A double-blind, randomized, placebo-controlled, active-reference study of Lu AA21004 in patients with major depressive disorder (MDD)

Servei de Psiquiatría, Hospital de Sant Pau, Universidat Autonoma de Barcelona, Barcelona, Spain.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 07/2011; 15(5):589-600. DOI: 10.1017/S1461145711001027
Source: PubMed


The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs)--placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD.

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Available from: Perez Victor, Apr 25, 2014
    • "Currently, there are seven positive placebo-controlled 6–8- week studies (e.g. Alvarez et al., 2012; Baldwin et al., 2012; Jain et al., 2013), including one study of elderly subjects (Katona et al., 2012) and one positive maintenance study of adults (Baldwin et al., 2012) which have demonstrated the efficacy of vortioxetine in MDD in a dose range from 5 to 20 mg/day. Two low-dose studies (2.5 mg/day and 5 mg/day of vortioxetine) did not yield differences to placebo. "
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    ABSTRACT: Abstract The monoamine hypothesis of depression posits that an imbalance in monoaminergic neurotransmission is causally related to the clinical features of depression. Antidepressants influencing serotonin mainly aim at raising serotonin concentrations, thereby increasing serotonergic transmission at the level of the synapse, for example by inhibiting the serotonin transporter. However, the serotonin system is multifaceted. Different serotonin receptor subtypes turn the serotonergic system into a complex neurochemical arrangement that influences diverse neurotransmitters in various brain regions. Classical antidepressants as well as other psychopharmacological agents have various crucial effects on serotonin receptors. We aim at providing a clinically useful characterization of serotonin receptor subtypes in the treatment of depression. Clarifying the mode of action and the interplay of serotonin receptors with pharmacological agents should help antidepressant mechanisms and typical side effects to be better understood. Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile.
    No preview · Article · Oct 2015 · Journal of Psychopharmacology
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    • "Major depressive disorder (MDD) is a serious public health problem affecting the lives of millions in the worldwide and leading causes of disability and disease [1]. This disease causes disorder in social, mental and physical functions of patients [2]. "
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    ABSTRACT: Background: Major depressive disorder is a serious public health problem affecting the lives of millions in the worldwide and leading causes of disability and disease. This study aimed to evaluate the efficacy and safety of Vortioxetine and Duloxetine 60 mg compared to placebo for the treatment of major depressive disorder. Method: We searched the Cochrane library, Pub Med, CRD, Scopus, and Central Register of Controlled Trials to January 2015. We also searched, International depressive disorder Conference and the Anxiety Disorders and Depression Conference. We identified that five randomized clinical trials were ultimately included in a Meta analysis. Data analysis was conducted by Standardized Mean Differences (SMD) for Mont-gomery-Åsberg Depression Rating Scale (MADRS), and Odds Ratio (OR) for adverse events. The SMD and OR reported by 95% CI. Results: Results showed statistical significance in the MADRS for Vortioxetine (SMD = −3.29; 95% CI −4.47 to −2.10; I 2 = 99.3%) and for Duloxetine 60 mg (SMD = −6.35; 95% CI −8.84, −3.87; I 2 = 99.3%). Results showed that the Vortioxetine 2.5, 5, 10, 15, 20 mg and overall compared to placebo showed a significance for Nausea and no significance for diarrhea , dry mouth, dizziness, fatigue and headache. Also results of Duloxetine 60 mg showed a significant effect for dry mouth, dizziness, fatigue and nausea. Conclusion: It is necessary to do more studies so as to better assess and much more powerful than the evidence for the use of this drug in the treatment of depression.
    Full-text · Article · Oct 2015 · Journal of Behavioral and Brain Science
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    • "Vortioxetine 20 mg has been shown to be significantly superior to placebo on multiple depression endpoints (MADRS total score, response rate, CGI-I, SDS, and MADRS in patients with high baseline HAM-A) after 8 weeks of treatment in two other studies, one conducted in the USA and the other conducted outside of the USA (Jacobsen et al. 2013;Boulenger et al. 2014). Additionally, there has been a tendency across studies to see increasing efficacy at higher doses (Alvarez et al. 2012;Henigsberg et al. 2012;Baldwin et al. 2012b;Jacobsen et al. 2013;Boulenger et al. 2014). The reasons for failure of the vortioxetine 15-mg dose to separate from placebo in the current study remain unclear as this dose did demonstrate statistically significant improvement over placebo in a previous study conducted outside of the USA (Boulenger et al. 2014). "
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    ABSTRACT: Rationale Vortioxetine has reduced depressive symptoms in adults with major depressive disorder (MDD) in multiple clinical trials. Objectives The aim of this study is to evaluate the efficacy, safety, and tolerability of vortioxetine 15 and 20 mg vs placebo in adults with MDD. Methods Patients were randomized 1:1:1:1 to vortioxetine 15 mg, vortioxetine 20 mg, duloxetine 60 mg (active reference), or placebo. The primary efficacy endpoint was mean change in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at week 8 (MMRM). Safety/tolerability assessments included physical examinations, vital signs, laboratory evaluations, electrocardiograms, adverse events (AEs), Columbia–Suicide Severity Rating Scale, Arizona Sexual Experiences Scale, and Discontinuation–Emergent Signs and Symptoms checklist. Results Six hundred and fourteen patients were randomized. Mean changes in MADRS scores were −12.83 (±0.834), −14.30 (±0.890), −15.57 (±0.880), and −16.90 (±0.884) for placebo, vortioxetine 15 mg (P = .224), vortioxetine 20 mg (P = .023), and duloxetine 60 mg (P P vs placebo), respectively. AEs reported by ≥5 % of vortioxetine patients included nausea, headache, diarrhea, dizziness, dry mouth, constipation, vomiting, insomnia, fatigue, and upper respiratory infection. Treatment-emergent sexual dysfunction, suicidal ideation or behavior, and discontinuation symptoms were not significantly different between vortioxetine and placebo. Conclusions Vortioxetine 20 mg significantly reduced MADRS total scores after 8 weeks of treatment. Both vortioxetine doses were well tolerated. Clinical trial registration identifier NCT01140906;
    Full-text · Article · Jan 2015 · Psychopharmacology
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