title: A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. 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† 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 A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder Occupancy of the serotonin transporter after administration of Lu AA21004 and its relation to plasma concentration in healthy subjects. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults Efficacy of vilazodone on anxiety symptoms in patients with major depressive disorder A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder. Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction. Extended-release Trazodone in Major Depressive Disorder: A Randomized, Double-blind, Placebo-controlled Study. 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 Review of Vilazodone, Serotonin, and Major Depressive Disorder A cohort study of adherence to antidepressants in primary care: the influence of antidepressant concerns and treatment preferences. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder Efficacy and safety of vilazodone in major depressive disorder: a randomized, double-blind, placebo-controlled trial. A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD) A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of Lu AA21004 in adults with major depressive disorder.
abstract: OBJECTIVE To evaluate the efficacy , and further establish the safety profile , of oral once-daily vilazodone , a potent and selective serotonin 1A receptor partial agonist and reuptake inhibitor , in the treatment of major depressive disorder ( MDD ) . METHOD This phase 3 , r and omized , double-blind , placebo-controlled , 8-week study ( conducted March 2008-February 2009 ) enrolled 481 adults with DSM-IV-TR-defined MDD . Patients received vilazodone ( titrated to 40 mg/d ) or placebo . The primary efficacy endpoint was change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score from baseline to end of treatment . Secondary efficacy measures included MADRS and 17-item Hamilton Depression Rating Scale ( HDRS-17 ) response and change in HDRS-17 , HDRS-21 , Hamilton Anxiety Rating Scale ( HARS ) , Clinical Global Impressions-Severity of Illness ( CGI-S ) , and Clinical Global Impressions-Improvement ( CGI-I ) scores . The Changes in Sexual Functioning Question naire ( CSFQ ) was administered at baseline and week 8 . RESULTS Vilazodone-treated patients had significantly greater improvement ( P = .009 ) according to the MADRS than placebo patients ( intent-to-treat ; least-squares mean changes : -13.3 , -10.8 ) . MADRS response rates were significantly higher with vilazodone than placebo ( 44 % vs 30 % , P = .002 ) . Remission rates for vilazodone were not significantly different based on the MADRS  ( vilazodone , 27.3 % vs placebo , 20.3 % ; P = .066 ) or HDRS-17  ( vilazodone , 24.2 % vs placebo , 17.7 % ; P = .088 ) . Vilazodone-treated patients had significantly greater improvements from baseline in HDRS-17 ( P = .026 ) , HDRS-21 ( P = .029 ) , HARS ( P = .037 ) , CGI-S ( P = .004 ) , and CGI-I ( P = .004 ) scores than placebo patients . Rates of discontinuation due to adverse events were 5.1 % ( vilazodone ) and 1.7 % ( placebo ) . The most common adverse events ( vilazodone vs placebo ) were diarrhea ( 31 % vs 11 % ) , nausea ( 26 % vs 6 % ) , and headache ( 13 % vs 10 % ) . Treatment-related effects on sexual function as measured by the CSFQ were small and similar to placebo . Effects on weight were no different from placebo . CONCLUSIONS Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00683592 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 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 The efficacy and tolerability of Lu AA21004 in the prevention of relapse of major depressive disorder ( MDD ) in patients in remission after acute treatment was evaluated . Patients ( n=639 ) aged 18–75 years with a primary diagnosis of MDD with a current major depressive episode ( MDE ) ≥4 weeks ’ duration , at least one prior MDE and a MADRS total score ≥26 received 12-week , open-label Lu AA21004 at 5 or 10mg/day . Patients in remission ( MADRS ≤10 ) at both weeks 10 and 12 were assigned to double-blind treatment with either placebo or Lu AA21004 ( fixed dose from Week 8) . Patients ( n=396 ) were treated , after r and om assignment to placebo ( n=192 ) or Lu AA21004 ( n=204 ) . The primary analysis of time to relapse ( full- analysis set , Cox proportional hazard model ) showed a statistically significant difference in favour of Lu AA21004 versus placebo with a hazard ratio of 2.01 ( 95 % confidence interval : 1.26–3.21 ; p=0.0035 ) . The proportion of patients who relapsed was 13 % in the Lu AA21004 group ( n=27 ) and 26 % in the placebo group ( n=50 ) . The withdrawal rates due to adverse events were 8 % ( open-label ) , and 3 % ( placebo ) and 