title: Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? Prevention of recurrent depressive episodes with milnacipran: consequences on quality of life. Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of authors Long‐term efficacy and safety of milnacipran compared to clomipramine in patients with major depression Pooling two controlled comparisons of milnacipran (F2207) and amitriptyline in endogenous inpatients. A new approach in dose ranging studies. A comparative study of milnacipran and paroxetine in outpatients with major depression. Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenaline reuptake inhibitor: a comparison with fluvoxamine Combination of direct and indirect evidence in mixed treatment comparisons. A comparative study of milnacipran and imipramine in the treatment of major depressive disorder Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. Double-blind placebo-controlled study of milnacipran in hospitalized patients with major depressive disorders. Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients A randomised, double-blind comparison of milnacipran and imipramine in the treatment of depression. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients Controlled comparison of two different doses of milnacipran in major depressive outpatients Interest of a loading dose of milnacipran in endogenous depressive inpatients: Comparison with the standard regimen and with fluvoxamine A double‐blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients Milnacipran efficacy in the prevention of recurrent depression: a 12‐month placebo‐controlled study Controlled comparison of milnacipran and fluoxetine in major depression Comparison of efficacy and safety of milnacipran and fluoxetine in Korean patients with major depression Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. A double‐blind six months comparative study of milnacipran and clomipramine in major depressive disorder
abstract: CONTEXT Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions . OBJECTIVE To explore whether the association between funding and conclusions in r and omized drug trials reflects treatment effects or adverse events . DESIGN Observational study of 370 r and omized drug trials included in meta-analyses from Cochrane review s selected from the Cochrane Library , May 2001 . From a r and om sample of 167 Cochrane review s , 25 contained eligible meta-analyses ( assessed a binary outcome ; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment ) . The primary binary outcome from each meta- analysis was considered the primary outcome for all trials included in each meta- analysis . The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect , adverse events , and additional confounding factors ( method ological quality , control intervention , sample size , publication year , and place of publication ) . MAIN OUTCOME MEASURE Conclusions in trials , classified into whether the experimental drug was recommended as the treatment of choice or not . RESULTS The experimental drug was recommended as treatment of choice in 16 % of trials funded by nonprofit organizations , 30 % of trials not reporting funding , 35 % of trials funded by both nonprofit and for-profit organizations , and 51 % of trials funded by for-profit organizations ( P<.001 ; chi2 test ) . Logistic regression analyses indicated that funding , treatment effect , and double blinding were the only significant predictors of conclusions . Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice ( odds ratio , 5.3 ; 95 % confidence interval , 2.0 - 14.4 ) compared with trials funded by nonprofit organizations . This association did not appear to reflect treatment effect or adverse events . CONCLUSIONS Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results . Readers should carefully evaluate whether conclusions in r and omized trials are supported by data BACKGROUND Depression is now seen as a chronic disabling condition that spans the patient 's lifetime and creates significant medical , economic and quality of life consequences . METHODS 500 depressed patients were treated with milnacipran for 6 months . A total of 214 recovered patients were r and omised to receive either milnacipran ( 50 mg bid ) or a matching placebo for a 1-year recurrence prevention phase . Recurrence rate was the primary criteria ; quality of life ( QoL ) consequences were evaluated through a shortened version of the French Sickness Impact Profile ( SIP ) , the Depression Impact Profile ( DIP ) . RESULTS Milnacipran demonstrated its ability to reduce recurrences ( Odds-Ratio=1.5 ; P<0.05 ) , with a more marked effect in recovered patients with few residual symptoms ( Odds-Ratio=3.0 ) . Responders who continued treatment with milnacipran had a dramatic improvement in their quality of life , although patients with residual symptoms