title: Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. A Randomised Study Comparing Escitalopram with Venlafaxine XR in Primary Care Patients with Major Depressive Disorder A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder Differential Antidepressant Symptom Efficacy: Placebo-Controlled Comparisons of Duloxetine and SSRIs (Fluoxetine, Paroxetine, Escitalopram) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. MMRM vs. LOCF: A Comprehensive Comparison Based on Simulation Study and 25 NDA Datasets Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. Efficacy and tolerability of venlafaxine in geriatric outpatients with major depression: a double-blind, randomised 6-month comparative trial with citalopram. A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. Venlafaxine XR demonstrates higher rates of sustained remission compared to fluoxetine, paroxetine or placebo ACCOUNTING FOR DROPOUT BIAS USING MIXED-EFFECTS MODELS Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor Venlafaxine extended release versus conventional antidepressants in the remission of depressive disorders after previous antidepressant failure: ARGOS study. Remission with venlafaxine extended release or selective serotonin reuptake inhibitors in depressed patients: a randomized, open-label study. Probing the safety of medications in the frail elderly: evidence from a randomized clinical trial of sertraline and venlafaxine in depressed nursing home residents. Double-Blind Comparison of Escitalopram and Duloxetine in the Acute Treatment of Major Depressive Disorder Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches.
abstract: Antidepressant effects and unintended effects of paroxetine ( 30 mg/day ) and clomipramine ( 150 mg/day ) were compared in a double-blind , r and omized , inpatient , fixed-dose , plasma-level-controlled study . Patients with a DSM-III diagnosis of major depressive disorder participated . After 1 week of single-blind placebo treatment  120 patients fulfilled the criterion of a Hamilton ( 17-item ) score of greater than or equal to 18 and were started on active treatment for 6 weeks . Drop-outs on paroxetine ( n = 12 ) were largely due to lack of effect , and on clomipramine ( n = 19 ) due to lack of effect ( n = 7 ) , adverse reactions or severe side effects ( n = 10 ) and development of mania ( n = 2 ) . According to the protocol , non-responders ( Hamilton total greater than or equal to 16 ) after 4 weeks active treatment were terminated , and this occurred to 23 patients on paroxetine and four patients on clomipramine . Categorical response measures and group averages of rating scores showed a significantly better therapeutic effect of clomipramine from the second week of treatment on . These results are very similar to our earlier results with another selective serotonin reuptake inhibitor ( citalopram ) , but generally at variance with the literature on this class of antidepressants , which , however , mostly deals with outpatient studies This 8-week , r and omised , double-blind study compared the efficacy and tolerability of escitalopram to that of venlafaxine XR in primary care patients with major depressive disorder . The efficacy of escitalopram ( 10– 20 mg ; n = 148 ) was similar to venlafaxine XR ( 75– 150 mg ; n = 145 ) , based on mean change from baseline to week 8 in Montgomery and Åsberg Depression Rating Scale total score . In ad hoc analyses , escitalopram-treated patients achieved sustained remission significantly faster than did venlafaxine-treated patients . More venlafaxine-treated patients had nausea , constipation , and increased sweating ( p < 0.05 ) . When treatment was completed after 8 weeks , significantly more venlafaxine-treated patients had discontinuation symptoms ( p < 0.01 ) . Thus escitalopram treatment was similar to venlafaxine treatment with respect to efficacy and was better tolerated by patients in primary care ABSTRACT Objective : This study evaluated the efficacy and tolerability of escitalopram and duloxetine in the treatment of major depressive disorder ( MDD ) . Research design and methods : Patients were r and omised to 24 weeks of double-blind treatment with fixed doses of escitalopram ( 20 mg ) ( n = 143 ) or duloxetine ( 60 mg ) ( n = 151 ) . The primary analysis of efficacy was an analysis of covariance ( ANCOVA ) of change from baseline to endpoint ( week 24 ) in MADRS total score ( last observation carried