8 % ( Lu AA21004 ) ( double-blind ) . Thus , Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment Owing to the lack of biologically based clinical measures and reliable biomarkers for many indications within the CNS area , the use of imaging tools , such as lig and -based positron emission tomography ( PET ) , has become more and more important in the development of new CNS drugs . A well-grounded and reliable relationship between the plasma concentration of the drug and the occupancy of the receptor ⁄ transporter is a powerful tool to investigate the mechanism of action of a new drug and to guide dose selection 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 Anxiety symptoms are prevalent in patients with major depressive disorder . A post-hoc analysis of two phase III trials was conducted to evaluate the efficacy of vilazodone on depression-related anxiety . Using the 17-item Hamilton Depression Rating Scale ( HAMD17 ) Anxiety/Somatization subscale , patients were classified as anxious or nonanxious . Improvements in depressive symptoms were based on least squares mean changes in HAMD17 and Montgomery – Asberg Depression Rating Scale total scores . Anxiety symptoms in the anxious subgroup were evaluated using Hamilton Anxiety Rating Scale ( HAMA ) total and subscale ( Psychic Anxiety , Somatic Anxiety ) scores , HAMD17 Anxiety/Somatization subscale and item ( Psychic Anxiety , Somatic Anxiety ) scores , and the Montgomery – Asberg Depression Rating Scale Inner Tension item score . Most of the pooled study population [ 82.0 % ( 708/863 ) ] was classified with anxious depression . After 8 weeks of treatment , least squares mean differences between vilazodone and placebo for changes in HAMA total and HAMD17 Anxiety/Somatization subscale scores were −1.82 ( 95 % confidence interval −2.81 to −0.83 ; P<0.001 ) and −0.75 ( 95 % confidence interval −1.17 to −0.32 ; P<0.001 ) , respectively . Statistically significant improvements with vilazodone were also found on all other anxiety-related measures , except the HAMA Somatic Anxiety subscale .  Vilazodone may be effective in treating patients with major depressive disorder who exhibit somatic and /or psychic symptoms of anxiety 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 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 The efficacy , safety , and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder ( MDD ) were evaluated . Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist , 5-HT1A receptor agonist , 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines . In this 6-wk , multi-site study , 429 patients were r and omly assigned ( 1:1:1:1 ) to 5 or 10 mg Lu AA21004 , placebo or 225 mg venlafaxine XR .  All patients had a baseline Montgomery – Åsberg Depression Rating Scale ( MADRS ) total score ⩾30 . The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo . Lu AA21004 was statistically significantly superior to placebo ( n=105 ) in mean change from baseline in MADRS total score at week 6 ( p<0.0001 , last observation carried forward ) , with a mean treatment difference vs. placebo of 5.9 ( 5 mg , n=108 ) , and 5.7 ( 10 mg , n=100 ) points . Venlafaxine XR ( n=112 ) was also significantly superior to placebo at week 6 ( p<0.0001 ) . In total , 30 patients withdrew due to adverse events ( AEs ) – placebo : four ( 4 % ) ; 5 mg Lu AA21004 : three ( 3 % ) ; 10 mg Lu AA21004 : seven ( 7 % ) ; and venlafaxine : 16 ( 14 % ) . The most common AEs were nausea , headache , hyperhidrosis , and dry mouth . No clinical ly relevant changes over time were seen in the clinical laboratory results , vital signs , weight , or ECG parameters . In this study , treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD 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 OBJECTIVE To investigate the efficacy , safety , and clinical benefit of a once-daily formulation of trazodone ( Trazodone Contramid((c ) ) OAD ) in the treatment of major depressive disorder . DESIGN / PARTICIPANTS In this double-blind study , 412 patients with major depressive disorder ( Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria ) were r and omized 1:1 to receive either Trazodone Contramid OAD ( 150 to 375 mg ) or placebo . Treatment was titrated over two weeks to each individual optimal dose . Patients then continued six weeks of treatment ; further dose adjustments were allowed based on efficacy and tolerability . MEASUREMENTS The primary end point was change in the 17-item Hamilton Depression Rating Scale total score from baseline to last study visit . Secondary end points included Hamilton Depression Rating Scale responders/remitters , change in Montgomery-Asberg Depression Rating Scale , Clinician and Patient Global Improvement Scales , and quality of sleep . RESULTS From the end of titration to the end of the six-week treatment