Vortioxetine

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Christina Kurre Olsen - One of the best experts on this subject based on the ideXlab platform.

  • treatment effects on residual cognitive symptoms among partially or fully remitted patients with major depressive disorder a randomized double blinded exploratory study with Vortioxetine
    Journal of Affective Disorders, 2019
    Co-Authors: Andrew A Nierenberg, Henrik Loft, Christina Kurre Olsen
    Abstract:

    Abstract Background Residual cognitive symptoms in major depressive disorder (MDD) are common, yet poorly investigated. We explored the effectiveness of Vortioxetine as adjunctive treatment to selective serotonin reuptake inhibitors (SSRI) and as monotherapy versus continued SSRI, in patients with MDD who achieved full or partial remission with SSRI, but report residual cognitive symptoms. Methods Patients (18–65 years old, N =151) diagnosed with MDD, with a Hamilton Depression Rating Scale 17-items total score ≤10 and a Perceived Deficits Questionnaire–Depression total score >25, were randomized 1:1:1 to 8 weeks of double-blind treatment with current SSRI + placebo, SSRI + Vortioxetine (10–20 mg/day), or Vortioxetine (10–20 mg/day) + placebo. The primary efficacy measure was the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements. Secondary outcomes comprised cognitive functioning, subjectively-rated cognitive symptoms, patient functioning, and mood symptoms. Results From baseline to week 8, all treatment groups improved DSST performance, with statistically nonsignificant treatment differences. Similar results were seen for secondary endpoints. Improvement in cognitive performance tended to be numerically larger with Vortioxetine monotherapy than with SSRI monotherapy, while Vortioxetine as adjunctive treatment tended to perform numerically better in further improving depressive symptoms. Most adverse events were mild or moderate. Nausea was the most common adverse event for Vortioxetine. Limitations Small sample sizes limited statistical power. Conclusion In this explorative study, remitted patients with MDD improved their cognitive performance with no treatment differences. Secondary results indicate numerical benefits for cognitive performance with Vortioxetine monotherapy, and for depressive symptoms with Vortioxetine augmentation.

  • the effects of Vortioxetine on cognitive performance in working patients with major depressive disorder a short term randomized double blind exploratory study
    Journal of Affective Disorders, 2018
    Co-Authors: Bernhard T. Baune, Lasse B. Sluth, Christina Kurre Olsen
    Abstract:

    Abstract Background Major Depressive Disorder (MDD) is a complex disease characterized by emotional, physical and cognitive symptoms. We explored the efficacy of Vortioxetine versus placebo on outcomes of cognition, functioning and mood symptoms in working patients with depression, using paroxetine as an active reference. Methods Gainfully employed patients (18–65 years, N = 152) with MDD were randomized 1:1:1 to 8 weeks’ double-blind, parallel treatment either with Vortioxetine (10 mg/day) or paroxetine (20 mg/day), or with placebo. The primary efficacy measure was the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements, and the key secondary efficacy measure was the University of San Diego Performance-based Skills Assessment – Brief (UPSA-B), analyzed using analysis of covariance (last observation carried forward). Results At week 8, DSST and UPSA-B performance had improved relative to baseline in all treatment groups, with no statistically significant differences between treatment groups. While improvements in mood were comparable for Vortioxetine and paroxetine, numerical improvements in cognitive performance (DSST) were larger with Vortioxetine. Vortioxetine significantly improved overall cognitive performance and clinician-rated functioning relative to placebo. The majority of adverse events were mild or moderate, with nausea being the most common adverse event for Vortioxetine. Limitations Small sample sizes implied limited statistical power. Conclusion This explorative study showed no significant differences versus placebo in DSST or UPSA-B performance at week 8. However, secondary results support Vortioxetine as an effective and well-tolerated antidepressant, supporting an added benefit for cognition and functioning, which could have particular therapeutic relevance for the working patient population.

