A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin–noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine† Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study 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. 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. A randomized, double-blind, duloxetine-referenced study comparing efficacy and tolerability of 2 fixed doses of vortioxetine in the acute treatment of adults with MDD Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder A randomized, double-blind trial of 2.5 mg and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults with major depressive disorder A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). Vortioxetine (Lu AA21004) 5mg in generalized anxiety disorder: Results of an 8-week randomized, double-blind, placebo-controlled clinical trial in the United States Compliance with antidepressant medication in the treatment of major depressive disorder in primary care: a randomized comparison of fluoxetine and a tricyclic antidepressant. Reboxetine, the first selective noradrenaline reuptake inhibitor antidepressant: Efficacy and tolerability in 2613 patients Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials Is Baseline Agitation a Relative Contraindication for a Selective Serotonin Reuptake Inhibitor: A Comparative Trial of Fluoxetine Versus Imipramine Cardiac side‐effects of two selective serotonin reuptake inhibitors in middle- aged and elderly depressed patients Fluoxetine, but not Tricyclic Antidepressants, Potentiates the 5-Hydroxytryptophan-Mediated Increase in Plasma Cortisol and Prolactin Secretion in Subjects with Major Depression or with Obsessive Compulsive Disorder
Objective This r and omised , double-blind , 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine ( 10–20 mg/day ) versus agomelatine ( 25–50 mg/day ) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin – noradrenaline reuptake inhibitor ( SNRI ) monotherapy . Methods Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine . Primary endpoint was change from baseline to week 8 in the Montgomery – Åsberg Depression Rating Scale ( MADRS ) total score analysed by mixed model for repeated measurements , using a noninferiority test followed by a superiority test . Secondary endpoints included response and remission rates , anxiety symptoms ( Hamilton Anxiety Rating Scale ) , Clinical Global Impression , overall functioning ( Sheehan Disability Scale ) , health-related quality of life ( EuroQol 5 Dimensions ) , productivity ( work limitation question naire ) and family functioning ( Depression and Family Functioning Scale ) . Results Primary endpoint noninferiority was established and vortioxetine ( n = 252 ) was superior to agomelatine ( n = 241 ) by 2.2 MADRS points ( p < 0.01 ) . Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12 ; MADRS , Hamilton Anxiety Rating Scale , Clinical Global Impression , Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards ; work limitation question naire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12 . Fewer patients withdrew because of adverse events with vortioxetine ( 5.9 % vs 9.5 % ) . Adverse events ( incidence ≥5 % ) were nausea , headache , dizziness and somnolence . Conclusions Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy . Vortioxetine was safe and well tolerated Patients with major depressive disorder often experience relapse after responding to treatment ; therefore , maintenance therapy with antidepressants is recommended for maintaining response or remission . This multicenter , open-label , flexible-dose , 52-week extension study evaluated the long-term safety , tolerability , and maintenance of efficacy in study participants who had completed one of two r and omized , double-blind , placebo-controlled , 8-week dose-ranging vortioxetine trials in study participants with major depressive disorder . At the open-label baseline , all study participants were switched to vortioxetine 5 mg/day for the first week , with subsequent dose adjustments from 2.5 to 10 mg/day on the basis of response and tolerability . Treatment with vortioxetine for 52 weeks was well tolerated , with no new safety signals identified . Among the 834 evaluable study participants , treatment-emergent adverse events were reported in 70.6 % , with the most common in the combined ( all doses ) population of nausea ( 15.2 % ) , headache ( 12.4 % ) , nasopharyngitis ( 9.8 % ) , diarrhea ( 7.2 % ) , and dizziness ( 6.8 % ) . The rate of adverse events related to sexual dysfunction was low and weight gain was minimal . Laboratory values , vital signs , ECGs , physical examinations , and Columbia-Suicide Severity Rating Scale results showed no trends of clinical concern . The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 ( from 17.6 at open-label baseline ) in the observed case data set 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 r and omized 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 Question naire Short Form ( CSFQ-14 ) , and antidepressant efficacy was assessed using the Montgomery-Åsberg 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 ± st and ard 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 < 0.05 ) . Antidepressant efficacy continued in both groups , with similar , but slight , improvements in MADRS and CGI scores . Vortioxetine and escitalopram had similar clinical efficacy profiles in this study , with safety profiles similar to previous trials . Nausea ( n = 9 , 4.0 % ) was the most common treatment-emergent adverse event leading to discontinuation of vortioxetine . CONCLUSION Switching antidepressant therapy to vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs BACKGROUND This 8-week , r and omized , 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 r and omized ( 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 r and omized : 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 clinical ly 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 Clinical Trials.gov identifier : NCT01179516 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 out patients with major depressive disorder . DESIGN , SETTING , AND PARTICIPANTS This 8-week , multicenter , r and omized , 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 r and omized 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 r and omized 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 Clinical Trials.gov identifier : NCT01163266 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 r and omized 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 assessment s 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 r and omized . 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 < .001 ) ( 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 Clinical Trials.gov identifier NCT01153009 ; www . clinical Abstract Objective : The primary objective of this study was to evaluate the safety and tolerability of the investigational drug vortioxetine ( Lu AA21004 ) in the long-term treatment of patients with major depressive disorder . Methods : Patients entered this 52-week , open-label extension study after completing an 8-week lead-in study . Safety and tolerability were evaluated at regular intervals on the basis of spontaneously reported adverse events ( AEs ) , clinical safety laboratory tests , vital signs , ECG and physical examination . Effectiveness of treatment was assessed using the Montgomery – Åsberg Depression Rating Scale ( MADRS ) total score . Results : A total of 535 patients were treated and 61.3 % ( n = 328 ) completed the study , result ing in 393 patient years of exposure to vortioxetine . AEs reported by ≥10 % of patients were nausea , headache , and nasopharyngitis . Taken together , six patients had eight AEs related to sexual dysfunction . There were no clinical ly significant safety findings with respect to mean changes of vital signs , weight , ECG parameters , or clinical laboratory values . Patients entered the extension study with a mean MADRS total score of 13.5 ± 8.7 . The mean MADRS total score decreased ( improved ) by approximately 8 points to 5.5 ± 6.0 at Week 52 ( OC ) . By the end of the study , the proportion of responders had increased from 63 % to 94 % ( OC ) , as had the proportion in remission ( MADRS ≤10 ) , increasing from 42 % to 83 % ( OC ) . Patients in remission ( n = 226 ) at the start of this study had a relapse rate ( MADRS ≥22 ) of 9.7 % . Conclusions : As with all open-label studies , the conclusions that can be drawn are limited by the lack of a placebo control , making it difficult to assess causality of any changes in outcome measures . However , on the basis of these findings , vortioxetine ( 2.5 , 5 , 10 mg/day ) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment . Trial Registration : Clinical Trials.gov identifier : NCT00694304 Abstract Objective : Vortioxetine ( Lu AA21004 ) is an investigational antidepressant . In vitro studies indicate that vortioxetine is a 5-HT3 , 5-HT7 , and 5-HT1D receptor antagonist , 5-HT1B receptor partial agonist , 5-HT1A receptor agonist and inhibitor of the 5-HT transporter . This trial assessed the efficacy and tolerability of 2.5 and 5 mg vortioxetine for the treatment of MDD . Research design and methods : Adults ( N = 611 ) with MDD were r and omized to 8 weeks of double-blind treatment with placebo , vortioxetine ( 2.5 or 5 mg ) or active reference ( duloxetine 60 mg ) . The primary measure was change from