period , the mean maximum daily dose of the intent-to-treat population was 310 mg for the active group and 355 mg for the placebo group . There was a statistically significant difference between trazodone and placebo on the mean HAMD-17 score ( -11.4 vs. -9.3 , P=0.012 ) . A significant difference was present as early as Week 1 and was maintained at all subsequent study visits . Many secondary end points supported these findings , including improvements in quality of sleep . The most frequent adverse events were the same for both the treatment and placebo groups : headache and somnolence . There were no serious adverse events that were considered related to treatment . There were no clinical ly significant electrocardiogram or laboratory abnormalities . CONCLUSIONS The trazodone Contramid formulation was more effective than placebo in major depressive disorder and was well tolerated 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 # Objective : To review the mechanism of selective serotonin reuptake inhibitor (SSRI)–mediated serotonergic neurotransmission , focusing on serotonin 1A ( 5-HT1A ) autoreceptors , which are proposed to be involved in delaying therapeutic efficacy . Vilazodone was specifically design ed to function both as an SSRI and a partial agonist at 5-HT1A receptors . This combined mechanism is proposed to decrease time to efficacy , minimize sexual side effects , and provide concomitant anxiolytic properties . Data Sources : A PubMed search of all English- language articles from January 1990 to January 2013 was conducted using the search terms depression and 5-HT1A , depression and buspirone , depression and pindolol , and vilazodone . Study Selection : We found 47 articles and abstract s that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol , buspirone , and vilazodone in depression . Data Extraction : This review summarizes current literature involving antidepressant activity , the role of 5-HT1A autoreceptors , and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists , with a focus on vilazodone . Results : Vilazodone has demonstrated efficacy in 2 large , r and omized , double-blind , placebo-controlled trials in major depressive disorder . Results suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety . A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy . Conclusions : If future studies corroborate the clinical benefits attributed to its mechanism of action , vilazodone may show potential advantages in terms of onset of action , sexual side effects , and anxiolytic activity in patients with major depressive disorder OBJECTIVE Clinical guidelines recommend that antidepressant treatment should be continued for a minimum of 6 months following response in depression and anxiety disorders . However , adherence to antidepressants is low . This prospect i ve cohort study investigated the influence of patients ' antidepressant concerns , treatment preferences , and illness perceptions on adherence to antidepressants over a 6-month period . METHOD A cohort of 178 patients aged 18 to 74 years and newly issued with a prescription for antidepressants to treat any condition was followed up prospect ively at 5 primary care practice s in Southeast Engl and .  Adherence was measured through self-report and prescription refill data . Patient perceptions were quantified using vali date d outcome measures , the  Beliefs about Medicine Question  naire and the  Illness Perception Question  naire , at 4 timepoints . Patient treatment preferences were recorded using a specially design ed question naire . Data collection took place between September 2000 and May 2002 . RESULTS Of 147 participants ( 83 % ) who completed the study , 19 % persisted with antidepressants in accordance with guideline recommendations throughout the 6-month period . Specific concern about antidepressant side effects ( OR = 3.30 , 95 % CI = 2.20 to 4.97 ) and general worry about taking antidepressants ( OR = 1.65 , 95 % CI = 1.13 to 2.40 ) were independent predictors of antidepressant nonuse . Preference for different treatment/uncertainty about preferred treatment was also a strong predictor ( OR = 3.82 , 95 % CI = 1.35 to 10.77 ) . However , illness perceptions were not associated with adherence . CONCLUSIONS Concerns about antidepressants and a mismatch between patients ' preferred and prescribed treatment act as significant barriers to sustained adherence . This study highlights the central role of the patient-physician partnership in exploring antidepressant concerns , working with treatment preferences , and providing supportive continued management . The findings may inform the development of interventions within primary care programs to enhance commitment to treatment for common mental disorders OBJECTIVE The efficacy and tolerability of vilazodone , a combined selective serotonin reuptake inhibitor and partial 5-hydroxytryptamine-1A ( 5-HT(1A ) ) receptor agonist , were evaluated in adult patients with major depressive disorder ( MDD ) . METHOD This was a r and omized , double-blind , placebo-controlled trial conducted from February 2006 to May 2007 . Patients aged 18 through 65 years with MDD ( DSM-IV criteria ) and a baseline 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) score of > or= 22 were r and omly assigned to vilazodone or placebo for 8 weeks .  