  • the effects of Vortioxetine on cognitive dysfunction in patients with inadequate response to current antidepressants in major depressive disorder a short term randomized double blind exploratory study versus escitalopram
    Journal of Affective Disorders, 2018
    Co-Authors: Eduard Vieta, Lasse B. Sluth, Christina Kurre Olsen
    Abstract:

    Abstract Background Major Depressive Disorder (MDD) is a heterogeneous disease characterized by emotional, physical and cognitive symptoms. This study explored the effects of Vortioxetine versus escitalopram on outcomes of cognition, functioning and mood symptoms in depressed patients with inadequate response to current antidepressant treatment. Methods In this parallel-group, active-comparator study, adult patients (18–65 years, N = 101) with MDD, with inadequate response to current antidepressant monotherapy, were randomized 1:1 to 8 weeks’ double-blind treatment with flexible doses (10–20 mg/day) of either Vortioxetine or escitalopram. Primary and key secondary efficacy measures were the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements, and the University of San Diego Performance-based Skills Assessment – Brief (UPSA-B), analyzed using analysis of covariance (last observation carried forward method). Results At week 8, DSST and UPSA-B performance had improved in both treatment groups, with no statistically significant treatment differences. Numerical improvements across measures of cognition, functioning and mood symptoms generally favored Vortioxetine. Most adverse events were mild or moderate, with nausea being the most common adverse event. Limitations This was an exploratory study with small sample sizes implying limited statistical power. Conclusion Although this explorative study did not meet primary endpoints, the results confirm Vortioxetine in doses of 10–20 mg/day as an efficacious and well-tolerated antidepressant switch treatment. The overall direction of numerical effect sizes across cognition endpoints support previous findings that Vortioxetine specifically benefits cognitive function in MDD.

  • the effects of Vortioxetine on cognitive function in patients with major depressive disorder a meta analysis of three randomized controlled trials
    The International Journal of Neuropsychopharmacology, 2016
    Co-Authors: Roger S Mcintyre, Henrik Loft, John Harrison, William Jacobson, Christina Kurre Olsen
    Abstract:

    Background: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of Vortioxetine on cognition in patients with MDD. Methods: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of Vortioxetine (5–20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen’s d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Asberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). Results: Before adjustment for MADRS, Vortioxetine separated from placebo on DSST score (SES 0.25–0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, Vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored Vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). Conclusions: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.

  • a randomized double blind placebo controlled study of Vortioxetine on cognitive function in depressed adults
    The International Journal of Neuropsychopharmacology, 2014
    Co-Authors: Roger S Mcintyre, Soren Lophaven, Christina Kurre Olsen
    Abstract:

    The efficacy of Vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18–65 yr, N = 602) were randomized (1:1:1) to Vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of Vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (Vortioxetine 10 mg, p < 0.0001) and 0.33 (Vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for Vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were −4.7 (10 mg: p < 0.0001) and −6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of Vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with Vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.

Connie Sanchez - One of the best experts on this subject based on the ideXlab platform.

  • Effect of clinically relevant doses of Vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain
    Neuropsychopharmacology, 2019
    Co-Authors: Kai-chun Yang, Connie Sanchez, Vladimir Stepanov, Nahid Amini, Stefan Martinsson, Akihiro Takano, Christoffer Bundgaard, Benny Bang-andersen, Christer Halldin, Lars Farde
    Abstract:

    Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of Vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of Vortioxetine by comparing its effect to the SSRI citalopram on the binding of [^11C]AZ10419369 to the 5-HT_1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of Vortioxetine was determined by [^11C]MADAM PET measurements before and after administration of Vortioxetine (0.1–3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [^11C]AZ10419369. The 5-HT_1B receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of Vortioxetine in six brain regions (~25%) or 1.0 mg/kg of Vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of Vortioxetine on the binding of [^11C]Cimbi-36 to the 5-HT_2A receptor, which has comparable sensitivity to 5-HT release as [^11C]AZ10419369 binding. In conclusion, at clinically relevant doses, Vortioxetine induced larger reductions in [^11C]AZ10419369 binding than citalopram. These observations suggest that Vortioxetine binds to the 5-HT_1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT_1B receptor in the therapeutic effects of Vortioxetine and as a potential target for the development of novel antidepressant drugs.

  • Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity.
    Frontiers in pharmacology, 2018
    Co-Authors: Todd M. Hillhouse, Connie Sanchez, Christina R. Merritt, Douglas A. Smith, Manuel Cajina, Joseph H. Porter, Alan L. Pehrson
    Abstract:

    Attention impairment is a common feature of Major Depressive Disorder (MDD), and MDD-associated cognitive dysfunction may play an important role in determining functional status among this patient population. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in MDD patients, and may indirectly increase glutamate neurotransmission in brain regions classically associated with attention function. Previous nonclinical research suggests that Vortioxetine has limited effects on attention. This laboratory previously found that Vortioxetine did not improve attention function in animals impaired by acute scopolamine administration, using the visual signal detection task (VSDT). However, Vortioxetine has limited effects on acetylcholinergic neurotransmission, and thus it is possible that attention impaired by other mechanisms would be attenuated by Vortioxetine. This study sought to investigate whether acute Vortioxetine administration can attenuate VSDT impairments and hyperlocomotion induced by the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. We found that acute Vortioxetine administration had no effect on VSDT performance on its own, but potentiated MK-801-induced VSDT impairments. Furthermore, Vortioxetine had no effect on locomotor activity on its own, and did not alter MK-801-induced hyperlocomotion. We further investigated whether Vortioxetine’s effect on MK-801 could be driven by a kinetic interaction, but found that plasma and brain exposure for Vortioxetine and MK-801 were similar whether administered alone or in combination. Thus, it appears that Vortioxetine selectively potentiates MK-801-induced impairments in attention without altering its effects on locomotion, and further that this interaction must be pharmacodynamic in nature. A theoretical mechanism for this interaction is discussed.

  • A critical role of mitochondria in BDNF-associated synaptic plasticity after one-week Vortioxetine treatment
    The international journal of neuropsychopharmacology, 2018
    Co-Authors: Fenghua Chen, Betina Elfving, Connie Sanchez, Jibrin Danladi, Maryam Ardalan, Heidi Kaastrup Müller, Gregers Wegener, Jens R. Nyengaard
    Abstract:

    Background Preclinical studies have indicated that antidepressant effect of Vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that Vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by Vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling. Methods Rats were treated for 1 week with Vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Results Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after Vortioxetine treatment. Gene expression levels of Rac1 after Vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Conclusion Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following Vortioxetine compared with fluoxetine may be ascribed to Vortioxetine's modulation of serotonin receptors.

  • Data_Sheet_1.pdf
    2018
    Co-Authors: Alan L. Pehrson, Christian S. Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
    Abstract:

    Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant Vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that Vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected Vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating Vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic Vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute Vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic Vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to Vortioxetine treatment, and subchronic Vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that Vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that Vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function.

  • Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission
    Frontiers Media S.A., 2018
    Co-Authors: Alan L. Pehrson, Christian S. Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
    Abstract:

    Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant Vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that Vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected Vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating Vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic Vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute Vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic Vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to Vortioxetine treatment, and subchronic Vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that Vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that Vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function

Atul R. Mahableshwarkar - One of the best experts on this subject based on the ideXlab platform.

  • treatment emergent sexual dysfunction in randomized trials of Vortioxetine for major depressive disorder or generalized anxiety disorder a pooled analysis
    Cns Spectrums, 2016
    Co-Authors: Paula L. Jacobsen, Atul R. Mahableshwarkar, Yinzhong Chen, William Palo, Marianne Dragheim, Anita H Clayton
    Abstract:

    Objective Antidepressants are frequently associated with treatment-emergent sexual dysfunction (TESD). Vortioxetine, which was approved for patients with major depressive disorder (MDD), has a receptor profile that suggests limited impact on sexual functioning. Methods Arizona Sexual Experiences Scale (ASEX) patient-level data were pooled from 7 short-term Vortioxetine trials (6 in MDD, 1 in generalized anxiety disorder) and analyzed for incidence of TESD at any post-baseline visit in patients without sexual dysfunction at baseline (defined as ASEX total score ≥19; individual ASEX item score ≥5; or a score ≥4 on any 3 ASEX items). The primary objective was to confirm the non-inferiority of Vortioxetine 5–20 mg/day to placebo on the incidence of TESD. Comparisons were based on the common risk difference (95% confidence interval). Additional analyses compared Vortioxetine to duloxetine and duloxetine to placebo. A sensitivity analysis, defined as TESD at 2 consecutive post-baseline visits, was conducted. Results TESD incidence, relative to placebo, generally increased with Vortioxetine dose with Vortioxetine 5 mg non-inferior to placebo. Vortioxetine 10, 15, and 20 mg did not meet the non-inferiority criterion, but no dose had a significantly higher risk of developing TESD versus placebo. Changes in ASEX individual item scores supported the similarity of Vortioxetine doses to placebo. Significantly higher TESD risk occurred with duloxetine 60 mg/day versus placebo and versus Vortioxetine 5 or 10 mg. The sensitivity analysis was generally consistent with the primary analysis. Rates of spontaneously reported sexual adverse events were low. Conclusions Vortioxetine was associated with rates of TESD that were not significantly different from placebo in short-term clinical trials.

