Vortioxetine for generalised anxiety disorder in adults. / Vortioxetina para el trastorno de ansiedad generalizada en adultos.

INTRODUCTION: The currently accepted psychopharmacological treatment for generalised anxiety disorder in adults is associated with several adverse effects which threaten its acceptability. In this line, vortioxetine has been proposed as an alternative with less adverse effects in the treatment of this pathology. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified seven systematic reviews including five primary studies, all corresponding to randomized trials evaluating the effectiveness of vortioxetine in adult patients with generalized anxiety disorder without current treatment. We conclude that there is uncertainty whether vortioxetine increases the response to treatment or improves anxious symptoms, because the certainty of the existing evidence has been assessed as very low. Furthermore, vortioxetine may increase nausea (low certainty evidence).

INTRODUCCION: El tratamiento psicofarmacológico actualmente aceptado para el trastorno de ansiedad generalizada en adultos está asociado a efectos adversos que amenazan su aceptabilidad. En esta línea, se ha propuesto a la vortioxetina como una alternativa con un mejor perfil de efectos adversos en el tratamiento de dicha patología. MÉTODO: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos siete revisiones sistemáticas que en conjunto incluyeron cinco estudios primarios, todos correspondientes a ensayos aleatorizados que evaluaron la efectividad de la vortioxetina en pacientes adultos con trastorno de ansiedad generalizada sin tratamiento actual. Concluimos que no es posible establecer con claridad si la vortioxetina aumenta la respuesta a tratamiento o mejora los síntomas ansiosos, debido a que la certeza de la evidencia existente ha sido evaluada como muy baja. Además, la vortioxetina podría aumentar los efectos adversos (náuseas) (certeza de la evidencia baja).

Vortioxetine Reduces Marble Burying but Only Transiently Enhances Social Interaction Preference in Adult Male BTBR T+Itpr3tf/J Mice.

Vortioxetine is a multimodal antidepressant with agonist activity at serotonin (5-HT)1A and 5-HT1B receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR T+Itpr3tf/J (BTBR) mice, the 5-HT1A partial agonist buspirone and SERT blocker fluoxetine enhanced social interaction but did not reduce marble burying. We hypothesized that vortioxetine through its actions at SERT and 5-HT1A could improve BTBR sociability and via 5-HT1B could reduce burying better than sertraline, a selective SERT blocker. Vortioxetine (5-10 mg/kg) or sertraline (2 mg/kg) was administered 30 min presociability and 75 min prior to marble burying tests. Vortioxetine (10 mg/kg) occupancy (%) was 84 ± 1 for SERT, 31 ± 12 for 5-HT1A, and 80 ± 5 for 5-HT1B in brain at 110 min postinjection, and serum oxytocin was 24% lower (p < 0.01) in vortioxetine-treated mice. Vortioxetine reduced novel object investigation, whereas sertraline enhanced overall sociability. However, the vortioxetine-induced increase in social sniffing was transient, as it was lost with 60-120 min presociability test delays in subsequent experiments. Vortioxetine and sertraline both reduced BTBR marble burying. Based on vortioxetine occupancy, actions at SERT and/or 5-HT1B are more likely to underlie its behavioral effects than 5-HT1A. Overall, vortioxetine has great potential for suppressing restrictive-repetitive behaviors, but it appears less promising as a sociability enhancer.

Vortioxetine: A review of the pharmacology and clinical profile of the novel antidepressant.

The aim of this paper was to review the up-to-date evidence base on pharmacology and clinical properties of vortioxetine. Vortioxetine is a novel antidepressant, approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). Because vortioxetine exhibits both an antidepressant and anxiolytic effect, it may be effective in treating both depressive and anxiety disorders, such as generalized anxiety disorder (GAD). Based on its pharmacodynamics profile and preclinical studies, it is believe that the drug's clinical action is mediated mainly by selective blockade of serotonin reuptake (by inhibiting the serotonin transporter [SERT]) and direct modulation of 5-HT receptors activity (such as 5-HT3, 5-HT7, 5-HT1D and 5-HT1B). In patients with MDD the recommended doses range is 5-20mg/day. Vortioxetine was shown to be more effective than placebo both in MDD and GAD. In terms of side effects, nausea, vomiting, diarrhea, and dry mouth were most commonly observed in individuals receiving vortioxetine. In direct comparison to duloxetine, vortioxetine is found to have a smaller efficacy but had a lower risk of developing the common antidepressant-induced adverse effects.

