title: Incidence and duration of antidepressant-induced nausea: duloxetine compared with paroxetine and fluoxetine. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. A comparative clinical trial of fluoxetine, mianserin and placebo in depressed outpatients A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression. Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial Fluoxetine, a Selective Serotonin Uptake Inhibitor, for the Treatment of Outpatients with Major Depression Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group. A double-blind study of paroxetine, fluoxetine, and placebo in outpatients with major depression. Fluoxetine Response: Endpoint vs Pattern Analysis A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. A comparison of fluoxetine, imipramine, and placebo in patients with major depressive disorder. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. The Venlafaxine XR 209 Study Group. A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine. Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled trial of fluoxetine versus placebo. Indirect comparisons of competing interventions. Placebo‐Controlled Trial of Venlafaxine for the Treatment of Major Depression Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. Indirect comparison in evaluating relative efficacy illustrated by antimicrobial prophylaxis in colorectal surgery. A fixed-dose clinical trial of fluoxetine in outpatients with major depression. Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients. A comparison of venlafaxine, trazodone, and placebo in major depression. Venlafaxine in depressed outpatients. A double-blind comparison of fluoxetine, imipramine and placebo in outpatients with major depression.
abstract: OBJECTIVE This analysis assessed the incidence , severity , onset , and duration of nausea among patients with major depressive disorder ( MDD ) treated with the new antidepressant duloxetine .  METHODS Data were pooled from 8 double-blind , r and omized , placebo- and active comparator-controlled trials employing patients with MDD that were su bmi tted to the US Food and Drug Administration to support duloxetine 's new drug application for treatment of MDD . RESULTS The numbers of patients receiving each regimen were as follows : placebo , n = 777 ;  duloxetine 40 mg/d , n = 177 ; duloxetine 60 mg/d , n = 251 ; duloxetine 80 mg/d , n = 363 ; duloxetine 120 mg/d , n = 348 ; paroxetine 20 mg/d , n = 359 ; and fluoxetine 20 mg/d , n = 70 . In acute placebo-controlled trials of duloxetine 40 to 120 mg/d , treatment-emergent nausea was reported by more duloxetine-treated patients than those receiving placebo ( 19.9 % [ 227/1139 ] vs 6.9 % [ 154/777 ] , respectively ; P < 0.001 ) . Among duloxetine-treated patients , the median time to onset of nausea was 1 day , and the median duration of nausea was 7 days . The incidence of nausea was similar to placebo rates after 1 week . In paroxetine-controlled studies , the incidence of treatment-emergent nausea in patients receiving duloxetine did not differ significantly from paroxetine ( 14.4 % vs 12.0 % , respectively ) . In head-to-head studies , the incidence of treatment-emergent nausea with duloxetine did not differ significantly from that with fluoxetine ( 17.1 % vs 15.7 % , respectively ) . Most duloxetine-treated patients reported nausea to be mild ( 52.9 % ) or moderate ( 41.4 % ) . Treatment discontinuation secondary to nausea occurred in more duloxetine-treated patients than those receiving placebo ( 1.4 % [ 16/1139 ] vs 0.1 % [ 1/777 ] , respectively ; P = 0.002 ) . Following abrupt discontinuation after acute treatment , 5.9 % of duloxetine-treated patients exhibited nausea compared with 0.3 % of patients receiving placebo ( P < 0.001 ) . The incidence of treatment-emergent nausea during 6-month continuation of duloxetine treatment ( 80 mg/d , 2.1 % ; 120 mg/d , 1.3 % ) was similar to placebo ( 1.6 % ) . Following abrupt discontinuation after 8 months of treatment , nausea was reported by 1.6 % of patients receiving duloxetine 120 mg/d compared with 0 % for those receiving duloxetine 80 mg/d and 0 % for placebo . CONCLUSIONS Duloxetine induced mild to moderate nausea in a subset of patients with MDD during treatment initiation . Nausea resolved rapidly with continued treatment . The incidence of duloxetine-induced nausea resembled that produced by paroxetine and fluoxetine Pramipexole , a dopamine D2 receptor agonist , was tested in 174 patients with major depression , with or without melancholia and without psychotic features . Three daily dose levels ( 0.375 mg , 1.0 mg , and 5.0 mg ) were compared to fluoxetine ( Prozac ) at 20 mg and placebo in a r and omized , double-blind , parallel-group study . After a 1 week placebo run-in period , patients were treated for 8 weeks , had a post- study follow-up ( week 9 ) , and were evaluated primarily with the Hamilton Psychiatric Rating Scale for Depression ( HAM-D ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , and the Clinician 's Global Impressions-Severity of Illness scale ( CGI-SI ) .  