  • a meta analysis of randomized placebo controlled trials of Vortioxetine for the treatment of major depressive disorder in adults
    European Neuropsychopharmacology, 2016
    Co-Authors: Michael E. Thase, Henrik Loft, Atul R. Mahableshwarkar, Marianne Dragheim, Eduard Vieta
    Abstract:

    The efficacy and safety of Vortioxetine, an antidepressant approved for the treatment of adults with major depressive disorder (MDD), was studied in 11 randomized, double-blind, placebo-controlled trials of 6/8 weeks׳ treatment duration. An aggregated study-level meta-analysis was conducted to estimate the magnitude and dose-relationship of the clinical effect of approved doses of Vortioxetine (5-20mg/day). The primary outcome measure was change from baseline to endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Differences from placebo were analyzed using mixed model for repeated measurements (MMRM) analysis, with a sensitivity analysis also conducted using last observation carried forward. Secondary outcomes included MADRS single-item scores, response rate (≥50% reduction in baseline MADRS), remission rate (MADRS ≤10), and Clinical Global Impressions scores. Across the 11 studies, 1824 patients were treated with placebo and 3304 with Vortioxetine (5mg/day: n=1001; 10mg/day: n=1042; 15mg/day: n=449; 20mg/day: n=812). The MMRM meta-analysis demonstrated that Vortioxetine 5, 10, and 20mg/day were associated with significant reductions in MADRS total score (Δ-2.27, Δ-3.57, and Δ-4.57, respectively; p<0.01) versus placebo. The effects of 15mg/day (Δ-2.60; p=0.105) were not significantly different from placebo. Vortioxetine 10 and 20mg/day were associated with significant reductions in 9 of 10 MADRS single-item scores. Vortioxetine treatment was also associated with significantly higher rates of response and remission and with significant improvements in other depression-related scores versus placebo. This meta-analysis of Vortioxetine (5-20mg/day) in adults with MDD supports the efficacy demonstrated in the individual studies, with treatment effect increasing with dose.

  • effect of Vortioxetine vs escitalopram on sexual functioning in adults with well treated major depressive disorder experiencing ssri induced sexual dysfunction
    The Journal of Sexual Medicine, 2015
    Co-Authors: Paula L. Jacobsen, Atul R. Mahableshwarkar, Yinzhong Chen, Lambros Chrones, Anita H Clayton
    Abstract:

    Abstract Introduction Sexual dysfunction is common with serotonergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), and does not resolve in most patients. Vortioxetine, an antidepressant with a multimodal mechanism of action, has shown low rates of sexual dysfunction in previous major depressive disorder (MDD) trials. Aim This study compared the effects of Vortioxetine and escitalopram on sexual functioning in adults with well-treated MDD experiencing treatment-emergent sexual dysfunction (TESD). Methods Participants treated with, and responding to, citalopram, paroxetine, or sertraline were randomized to switch to either Vortioxetine (10/20 mg; n = 225) or escitalopram (10/20 mg; n = 222) for 8 weeks. Sexual function was assessed using the Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14), and antidepressant efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI) scale, and Profile of Mood States brief form (POMS-brief). Safety and tolerability were also assessed. Main Outcome Measures The primary endpoint was change from baseline in the CSFQ-14 total score after 8 weeks of treatment. The MADRS, CGI, and POMS-brief were used to assess antidepressant efficacy. Safety was assessed via adverse events, vital signs, electrocardiograms, laboratory values, weight, and physical examination findings. Results Vortioxetine showed significantly greater improvements in CSFQ-14 total score (8.8 ± 0.64, mean ± standard error) vs. escitalopram (6.6 ± 0.64; P  = 0.013). Benefits vs. escitalopram were significant on four of five dimensions and all three phases of sexual functioning assessed by the CSFQ-14 ( P Conclusion Switching antidepressant therapy to Vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, and Clayton AH. Effect of Vortioxetine vs. escitalopram on sexual functioning in adults with well-treated major depressive disorder experiencing SSRI-induced sexual dysfunction.