forward ) . Main outcome measures ; Results : At week 8 , the mean change from baseline in total MADRS score was –19.5 for patients treated with escitalopram ( n = 141 ) and –17.4 for patients treated with duloxetine ( n = 146 ) , a difference of 2.1 points ( p < 0.05 ) . At week 8 , the proportion of responders ( ≥ 50 % decrease in MADRS ) was 69 % ( escitalopram ) and 58 % ( duloxetine ) ( p < 0.05 ) and remission ( MADRS ≤ 12 ) rates were 56 % ( escitalopram ) and 48 % ( duloxetine ) ( NS ) . For the primary endpoint , the mean change from baseline in total MADRS score at week 24 was –23.4 for patients treated with escitalopram and –21.7 for patients treated with duloxetine , a difference of 1.7 points ( p = 0.055 , one-sided ) . The difference in mean change from baseline in MADRS total score favoured escitalopram at weeks 1 , 2 , 4 , 8 , 12 and 16 ( p < 0.05 ) . The overall withdrawal rates were 22 % ( escitalopram ) and 25 % ( duloxetine ) ( NS ) . The withdrawal rate due to adverse events was lower for escitalopram ( 9 % ) compared to duloxetine ( 17 % ) ( p < 0.05 ) and significantly more patients treated with duloxetine reported insomnia ( 12.6 % vs. 4.9 % ) and constipation ( 8.6 % vs. 2.8 % ) . Conclusion : Escitalopram was superior to duloxetine in acute treatment and at least as efficacious and better tolerated in long-term treatment of MDD Objective : To test the hypothesis that in patients with major depressive disorder ( MDD ) , the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors ( SSRIs ) and that patterns of response will differ based on symptom severity at baseline . Method : Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD : 7 r and omized , double-blind , fixed-dose , 8-week studies of duloxetine  ( n = 1,133 )  versus SSRI  ( n = 689 )  versus placebo  ( n = 641 ) .  Duloxetine doses were 40 , 60 , 80 and 120 mg/day . SSRI doses were 10 mg/day ( escitalopram ) and 20 mg/day ( fluoxetine and paroxetine ) . Results : Compared to SSRI-treated patients , duloxetine-treated patients had a significantly greater ( p ≤ 0.05 ) reduction in the 17-item Hamilton Depression Rating Scale ( HAMD17 ) total score and HAMD17 items of work and activities , psychomotor retardation , genital symptoms and hypochondriasis . Differences favoring the SSRIs approached significance for middle insomnia ( p = 0.057 ) and late insomnia ( p = 0.06 ) , with effect sizes at least twice the magnitude of the corresponding effect sizes for duloxetine . Similarly , the advantage for duloxetine versus the SSRIs approached significance for general somatic symptoms ( p = 0.056 ) , with an effect size twice that observed for the SSRIs . The HAMD17 total score difference was driven mostly by patients with lower baseline MDD severity ( HAMD17 total score ≤19 ) , where the HAMD17 effect size advantage for duloxetine over combined SSRIs was statistically significant ( p = 0.031 ) . Conclusion : Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity , and different HAMD17 items responded differently to duloxetine compared with SSRIs . Underst and ing these differences may be useful in tailoring antidepressant therapy for individual patients OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are widely used to treat depression , but the rates , timing , and baseline predictors of remission in " real world " patients are not established . The authors ' primary objectives in this study were to evaluate the effectiveness of citalopram , an SSRI , using measurement-based care in actual practice , and to identify predictors of symptom remission in out patients with major depressive disorder . METHOD This clinical study included out patients with major depressive disorder who were treated in 23 psychiatric and 18 primary care " real world " setting s. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks . The clinicians were assisted by a clinical research coordinator in the application of measurement-based care , which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures . Remission was defined as an exit score of < or=7 on the 17-item Hamilton Depression Rating Scale ( HAM-D ) ( primary outcome ) or a score of < or=5 on the 16-item Quick Inventory of Depressive Symptomatology , Self-Report ( QIDS-SR ) ( secondary outcome ) . Response was defined as a reduction of > or=50 % in baseline QIDS-SR score . RESULTS Nearly 80 % of the 2,876 out patients in the analyzed sample had chronic or recurrent major depression ; most also had a number of comorbid general medical and psychiatric conditions . The mean exit citalopram dose was 41.8 mg/day . Remission rates were 28 % ( HAM-D ) and 33 % ( QIDS-SR ) . The response rate was 47 % ( QIDS-SR ) . Patients in primary and psychiatric care setting s did not differ in remission or response rates . A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment . Participants who were Caucasian , female , employed , or had higher levels of education or income had higher HAM-D remission rates ; longer index episodes , more concurrent psychiatric disorders ( especially anxiety disorders or drug abuse ) , more general medical disorders , and lower baseline function and quality of life were associated with lower HAM-D remission rates . CONCLUSIONS The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials . The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results In recent years , the use of the last observation carried forward ( LOCF ) approach in imputing missing data in clinical trials has been greatly criticized , and several likelihood-based modeling approaches are proposed to analyze such incomplete data . One of the proposed likelihood-based methods is the Mixed-Effect Model Repeated Measure ( MMRM ) model . To compare the performance of LOCF and MMRM approaches in analyzing incomplete data , two extensive simulation studies are conducted , and the empirical bias and Type I error rates associated with estimators and tests of treatment effects under three missing data paradigms are evaluated . The simulation studies demonstrate that LOCF analysis can lead to substantial biases in estimators of treatment effects and can greatly inflate Type I error rates of the statistical tests , whereas MMRM analysis on the available data leads to estimators with comparatively small bias , and controls Type I error rates at a nominal level in the presence of missing completely at r and om ( MCAR ) or missing at r and om ( MAR ) and some possibility of missing not at r and om ( MNAR ) data . In a sensitivity analysis of 48 clinical trial data sets obtained from 25 New Drug Applications ( NDA ) su bmi ssions of neurological and psychiatric drug products , MMRM analysis appears to be a superior approach in controlling Type I error rates and minimizing biases , as compared to LOCF ANCOVA analysis . In the exploratory analyses of the data sets , no clear evidence of the presence of MNAR missingness is found BACKGROUND After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor ( SSRI ) , it is not known whether switching to one antidepressant is more effective than switching to another . METHODS We r and omly assigned 727 adult out patients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram  to receive one of the following drugs for up to 14 weeks : sustained-release bupropion ( 239 patients ) at a maximal daily dose of 400 mg , sertraline ( 238 patients ) at a maximal daily dose of 200 mg , or extended-release venlafaxine ( 250 patients ) at a maximal daily dose of 375 mg . The study was conducted in 18 primary and 23 psychiatric care setting s. The primary outcome was symptom remission , defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of the study . Scores on the Quick Inventory of Depressive Symptomatology - Self Report ( QIDS-SR-16 ) , obtained at treatment visits , determined secondary outcomes , including remission ( a score of 5 or less at exit ) and response ( a reduction of 50 percent or more on baseline scores ) . RESULTS Remission rates as assessed by the HRSD-17 and the QIDS-SR-16 , respectively , were 21.3 percent and 25.5 percent for sustained-release bupropion , 17.6 percent and 26.6 percent for sertraline , and 24.8 percent and 25.0 percent for extended-release venlafaxine . QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion , 26.7 percent for sertraline , and 28.2 percent for extended-release venlafaxine . These treatments did not differ significantly with respect to outcomes , tolerability , or adverse events . CONCLUSIONS After unsuccessful treatment with an SSRI , approximately one in four patients had a remission of symptoms after switching to another antidepressant . Any one of the medications in the study provided a reasonable second-step choice for patients with depression . ( Clinical Trials.gov number , NCT00021528 . ) BACKGROUND The objectives of the study were to compare efficacy and