A randomised, double-blind comparison of milnacipran and imipramine in the treatment of depression. 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 Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major depressive episode. (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). A comparative study of milnacipran and imipramine in the treatment of major depressive disorder The Alpha 2A-Adrenergic Receptor Gene Polymorphism Modifies Antidepressant Responses to Milnacipran Controlled comparison of milnacipran and fluoxetine in major depression Influence of the tyrosine hydroxylase val81met polymorphism and catechol-O-methyltransferase val158met polymorphism on the antidepressant effect of milnacipran. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. 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† Antidepressants and driving ability: results from a clinical study. A double‐blind six months comparative study of milnacipran and clomipramine in major depressive disorder Comparison of efficacy and safety of milnacipran and fluoxetine in Korean patients with major depression Efficacy of milnacipran in patients with fibromyalgia. The G196A polymorphism of the brain-derived neurotrophic factor gene and the antidepressant effect of milnacipran and fluvoxamine
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 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 The novel antidepressant agent milnacipran is a dual and equipotent serotonin and noradrenaline reuptake inhibitor . The aim of this double-blind study was to compare the efficacy and safety of milnacipran ( 50 mg twice daily ) with that of imipramine ( 50 mg twice daily ) in elderly patients with major depressive episode . A total of 219 patients were r and omly assigned to 8 weeks of double-blind treatment with either milnacipran or imipramine ;  72 patients withdrew from the study . At the end of treatment no significant differences were found between milnacipran and imipramine in antidepressant efficacy . A significantly greater number of side-effects , particularly anticholinergic effects , was observed in the imipramine group . Milnacipran may be preferable to imipramine in elderly depressed patients , as it provides the same antidepressant activity as imipramine with a lower incidence of side-effects , and does not impair cognitive ability Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited 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 Objective : The alpha 2A-adrenergic receptor ( ADRA2A ) plays a central role in the regulation of systemic sympathetic activity . Recently , the functional defect of ADRA2A has been implicated as a cause of depression , attention deficit hyperactivity disorder , and Tourette syndrome . In this study , the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors ( SNRIs ) was examined in depressed patients . Method : Ninety-three Japanese depressed patients were recruited in the present study , assigned r and omly to paroxetine or milnacipran , and assessed by the Hamilton Rating Scale for Depression ( HAM-D ) scoring every 2 weeks before and after drug administration . The ADRA2A C-1297 G polymorphism was considered in the association analysis with the efficacy of antidepressants . Results : There were significant differences in the HAM-D percent score change over time ( P = 0.019 ) among C/C , C/G , and G/G of the ADRA2A C-1297 G polymorphism in the total subjects . The C allele carriers of the ADRA2A C-1297 G polymorphism showed a significantly better improvement than G/G subjects at weeks 2 , 4 , and over time ( P = 0.037 ) in the milnacipran group . Discussion : Our findings suggest that ADRA2A plays an important role in depression therapy . The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs , especially milnacipran , although the functional change brought about by C-1297 G polymorphism has not yet been fully identified in vivo and in vitro . Conclusions : The ADRA2A polymorphism could be a reasonable c and i date to predict the response to milnacipran . Our results are still preliminary , and a large sample size will be required to confirm our findings . However , to the best of our knowledge , this study is the first to suggest a possible association of ADRA2A variants with the SNRI response 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 OBJECTIVE Genetic polymorphisms of the noradrenergic pathway can be factors to predict the effect of antidepressants when their pharmacological mechanisms of action include the noradrenergic system . The purpose of the present study was to determine whether the tyrosine hydroxylase ( TH ) val81met and catechol-O-methyltransferase ( COMT ) val158met polymorphisms are associated with the antidepressant effect of milnacipran , a serotonin/noradrenaline reuptake inhibitor . METHOD Eighty-one Japanese patients with major depressive disorder were treated with milnacipran for 6 weeks . Severity of depression was assessed with the Montgomery and Asberg Depression Rating Scale ( MADRS ) . Assessment s were carried out at baseline and at 1 , 2 , 4 and 6 weeks of treatment . The method of polymerase chain reaction was used to determine allelic variants . RESULTS The met/met genotype of the COMT val158met polymorphism was associated with a significantly faster therapeutic effect of milnacipran in the MADRS score during this study . No influence of the TH val81met polymorphism on the antidepressant effect of milnacipran was detected . CONCLUSION These results suggest that the COMT val158met polymorphism in part determines the antidepressant effect of milnacipran OBJECTIVE To determine the relative cost-effectiveness