  • a randomized double blind placebo controlled study of the efficacy and safety of 2 doses of Vortioxetine in adults with major depressive disorder
    The Journal of Clinical Psychiatry, 2015
    Co-Authors: Atul R. Mahableshwarkar, Paula L. Jacobsen, Michael Serenko, Yinzhong Chen, Madhukar H Trivedi
    Abstract:

    Background This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of Vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of Vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter. Method Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 26 were randomized (1:1:1) to receive Vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. Results Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to Vortioxetine 10 mg, and 152 to Vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for Vortioxetine 10 mg or Vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving Vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the Vortioxetine 10 mg group, and 12 (7.9%) in the Vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C-SSRS, laboratory values, electrocardiogram, or vital sign parameters. Conclusions In this study, Vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. Trial registration ClinicalTrials.gov identifier: NCT01179516.

  • a randomized double blind placebo controlled study of the efficacy and safety of Vortioxetine 10 mg and 20 mg in adults with major depressive disorder
    The Journal of Clinical Psychiatry, 2015
    Co-Authors: Paula L. Jacobsen, Serena Chan, Atul R. Mahableshwarkar, Michael Serenko, Madhukar H Trivedi
    Abstract:

    Context Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter. Objective To evaluate the efficacy of Vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder. Design, setting, and participants This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR). Intervention Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: Vortioxetine 10 mg, Vortioxetine 20 mg, or placebo once daily for 8 weeks. Subjects who completed the 8-week trial entered a 2-week blinded discontinuation period to assess potential discontinuation symptoms. Main outcome measure The primary endpoint was the least squares mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline. Key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (≥ 50% decrease from baseline in total score), Clinical Global Impressions-Improvement score, change from baseline in MADRS total score in subjects with baseline Hamilton Anxiety Rating Scale score ≥ 20, MADRS remission (total score ≤ 10), and change from baseline in Sheehan Disability Scale total score (all at week 8). Results A total of 462 subjects were randomized to placebo (n = 157), Vortioxetine 10 mg (n = 155), and Vortioxetine 20 mg (n = 150). Mean (SE) reductions from baseline in MADRS total score (week 8) were -10.77 (± 0.807), -12.96 (± 0.832), and -14.41 (± 0.845) for the placebo, Vortioxetine 10 mg (P = .058 vs placebo), and Vortioxetine 20 mg (P = .002 vs placebo) groups. MADRS response/remission was achieved in 28.4%/14.2%, 33.8%/21.4%, and 39.2%/22.3% of subjects, respectively, in the 3 groups. Only MADRS response for Vortioxetine 20 mg significantly separated from placebo (P = .044). Treatment was well tolerated, with the most frequently reported adverse events consisting of nausea, headache, diarrhea, and dizziness. Conclusions Vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in this study population. Overall, Vortioxetine was well tolerated in this study. Trial registration ClinicalTrials.gov identifier: NCT01163266.

Paula L. Jacobsen - One of the best experts on this subject based on the ideXlab platform.

  • Comparative evaluation of Vortioxetine as a switch therapy in patients with major depressive disorder
    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2017
    Co-Authors: Michael E. Thase, Ioana Florea, Natalya Danchenko, M. Brignone, F. Diamand, Paula L. Jacobsen, Eduard Vieta
    Abstract:

    Switching antidepressant therapy is a recommended strategy for depressed patients who neither respond to nor tolerate an initial pharmacotherapy course. This paper reviews the efficacy and tolerability of switching to Vortioxetine. All three published studies of patients with major depressive disorder (MDD) switched from SSRI/SNRI therapy to Vortioxetine due to lack of efficacy or tolerability were selected. Vortioxetine was evaluated versus agomelatine directly (REVIVE) and versus sertraline, venlafaxine, bupropion, and citalopram in an indirect treatment comparison (ITC) from switch studies retrieved in a literature review. Vortioxetine׳s impact on SSRI-induced treatment-emergent sexual dysfunction (TESD) was assessed directly versus escitalopram (NCT01364649) in stable patients with MDD. Vortioxetine׳s tolerability in the switch population was compared to the overall MDD population. Vortioxetine showed significant benefits over agomelatine on efficacy, functioning, and quality-of-life outcomes, with fewer withdrawals due to adverse events (AEs) (REVIVE). Vortioxetine had numerically higher remission rates versus all therapies included (ITC). Withdrawal rates due to AEs were significantly lower for Vortioxetine versus sertraline, venlafaxine, and bupropion, and numerically lower versus citalopram. Switching to Vortioxetine was statistically superior to escitalopram in improving TESD (NCT01364649). Tolerability was similar in the switch and overall MDD populations. These findings suggest that Vortioxetine is an effective switch therapy for patients with MDD whose response to SSRI/SNRI therapy is inadequate. Vortioxetine was well tolerated and, for patients with a history of TESD, showed significant advantages versus escitalopram. Vortioxetine appears to be a valid option for patients with MDD who have not been effectively treated with first-line pharmacotherapies.