tolerability of venlafaxine ER 75 - 150 mg/day with that of citalopram 10 - 20 mg/day in elderly patients with major depression according to DSM-IV criteria . METHODS A r and omised , double-blind , parallel group 6-month study . Efficacy was assessed by MADRS , CGI Global Improvement , CGI Severity of Illness and GDS-20 scores and safety by physical examinations , vital signs , adverse events and UKU side effect rating . Plasma levels of venlafaxine , its major metabolite O-desmethylvenlafaxine and citalopram were followed . RESULTS One hundred and fifty-one male and female patients ( 64 - 89 years ) were enrolled and 118 patients completed the study . Comparable improvements in MADRS , CGI Severity of Illness , CGI Global Improvement and GDS-20 were observed during venlafaxine and citalopram treatment . The MADRS remission rate was 19 % for venlafaxine and 23 % for citalopram .  Side effects were common during both treatments but differed in tremor being more common during citalopram and nausea/vomiting during venlafaxine treatment . There were no clinical ly significant changes in blood pressure or body weight . CONCLUSION The observed benefits of venlafaxine treatment in elderly patients with major depression were similar to those observed in younger adults as were reported adverse events and side effects . Treatment with venlafaxine ER was well tolerated and induced beneficial effects of similar magnitude as those of citalopram Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors ( SSRIs ) in severe major depressive disorder ( MDD ) . This prospect i ve pragmatic trial tests this hypothesis . Patients with severe MDD were r and omly assigned to either duloxetine ( a serotonin and norepinephrine-reuptake inhibitor ) or physicians ’ choice of four generic SSRIs . Nonblinded , flexibly dosed treatment was used to mimic clinical practice . To address potential investigator bias , the patient-reported Quick Inventory of Depressive Symptomatology Self-Report ( QIDS-SR ) was used as the primary efficacy outcome measure . A total of 750 out patients ( 19.2 % , African descent ; 14.8 % , Hispanic ) were r and omized . The primary outcome , remission at week 12 by QIDS-SR , was numerically greater for duloxetine compared with SSRIs ( 36 vs. 32 % ) , but this difference was not statistically significant . Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item , the Brief Pain Inventory , and the Sheehan Disability Scale . Remission superiority on the QIDS-SR was not achieved . Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning . Study demographics suggest a more generalizable racial and ethnic population than is typical in r and omized clinical trials BACKGROUND Escitalopram is the most selective serotonin reuptake inhibitor ( SRI ) antidepressant available . Venlafaxine is a non-selective SRI that also inhibits noradrenergic re-uptake . This study compared escitalopram and venlafaxine extended release ( XR ) in depressed out patients at the highest doses recommended in the United States . METHOD In this r and omized trial , patients ( diagnosis of DSM-IV-defined major depressive disorder ; baseline Hamilton Rating Scale for Depression score of > /= 20 ) received 1 week of single-blind placebo treatment , followed by 8 weeks of double-blind , fixed-dose treatment with either escitalopram or venlafaxine XR ( rapidly titrated to 20 mg/day and 225 mg/day , respectively , in accordance with prescribing information ) . The primary efficacy variable was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score . Data were collected from May to December 2002 . RESULTS Mean baseline MADRS scores for the escitalopram ( N = 97 ) and venlafaxine XR ( N = 98 ) groups were 30.7 and 30.0 , respectively . There were no significant differences in measures of efficacy between the 2 antidepressants . Mean changes from baseline to endpoint in MADRS total score for escitalopram and venlafaxine XR were -15.9 and -13.6 , respectively . Remission ( MADRS score of < /= 10 ) rates at endpoint were 41.2 % for escitalopram and 36.7 % for venlafaxine XR . Response ( > /= 50 % reduction from baseline MADRS score ) rates for the escitalopram and venlafaxine XR groups were 58.8 % and 48.0 % , respectively . Tolerability measures favored escitalopram over venlafaxine XR treatment . The venlafaxine XR group had a higher incidence than the escitalopram group of treatment-emergent adverse events ( 85.0 % vs. 