All patients who received one dose of study medication were included in the observed-case analysis ( no missing data were replaced ) . Results indicated that by endpoint ( week 8) , patients receiving pramipexole at the 1.0 mg per day dose had significant improvement over baseline compared to the placebo group by measure of the HAM-D , MADRS , and CGI-SI . Significant improvement in this dose group was seen at other timepoints as well . The most obvious improvement was seen in the pramipexole 5.0 mg group , although a substantial dropout rate for this group precluded statistical tests vs. placebo late in the study . Patients taking fluoxetine also showed significant improvements at endpoint on the MADRS and earlier in the study on the HAM-D. No new or unusual safety concerns were generated during this study . Pramipexole helped safely alleviate the symptoms of depression at 1.0 mg per day and especially in those patients who could tolerate the escalation to 5 mg per day Fluoxetine , a selective serotonin reuptake inhibitor , was compared with mianserin and placebo in a double‐blind study . In total , 81 depressed patients were included . Patients were rated weekly on the Hamilton Depression Rating Scale ( HDRS ) and the Montgomery & Asberg Depression Rating Scale ( MADRS ) . The duration was 6 weeks , and 52 patients completed the study . Significantly more patients on fluoxetine improved than patients on placebo . For mianserin no significant differences were found with either fluoxetine or placebo . Mean HDRS at the end of the study was also statistically significantly lower for fluoxetine , but not for mianserin , than placebo . Subscores of the MADRS showed improved sleep on mianserin at weeks 2 and 3 . Suicidal feelings were reduced to a greater degree on fluoxetine than on mianserin and placebo at weeks 6 and 7 . Fluoxetine  induced weight loss , while patients on mianserin gained weight . Side effects were present in most patients on the two active drugs ; those on fluoxetine experienced nausea and vomiting , and those on mianserin drowsiness BACKGROUND We compared the efficacy and tolerability of venlafaxine XR with that of fluoxetine in a multicenter , r and omized , double-blind , placebo-controlled study in depressed out patients . METHODS Out patients , 18 years and older , who met DSM-IV criteria for major depressive disorder were included ( n = 301 r and omized ; 232 completed ) . Patients were r and omly assigned to eight weeks of treatment with either venlafaxine XR 75 - 225 mg/day ( n = 100 ) , fluoxetine 20 - 60 mg/day ( n = 103 ) , or placebo ( n = 98 ) . The primary efficacy outcome measures were the final ratings on the Hamilton Rating Scale for Depression ( HAM-D21 ) total score , HAM-D21 depressed mood item , Montgomery-Asberg Depression Rating Scale total score , and Clinical Global Impressions Scale . RESULTS Withdrawal from the study due to adverse events occurred in 6 % of the patients in the venlafaxine XR group and 9 % of the patients in the fluoxetine group . Patients treated with venlafaxine XR , but only rarely those treated with fluoxetine , had statistically significant improvements in their depression ratings compared with placebo at the end of the study . The percentages of patients who achieved full remission of their depression ( HAM-D21 total score < or = 7 ) at the end of treatment were 37 % , 22 % and 18 % for the venlafaxine XR , fluoxetine and placebo groups , respectively . The differences in remission rates between venlafaxine XR and the other groups were statistically significant ( p < 0.05 ) . LIMITATIONS The superior remission outcome observed with venlafaxine XR treatment needs to be replicated in additional studies . CONCLUSION Venlafaxine XR is a well-tolerated