  • a meta analysis of the efficacy of Vortioxetine in patients with major depressive disorder mdd and high levels of anxiety symptoms
    Journal of Affective Disorders, 2016
    Co-Authors: David S Baldwin, Ioana Florea, Paula L. Jacobsen, Wei Zhong, George G Nomikos
    Abstract:

    Abstract Background Coexisting anxiety is common in major depressive disorder (MDD) and more difficult to treat than depression without anxiety. This analysis assessed the efficacy, safety, and tolerability of Vortioxetine in MDD patients with high levels of anxiety (baseline Hamilton Anxiety Rating Scale [HAM-A] total score ≥20). Methods Efficacy was assessed using an aggregated, study-level meta-analysis of 10 randomized, placebo-controlled, 6/8-week trials of Vortioxetine 5–20 mg/day in adults (18–75 years), with a study in elderly patients (≥65 years) analyzed separately. Outcome measures included mean differences from placebo in change from baseline to endpoint (Δ) in the Montgomery-Asberg Depression Rating Scale (MADRS), HAM-A total, and HAM-A subscales. Safety and tolerability were assessed by treatment-emergent adverse events (TEAEs). Results A total of 1497 (48.6%) Vortioxetine-treated and 860 (49.1%) placebo-treated patients had baseline HAM-A≥20. There were significant differences from placebo in MADRS (Vortioxetine 5 mg/day, n=415, Δ−2.68, P=0.005; 10 mg/day, n=373, Δ−3.59, P Limitations Study heterogeneity limits this analysis. Patients with baseline HAM-A≥20 were not directly compared to baseline HAM-A Conclusions Vortioxetine was efficacious in reducing depressive and anxiety symptoms in patients with MDD and high levels of anxiety.

  • treatment emergent sexual dysfunction in randomized trials of Vortioxetine for major depressive disorder or generalized anxiety disorder a pooled analysis
    Cns Spectrums, 2016
    Co-Authors: Paula L. Jacobsen, Atul R. Mahableshwarkar, Yinzhong Chen, William Palo, Marianne Dragheim, Anita H Clayton
    Abstract:

    Objective Antidepressants are frequently associated with treatment-emergent sexual dysfunction (TESD). Vortioxetine, which was approved for patients with major depressive disorder (MDD), has a receptor profile that suggests limited impact on sexual functioning. Methods Arizona Sexual Experiences Scale (ASEX) patient-level data were pooled from 7 short-term Vortioxetine trials (6 in MDD, 1 in generalized anxiety disorder) and analyzed for incidence of TESD at any post-baseline visit in patients without sexual dysfunction at baseline (defined as ASEX total score ≥19; individual ASEX item score ≥5; or a score ≥4 on any 3 ASEX items). The primary objective was to confirm the non-inferiority of Vortioxetine 5–20 mg/day to placebo on the incidence of TESD. Comparisons were based on the common risk difference (95% confidence interval). Additional analyses compared Vortioxetine to duloxetine and duloxetine to placebo. A sensitivity analysis, defined as TESD at 2 consecutive post-baseline visits, was conducted. Results TESD incidence, relative to placebo, generally increased with Vortioxetine dose with Vortioxetine 5 mg non-inferior to placebo. Vortioxetine 10, 15, and 20 mg did not meet the non-inferiority criterion, but no dose had a significantly higher risk of developing TESD versus placebo. Changes in ASEX individual item scores supported the similarity of Vortioxetine doses to placebo. Significantly higher TESD risk occurred with duloxetine 60 mg/day versus placebo and versus Vortioxetine 5 or 10 mg. The sensitivity analysis was generally consistent with the primary analysis. Rates of spontaneously reported sexual adverse events were low. Conclusions Vortioxetine was associated with rates of TESD that were not significantly different from placebo in short-term clinical trials.