Current and Future Perspectives on the Major Depressive Disorder: Focus on the New Multimodal Antidepressant Vortioxetine.

BACKGROUND: Vortioxetine (VRX) is a multimodal antidepressant that acts as serotonin (5HT) transporter inhibitor as well as 5HT3A and 5HT7 receptors antagonist, 5HT1A and 5HT1B receptors partial agonist. It was recently approved in the US and the EU for the treatment of adult patients with Major Depressive Disorder (MDD). OBJECTIVE: The present article aims at systematically reviewing findings of the published and unpublished research on the pharmacological properties, efficacy, safety and tolerability of oral VRX in the treatment of MDD. METHOD: A systematic review, in accordance with the Cochrane Collaboration and the PRISMA guidelines, was conducted searching the electronic databases MEDLINE, by combining the following keyterms: ((vortioxetine OR LU AA21004 OR brintellix) AND (antidepressant OR depression OR major depressive disorder), without language/time restrictions. Further studies were retrieved from reference listing of relevant articles or manual search. Preclinical and clinical studies (RCT and open label trials) were here retrieved. RESULTS: Several placebo-controlled and active-treatment studies demonstrated the antidepressant efficacy and tolerability of VRX in adult patients affected with MDD. In addition, VRX seems to own procognitive activity. VRX seems generally well tolerated, without significant cardiovascular or weight gain effects. The most common adverse events reported included nausea, vomiting, hyperhidrosis, headache, dizziness, somnolence, diarrhoea and dry mouth. CONCLUSION: Overall, placebo controlled and active treatment trials support that VRX is effective and well tolerated in MDD. Its combined serotonin reuptake inhibition with agonism, partial agonism and antagonism of a number of receptors might provide a broader spectrum of antidepressant activity than currently available agents.

New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine.

Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, exaggerated worry and tension, mainly comorbid with Major Depressive Disorder (MDD). Currently, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recommended as first-line treatment of GAD. However, some patients may not respond to the treatment or discontinue due to adverse effects. Vortioxetine (VRX) is a multimodal antidepressant with a unique mechanism of action, by acting as 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, partial agonist at the 5-HT1A and 5-HT1B receptors and inhibitor at the 5-HT transporter. Preliminary clinical trials showed contrasting findings in terms of improvement of the anxiety symptomatology and/or cognitive impairment. Here, we aim to systematically review the evidence currently available on the efficacy, safety and tolerability of VRX in the treatment of GAD. The generalizability of results on the efficacy of VRX in patients with anxiety symptomatology and GAD is limited due to few and contrasting RCTs so far available. Only two studies, of which one prevention relapse trial, reported a significant improvement in anxiety symptomatology compared to three with negative findings.

Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission.

Previous work from this laboratory hypothesized that the multimodal antidepressant vortioxetine enhances cognitive function through a complex mechanism, using serotonergic (5-hydroxytryptamine, 5-HT) receptor actions to modulate gamma-butyric acid (GABA) and glutamate neurotransmission in key brain regions like the prefrontal cortex (PFC) and hippocampus. However, serotonergic receptors have circumscribed expression patterns, and therefore vortioxetine's effects on GABA and glutamate neurotransmission will probably be regionally selective. In this article, we attempt to develop a conceptual framework in which the effects of 5-HT, selective serotonin reuptake inhibitors (SSRIs), and vortioxetine on GABA and glutamate neurotransmission can be understood in the PFC and striatum-2 regions with roles in cognition and substantially different 5-HT receptor expression patterns. Thus, we review the anatomy of the neuronal microcircuitry in the PFC and striatum, anatomical data on 5-HT receptor expression within these microcircuits, and electrophysiological evidence on the effects of 5-HT on the behavior of each cell type. This analysis suggests that 5-HT and SSRIs will have markedly different effects within the PFC, where they will induce mixed effects on GABA and glutamate neurotransmission, compared to the striatum, where they will enhance GABAergic interneuron activity and drive down the activity of medium spiny neurons. Vortioxetine is expected to reduce GABAergic interneuron activity in the PFC and concomitantly increase cortical pyramidal neuron firing. However in the striatum, vortioxetine is expected to increase activity at GABAergic interneurons and have mixed excitatory and inhibitory effects in medium spiny neurons. Thus the conceptual framework developed here suggests that vortioxetine will have regionally selective effects on GABA and glutamate neurotransmission.