still experienced some deterioration in their QoL ( recreation , emotional , social , alertness and home assistance scores ) . Even recovered patients having zero scores on the Hamilton Depression Rating Scale-21 items ( HDRS ) had some QoL deterioration . The DIP emotional score was found to be more predictive of recurrence than the HDRS . Overall , the QoL was improved for those in the milnacipran group in comparison to placebo on the mobility , communication , psycho-social and total scores . LIMITATIONS The QoL evaluation was a secondary criteria ; no a priori sample size estimate was performed . The choice of a generic QoL instrument might have reduced the sensitivity to clinical changes in depression . CONCLUSIONS Prevention of recurrence in MDD with milnacipran contributes to an improvement in the Abstract Objective To examine the extent and nature of outcome reporting bias in a broad cohort of published r and omised trials . Design Retrospective review of publications and follow up survey of authors . Cohort All journal articles of r and omised trials indexed in PubMed whose primary publication appeared in December 2000 . Main outcome measures Prevalence of incompletely reported outcomes per trial ; reasons for not reporting outcomes ; association between completeness of reporting and statistical significance . Results 519 trials with 553 publications and 10 557 outcomes were identified . Survey responders ( response rate 69 % ) provided information on unreported outcomes but were often unreliable — for 32 % of those who denied the existence of such outcomes there was evidence to the contrary in their publications . On average , over 20 % of the outcomes measured in a parallel group trial were incompletely reported . Within a trial , such outcomes had a higher odds of being statistically non-significant compared with fully reported outcomes ( odds ratio 2.0 ( 95 % confidence interval 1.6 to 2.7 ) for efficacy outcomes ; 1.9 ( 1.1 to 3.5 ) for harm outcomes ) . The most commonly reported reasons for omitting efficacy outcomes included space constraints , lack of clinical importance , and lack of statistical significance . Conclusions Incomplete reporting of outcomes within published articles of r and omised trials is common and is associated with statistical non- significance . The medical literature therefore represents a selective and biased subset of study outcomes , and trial protocol s should be made publicly available Milnacipran is a new antidepressive drug , a combined noradrenaline/serotonin ( NA/5‐HT ) reuptake inhibitor , which has been suggested to be as effective as and better tolerated than tricyclic antidepressants . Since long‐term studies are lacking , we compared the efficacy , safety and tolerability of milnacipran and clomipramine in a double‐blind , r and omized , parallel‐group study setting during 26 weeks of treatment in patients with major depression . A total of 107 patients were treated with either milnacipran  ( n=52 ) or clomipramine ( n=55 ) . Due to active treatment of duration less than 12 days in four patients and protocol deviation in one patient , in total 47 milnacipran‐treated patients were eligible for efficacy analysis . Nine patients in the clomipramine group continued on active treatment for less than 12 days . Thus 46 clomipramine‐treated patients were finally included in the efficacy analysis . After 1 week of dose escalation , there was a fixed dosage regimen of either milnacipran ( 200 mg daily ) or clomipramine ( 150 mg daily ) during weeks 2 to 10 , followed by flexible dosing of milnacipran ( 100,150 or 200 mg daily ) or clomipramine ( 75 , 100 or 150 mg daily ) during weeks 11 to 26 . A total of 53 patients ( 49 % ) completed the 26‐week study period ; 21 % ( 11/52 ) of the patients in the milnacipran group and 38 % ( 21/55 ) of the patients in the clomipramine group discontinued their medication prematurely due to adverse events , whereas 19 % ( 10/52 ) of those on milnacipran and 7 % ( 4/55 ) of those on clomipramine treatment withdrew due to either lack of efficacy or clinical deterioration . The mean change ( ±SD ) in the Hamilton Depression Rating Scale ( HAMD ) score between the baseline and the last rating ranged from 23.7±3.1 to 12.0±9.5 in the milnacipran‐treated patients and from 23.1±3.5 to 8.0±8.5 in the clomipramine‐treated patients , revealing a significant difference in favour of clomipramine . In total 58 % of the milnacipran‐treated patients vs. 72 % of the clomipramine‐treated patients showed a ≥50 % reduction in their baseline HAMD scores and 45 % vs. 63 % had an HAMD score of ≤7 at the last rating , respectively . Moreover , the time to the onset of the antidepressant action ( defined as ≥50 % reduction of the baseline HAMD score ) showed a significant difference in favour of clomipramine . In addition , clomipramine was significantly more efficacious in patients with a baseline HAMD score of ≥24 as evidence d by the analysis of the HAMD score at week 6 and at the last rating . The Montgomery Åsberg Depression Rating Scale ( MADRS ) and the Clinical Global Impression ( CGI ) scale did not show significant differences between the treatment groups . The safety analysis did not reveal any differences of clinical significance in cardiovascular variables between the study drugs . Dry mouth was significantly less frequently reported by the milnacipran‐treated patients during the early and later phases ( weeks 6 to 26 ) of the study , while insomnia was more common in the milnacipran group during weeks 1 to 6 . In conclusion , milnacipran appeared to be less effective  than clomipramine in the long‐term treatment of depression . The side‐effects of the drugs differed to a certain extent , and milnacipran tended to be somewhat better tolerated  than clomipramine Milnacipran is a new potential antidepressant selected for its equipotent inhibition of noradrenaline and serotonin uptake and its lack of effect at any postsynaptic receptor . We recently compared milnacipran 100 and 50 mg/d and amitriptyline 150 mg/d in three parallel r and omized groups of major depressive in patients and found a statistically significant superiority of milnacipran 100 mg/d and amitriptyline over milnacipran 50 mg/d after 4 weeks of treatment . Later on we found similar improvement with milnacipran 200 mg and amitriptyline 150 mg but better tolerance with milnacipran . In order to compare the therapeutic activity of the three doses of milnacipran ( 50 mg/d , 100 mg/d , and 200 mg/d ) we used the responses to amitriptyline  as a reference against which to compare the 3 doses of the new drug using analysis of variance on the adjusted data . This approach reveals milnacipran 200 mg is more effective than milnacipran 50 and 100 mg and is the only dose which shows efficacy at least equivalent to that of amitriptyline 150 mg . The dose/efficacy relationship was linear BACKGROUND Milnacipran is a dual-action antidepressant which inhibits both serotonin and noradrenaline reuptake with no affinity for any neurotransmitter receptor studied . METHODS A 6-week double-blind multicentre study compared milnacipran ( 100 mg/day ) with paroxetine ( 20 mg/day ) in 300 out patients with major depression . Efficacy was evaluated using HAMD17 , MADRS and CGI for severity of illness and global improvement . Data were analysed on an intention to treat , last observation carried forward , basis . RESULTS Milnacipran and paroxetine were both effective and well tolerated with no significant difference in their effects . After treatment discontinuation , milnacipran was associated with significantly less emergent symptoms . Responders , at endpoint , to milnacipran had significantly greater levels of psychomotor retardation at baseline than non-responders . LIMITATIONS The study did not include a placebo group so that it is impossible to determine absolute levels of efficacy . CONCLUSIONS Both milnacipran and paroxetine were effective and well tolerated by out patients with major depression treated for 6 weeks . After treatment discontinuation milnacipran was associated with less emergent symptoms . Psychomotor retardation at baseline may be a predictive factor of a favourable response to milnacipran The antidepressant efficacy and tolerability of milnacipran , a dual action serotonin-noradrenaline reuptake inhibitor , were compared with those of the selective serotonin reuptake inhibitor , fluvoxamine , in 113 patients with moderate to severe major depression . Treatment with milnacipran , 50 mg b.d . for 6 weeks , produced a significantly greater reduction in Montgomery-Asberg Depression Rating Scale ( MADRS ) scores than fluvoxamine , 100 mg b.d . ( P = 0.007 ; 65.4 % versus 49.9 % , respectively ) ; significantly greater decreases were also seen on days 7 ( P = 0.04 ) and 28 ( P = 0.03 ) . The response rate ( the proportion of patients showing a decrease in MADRS scores of at least 50 % ) was 78.9 % in patients receiving milnacipran , compared with 60.7 % in fluvoxamine-treated patients ( P = 0.04 ) . Milnacipran also produced greater improvements in 24-item Hamilton Depression Rating Scale scores ( P = 0.05 ) . On the Clinical Global Impression Improvement scale , 77.2 % of milnacipran-treated patients were rated as considerably or markedly improved , compared with 60.7 % of patients receiving fluvoxamine ( P = 0.06 chi-squared ) . Both treatments were well tolerated ; the only significant difference between the two groups was a higher incidence of tremor and drowsiness in patients treated with fluvoxamine . It is concluded that milnacipran may offer some advantages over selective serotonin reuptake inhibitors , such as fluvoxamine , in the treatment of moderate to severe major depression Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed SUMMARY The antidepressant efficacy and safety of milnacipran , a dual action antidepressant drug which inhibits the reuptake of serotonin and noradrenaline , was compared with that of the tricyclic antidepressant , imipramine , in a multi-centre , double-blind , r and omised , parallel group , comparative trial in 5 hospital centres in Spain . One hundred patients hospitalised with a diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of the American Psychiatry Association ( third revision ) , with a minimum score of 25 on the Montgomery and Åsberg Depression Rating Scale were treated for 6 weeks with milnacipran ( 100 mg/day ) or imipramine ( 150 mg/day ) . Both treatments showed similar efficacy in reducing depressive symptoms . The frequency of most adverse events in the milnacipran-treated patients was lower than that observed in the imipramine group , particularly those related to anticholinergic symptoms . Dysuria and shivering , however , were more common with milnacipran . The results of this study support others which have demonstrated that milnacipran has equivalent efficacy but superior tolerability to a tricyclic antidepressant such as imipramine CONTEXT Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected , but direct evidence of such bias is currently limited to case reports . OBJECTIVE To study empirically the extent and nature of outcome reporting bias in a cohort of r and omized trials . DESIGN Cohort study using protocol s and published reports of r and omized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg , Denmark , in 1994 - 1995 . The number and characteristics of reported and unreported trial outcomes were recorded from protocol s , journal articles , and a survey of trialists . An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta- analysis . Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias . Protocol s and published articles were also compared to identify discrepancies in primary outcomes . MAIN OUTCOME MEASURES Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes ; consistency between primary outcomes defined in the most recent protocol s and those defined in published articles . RESULTS One hundred two trials with 122 published journal articles and 3736 outcomes were identified . Overall , 50 % of efficacy and 65 % of harm outcomes per trial were incompletely reported . Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy ( pooled odds ratio , 2.4 ; 95 % confidence interval [ CI ] , 1.4 - 4.0 ) and harm ( pooled odds ratio , 4.7 ; 95 % CI , 1.8 - 12.0 ) data . In comparing published articles with protocol s , 62 % of trials had at least 1 primary outcome that was changed , introduced , or omitted . Eighty-six percent of survey responders ( 42/49 ) denied the existence of unreported outcomes despite clear evidence to the contrary . CONCLUSIONS The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocol s. Published articles , as well as review s that incorporate them , may therefore be unreliable and overestimate the benefits of an intervention . To ensure transparency , planned trials should be registered and protocol s should be made publicly available prior to trial completion Fifty-eight in patients with a DSM-III diagnosis of major depressive disorder participated in a 5-week double-blind trial of milnacipran and placebo . Milnacipran was superior to placebo on all measures of depression . The first index of milnacipran superiority was the difference of dropouts due to treatment failure between milnacipran ( 10.3 % ) and placebo ( 55.2 % ) . All patients were evaluated up to day 14 . The improvement with milnacipran was statistically significant at day 14 . Side effects were identical for milnacipran and placebo A multicenter study compared the antidepressant efficacy and the tolerance of two doses of milnacipran ( 50 mg and 100 mg/day ) and amitriptyline ( 150 mg/day ) in three parallel groups of 45 major depressive in patients defined by Research Diagnostic Criteria . After a wash-out period of 4–7 days on placebo with lorazepam and /or nitrazepam if necessary , patients were r and omly assigned to a daily dose of milnacipran 50 mg , milnacipran 100 mg or amitriptyline 150 mg reached on the 5th day and then stable over a 4-week period , with weekly assessment s by means of the Montgomery and Asberg depression scale , the Hamilton depression scale , the Clinical Global Impressions ( CGI ) and the Target Emergent Signs and Symptoms . Results showed significant superiority of both milnacipran 100 mg/day and amitriptyline over milnacipran 50 mg/day at the end of the treatment period . However , amitriptyline induced a nonsignificant trend toward more rapid improvement after 2 weeks of treatment , mainly