baseline in the 24-item Hamilton Depression Scale ( HAM-D24 ) . Secondary endpoints included responder rate , Clinical Global Impression Scale-Global Improvement scale ( CGI-I ) , and remission rate . Participants were monitored for adverse events ( AEs ) , and treatment-emergent sexual dysfunction using the Arizona Sexual Experiences ( ASEX ) scale . Results : Both doses of vortioxetine were associated with declines in HAM-D24 total scores compared to placebo but were not statistically significant . At 8 weeks , changes from baseline were [ mean ( SE ) ] : −10.50 ( 0.76 ) placebo , −12.04 ( 0.74 ) 2.5 mg vortioxetine , and −11.08 ( 0.74 ) 5 mg vortioxetine . Secondary outcome measures in the vortioxetine groups , including responder rate , CGI-I , and remission rate , were also not significantly different from placebo . Duloxetine treatment was associated with declines in HAM-D24 total score [ −13.47(0.75 ) ; p = 0.005 ] as well as significant improvements in secondary outcome measures versus placebo ( p ≤ 0.05 ) . The most common AEs for vortioxetine  were nausea , dry mouth , and headache . Rates of sexual dysfunction ( ASEX ) were 51.0 % , 37.5 % , 46.9 % , and 33.3 % in the vortioxetine 2.5 mg , vortioxetine 5 mg , duloxetine , and placebo groups , respectively . Conclusions : In this study of adults with MDD treated for 8 weeks with vortioxetine 2.5 mg or 5 mg per day , reductions in depression symptoms were not statistically significant compared with placebo . Study limitations are discussed , including patient characteristics , MDD severity , drug dosing , and aspects of trial design . Both doses of vortioxetine were well tolerated . This trial has been registered at clinical trials.gov # 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 r and omized ( 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-Åsberg 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 Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited The goal of the current clinical study , conducted in the United States ( US ) , was to evaluate the efficacy and tolerability of vortioxetine 5 mg vs placebo in adults with a primary diagnosis of generalized anxiety disorder ( GAD ; HAM-A total score ≥20 and MADRS score ≤16 ) . Subjects were r and omized ( 1:1 ) to receive vortioxetine 5 mg ( n=152 ) or placebo ( n=152 ) for 8 weeks . Efficacy was assessed using change from baseline in HAM-A total scores after 8 weeks of treatment compared with placebo , using mixed-model repeated measures ( MMRM ) analyses . Adverse events ( AEs ) were assessed throughout the study . A total of 304 subjects were r and omized ( mean age , 41.2 years ) . After 8 weeks of treatment , there was no statistically significant difference in the reduction in HAM-A total score from baseline between the Vortioxetine ( n=145 ) and placebo ( n=145 ) groups . There were no statistically significant differences in any key secondary efficacy outcome  between vortioxetine and placebo . Factors potentially contributing to the differences between the results of this study and those of one of identical design conducted outside the US are discussed . The most common treatment-emergent AEs were nausea , headache , dizziness , and dry mouth . Nausea was more frequently reported in the vortioxetine group ( 25 % vs 4.6 % for the placebo group ) . Most AEs were mild to moderate in severity . In conclusion , in this trial , vortioxetine did not improve symptoms of GAD ( compared with placebo ) over 8 weeks of treatment . Vortioxetine was well tolerated in this study OBJECTIVE Many cl aims have been made for superior compliance with selective serotonin reuptake inhibitors ( SSRIs ) compared with tricyclic antidepressants , but to date meta-analyses have not confirmed reduced dropouts in r and omized controlled trials . The authors used a r and omized study design to evaluate differential compliance with antidepressant medications in a primary care setting . METHOD A total of 152 patients treated in 10 primary care practice s in the United Kingdom were included in a r and omized , open-label , parallel-group study of fluoxetine and dothiepin at therapeutic doses for 12 weeks . Compliance was assessed by using pill count , patient question naires , and the Medication Event Monitoring System . RESULTS The level of compliance with fluoxetine was numerically higher than the level of compliance with dothiepin on all three primary outcome measures , although the differences were not significant . In a secondary analysis using data from the Medication Event Monitoring System , both a survival analysis for length of time without a gap in medicine taking and a derived compliance index showed a significant advantage to fluoxetine . Patients