of three classes of antidepressants : tricyclic antidepressants ( TCAs ) , selective serotonin reuptake inhibitors ( SSRIs ) , and the modified TCA lofepramine , as first choice treatments for depression in primary care . DESIGN Open , pragmatic , controlled trial with three r and omised arms and one preference arm . Patients were followed up for 12 months . SETTING UK primary care : 73 practice s in urban and rural areas in Engl and . PARTICIPANTS Patients with a new episode of depressive illness according to GP diagnosis . INTERVENTIONS Patients were r and omised to receive a TCA ( amitriptyline , dothiepin or imipramine ) , an SSRI ( fluoxetine , sertraline or paroxetine ) or lofepramine . Patients or GPs were able to choose an alternative treatment if preferred . MAIN OUTCOME MEASURES At baseline the Clinical Interview Schedule , Revised ( CIS-R PROQSY computerised version ) was administered to establish symptom profiles . Outcome measures over the 12-month follow-up included the Hospital Anxiety and Depression Scale self-rating of depression ( HAD-D ) , CIS-R , EuroQol ( EQ-5D ) for quality of life , Short Form ( SF-36 ) for generic health status , and patient and practice records of use of health and social services . The primary effectiveness outcome was the number of depression-free weeks ( HAD-D less than 8 , with interpolation of intervening values ) and the primary cost outcome total direct NHS costs . Quality -adjusted life-years ( QALYs ) were used as the outcome measure in a secondary analysis . Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were computed . Estimates were bootstrapped with 5000 replications . RESULTS In total , 327 patients were r and omised . Follow-up rates were 68 % at 3 months and 52 % at 1 year . Linear regression analysis revealed no significant differences between groups in number of depression-free weeks when adjusted for baseline HAD-D. A higher proportion of patients r and omised to TCAs entered the preference arm than those allocated to the other choices . Switching to another class of antidepressant in the first few weeks of treatment occurred significantly more often in the lofepramine arm and less in the preference arm . There were no significant differences between arms in mean cost per depression-free week . For values placed on an additional QALY of over 5000 pounds , treatment with SSRIs was likely to be the most cost-effective strategy .  TCAs were the least likely to be cost-effective as first choice of antidepressant for most values of a depression-free week or QALY respectively , but these differences were relatively modest . CONCLUSIONS When comparing the different treatment options , no significant differences were found in outcomes or costs within the sample , but when outcomes and costs were analysed together , the result ing cost-effectiveness acceptability curves suggested that SSRIs were likely to be the most cost-effective option , although the probability of this did not rise above 0.6 . Choosing lofepramine is likely to lead to a greater proportion of patients switching treatment in the first few weeks . Further research is still needed on the management of depressive illness in primary care . This should address areas such as the optimum severity threshold at which medication should be used ; the feasibility and effectiveness of adopting structured depression management programmes in the UK context ; the importance of factors such as physical co-morbidity and recent life events in GPs ' prescribing decisions ; alternative ways of collecting data ; and the factors that give rise to many patients being reluctant to accept medication and discontinue treatment early OBJECTIVE Despite the progressive increase in the number of antidepressants , many patients with major depressive disorder continue to be symptomatic . Clearly , there is an urgent need to develop better tolerated and more effective treatments for this disorder . The use of S-adenosyl methionine ( SAMe ) , a naturally occurring molecule that serves as a methyl donor in human cellular metabolism , as adjunctive treatment for antidepressant nonresponders with major depressive disorder represents one such effort toward novel pharmacotherapy development . METHOD Participants were 73 serotonin reuptake inhibitor ( SRI ) nonresponders with major depressive disorder enrolled in a 6-week , double-blind , r and omized trial of adjunctive oral SAMe ( target dose : 800 mg/twice daily ) . Patients continued to receive their SRI treatment at a stable dose throughout the 6-week trial . The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale ( HAM-D ) . RESULTS The HAM-D response and remission rates were higher for patients treated with adjunctive SAMe ( 36.1 % and 25.8 % , respectively ) than adjunctive placebo ( 17.6 % versus 11.7 % , respectively ) . The number needed to treat for response and remission was approximately one in six and one in seven , respectively . There was no statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason ( 20.6 % versus 29.5 % , respectively ) , due to adverse events ( 5.1 % versus 8.8 % , respectively ) , or due to inefficacy ( 5.1 % versus 11.7 % , respectively ) . CONCLUSIONS These preliminary results suggest that SAMe can be an effective , well-tolerated , and safe adjunctive treatment strategy for SRI nonresponders with major depressive disorder and warrant replication 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 OBJECTIVE Psychomotor disturbances can frequently be found in depressed patients and may have an important influence on the ability to drive . Additionally , effects of sedation , as seen with some