  • effect of Vortioxetine vs escitalopram on sexual functioning in adults with well treated major depressive disorder experiencing ssri induced sexual dysfunction
    The Journal of Sexual Medicine, 2015
    Co-Authors: Paula L. Jacobsen, Atul R. Mahableshwarkar, Yinzhong Chen, Lambros Chrones, Anita H Clayton
    Abstract:

    Abstract Introduction Sexual dysfunction is common with serotonergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), and does not resolve in most patients. Vortioxetine, an antidepressant with a multimodal mechanism of action, has shown low rates of sexual dysfunction in previous major depressive disorder (MDD) trials. Aim This study compared the effects of Vortioxetine and escitalopram on sexual functioning in adults with well-treated MDD experiencing treatment-emergent sexual dysfunction (TESD). Methods Participants treated with, and responding to, citalopram, paroxetine, or sertraline were randomized to switch to either Vortioxetine (10/20 mg; n = 225) or escitalopram (10/20 mg; n = 222) for 8 weeks. Sexual function was assessed using the Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14), and antidepressant efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI) scale, and Profile of Mood States brief form (POMS-brief). Safety and tolerability were also assessed. Main Outcome Measures The primary endpoint was change from baseline in the CSFQ-14 total score after 8 weeks of treatment. The MADRS, CGI, and POMS-brief were used to assess antidepressant efficacy. Safety was assessed via adverse events, vital signs, electrocardiograms, laboratory values, weight, and physical examination findings. Results Vortioxetine showed significantly greater improvements in CSFQ-14 total score (8.8 ± 0.64, mean ± standard error) vs. escitalopram (6.6 ± 0.64; P  = 0.013). Benefits vs. escitalopram were significant on four of five dimensions and all three phases of sexual functioning assessed by the CSFQ-14 ( P Conclusion Switching antidepressant therapy to Vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, and Clayton AH. Effect of Vortioxetine vs. escitalopram on sexual functioning in adults with well-treated major depressive disorder experiencing SSRI-induced sexual dysfunction.

  • a randomized double blind placebo controlled study of the efficacy and safety of 2 doses of Vortioxetine in adults with major depressive disorder
    The Journal of Clinical Psychiatry, 2015
    Co-Authors: Atul R. Mahableshwarkar, Paula L. Jacobsen, Michael Serenko, Yinzhong Chen, Madhukar H Trivedi
    Abstract:

    Background This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of Vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of Vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter. Method Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 26 were randomized (1:1:1) to receive Vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. Results Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to Vortioxetine 10 mg, and 152 to Vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for Vortioxetine 10 mg or Vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving Vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the Vortioxetine 10 mg group, and 12 (7.9%) in the Vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C-SSRS, laboratory values, electrocardiogram, or vital sign parameters. Conclusions In this study, Vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. Trial registration ClinicalTrials.gov identifier: NCT01179516.

Alan L. Pehrson - One of the best experts on this subject based on the ideXlab platform.

  • Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity.
    Frontiers in pharmacology, 2018
    Co-Authors: Todd M. Hillhouse, Connie Sanchez, Christina R. Merritt, Douglas A. Smith, Manuel Cajina, Joseph H. Porter, Alan L. Pehrson
    Abstract:

    Attention impairment is a common feature of Major Depressive Disorder (MDD), and MDD-associated cognitive dysfunction may play an important role in determining functional status among this patient population. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in MDD patients, and may indirectly increase glutamate neurotransmission in brain regions classically associated with attention function. Previous nonclinical research suggests that Vortioxetine has limited effects on attention. This laboratory previously found that Vortioxetine did not improve attention function in animals impaired by acute scopolamine administration, using the visual signal detection task (VSDT). However, Vortioxetine has limited effects on acetylcholinergic neurotransmission, and thus it is possible that attention impaired by other mechanisms would be attenuated by Vortioxetine. This study sought to investigate whether acute Vortioxetine administration can attenuate VSDT impairments and hyperlocomotion induced by the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. We found that acute Vortioxetine administration had no effect on VSDT performance on its own, but potentiated MK-801-induced VSDT impairments. Furthermore, Vortioxetine had no effect on locomotor activity on its own, and did not alter MK-801-induced hyperlocomotion. We further investigated whether Vortioxetine’s effect on MK-801 could be driven by a kinetic interaction, but found that plasma and brain exposure for Vortioxetine and MK-801 were similar whether administered alone or in combination. Thus, it appears that Vortioxetine selectively potentiates MK-801-induced impairments in attention without altering its effects on locomotion, and further that this interaction must be pharmacodynamic in nature. A theoretical mechanism for this interaction is discussed.