68.4 % ) and discontinuation due to adverse events ( 16.0 % vs. 4.1 % ; p < .01 ) . CONCLUSION Results of this study indicate that , when titrated rapidly to their maximum recommended doses , escitalopram is at least as effective as venlafaxine XR and significantly better tolerated . These results do not support the hypothesis that nonselective SRIs have greater efficacy than selective SRIs The combined serotonin – norepinephrine reuptake inhibitor , venlafaxine XR , has demonstrated significant response and remission in patients diagnosed with depression when measured with the Hamilton Depression Rating Scale ( HAM-D ) . This pooled analysis of data from five studies compared the sustained remission of depressive symptoms in patients treated with venlafaxine XR , the selective serotonin reuptake inhibitors ( SSRIs ) fluoxetine or paroxetine , or placebo .  Data from 1391 subjects enrolled in five active and placebo-controlled studies who met the DSM-III-R or DSM-IV criteria for major depressive disorder were analysed . Three treatment groups were compared : venlafaxine XR ( n=560 ) , fluoxetine/paroxetine ( n=298 ) and placebo ( n=496 ) . Mean treatment duration was 8 weeks . Responders were defined as those patients whose HAM-D-21 score decreased by ≥50 % from baseline . Remission was defined as a HAM-D-17 score ≤7 . Sustained remission was defined as maintenance of remission through week 8 or the end of treatment ( if before week 8) and for ≥2 weeks . Between-group rate comparisons in outcome measures were carried out using Fisher 's exact and log-rank tests . Venlafaxine XR produced significantly higher rates of sustained remission in depressed patients compared to fluoxetine/paroxetine or placebo over this 8-week treatment period . As early as week 2 , a significantly greater proportion of patients treated with venlafaxine  achieved improved depression scores ( remission and response ) . A significantly greater rate of remission and sustained remission  occurred with venlafaxine compared to placebo  . Remission was achieved earlier with venlafaxine and lasted throughout the remainder of the study . These results demonstrate that venlafaxine XR is more effective than fluoxetine/paroxetine for sustaining remission of depressive symptoms Treatment effects are often evaluated by comparing change over time in outcome measures . However , valid analyses of longitudinal data can be problematic when subjects discontinue ( dropout ) prior to completing the study . This study assessed the merits of likelihood-based repeated measures analyses ( MMRM ) compared with fixed-effects analysis of variance where missing values were imputed using the last observation carried forward approach ( LOCF ) in accounting for dropout bias . Comparisons were made in simulated data and in data from a r and omized clinical trial . Subject dropout was introduced in the simulated data to generate ignorable and nonignorable missingness . Estimates of treatment group differences in mean change from baseline to endpoint from MMRM were , on average , markedly closer to the true value than estimates from LOCF in every scenario simulated . St and ard errors and confidence intervals from MMRM accurately reflected the uncertainty of the estimates , whereas st and ard errors and confidence intervals from LOCF underestimated uncertainty Findings from the National Institute of Mental Health 's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50 % of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor ( SSRI ) . This study was design ed to test the hypothesis that , after treatment failure with an SSRI , switching to venlafaxine extended release ( ER ) would offer advantages over switching to another SSRI , citalopram . The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram  and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity . This was a 12-week , double-blind , r and omized , parallel-group , multicenter study . Participants were adult out patients who , following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram  and had not responded , met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders , fourth edition , and had a score ≥20 on the 21-item Hamilton Rating Scale for Depression ( HAM-D21 ) . After a 7-day screening period , patients were r and omly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks . Doses could be increased every 2 weeks through week 6 . Treatment lasted 12 weeks and was followed by a 1-week tapering period . Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day . The primary end point was the final on-therapy total HAM-D21 score . To investigate the treatment effects of the severity of depression on efficacy , a subgroup analysis was performed for baseline HAM-D21 total score ≤31 and > 31 . The analyses for HAM-D21 , Montgomery – Åsberg Depression Rating Scale ( MADRS ) , Clinical Global Impressions – Severity ( CGI-S ) , and Clinical Global Impressions – Improvement scores were based on intent-to-treat ( ITT ) population , for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores ≤31 or > 31 . Safety assessment s included the recording of adverse events ( AEs ) . A total of 406 patients ( 200 venlafaxine ER , 206 citalopram ) were r and omly assigned and 396 patients were included in the ITT population ( 194 venlafaxine ER , 202 citalopram ) . Treatment groups were similar in terms of demographics and baseline psychiatric assessment s. Two hundred and eighty-four patients ( 137 venlafaxine ER , 147 citalopram ) were present in the ITT population with a baseline HAM-D21 total score ≤31 and 112 patients ( 57 venlafaxine ER , 55 citalopram ) in the > 31 group . In the primary analysis , there was no statistical difference between groups . The group with a baseline HAM-D21 total score of 20–31 did not differ significantly in any efficacy parameters . In the group with a baseline HAM-D21 total score > 31 , the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score ( P=0.0121 ) . The secondary end point CGI-S score was statistically significant ( P=0.0359 ) , although the MADRS total score ( P=0.0930 ) was not . AEs were reported by 57.8 and 63.4 % of venlafaxine ER and citalopram patients , respectively . Overall discontinuation rates were 24.5 % for venlafaxine ER and 20.9 % for citalopram  . Discontinuation rates owing to an AE as a primary or secondary reason were 5.5 % for venlafaxine ER and 5.3 % for citalopram . Overall , venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI . In the subset of more severely depressed patients , venlafaxine ER was significantly more effective on a number of efficacy measures . Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine , rather than switching to another SSRI Serotonin-norepinephrine reuptake inhibitors ( SNRIs ) may be used as an alternative treatment for depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant . This r and omized , open-label , multicenter study compared the effectiveness of the SNRI venlafaxine extended release ( VXR ) with that of conventional antidepressants ( CA ) in patients who were referred to an outpatient psychiatric specialty care setting for treatment after failure to tolerate or respond to at least 4 weeks of treatment with a CA in a primary care setting . Patients with a Hamilton Depression Rating Scale ( HAM-D17 ) score > or = 17 were r and omly assigned to treatment with an alternative CA or VXR .  Remission was defined as a score < or = 7 on the HAM-D17 . Efficacy analyses were carried out on 3,097 patients from the intent-to-treat ( ITT ) population ( 1,632 VXR ; 1,465 CA ) . The antidepressants prescribed most frequently in the CA group were paroxetine ( 21.3 % ) , citalopram ( 20.1 % ) , sertraline ( 19.1 % ) , fluoxetine ( 17.0 % ) , and mirtazapine ( 7.9 % ) . After 24 weeks of treatment , the VXR group demonstrated a significantly higher remission rate than did the CA group ( 59.3 % VXR ; 51.5 % CA ; P<.0001 ; odds ratio : 1.37 ; 95 % CI : 1.19 - 1.58 ; P<.01 ) . Despite the limitations of the open design , the results of this study suggest that venlafaxine extended release may be more effective than the conventional antidepressants used in this study when treating depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant BACKGROUND This r and omized , open-label , rater-blinded , multicenter study compared treatment outcomes with the serotonin-norepinephrine reuptake inhibitor ( SNRI ) venlafaxine extended release ( ER ) with selective serotonin reuptake inhibitors ( SSRIs ) in primary care patients with major depressive disorder . METHOD Study data were collected from November 29 , 2000 , to March 4 , 2003 . Out patients who met diagnostic criteria for major depressive disorder according to the Mental Health Screener , a computer-administered telephone interview program that screens for the most common mental disorders , and