and efficacious treatment for depression . The results of this study suggest that venlafaxine XR is as well-tolerated as fluoxetine but may have some efficacy advantages over fluoxetine BACKGROUND While emotional symptoms such as depressed mood and loss of interest have traditionally been considered to constitute the core symptoms of major depressive disorder ( MDD ) , the prevalence and importance of painful physical symptoms such as back pain , abdominal pain , and musculoskeletal pain is becoming increasingly appreciated . Antidepressants possessing dual serotonin/norepinephrine ( 5-HT/NE ) reuptake inhibition may demonstrate greater efficacy in the alleviation of pain . The efficacy of duloxetine , a balanced and potent dual reuptake inhibitor of 5-HT and NE , was evaluated within a cohort of depressed patients with associated painful physical symptoms . METHODS In this multicenter , double-blind , placebo-controlled study , patients meeting DSM-IV criteria for MDD were r and omized to receive placebo ( N=141 ) or duloxetine 60 mg QD ( N=141 ) . Patients were required to have a 17-item Hamilton Rating Scale for Depression ( HAMD17 ) total score 15 , a Clinical Global Impression of Severity ( CGI-S ) score 4 , and a Brief Pain Inventory ( BPI ) Average Pain score 2 at baseline . The primary efficacy measure was the BPI Average Pain score , while secondary measures included other BPI items , the HAMD17 total score , CGI-S , the Patient Global Impression of Improvement ( PGI-I ) scale , Visual Analog Scales ( VAS ) for pain , and the Symptom Question naire , Somatic Subscale ( SQSS ) . Safety was evaluated by recording treatment-emergent adverse events ( spontaneously reported ) , vital signs , and laboratory analytes . RESULTS Mean changes in BPI Average Pain for duloxetine- and placebo-treated patients differed significantly at most visits , but only approached significance at endpoint p=0.066 . For the main effect of treatment ( pooling all visits ) , significant advantages for duloxetine-treated patients were found in 10 of 11 assessed BPI pain severity and pain interference items , in addition to VAS overall pain and back pain . Mean changes in pain measures for duloxetine-treated patients corresponded to improvements of 25 - 50 % , compared with 19 - 39 % for placebo . Mean changes at endpoint in depression rating scales ( HAMD17 , CGI-S , PGI-I ) did not differ significantly between duloxetine and placebo treatment groups due to unusually high placebo response . The magnitude of placebo treatment effects ( as measured by HAMD17 total score and Maier subscale ) was significantly smaller in patients with 1 previous depressive episode , compared to those patients with no previous episodes . In patients with 1 previous depressive episode the advantage of duloxetine over placebo was similar to previous studies . Rates of discontinuation due to adverse events were 14.2 % vs. 2.1 % for duloxetine and placebo , respectively p<0.001 . Treatment-emergent adverse events reported at a significantly higher rate by duloxetine-treated patients included nausea , dry mouth , fatigue , and decreased appetite . CONCLUSIONS In this study , duloxetine ( 60 mg QD ) was shown to be an effective treatment for the painful physical symptoms which are frequently associated with depression . Improvements in pain severity occurred independently of changes in depressive symptom severity Existing therapies for major depressive disorder ( MDD ) have either limited efficacy and /or poor tolerability . The present study examined the effects of duloxetine , a potent and balanced dual reuptake inhibitor of serotonin ( 5-HT ) and norepinephrine ( NE ) , in patients with MDD . Adult patients ( N = 267 ) with MDD were r and omly assigned to receive duloxetine ( 60 mg/day ) or placebo in this 9-week , multi-center , double-blind , parallel-group clinical trial . Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale ( HAMD(17 ) ) , Visual Analog Scales ( VAS ) for pain , Clinical Global Impression of Severity ( CGI-S ) , Patient 's Global Impression of Improvement ( PGI-I ) , and Quality of Life in Depression Scale ( QLDS ) . Safety was evaluated by assessing discontinuation rates , adverse event rates , vital signs , and laboratory tests .  