Vilazodone was titrated from 10 mg to 40 mg once a day over 2 weeks .  Efficacy was assessed by mean change from baseline to week 8 on the Montgomery-Asberg Depression Rating Scale ( MADRS ) , HAM-D-17 , and Hamilton Rating Scale for Anxiety . Response rates were determined at week 8 for the MADRS , HAM-D-17 , and Clinical Global Impressions-Severity of Illness ( CGI-S ) and -Improvement ( CGI-I ) scales . Data were analyzed using a modified last-observation-carried-forward method in the intention-to-treat ( ITT ) sample . The Arizona Sexual Experience Scale ( ASEX ) was also measured at baseline and week 8 . RESULTS Of 410 r and omly assigned patients , 198 receiving vilazodone and 199 receiving placebo were included in the ITT population . The mean changes in MADRS and HAM-D-17 total scores from baseline to week 8 were significantly ( p = .001 and p = .022 , respectively ) greater with vilazodone than with placebo . Significant ( p < .05 ) improvements in MADRS and HAM-D-17 scores were noted at week 1 , the earliest time point measured . Response rates were significantly higher with vilazodone than with placebo on the MADRS ( p = .007 ) , HAM-D-17 ( p = .011 ) , and CGI-I ( p = .001 ) . Treatment-emergent adverse events with vilazodone included diarrhea , nausea , and somnolence ; most adverse events were of mild or moderate intensity . There were no clinical ly significant differences for either gender in ASEX scores at end of treatment . CONCLUSIONS Vilazodone is effective for the treatment of MDD in adults , with symptom relief starting at 1 week , and is well tolerated at a dose of 40 mg/day . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00285376 The efficacy and tolerability of Lu AA21004 at 5 mg/day , a novel multimodal antidepressant , were assessed in elderly patients with recurrent major depressive disorder . Patients were r and omly assigned ( 1 : 1 : 1 ) to Lu AA21004 5 mg/day , duloxetine 60 mg/day ( reference ) or to placebo in an 8-week double-blind study . The primary efficacy measure was the 24-item Hamilton Depression Scale ( HAM-D24 ) total score ( analysis of covariance , last observation carried forward ) . Patients ( mean age 70.6 years ) had a mean baseline HAM-D24 score of 29.0 .  Lu AA21004 showed significantly ( P=0.0011 ) greater improvement on the primary efficacy endpoint compared with placebo at week 8 ( 3.3 points ) . Duloxetine also showed superiority to placebo at week 8 , thereby validating the study . HAM-D24 response ( 53.2 vs. 35.2 % ) and HAM-D17 remission ( 29.2 vs. 19.3 % ) rates at endpoint were higher for Lu AA21004 than for placebo . Lu AA21004 showed superiority to placebo in cognition tests of speed of processing , verbal learning and memory . The withdrawal rate due to adverse events was 5.8 % ( Lu AA21004 ) , 9.9 % ( duloxetine ) and 2.8 % ( placebo ) . Whereas nausea was the only adverse event with a significantly higher incidence on treatment with Lu AA21004 ( 21.8 % ) compared with placebo ( 8.3 % ) , the incidence of nausea , constipation , dry mouth , hyperhidrosis and somnolence was higher for duloxetine . In conclusion , Lu AA21004 was efficacious and well tolerated in the treatment of elderly patients with recurrent major depressive disorder INTRODUCTION Vilazodone is a potent serotonin ( 5-HT ) reuptake inhibitor and 5-HT₁A receptor partial agonist approved by the US Food and Drug Administration for the treatment of major depressive disorder ( MDD ) in adults . This study evaluated the efficacy and tolerability of vilazodone in the treatment of MDD . METHOD This 8-week , r and omized ( 1:1 ) , double-blind , placebo-controlled , parallel-group , fixed-dose study conducted from January 2012 to February 2013 compared  vilazodone 40 mg/d  with placebo in out patients with DSM-IV-TR-diagnosed MDD . The primary efficacy measure was Montgomery-Asberg Depression Rating Scale ( MADRS ) total score change from baseline to week 8 analyzed by a mixed-effects model for repeated measures on the intent-to-treat population ( placebo = 252 , vilazodone = 253 ) . Secondary efficacy outcomes were Clinical Global Impressions-Severity of Illness ( CGI-S ) Scale score change from baseline and MADRS sustained response rate ( total score ≤ 12 for at least the last 2 consecutive double-blind visits ) . RESULTS Approximately 83 % of patients completed the study . Least squares mean differences ( 95 % CI ) were statistically significant for vilazodone versus placebo  on MADRS ( -5.117 [ -6.886 to -3.347 ] , P < .00001 ) and CGI-S ( -0.622 [ -0.845 to -0.399 ] , P < .00001 ) change from baseline ; statistically significant improvements versus placebo occurred at week 2 and persisted for the study duration . The MADRS sustained response rate was 17 % for placebo and 27 % for vilazodone ( P < .01 ) . Patients taking vilazodone versus placebo had higher rates of diarrhea and nausea ; most incidences were mild in severity . Weight increase and sexual dysfunction adverse events were low in both groups . CONCLUSIONS A large and significant treatment effect on the MADRS and statistically significant improvement on the CGI-S demonstrated meaningful depressive symptom improvements . Vilazodone was generally well tolerated . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01473394 The efficacy , safety , and tolerability of Lu AA21004 versus placebo , using duloxetine as active reference , in patients with DSM-IV-TR diagnosed major depressive disorder ( MDD ) were evaluated in this 8-week , multi-site study . Patients ( n=766 ) had a baseline Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score ≥26 and were r and omly assigned ( 1:1:1:1:1 ) to 2.5 , 5 or 10 mg Lu AA21004 , placebo , or 60 mg duloxetine . The 5 mg and 10 mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specified order . In the pre-defined primary efficacy analysis [ mean change from baseline in MADRS total score at Week 8 , full analysis set , ANCOVA , last observation carried forward ( LOCF ) ] , the differences to placebo ( n=145 ) of -1.7 ( Lu AA21004 5 mg , n=155 ) and -1.5 points ( Lu AA21004 10 mg , n=151 ) were not statistically significant ; nor were those for Lu AA21004 2.5 mg ( -1.4 points , n=155 ) or duloxetine ( -2.0 points , n=149 ) . Using mixed model , repeated measures ( MMRM ) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine . Treatment-emergent adverse events led to the withdrawal of 72 patients : 8 % ( placebo ) , 12 % ( duloxetine ) , and 6 % , 11 % and 9 % in the Lu AA21004 groups ( 2.5 mg , 5 mg and 10 mg , respectively ) . The most common adverse events were nausea , headache , dizziness , and dry mouth . No clinical ly relevant changes were seen in vital signs , weight , ECG , or laboratory results . In summary , none of the active treatment groups , including duloxetine , separated from placebo in the primary analysis in this ' failed ' study . Findings on secondary outcome measures , using MMRM instead of LOCF , were supportive of likely efficacy  for Lu AA21004 5 mg and 10 mg and duloxetine . Lu AA21004 ( 2.5 , 5 and 10 mg ) was well tolerated OBJECTIVE Lu AA21004 is an investigational multimodal antidepressant . This r and omized controlled trial evaluated the efficacy and tolerability of multiple doses of Lu AA21004 versus placebo in adults with major depressive disorder ( MDD ) . METHOD Adults diagnosed with MDD ( based on DSM-IV-TR criteria ) with a Montgomery-Asberg Depression Rating Scale ( MADRS ) score ≥ 26 were r and omly assigned ( 1:1:1:1 ) to receive Lu AA21004  1 mg , 5 mg , or 10 mg or placebo for 8 weeks ( between August 2008 and August 2009 ) . The primary endpoint was reduction in 24-Item Hamilton Depression Rating Scale ( HDRS-24 ) total score after 8 weeks of treatment compared with placebo for Lu AA21004 10 mg . Additional outcomes included response and remission rates , Sheehan Disability Scale ( SDS ) , Clinical Global Impressions-Global Improvement scale ( CGI-I ) , MADRS total score , and HDRS-24 total score  in subjects with baseline Hamilton Anxiety Rating Scale ( HARS ) score ≥ 20 . Adverse events were assessed throughout the study . RESULTS A total of 560 subjects ( mean age = 46.4 years ) were r and omized . There was a statistically significant reduction from baseline in HDRS-24 total score at week 8 for Lu AA21004 10 mg vs placebo ( P < .001 ) . There were improvements ( nominal P values < .05 with no adjustment for multiplicity ) in HDRS-24 total score , response and remission rates , CGI-I score , MADRS total score , and HDRS-24 total score in subjects with baseline HARS score ≥ 20 at week 8 for all Lu AA21004 treatment groups vs placebo . No significant differences were seen in SDS scores between any dose of Lu AA21004 and placebo . The most common adverse events were nausea , headache , and dizziness . CONCLUSIONS After 8 weeks of treatment with Lu AA21004 10 mg , there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD . Lu AA21004 was well tolerated in this study . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00735709
target: 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
background: 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 .