had a total score on the 17-item Hamilton Depression Rating Scale ( HDRS(17 ) ) ≥ 20 were r and omly assigned to receive up to 6 months of open-label venlafaxine ER 75 - 225 mg/d ( n = 688 ) or an SSRI ( n = 697 ) : fluoxetine 20 - 80 mg/d , paroxetine 20 - 50 mg/d , citalopram 20 - 40 mg/d , and sertraline 50 - 200 mg/d . The primary outcome was remission ( HDRS(17 ) score ≤ 7 ) at study end point using the last-observation-carried-forward method to account for early termination . A mixed-effects model for repeated measures ( MMRM ) analysis evaluated secondary outcome measures . RESULTS Fifty-one percent of patients completed the study . Month 6 remission rates did not differ significantly for venlafaxine ER and the SSRIs ( 35.5 % vs 32.0 % , respectively ; P = .195 ) . The MMRM analysis of HDRS(17 ) scores also did not differ significantly ( P = .0538 ) . Significant treatment effects favoring the venlafaxine ER group were observed for remission rates at days 30 , 60 , 90 , and 135 and a survival analysis of time to remission ( P = .006 ) , as well as Clinical Global Impressions-severity of illness scale ( P = .0002 ) ; Hospital Anxiety and Depression Scale-Anxiety subscale ( P = .03 ) ; 6-item Hamilton Depression Rating Scale , Bech version ( P = .009 ) ; and Quick Inventory of Depressive Symptomatology-Self-Report ( P = .0003 ) . CONCLUSIONS Remission rates for patients treated with venlafaxine ER or an SSRI did not differ significantly after 6 months of treatment . Results of most secondary analyses suggested that SNRI treatment had a greater antidepressant effect versus the SSRIs studied BACKGROUND In nursing home residents and other frail elderly patients , old age and potential drug-drug and drug-disease interactions may affect the relative safety and efficacy of medications . The purpose of this study was to examine the efficacy and tolerability of venlafaxine and sertraline for the treatment of  depression among nursing home residents . METHOD The study was a 10-week r and omized , double-blind , controlled trial of venlafaxine ( doses up to 150 mg/day ) versus sertraline ( doses up to 100 mg/day ) among 52 elderly nursing home residents with a DSM-IV depressive disorder and , at most , moderate dementia . The primary measure of outcome was the Hamilton Rating Scale for Depression ( HAM-D ) . Adverse events were monitored and recorded systematic ally during the trial . RESULTS Twelve subjects were discontinued due to serious adverse events ( SAE ) , 5 were discontinued due to other significant side effects , and 2 withdrew consent . Tolerability estimated by the time to termination was lower for venlafaxine than sertraline for serious adverse events ( log rank statistic = 5.28 , p = .022 ) , for serious adverse events or side effects ( log rank statistic = 8.08 , p = .005 ) , or for serious adverse events , side effects , or withdrawal of consent ( log rank statistic = 10.04 , p = .002 ) . Mean ( SD ) HAM-D scores at baseline were 20.2 ( 3.4 ) for sertraline and 20.3 ( 3.7 ) for venlafaxine ; intent-to-treat endpoint HAM-D scores were 12.2 ( 5.1 ) and 15.7 ( 6.2 ) ( F = 3.45 ; p = .069 ) . There were no differences in categorical responses for the intent-to-treat sample or completers . CONCLUSION In this frail elderly population , venlafaxine was less well tolerated and , possibly , less safe than sertraline without evidence for an increase in efficacy . This unexpected finding demonstrates the need for systematic research on the safety of drugs in the frail elderly Abstract Background and objective : Escitalopram is the most selective serotonin reuptake inhibitor antidepressant ; in contrast , duloxetine inhibits both serotonin and norepinephrine reuptake . Double-blind comparison studies may help guide treatment decisions by revealing the relative benefits of different therapeutic approaches . This study evaluated the efficacy and safety of escitalopram versus duloxetine in the acute treatment of patients with moderate to severe major depressive disorder . Methods : A 1-week , single-blind , placebo lead-in period followed by an 8-week , r and omised , double-blind , multicentre , parallel-group comparison was conducted from 20 April 2005 to 10 March 2006 in independent psychiatric research facilities with principal investigators who were board certified in psychiatry . A total of 278 out patients of 382 patients screened with Diagnostic and Statistical Manual