based on items related to insomnia , supporting more sedative properties of amitriptyline as compared to milnacipran . Anticholinergic side-effects were significantly lower with milnacipran than with amitriptyline , explaining why milnacipran 100 mg exhibited at the end of the treatment period , a nonsignificantly better efficacy index on the CGI . Moreover , in contrast to milnacipran , amitriptyline was responsible for a significant decrease in blood pressure and a significant weight gain This multicentre , double-blind , r and omised trial in 109 patients compared the efficacy and tolerance of the novel selective serotonin and noradrenaline reuptake inhibitor ( SNRI ) antidepressant milnacipran ( 50 mg twice daily , n=53 ) with the established tricyclic agent imipramine ( 75 mg twice daily , n=56 ) over a period of 6 weeks , in patients with major depression ( Montgomery-Asberg depression rating score ( MADRS ) > or = 25 ) . Initiation of antidepressant medication was conducted during a 2-week period of hospitalisation , after a 3- to 7-day washout period . Concomitant psychiatric medication was limited to lorazepam , cyamemazine , chloral hydrate and long-term uncomplicated lithium therapy . Assessment for efficacy using the MADRS and Hamilton rating scales of depression , a visual analogue scale and global evaluation revealed both agents to be highly effective ( P=0.0001 ) in this group of patients . Milnacipran was found to be of similar efficacy to imipramine .  Tolerance , assessed by physiological and biochemical examinations with routine inventory and spontaneous report of adverse events , revealed a clear advantage for milnacipran . The incidence of anticholinergic events with milnacipran was about half that with imipramine and the overall incidence of adverse events by either reporting method was markedly lower with milnacipran than with imipramine . Furthermore , the patient drop-out rate with imipramine was double that experienced with milnacipran . Milnacipran appears to possess equal antidepressant efficacy to imipramine but with markedly superior tolerance . Therefore , milnacipran constitutes an important new treatment option in major depression OBJECTIVE Financial conflict of interest has been reported to be prevalent in clinical trials in general medicine and associated with a greater likelihood of reporting results favorable to the intervention being studied . The extent and implication s of industry sponsorship and financial conflict of interest in psychiatric clinical trials have not been investigated , to the authors ' knowledge . METHOD The authors examined funding source and author financial conflict of interest in all clinical trials published in the American Journal of Psychiatry , the Archives of General Psychiatry , the Journal of Clinical Psychopharmacology , and the Journal of Clinical Psychiatry between 2001 and 2003 . RESULTS Among 397 clinical trials identified , 239 ( 60 % ) reported receiving funding from a pharmaceutical company or other interested party , and 187 studies ( 47 % ) included at least one author with a reported financial conflict of interest . Among the 162 r and omized , double-blind , placebo-controlled studies examined , those that reported conflict of interest were 4.9 times more likely to report positive results ; this association was significant only among the subset of pharmaceutical industry-funded studies . CONCLUSIONS Author conflict of interest appears to be prevalent among psychiatric clinical trials and to be associated with a greater likelihood of reporting a drug to be superior to placebo BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions Brain-derived neurotrophic factor ( BDNF ) is an important member of the neurotrophin family of growth factors , abundant in the brain and periphery . Research ers have reported that serum BDNF levels in drug-free depressed patients are lower than those of healthy controls , and have proposed that these low levels might reflect a failure of neuronal plasticity in depression . In the present study , we investigated the effects of paroxetine , an SSRI , and milnacipran , an SNRI , on serum BDNF levels in depressed patients .  