Duloxetine ( 60 mg QD ) significantly reduced the HAMD(17 ) total score compared with placebo at the end of 9-week therapy . Estimated probabilities of response and remission were 65 and 43 % , respectively , for duloxetine compared with 42 and 28 % for placebo . Duloxetine also reduced overall pain , back pain , shoulder pain and time in pain while awake significantly more than placebo . Global measures of improvement , including PGI-I and QLDS , were significantly improved by duloxetine compared with placebo .  Discontinuations due to adverse events were more frequent for duloxetine-treated patients ( 12.5 % ) than for placebo-treated patients ( 4.3 % ) . Nausea , dry mouth , dizziness , and constipation were more frequent for duloxetine than placebo . There was no significant incidence of hypertension , nor any other safety issues . Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD BACKGROUND Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin ( 5-HT ) and norepinephrine ( NE ) that has previously been shown to be effective in the acute treatment of major depressive disorder ( MDD ) . This placebo-controlled study assesses the safety and efficacy of duloxetine ( 80 or 120 mg/day ) and paroxetine ( 20 mg QD ) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD . METHOD In this r and omized , double-blind , placebo-controlled trial , adult out patients ( age > or= 18 years ) meeting DSM-IV criteria for MDD received placebo ( n = 93 ) , duloxetine 80 mg/day ( 40 mg BID ; n = 95 ) , duloxetine 120 mg/day ( 60 mg BID ; n = 93 ) , or paroxetine ( 20 mg QD ; n = 86 ) for 8 weeks . Patients who had a > or= 30 % reduction from baseline in HAMD(17 ) total score during the acute phase were allowed to continue on the same ( blinded ) treatment for a 6-month continuation phase . Efficacy measures included the 17-item Hamilton Rating Scale for Depression ( HAMD(17 ) ) total score , HAMD(17 ) subscales , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Hamilton Anxiety Rating Scale ( HAMA ) , Visual Analog Scales ( VAS ) for pain , the Clinical Global Impression of Severity ( CGI-S ) and Patient Global Impression of Improvement ( PGI-I ) scales , the 28-item Somatic Symptom Inventory ( SSI ) , and the Sheehan Disability Scale ( SDS ) . Safety and tolerability were assessed using treatment-emergent adverse events , discontinuations due to adverse events , vital signs , ECGs , laboratory tests , and the Arizona Sexual Experiences Scale ( ASEX ) . RESULTS During the acute phase , patients receiving duloxetine 80 mg/day , duloxetine 120 mg/day , or paroxetine 20 mg QD had significantly greater reductions in HAMD(17 ) total score compared with placebo . Both duloxetine ( 80 and 120 mg/day ) and paroxetine treatment groups had significantly greater improvement , compared with placebo , in MADRS , HAMA , CGI-S , and PGI-I scales . Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day ( 51 % ) , duloxetine 120 mg/day ( 58 % ) , and paroxetine ( 47 % ) were significantly greater compared with those receiving placebo ( 30 % ) . The rate of discontinuation due to adverse events among duloxetine-treated patients ( 80 and 120 mg/day ) did not differ significantly from the rate in the placebo group . Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation ( 80 and 120 mg/day ) , increased sweating ( 120 mg/day ) , and somnolence ( 120 mg/day ) . The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5 % and 62.8 % , respectively . During the 6-month continuation phase , duloxetine ( 80 and 120 mg/day ) and paroxetine treatment groups demonstrated significant improvement in HAMD(17 ) total score . Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection  ( duloxetine 80 mg/day ) , diarrhea  ( duloxetine 120 mg/day ) , and headache  ( paroxetine 20 mg QD ) . CONCLUSION These data support previous findings that duloxetine is safe , efficacious , and well tolerated in the acute treatment of MDD . Furthermore , these data provide the first demonstration under double-blind , placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment In a double-blind , placebo-controlled study the authors found that fluoxetine , a potent and selective inhibitor of serotonin reuptake , was an effective antidepressant in moderately depressed , ambulatory out patients . Typical adverse effects reported by patients treated with fluoxetine  included agitation , nausea , fatigue , and insomnia . Compared to imipramine , fluoxetine was associated with fewer complaints of dry mouth , constipation , and dizziness BACKGROUND We conducted