of Mental Disorders ( 4th edition)-diagnosed major depressive disorder ( Montgomery-Åsberg Depression Rating Scale [ MADRS ] total score ≥26 ) were r and omised to the two treatment groups . Eight patients received no medication and were excluded from the safety group . Patients were treated with either escitalopram 10–20 mg/day ( fixed at 10 mg/day for the first 4 weeks ) or duloxetine 60 mg/day . The primary efficacy variable was change from baseline at week 8 in MADRS total score using the last observation carried forward ( LOCF ) approach . Efficacy , safety and tolerability measures were prospect ively defined in the statistical analysis plan prior to study initiation unless otherwise specifically noted as conducted post hoc . Results : A significantly greater proportion of escitalopram-treated patients completed the 8-week study compared with duloxetine-treated patients ( 87 % vs 69 % , respectively ; p < 0.01 ) . Mean baseline MADRS total scores were 31.0 for the escitalopram group and 31.6 for the duloxetine group . At week 8 , escitalopram treatment result ed in significantly greater improvement compared with duloxetine on the prospect ively defined primary efficacy endpoint of mean change from baseline in MADRS total score using the LOCF approach ( least-squares mean difference [ LSMD ] −2.42 ; 95 % CI −4.73 , −0.11 ; p < 0.05 ) . There was no difference between treatment groups in the observed cases ( OC ) analysis ( LSMD −0.32 ; 95 % CI −2.71 , 2.07 ; p = 0.79 ) . Significantly fewer escitalopram-treated patients discontinued because of adverse events  compared with duloxetine ( 2 % vs 13 % , respectively ; p < 0.01 ) . Conclusion : These findings suggest that escitalopram is better tolerated and at least as effective as the serotonin-norepinephrine reuptake inhibitor duloxetine in the treatment of major depressive disorder This study compares two methods for h and ling missing data in longitudinal trials : one using the last-observation-carried-forward ( LOCF ) method and one based on a multivariate or mixed model for repeated measurements ( MMRM ) . Using data sets simulated to match six actual trials , I imposed several drop-out mechanisms , and compared the methods in terms of bias in the treatment difference and power of the treatment comparison . With equal drop-out in Active and Placebo arms , LOCF generally underestimated the treatment effect ; but with unequal drop-out , bias could be much larger and in either direction . In contrast , bias with the MMRM method was much smaller ; and whereas MMRM rarely caused a difference in power of greater than 20 % , LOCF caused a difference in power of greater than 20 % in nearly half the simulations . Use of the LOCF method is therefore likely to misrepresent the results of a trial seriously , and so is not a good choice for primary analysis . In contrast , the MMRM method is unlikely to result in serious misinterpretation , unless the drop-out mechanism is missing not at r and om ( MNAR ) and there is substantially unequal drop-out . Moreover , MMRM is clearly more reliable and better grounded statistically . Neither method is capable of dealing on its own with trials involving MNAR drop-out mechanisms , for which sensitivity analysis is needed using more complex methods
target: Evidence from meta- analysis of r and omised controlled trials ( RCTs ) and r and omised pragmatic trials was found in support of greater efficacy of the serotonin noradrenaline reuptake inhibitors ( SNRIs ) , venlafaxine and duloxetine , in moderate to severe depression compared to SSRIs but no evidence was found for superiority of milnacipran .
  There is sufficient current evidence that demonstrates an increase in efficacy , when noradrenaline reuptake is added to serotonin ( 5-HT ) reuptake , to suggest that patients with severe depression or those who have failed to reach remission with a SSRI may benefit from treatment with a SNRI .
background: Selective serotonin reuptake inhibitors ( SSRIs ) are recommended as first-line pharmacological treatment for depression and are the most commonly prescribed class of antidepressants .
  However , there is substantial evidence that noradrenaline has a role in the pathogenesis and treatment of depression .
  This review aims to examine the evidence of including noradrenaline reuptake inhibition with serotonin reuptake inhibition with respect to increasing efficacy in the treatment of depression .