Serum levels of BDNF were measured by ELISA before , 4 weeks , and 8 weeks after the start of treatment with antidepressants . Forty-two patients were r and omly administered  paroxetine ( 21 cases ) or milnacipran ( 21 cases ) . A negative correlation was found between serum BDNF levels and baseline Ham-D scores . The response and remission rates for each drug were not significantly different . Serum BDNF levels in responders were significantly increased 2.6- and 1.8-fold 8 weeks after treatment with paroxetine or milnacipran , respectively . These results suggest that both drugs improve the depressive state by increasing BDNF levels We compared the antidepressant efficacy and patient tolerance of two different doses of milnacipran ( 75 mg and 150 mg daily ) in 66 out patients with major depression , using the 17-item Hamilton Depression Rating Scale ( HDRS ) . Only new patients who had never experienced frank depressive episodes before , or those who had remained free from thymoregulators for more than 1 year without recurrence of depressive symptoms , were recruited . Subjects were r and omly selected to receive a daily dose of milnacipran that reached either 75 mg or 150 mg within 2–3 weeks and then remained stable over an 8-week period . The results showed a significant superiority of milnacipran at 150 mg/day over 75 mg/day at the end of the study period in both response ( 50 % or more decrease in total score from baseline , P=0.026 ) and remission ( total HDRS score lower than 7 points , P=0.034 ) . A response was recorded for 56.0 % of the patients treated with 75 mg of milnacipran and for 84.6 % of those treated with 150 mg after the 8-week study period . No significant difference was seen between the treatment groups for either individual or total incidence of adverse events . Notably , nausea and vomiting occurred most often immediately after the first visit , when subjects in both groups started with a daily dose of 50 mg . We conclude that additional comparisons between different doses of milnacipran should be performed to confirm or deny the linear dose/efficacy relationship observed in the present study A multicenter controlled study was design ed to test the hypothesis that a loading dose of an antidepressant could shorten the latency of its clinical efficacy .  Three parallel groups of about 40 endogenous depressive in patients received either a loading dose of milnacipran ( 300 mg daily for 2 weeks and 150 mg daily during the 2 following weeks ) , the st and ard regimen of milnacipran in severe depression ( 200 mg daily for 4 weeks ) , or fluvoxamine ( 200 mg daily for 4 weeks ) . The duration of the study was 4 weeks , with assessment s at baseline and after 4 , 9 , 14 , 21 , and 28 days of therapy by means of Montgomery and Asberg depression scale ( MADS ) , the Hamilton depression scale , the Clinical Global Impressions ( CGI ) , and a checklist of symptoms and side-effects . Results showed very similar evolution in the 3 treatment groups . In addition , the level of side-effects did not exhibit significant differences among the treatment groups , except for excitement-nervousness and akathisia which were more frequently reported with fluvoxamine . These results do not support the usefulness of a loading dose of an antidepressant such as milnacipran . They demonstrate however that milnacipran can be given at a 300 mg daily dose from the very first day of treatment with an excellent tolerance This double-blind , r and omised , multicentre study compared the antidepressant efficacy and safety of two doses of milnacipran ( 100 mg/day and 200 mg/day ) and fluoxetine ( 20 mg/day ) in 289 in patients with endogenous depression . After a placebo washout period of 4–7 days , assessment s were performed weekly during ; the first 4 weeks , and then after 6 , 8 and 12 weeks , using the 17-itein Hamilton Depression Rating Scale ( HDRS ) . the Montgomery - Åsberg Depression Rating Scale ( MADRS ) and the Clinical Global Impression ( CGI ) . HDRS total score was reduced by a mean of 14.8 in the milnacipran 100 mg/day group , 12.9 in the milnacipran 200 mg/day group and 12.1 in the fluoxetine  20 mg/day group . MADRS total score decreased by 17.4 , 15.8 and 14.6 , respectively . No significant difference could be shown between the three treatment groups for either the HDRS or MADRS total scores . However , the time-by-time change showed a trend in favour of milnacipran 100 mg/day , which was found significantly superior to fluoxetine at day 28 for several converging parameters ( MADRS , CGI-3 ) . Overall , efficacy ratings for all parameters were highest for milnacipran 100 mg/day , followed by milnacipran 200 mg/day and fluoxetinc 20 mg/day . Side-effect profiles were not significantly different between groups except for a significantly greater frequency of dose-related increase hi heart rate ≥ 100 bpm in milnacipran recipients and a significantly greater weight loss in fluoxetine recipients & NA ; To compare the efficacy and assess the tolerability of milnacipran 50 mg p.o . b.i.d . to placebo in the prevention of recurrence in depressed patients who had responded an acute treatment and had remained in remission during a 4‐month continuation phase . Remission criteria were : a Hamilton Depression Rating Scale ( HDRS ) ( 21‐item ) ≤ 8 , improvement or disappearance of the initial symptoms , and an assessment of ‘ very much improved ’ or ‘ much improved ’ on the Clinical Global Impression ( CGI ) Subscale : Global