a r and omized , double-blind , placebo-controlled study of the efficacy and safety of once-daily venlafaxine extended release ( XR ) and fluoxetine in out patients with major depression and concomitant anxiety . METHOD Patients who met DSM-IV criteria for major depressive disorder and satisfied eligibility criteria were r and omly assigned to once-daily venlafaxine XR , fluoxetine , or placebo for 12 weeks . Efficacy was assessed with the Hamilton Rating Scale for Depression ( HAM-D ) , Hamilton Rating Scale for Anxiety ( HAM-A ) , and Clinical Global Impressions scale . RESULTS Among 359 out patients , venlafaxine XR and fluoxetine were significantly superior ( p < .05 ) to placebo on the HAM-D total score beginning at week 2 and continuing to the end of the study . Venlafaxine XR but not fluoxetine was significantly better than placebo at week 2 on the HAM-D depressed mood item . At week 12 , the HAM-D response rate was 43 % on placebo , 67 % on venlafaxine XR , and 62 % on fluoxetine ( p < .05 ) . The HAM-D remission rate was significantly higher ( p < .05 ) at weeks 3 , 4 , 6 , 8 , 12 , and final evaluation with venlafaxine XR and at weeks 8 , 12 , and final evaluation with fluoxetine than with placebo . The HAM-A response rate was significantly higher ( p < .05 ) with venlafaxine XR than with fluoxetine at week 12 . The incidence of discontinuation for adverse events was 5 % with placebo , 10 % with venlafaxine XR , and 7 % with fluoxetine . CONCLUSION Once-daily venlafaxine XR is effective and well tolerated for the treatment of major depression and concomitant anxiety and provides evidence for superiority over fluoxetine We report results from a multicenter , placebo-controlled , r and omized , double-blind comparison of the efficacy and tolerability of paroxetine and fluoxetine in out patients with major depression . Across five U.S. sites , 128 out patients ( mean age : 41.3 + /- 12.6 ; 63 men and 65 women ) with moderate to moderately severe major depression without a history of mania or hypomania were recruited between 1993 and 1994 . All 128 patients completed a 1-week placebo washout period , and were then r and omized to 12 weeks of double-blind treatment with paroxetine up to 50 mg/day ( n = 55 ) , fluoxetine up to 80 mg/day ( n = 54 ) , or placebo ( n = 19 ) . Subjects were evaluated weekly for the first 4 weeks , then at weeks 6 , 9 , and 12 with the 21-item HAMD and the Covi Anxiety Scale . There were no significant differences among the three treatment groups in baseline and endpoint depression and anxiety severity , as well as in the degree of depression and anxiety improvement . There were no statistically significant differences in rates or mean numbers of adverse events between paroxetine-treated patients and fluoxetine-treated patients . In summary , our results , although limited by the lack of a significant difference from placebo in treatment outcome , suggest that the SSRIs paroxetine and fluoxetine have comparable antidepressant and antianxiety efficacies among depressed out patients , as well as similar safety and tolerability profiles A 6-week double-blind trial of fluoxetine treatment of unipolar major depressive disorder in 49 patients was evaluated in terms of improvement in the Hamilton Depression Rating Scale ( HDRS ) and Clinical Global Improvement ( CGI ) scores . A relationship was found between change in HDRS ( absolute and percentage decrease from baseline ) and final CGI ratings . However , because of a few placebo-responders , endpoint analysis with both the HDRS and CGI showed no differences between active drug and placebo . Pattern analysis of persistent response did successively separate active drug from placebo ( < 0.05 ) The efficacy of fluoxetine was evaluated in depressed patients in double-blind imipramine- and placebo-controlled clinical trials . Fluoxetine produced greater improvement than placebo on all major efficacy parameters and was comparable to imipramine with respect to the primary indicators of depression . Fluoxetine had significantly less associated anticholinergic effects , dizziness , drowsiness , somatosensory disturbance , and excessive sweating than imipramine . Although nausea occurred more frequently in fluoxetine patients , it was generally mild and well tolerated . A significantly smaller percentage of fluoxetine than imipramine patients terminated therapy because of adverse experiences The efficacy and safety of fluoxetine were compared with those of imipramine and of placebo in a 6-week r and omized double-blind parallel study of patients with major depressive illness .  