antidepressants , probably impair driving performance . The present study was design ed to evaluate the effects of antidepressant monotherapy on psychomotor functions related to car-driving skills in depressive patients in a routine clinical setting . METHOD In patients ( N = 100 ) who met the ICD-10 and DSM-IV criteria for major depressive disorder were tested under steady-state plasma level conditions prior to being discharged to out-patient treatment . The study ran from January 2004 through March 2005 . All patients participated voluntarily and gave informed consent . According to the German guidelines for road and traffic safety , data were collected with the computerized Act & React Testsystem ART-90 and the Wiener Testsystem , measuring visual perception , reaction time , selective attention , vigilance , and stress tolerance . Psychopathologic symptoms were rated with the Hamilton Rating Scale for Depression . RESULTS Before discharge to outpatient treatment , 24 % of the patients tested were without clinical ly relevant psychomotor disturbances . In 60 % of the cases , mild to moderate impairments could be seen , and about 16 % of the patients were considered as severely impaired in psychomotor functions related to car-driving abilities . Data show that patients treated with selective serotonin reuptake inhibitors ( SSRIs ) or the noradrenergic and specific serotonergic antidepressant ( NaSSA ) mirtazapine had an altogether better test performance in comparison with patients receiving tricyclic antidepressants ( TCAs ) . Differences were most pronounced in measures of reactivity , stress tolerance , and selective attention . Statistically significant differences between patients treated with TCAs or the serotonin-norepinephrine reuptake inhibitor ( SNRI ) venlafaxine could not be found . Among the newer antidepressants there is an advantage for patients treated with mirtazapine , especially in tasks with high multi-channel perception and output dem and s. CONCLUSION About 16 % of depressive patients discharged from hospital to outpatient treatment must be considered unfit to drive . In 60 % of the cases , patients performed at a question able level of fitness for driving , and it seems justified to counsel patients individually , taking into account compensational factors . Data point to an advantage for patients treated with SSRIs or mirtazapine when compared with TCAs or venlafaxine . However , causal relationships can not be drawn from our data 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 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 OBJECTIVE Fibromyalgia ( FM ) is a common musculoskeletal condition characterized by widespread pain , tenderness , and a variety of other somatic symptoms . Current treatments are modestly effective . Arguably , the best studied and most effective compounds are tricyclic antidepressants ( TCA ) . Milnacipran , a nontricyclic compound that inhibits the reuptake of both serotonin and norepinephrine , may provide many of the beneficial effects of TCA with a superior side effect profile . METHODS One hundred twenty-five patients with FM were r and omly assigned in a 3:3:2 ratio to receive milnacipran twice daily , milnacipran once daily , or placebo for 3 months in a double-blind dose-escalation trial ; 92 % of twice-daily and 81 % of once-daily participants achieved dose escalation to the target milnacipran dose of 200 mg . RESULTS The primary endpoint was reduction of pain . Both the once- and twice-daily groups showed statistically significant improvements in pain , as well as improvements in global well being , fatigue , and other domains . Response rates for patients receiving milnacipran were equal in patients with and without comorbid depression , but placebo response rates were considerably higher in depressed patients , leading to significantly greater overall efficacy in the nondepressed group . CONCLUSION In this Phase II study , milnacipran led to statistically significant improvements in pain and other symptoms of FM . The effect sizes were equal to those previously found with TCA , and the drug was generally well tolerated Prediction of the response to different classes of antidepressants has been an important matter of concern in the field of psychopharmacology . The purpose of the present study was to investigate whether the G196A polymorphism of the brain-derived neurotrophic factor ( BDNF ) gene is associated with the antidepressant effect of milnacipran , a serotonin norepinephrine reuptake inhibitor , and fluvoxamine , a selective serotonin reuptake inhibitor .  The subjects of our previous study of milnacipran ( n = 80 ) and fluvoxamine ( n = 54 ) were included in the present study . Severity of depression was assessed with the Montgomery Åsberg depression rating scale ( MADRS ) . Assessment s were carried out at baseline and at 1 , 2 , 4 and 6 weeks of treatment . Polymerase chain reaction was used to determine allelic variants . In all subjects receiving milnacipran or fluvoxamine , the G/A genotype of the BDNF G196A polymorphism was associated with a significantly better therapeutic effect in the MADRS scores during this study . When milnacipran and fluvoxamine-treated subjects were analysed independently , the G/A genotype group showed greater reduction of MADRS scores than other genotype groups , irrespective of which antidepressant was administered . These results suggest that the BDNF G196A polymorphism in part determines the antidepressant effect of both milnacipran and fluvoxamine
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 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 .