Improvement . Recurrence was defined by a major depressive episode according to DSM‐III‐R criteria and a minimum score of 18 on the HDRS , with the need to treat the recurrence . The primary analysis was the rate of recurrence as a function of time in the intent‐to‐treat population . Groups were compared using the Cox model . Absolute recurrence rates were 16.3 % ( 17/104 ) in milnacipran‐treated patients and 23.6 % ( 26/110 ) in placebo‐treated patients , with a significant difference in the reduction of recurrence as a function of time ( Kaplan Meier Survival Analysis analysis , P < 0.05 ) . There was no difference in tolerability between groups . This study demonstrates that milnacipran is effective with good tolerability in preventing recurrence in major depressive disorder over 1 year in patients with recurrent depression who responded to acute treatment with milnacipran and continued their response for 18 weeks The efficacy and the tolerance of milnacipran ( 100 mg/day ) , a second generation antidepressant which equipotently inhibits both noradrenaline and serotonin reuptake , was compared to fluoxetine ( 20 mg/day ) , a selective serotonin reuptake inhibitor , in two parallel groups of , respectively , 97 and 93 major depressive out patients . The duration of the study was 6 weeks , with assessment s every 2 weeks by means of the Montgomery and Asberg depression scale ( MADRS ) , the Hamilton depression scale , the clinical global impressions ( CGI ) , and a checklist of symptoms and side-effects . Results showed significant superiority of fluoxetine over milnacipran on most rating instruments : MADRS ( P=0.01 ) including five individual items , Hamilton depression scale ( P=0.002 ) including ten individual items , CGI of severity ( P=0.01 ) and therapeutical index ( P=0.002 ) . On visual analogue scales assessing the clinical profile of the compounds , fluoxetine was rated as exhibiting more psychostimulating activity than milnacipran ( P=0.0008 ) . The tolerance of the two antidepressants was very similar , with the exception of symptoms of dizziness which were more frequently reported with milnacipran ( P=0.01 ) . These differences in efficacy favoring fluoxetine could result from the selection of a dose of milnacipran below the optimal therapeutic dose for this type of psychiatric patients or to the administration of the compounds in single daily intakes , whereas milnacipran possesses a plasma elimination half-life of only 7 ABSTRACT Object : To compare efficacy and safety of milnacipran and fluoxetine in a population of Korean patients with major depression . Research design and methods : The design was a multi-centre , r and omised , comparative clinical study . Patients with major depression ( DSM‐IV diagnostic criteria ) scoring over 17 points on the 17-item Hamilton Depression Scale ( HAM‐D ) and over 21 points on the Montgomery-Asberg Depression Rating Scale ( MADRS ) were recruited and r and omised to receive milnacipran ( 50 mg/day increasing after 1 week to 100 mg/day ) or fluoxetine ( 20 mg/day ) for 6 weeks . All previous medication was stopped at least 7 days before entry into the study . Patients were evaluated ( HAM‐D , MADRS and clinical global impression scale , CGI ) at baseline and after 1 , 2 , 4 and 6 weeks of treatment . All adverse events which developed during the study period were recorded . Results : 70 patients ( milnacipran 39 ; fluoxetine 31 ) were included in the study . Total score on both HAM‐D , MADRS and CGI decreased significantly in both groups after 1 week and continued to decrease throughout the study . There was no significant difference between the two groups for any measurement at any time point . Both antidepressants were well tolerated . In the milnacipran group , 13 patients reported 28 adverse reactions , and in the fluoxetine group 11 patients reported 18 adverse reactions . Two patients discontinued due to adverse events in the milnacipran group and three in the fluoxetine group . There were no clinical ly significant modifications in vital signs , routine blood laboratory tests , biochemistry or ECG throughout the study . Nausea and headache were the most frequently reported adverse events with milnacipran while digestive disturbances , diarrhoea and insomnia were more common with fluoxetine . Conclusion : Milnacipran , like fluoxetine , was found to be effective and well tolerated for the treatment of major depression in this population of depressed Korean patients . Principal limitations of the study were its open design , its small sample size and its relatively short duration BACKGROUND Duloxetine hydrochloride , a dual reuptake inhibitor of serotonin and norepinephrine , was evaluated for therapeutic efficacy and safety/tolerability in the treatment of major depression . METHOD In an 8-week multicenter , double-blind , placebo-controlled study , 173 patients ( aged 18 - 65 years ) with DSM-IV major depressive disorder were r and omly allocated to receive placebo ( N = 70 ) , duloxetine ( N = 70 ) , or fluoxetine , 20 mg q.d . ( N = 33 ) . Duloxetine dose was titrated in the first 3 weeks in a forced-titration regimen from 40 mg ( 20 mg b.i.d . ) to 120 mg/day ( 60 mg b.i.d . ) . Patients were required to have a Clinical Global Impressions (CGI)-Severity of Illness scale score of at least moderate severity ( > or = 4 ) and a 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) total score of at least 15 . Patients could not have had any current primary DSM-IV Axis I diagnosis other than major depressive disorder , or any anxiety disorder as a primary diagnosis within the past year , excluding specific phobias . The primary efficacy measurement was the HAM-D-17 total score , and secondary measures included the Montgomery-Asberg Depression Rating Scale , CGI-Severity of Illness and CGI-Improvement , and Patient Global Impression of Improvement . Safety was evaluated by recording the occurrence of discontinuation rates and treatment-emergent adverse events and by measurement of vital signs and laboratory analytes . RESULTS Duloxetine was superior to placebo in change on the HAM-D-17 ( p = .009 ) . Estimated probabilities of response and remission were 64 % and 56 % , respectively , for duloxetine , compared with 52 % and 30 % for fluoxetine and 48 % and 32 % for placebo . Duloxetine was numerically superior to fluoxetine on the primary and most of the secondary outcome measures . In general , duloxetine was well tolerated ; 76 % of patients achieved the maximum dose , and insomnia and asthenia were the only adverse events reported statistically significantly ( p < .05 ) more frequently by duloxetine-treated patients compared with placebo-treated patients . CONCLUSION These data indicate that duloxetine is efficacious for the treatment of major depressive disorder and is well tolerated and safe Milnacipran is a new antidepressant with similar effects on the reuptake of noradrenaline and serotonin in vivo and in vitro . The present study was design ed to study the efficary and tolerability of long-term treatment of depressed patients with milnacipran in comparison with clomipramine . The study was design ed as a double-blind , r and omized parallel group comparison at 10 different hospitals in The Netherl and s. The duration of treatment was 6 weeks , with an extension period of 20 weeks . The entire study period of 26 weeks was done under double-blind conditions . There was 1 week of dose escalation after which the patients received either treatment with milnacipran 200 mg/day or clomipramine 150 mg/day in fixed doses during weeks 2 to 10 . This was followed by flexible dosing with 200 , 150 , or 100 mg/day milnacipran or 150 , 100 or 75 mg/day clomipramine during weeks 11 to 26 . Both milnacipran and clomipramine showed poor antidepressant activity in this patient sample . There were no significant differences between the two treatment groups with respect to antidepressant efficacy . Several method ological reasons might explain the lack of antidepressant efficacy in the present study . In 45 % of the patients in the present study , the duration of the current episode of depression was longer than 6 months , whereas 48 % of the patients used antidepressants before the study and 73 % of these appeared to be non-responders . This raises the possibility that the present sample consisted of treatment-resistant depressive patients
target: There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events of sleepiness/ drowsiness , dry mouth or constipation compared with TCAs .
  AUTHORS ' CONCLUSIONS Currently , there is inadequate evidence to conclude whether milnacipran is superior , inferior or the same as other antidepressive agents in terms of efficacy , acceptability and tolerability in the acute phase treatment of major depression .
  However , there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events ( acceptability ) and the rates of experiencing adverse events ( tolerability ) .
  Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression
background: BACKGROUND Although pharmacological and psychological interventions are both effective for major depression , antidepressant drugs are frequently used as first-line treatment in primary and secondary care setting s. Milnacipran , a dual serotonin-norepinephrine reuptake inhibitor ( SNRI ) , is one of the antidepressant drugs that clinicians use for routine depression care .
  OBJECTIVES To assess the evidence for the efficacy , acceptability and tolerability of milnacipran in comparison with tricyclic antidepressants ( TCAs ) , heterocyclics , SSRIs and other newer antidepressive agents in the acute-phase treatment of major depression .