  • Data_Sheet_1.pdf
    2018
    Co-Authors: Alan L. Pehrson, Christian S. Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
    Abstract:

    Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant Vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that Vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected Vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating Vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic Vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute Vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic Vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to Vortioxetine treatment, and subchronic Vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that Vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that Vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function.

  • Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission
    Frontiers Media S.A., 2018
    Co-Authors: Alan L. Pehrson, Christian S. Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
    Abstract:

    Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant Vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that Vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected Vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating Vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic Vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute Vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic Vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to Vortioxetine treatment, and subchronic Vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that Vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that Vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function

  • Effects of Vortioxetine on biomarkers associated with glutamatergic activity in an SSRI insensitive model of depression in female rats.
    Progress in neuro-psychopharmacology & biological psychiatry, 2017
    Co-Authors: Natasa Hlavacova, Alan L. Pehrson, Connie Sanchez, Isabel Bermudez, A. Csanova, Daniela Jezova, M. Franklin
    Abstract:

    Abstract The aim of this study was to investigate the antidepressant activity of Vortioxetine in a tryptophan (TRP) depletion female rat model of depression and compare it to that of paroxetine using doses that fully occupy the serotonin transporter (SERT). We evaluated the effects of Vortioxetine on potential biomarkers associated with TRP depletion including serum aldosterone, corticosterone and IL-6 levels together with indirect indicators of glutamate neurotransmission. Female Sprague-Dawley rats were randomized to control, low TRP, low TRP/paroxetine or low TRP/Vortioxetine groups. Vortioxetine and paroxetine were administered via diet (10 mg/kg/day) and drinking water (10 mg/kg/day) respectively for 14 days. Vortioxetine but not paroxetine reversed TRP depletion-induced depressive-like behavior. Vortioxetine reduced TRP depletion-induced increases of serum corticosterone, aldosterone, IL-6 and N-methyl- d -aspartate and α7-nicotinic acetylcholine receptor expression in the amygdala and hippocampus, respectively. Paroxetine demonstrated little effect except a reduction of aldosterone. Vortioxetine but not paroxetine reversed TRP depletion-induced reductions of serum and brain kynurenic acid. In conclusion, Vortioxetine, but not paroxetine, enabled reversals of TRP depletion-induced changes of depression-like behavior and markers of glutamatergic activity. These observations support the hypothesis that Vortioxetine's antidepressant activity may involve mechanisms beyond SERT inhibition.

  • Acute Effects of Vortioxetine and Duloxetine On Resting-State Functional Connectivity in the Awake Rat
    Neuropharmacology, 2017
    Co-Authors: Pablo D. Perez, Alan L. Pehrson, Connie Sanchez, Christoffer Bundgaard, Arne Mørk, Christina Hamilton, Nanyin Zhang
    Abstract:

    The antidepressant Vortioxetine exerts its effects via modulation of several serotonin (5-HT) receptors and inhibition of the 5-HT transporter (SERT). Additionally, Vortioxetine has beneficial effects on aspects of cognitive dysfunction in depressed patients. However, a global examination of the drug effect on brain network connectivity is still missing. Here we compared the effects of Vortioxetine and a serotonin norepinephrine reuptake inhibitor, duloxetine, on resting-state functional connectivity (RSFC) across the whole brain in awake rats using a combination of pharmacological and awake animal resting-state functional magnetic resonance imaging (rsfMRI) techniques. Our data showed that Vortioxetine and duloxetine affected different inter-areal connections with limited overlap, indicating that in addition to different primary target profiles, these two antidepressants have distinct mechanisms of action at the systems level. Further, our data suggest that Vortioxetine can affect specific brain areas with distinct 5-HT receptor expression profiles. Taken together, this study demonstrates that the awake animal fMRI approach provides a powerful tool to elucidate the effects of drugs on the brain with high spatial specificity and a global field of view. This capability is valuable to understand how different drugs affect the systems-level brain function, and provides important guidance to dissect specific brain regions and connections for further detailed mechanistic studies. This study also highlights the translational opportunity of the awake animal fMRI approach between preclinical results and human studies.