in the fluoxetine group reported superior response on the health transition scale of the 36-item Short-Form Health Survey Question naire and numerically greater improvement on the Hamilton Depression Rating Scale . In both treatment arms patients with a superior compliance index were more likely to have improved in Hamilton depression scale scores by the last study visit . CONCLUSIONS This study supports recent meta-analyses of SSRIs versus tricyclic antidepressants in finding no significant differences in crude indices of compliance between fluoxetine and dothiepin , despite marked differences in side effect profile and dose regimen . However , both a survival analysis and a new measure that takes account of prolonged periods of noncompliance distinguished between the treatments and was associated with improvement in both groups INTRODUCTION : Reboxetine is the first available selective noradrenaline re-uptake inhibitor ( selective NRI ) . This paper gives an overview of its antidepressant efficacy and tolerability in eight r and omized double-blind , multicentre clinical trials . The clinical profile of reboxetine is also compared with that of the tricyclic antidepressants ( TCAs ) desipramine and imipramine and the selective serotonin re-uptake inhibitor ( SSRI ) fluoxetine . METHODS : Pooled data were analysed from seven short-term ( 4 - 8 weeks ) and one long-term ( up to 1 year ) trials comparing reboxetine with placebo , imipramine , desipramine or fluoxetine . The tolerability of reboxetine was evaluated in 2613 patients with major depression or dysthymia . Data from 1959 patients with major depressive disorder were included to assess drug efficacy . Efficacy was principally assessed using the Hamilton Depression Rating Scale ( HAM-D ) . RESULTS : Reboxetine was more effective than placebo in three of four short-term trials , and it was as effective as fluoxetine , imipramine and desipramine . In long-term treatment , reboxetine was more effective than placebo in preventing relapse ( S 50 % increase in HAM-D ) and recurrence ( HAM-D total score h 10 ) . In a subset of severely depressed patients , reboxetine was as effective as imipramine and significantly more effective than fluoxetine . Reboxetine was as effective as imipramine in the elderly , but better tolerated . The most common adverse events among the 1503 patients ( adults and elderly ) who received reboxetine were dry mouth ( 22 % ) , constipation ( 15 % ) , sweating ( 12 % ) and insomnia ( 11 % ) . Overall , reboxetine was well tolerated , as well as the SSRI fluoxetine and better than the TCAs imipramine and desipramine . CONCLUSIONS : Reboxetine is effective and well tolerated in the short and long-term treatment of depression . It is as well tolerated as fluoxetine and better than imipramine and desipramine . ( Int J Psych Clin Pract 2000 ; 4 : 201 - 208 GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin , norepinephrine , and dopamine transporters . Two r and omized , placebo- and active-controlled , double-blind studies examined the efficacy and safety of GSK372475 in out patients ( aged 18–64 years ) with a diagnosis of major depressive episode associated with major depressive disorder ( MDD ) . Patients were r and omized 1:1:1 to placebo , GSK372475 ( 1–2 mg/d ) , or active control ( Study 1 :  venlafaxine XR 150–225 mg/d ; Study 2 : paroxetine 20–30 mg/d ) .  GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints ( six-item Bech scale , IDS-Clinician Rated , MADRS ) in either study . Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints . The most common adverse effects ( AEs ) with GSK372475  were dry mouth , headache , insomnia , and nausea . AEs were more frequent for GSK372475 versus placebo for sleep , anxiety-related , gastrointestinal , and tachycardia events . Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups . Completion rates were lower for GSK372475 ( 49 % , 58 % ) compared with placebo ( 67 % , 74 % ) , venlafaxine XR ( 63 % ) , or paroxetine ( 77 % ) . GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies A common presentation for major depression includes psychomotor agitation . However , this subtype has been the infrequent subject of controlled investigation during depression trials . Yet , the subcategorization of agitated depression has historically been associated with the belief that older , sedating compounds have a superior risk : benefit profile . In the 8-week , double-blind , r and omized , parallel trial , 124 subjects with Research Diagnostic Criteria -compatible agitated depression were r and omized to either imipramine ( IMI ) or fluoxetine ( FLU ) . Both compounds proved to be similarly effective as measured by change in HAM-D17 , HAM-D17 