Mean values for all efficacy measurements were improved over baseline with fluoxetine and imipramine treatment ( p less than .001 ) . More fluoxetine patients completed the study than did  imipramine or placebo patients . Predominant adverse experiences reported by imipramine patients were dry mouth and dizziness/lightheadedness . Predominant adverse experiences reported by fluoxetine patients were drowsiness/sedation and excessive sweating . In a subsequent 48-week open-label study , the predominant adverse experience in the fluoxetine group was excessive sweating and in the imipramine group was still dry mouth . In this study , fluoxetine relieved the symptoms of major depressive illness effectively and significantly better than placebo and was better tolerated than imipramine BACKGROUND Despite treatment advances , major depressive disorder ( MDD ) is still a significant cause of morbidity and mortality . Current therapies frequently fall short of providing full remission . In addition , physical symptoms are commonly seen in MDD patients , increasing overall morbidity and health care utilization . Duloxetine hydrochloride , a dual reuptake inhibitor of serotonin and norepinephrine , was evaluated for efficacy and tolerability/safety in the treatment of MDD and associated physical symptoms . METHOD In this multicenter , double-blind , parallel-group study , adult patients with DSM-IV MDD were r and omly assigned to receive placebo ( N = 122 ) or duloxetine ( 60 mg/day , N = 123 ) for 9 weeks . The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) total score . Painful physical symptoms were assessed using visual analog scales , and global illness and quality of life were evaluated using the Clinical Global Impressions-Severity scale , the Patient Global Impressions-Improvement scale , and the Quality of Life in Depression Scale . Safety and tolerability were determined by monitoring discontinuation rates , adverse events , vital signs , and laboratory results . RESULTS Duloxetine was significantly superior to placebo ( p < .001 ) in reducing HAM-D-17 total scores , starting at week 2 . The estimated probability of remission for duloxetine-treated patients ( 44 % ) was almost 3 times that of placebo patients ( 16 % ) . Duloxetine significantly reduced painful physical symptoms in comparison with placebo .  Discontinuation due to adverse events for duloxetine-treated patients ( 13.8 % ) compared favorably with the rates reported for SSRIs in other studies . Nausea , dry mouth , and somnolence were the most common adverse events ; no significant incidence of hypertension was seen . CONCLUSION Duloxetine , 60 mg/day , is a well-tolerated and effective treatment for MDD that reduces painful physical symptoms . These findings suggest that duloxetine may be a first-line treatment for patients with MDD and associated painful physical symptoms BACKGROUND This was a r and omized , double-blind , placebo-controlled evaluation of the efficacy and safety of once-daily venlafaxine extended release ( XR ) in out- patients with DSM-IV major depression . METHOD Patients were r and omly assigned to venlafaxine XR ( 75 - 225 mg ) once daily or placebo for up to 8 weeks . The primary efficacy variables were the 21-item Hamilton Rating Scale for Depression ( HAM-D ) total score and HAM-D depressed mood item , the Montgomery-Asberg Depression Rating Scale ( MADRS ) total scores , and the Clinical Global Impressions ( CGI ) Severity scale . Data were analyzed on a modified intent-to-treat basis using the last-observation-carried-forward method . RESULTS Venlafaxine XR ( N = 91 ) was significantly more effective than placebo ( N = 100 ) beginning at Week 2 on the CGI Severity scale , at Week 3 on the HAM-D depressed mood item , and at Week 4 on the HAM-D and MADRS ; this superiority was maintained through Week 8 . The most common treatment-emergent adverse events associated with venlafaxine XR were nausea , insomnia , and somnolence . The incidence of nausea was highest during the first week , decreased by 50 % during the second week , and was comparable to that of placebo from Week 3 onward . CONCLUSION These results demonstrate that venlafaxine XR is an effective and well-tolerated treatment of major depression BACKGROUND Many antidepressants are associated with  sexual dysfunction  , a side effect that may lead to patients ' dissatisfaction and noncompliance with treatment . OBJECTIVE This study compared the efficacy , tolerability , and effects on sexual functioning of bupropion sustained release ( bupropion SR ) and the selective serotonin reuptake inhibitor fluoxetine . METHODS In this multicenter , r and omized , double-blind , double-dummy , parallel-group study , patients with recurrent major depression were treated with bupropion SR 150 to 400 mg/d , fluoxetine 20 to 60 mg/d , or placebo for up to 8 weeks .  