT7 and 5HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the serotonin transporter [6,7]. Vortioxetine showed an extended absorption, a medium clearance, a large volume of distribution and a relatively long elimination half-life in healthy young volunteers [8]. "
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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.
    Full-text · Article · Sep 2014 · BMC Psychiatry
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    • "Escitalopram was tested at half the concentration of vortioxetine since it has a higher affinity for the SERT (Ki=1.1nM for escitalopram vs 1.6 nM for vortioxetine, (Mørk et al., 2012; Owens et al., 2001). In conclusion, additional studies are needed to elucidate which targets of vortioxetine apart from 5-HT 3 receptors might be involved in its inhibitory effect. "
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    ABSTRACT: Vortioxetine, a novel antidepressant with multimodal action, is a serotonin (5-HT)3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and a 5-HT transporter (SERT) inhibitor. Vortioxetine has been shown to improve cognitive performance in several preclinical rat models and in patients with major depressive disorder. Here we investigated the mechanistic basis for these effects by studying the effect of vortioxetine on synaptic transmission, long-term potentiation (LTP), a cellular correlate of learning and memory, and theta oscillations in the rat hippocampus and frontal cortex. Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism. Vortioxetine also enhanced LTP in the CA1 region of the hippocampus. Finally, vortioxetine increased fronto-cortical theta power during active wake in whole animal electroencephalographic recordings. In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures. Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus. Given the central role of the hippocampus in cognition, these findings may provide a cellular correlate to the observed preclinical and clinical cognition-enhancing effects of vortioxetine.
    Full-text · Article · Aug 2014 · Journal of Psychopharmacology
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