response , and HAM-D17 remission rates . Similar comparability was seen in secondary measures of agitation , anxiety , suicidality , and global impressions . However , of note , a statistically significant difference in early discontinuations because of intolerable adverse events emerged . Whereas 43.5 % of IMI subjects discontinued early , only 9.7 % of FLU subjects ( p < 0.001 ) did . Significantly more central nervous system events characterized the IMI than the FLU subgroup ( IMI , 24.2 % , vs. FLU , 6.5 % ; p = 0.006 ) . In conclusion , among subjects with major depression , subtype agitated , the risk : benefit profile favored FLU over IMI . This was driven by the superior tolerance of FLU . No evidence emerged in support of the clinical hypothesis that a “ sedating ” agent is the treatment of choice for this group . The results are important when striving to maximize compliance with pharmacotherapy in order to minimize recidivism and associated psychological and economic morbidity . ( J Clin Psychopharmacol 1994;14:385–391 Selective serotonin reuptake inhibitors ( SSRIs ) are the ‘ new ’ drugs of first choice for the treatment of depression in the older patient . Systematic studies on the effects of SSRIs on cardiac function are scarce , despite the high prevalence of cardiac disorders in the older depressed patient . This is a study which systematic ally assesed cardiac function by echo-cardiography in middle-aged and elderly depressed patients treated with SSRI . In a double-blind r and omized trial , 20 patients were assigned to receive fluvoxamine 20 mg/day or fluoxetine 100mg/day for 6 weeks . Cardiac function was assessed by left ventricle ejection fraction , aortic flow integral and early or passive/late or active mitral inflow , and electrocardiography . Neither SSRI significantly affected cardiac function . Compared with patients without a history of myocardial infa rct ion and /or hypertension , patients with such a history showed a significant improvement in left ventricular ejection fraction . Despite our small study sample , these data indicate that both fluoxetine and fluvoxamine do not affect cardiac function adversely It has been suggested that the clinical efficacy of chronic treatment with selective serotonin reuptake inhibitors ( SSRIs ) such as fluoxetine and perhaps all antidepressants is due to their ability to enhance serotonergic activity . The effects of chronic treatment with fluoxetine or tricyclic antidepressants on the L-5-hydroxytryptophan ( 200 mg , L-5-HTP ; PO)–induced increases in plasma cortisol and prolactin ( PRL ) concentrations were studied in patients with major depression or obsessive compulsive disorder ( OCD ) . Administration of L-5-HTP increased plasma cortisol and PRL levels in medicated and unmedicated patients with major depression or OCD . The  L-5-HTP – induced cortisol and PRL responses were significantly higher in fluoxetine-treated than in tricyclic-treated or unmedicated major depressed patients . The latter two groups did not differ significantly in their cortisol or PRL responses to L-5-HTP . The L-5-HTP – induced increases in cortisol and PRL in fluoxetine-treated patients with major depression or OCD were not significantly different . The results suggest that fluoxetine , but not tricyclic antidepressants , potentiates 5-HT receptor – mediated stimulation of cortisol and PRL secretion in humans , consistent with available evidence that fluoxetine treatment , but not tricyclic antidepressants , increases central serotonergic activity in patients with MD or OCD by a presynaptic mechanism
EXPERT OPINION Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants .
The most common side effects are nausea , vomiting and constipation .
Results of several studies indicate that vortioxetine may have therapeutic effects on cognition ( e.g. , memory and executive functioning ) that exceed that of st and ard antidepressants .
The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise , pending additional long-term data , to become a first-line antidepressant option
INTRODUCTION Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder ( MDD ) .
This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors , which may differentiate the drug 's effects from those of current first-line antidepressants , such as selective serotonin reuptake inhibitors ( SSRIs ) and serotonin norepinephrine reuptake inhibitors ( SNRIs ) .
AREAS COVERED This article will review the basic clinical pharmacology of vortioxetine , summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration ( FDA ) , discuss relevant post-marketing studies of this drug , and offer expert commentary on the significance of this new agent in clinical practice .