Profile of vortioxetine in the treatment of major depressive disorder: an overview of the primary and secondary literature.

This article reviews the pharmacological profile and available efficacy and tolerability/safety data for vortioxetine, one of the most recent antidepressant drugs to be approved in the USA for the treatment of major depressive disorder (MDD) in adults. The efficacy of vortioxetine for treating MDD in adults is supported by eight positive short-term (6- to 12-weeks) randomized, placebo-controlled trials, and one positive randomized, double-blind, 52-week relapse prevention trial. Based on pooled data from short-term randomized trials and from longer-term studies, vortioxetine appears to be well tolerated and to have a low incidence of adverse effects on sexual functioning. Vortioxetine also appears to be effective for treating symptoms of MDD in the elderly based on the results of one randomized trial for which recruitment was focused on this specific population. Nevertheless, effectiveness studies that directly compare the clinical effects of vortioxetine with other established antidepressant drugs are lacking, and there is no evidence as yet that vortioxetine is more clinically effective than other types of antidepressants. Some preliminary suggestions concerning the place of vortioxetine among the broad range of pharmacological treatments for adults with MDD are provided.

Treatment of cognitive dysfunction in major depressive disorder--a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine.

Although major depressive disorder is primarily considered a mood disorder, depressed patients commonly present with clinically significant cognitive dysfunction that may add to their functional disability. This review paper summarizes the available preclinical data on the effects of antidepressants, including monoamine reuptake inhibitors and the multimodal antidepressant vortioxetine, in behavioral tests of cognition such as cognitive flexibility, attention, and memory, or in potentially cognition-relevant mechanistic assays such as electroencephalography, in vivo microdialysis, in vivo or in vitro electrophysiology, and molecular assays related to neurogenesis or synaptic sprouting. The available data are discussed in context with clinically relevant doses and their relationship to target occupancy levels, in order to evaluate the translational relevance of preclinical doses used during testing. We conclude that there is preclinical evidence suggesting that traditional treatment with monoamine reuptake inhibitors can induce improved cognitive function, for example in cognitive flexibility and memory, and that the multimodal-acting antidepressant vortioxetine may have some advantages by comparison to these treatments. However, the translational value of the reviewed preclinical data can be questioned at times, due to the use of doses outside the therapeutically-relevant range, the lack of data on target engagement or exposure, the tendency to investigate acute rather than long term antidepressant administration, and the trend towards using normal rodents rather than models with translational relevance for depression. Finally, several suggestions are made for advancing this field, including expanded use of target occupancy assessments in preclinical and clinical experiments, and the use of translationally valuable techniques such as electroencephalography.

The efficacy of vortioxetine for the treatment of major depressive disorder.

Vortioxetine (Lu AA21004; Brintellix(®)) has received approval from various international regulatory agencies for the treatment of major depression. The drug molecule has a multimodal mechanism of action that projects it as a unique molecule for the treatment of major depression. These mechanisms include property to inhibit serotonin reuptake via inhibiting serotonin transporters and acting on multiple serotonin receptor subtypes. Vortioxetine is an agonist of 5-HT1A, a partial agonist of 5-HT1B and an antagonist of 5-HT1D, 5-HT3 and 5-HT7 serotoninergic receptors. The molecule has been found to be effective and well-tolerable to be administered in humans for the treatment of major depression. Precautions should be exercised when vortioxetine is prescribed with cytochrome P450 inducers and inhibitors. This review attempts to compile the efficacy profile of vortioxetine in different clinical trials and the results are compared with other standard antidepressants.

Vortioxetine for the treatment of depression.

OBJECTIVE: To evaluate the clinical literature and potential clinical role of vortioxetine (Brintellix) for the treatment of major depressive disorder (MDD). DATA SOURCES: A MEDLINE search (1966-February 2014) was conducted using the search terms vortioxetine, Lu AA21004, and depression. Bibliographies of all articles retrieved were also reviewed. All references included were published between 1999 and 2014. STUDY SELECTION/DATA EXTRACTION: All studies that included humans and were published in English, with data describing vortioxetine for the treatment of MDD, were reviewed. DATA SYNTHESIS: Vortioxetine is a novel multimodal antidepressant agent, which inhibits the 5-HT transporter protein, acts as a 5-HT3 antagonist, 5-HT1A receptor agonist, 5-HT7 receptor antagonist, and a partial agonist of the 5-HT1B receptor. It has been studied in 10 short-term (6-8 weeks), 1 relapse-prevention, and 3 long-term extension trials. Vortioxetine demonstrated efficacy in reducing Montgomery-Asberg Depression Rating Scale or Hamilton Rating Scale for Depression scores in 6 of the short-term trials. The proportion of individuals who responded to treatment and achieved remission increased over time in all 3 long-term trials. The most common adverse effects, consistently reported by >10% of individuals in the clinical trials include nausea and headache. CONCLUSIONS: Vortioxetine is an effective agent for the treatment of MDD, but it does not have any clear advantages over other available treatment options.

Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.

5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects.

Vortioxetine (Lu AA21004) is a new potential substance for the treatment of anxiety and mood disorders. It has high affinity for the 5-HT transporter (5-HTT) and moderate affinity for the 5-HT1A receptor in vitro. Positron emission tomography (PET) has commonly been used to examine the relation between dose/plasma concentration and occupancy to predict relevant dose intervals in a clinical setting. In this study 11 control subjects were examined with PET and [¹¹C]MADAM at baseline, after a single dose and after 9 days of dosing with Lu AA21004 (2.5, 10 or 60 mg) for quantification of 5-HTT occupancy. Four subjects were examined with PET and [¹¹C]WAY 100635 at baseline, after a single dose and after 9 days of dosing of Lu AA21004 (30 mg) for quantification of 5-HT(1A) occupancy. To allow for quantification of binding in the raphe nuclei, PET data were analyzed using wavelet aided parametric imaging. 5-HTT occupancy ranged from 2 (mean, 2.5 mg day 1) to 97% (60 mg day 9). The apparent affinity of Lu AA21004 binding to 5-HTT (KD(ND)) was calculated to 16.7 nM (R=0.95), and the corresponding oral dose (KD(ND)-dose) to 8.5 mg (R=0.91). No significant occupancy of 5-HT(1A) receptors was found after dosing of 30 mg Lu AA21004. Based on the literature and the present [¹¹C]MADAM binding data, a dose of 20-30 mg Lu AA21004 is suggested to give clinically relevant occupancy of the 5-HTT.

Effect of Vortioxetine on Cardiac Repolarization in Healthy Adult Male Subjects: Results of a Thorough QT/QTc Study.

This double-blind, randomized, placebo- and positive-controlled, parallel-group study evaluated the effect of vortioxetine (Lu AA21004), an investigational multimodal antidepressant, on QT interval in accordance with current guidelines of the International Conference on Harmonisation (ICH-E14). A total of 340 healthy men were randomized to receive 1 of 4 treatments for 14 days: (1) vortioxetine 10 mg once daily (QD), (2) vortioxetine 40 mg QD, (3) placebo QD, or (4) placebo QD on Days 1 through 13 followed by a single dose of moxifloxacin 400 mg (positive control). The primary endpoint was the largest time-matched, baseline-adjusted least-squares (LS) mean difference for the individual-corrected QT interval (QTcNi [linear]) between vortioxetine and placebo. Alternative QT correction formulas (i.e., Fredericia [QTcF], Bazett [QTcB], Framingham [QTcFm], and QTcNi [nonlinear]) were used as secondary endpoints. The upper bound of the 2-sided 90% confidence interval around the LS mean difference from placebo for baseline-adjusted QTcNi (linear), QTcF, QTcB, QTcFm, and QTcNi (nonlinear) did not exceed 10 ms at any time point after multiple doses of vortioxetine 10 mg (therapeutic) or 40 mg (supratherapeutic). Overall, the study results indicate that vortioxetine is unlikely to affect cardiac repolarization in healthy subjects.

Vortioxetine for the treatment of major depression.

Vortioxetine (Lu-AA-21004; 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide) is a novel orally active molecule that is being investigated by Lundbeck and Takeda for the treatment of major depression and generalized anxiety disorders. Vortioxetine has a unique "multi-modal" mechanism of action. It inhibits the activity of serotonin transporters and is an agonist of serotonin 5-HT1A receptor, partial agonist of 5-HT1B and antagonist of 5-HT3A, 5-HT7 and 5-HT1D receptors. Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day. Vortioxetine reverses cognitive decline in patients with depression making it a unique molecule. The molecule lacks any serious side effects and drug-drug interactions. However, dose adjustments are required if vortioxetine is co-administered with rifampicin or bupropion. The molecule is under review by various regulatory agencies around the world for the treatment of major depression.