Depression and sexual-functioning status were assessed by site-specific trained investigators at weekly clinic visits ; tolerability was assessed primarily by monitoring adverse events . RESULTS Four hundred fifty-six patients participated in the study , 150 receiving bupropion SR , 154 fluoxetine , and 152 placebo .  The majority of patients in each group completed the study ( 63 % each , bupropion SR [ n = 94 ] and fluoxetine [ n = 97 ] ; 67 % , placebo [ n = 102 ] ) . Bupropion SR and fluoxetine were similarly effective in the treatment of depressive symptoms . Beginning at week 2 and continuing throughout the study , significantly more fluoxetine-treated patients experienced orgasm dysfunction than did patients receiving bupropion SR or placebo ( P < 0.001 ) ; similar results were seen in patients defined as clinical responders ( > or = 50 % decrease from baseline in 21-item Hamilton Rating Scale for Depression [ HAM-D ] total score ) ( P < 0.001 ) and in those experiencing remission of depression ( HAM-D total score < 8) ( P < 0.05 ) . At various time points , worsened sexual functioning , sexual desire disorder , sexual arousal disorder , and dissatisfaction with sexual functioning in those satistied at baseline were more frequently associated with fluoxetine treatment than with bupropion SR or placebo . Both active treatments were well tolerated . CONCLUSIONS Bupropion SR and fluoxetine were similarly effective and well tolerated in the treatment of depression . Fluoxetine , however , was more frequently associated with sexual dysfunction compared with bupropion SR . Bupropion SR may be an appropriate initial choice for the treatment of depression in patients concerned about sexual functioning Fluoxetine ( 20 mg/day ) and placebo were compared in 89 outpatient men and women with major depression with ( n = 52 ) or without ( n = 37 ) DSM-III-R melancholia in an 8-week double-blind study to determine predictors of treatment response . Fluoxetine was statistically superior to placebo both within the melancholic subtype and in the total patient group ( all measures ) . Response rate and mean decrease in 17-item Hamilton Depression Rating Scale total score approached statistical significance in favor of fluoxetine-treated melancholic patients compared with fluoxetine-treated non-melancholic patients . There were no statistically significant differences between fluoxetine-treated and placebo-treated non-melancholic patients . Results support DSM-III-R melancholia as a predictor of antidepressant response OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin  and  heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful Results are presented of the first double-blind , placebo-controlled trial of a novel antidepressant venlafaxine , which pre clinical ly has demonstrated serotonin , norepinephrine , and dopamine reuptake inhibiting effects . Sixty out patients meeting DSM-III-R criteria for major depression were r and omized to receive 6 weeks of treatment with one of three fixed doses of venlafaxine—25 mg three times a day , 75 mg three times a day , or 125 mg three times a day — or placebo . Significant improvement was observed in depression scores at all doses , with the high dose result ing in earlier improvement , by week 2 . For the combined venlafaxine treatment groups , 68 % achieved a moderate or marked improvement on the Clinical Global Impression scale , compared with only 31 % for the placebo group . Venlafaxine was well tolerated , and nervousness , sweating , and nausea were the only adverse effects observed more frequently with drug compared with placebo In a multicentered study , 372 patients with mild major depressive disorder with a Hamilton Rating Scale for Depression ( HAM-D ) score of 15 to 19 were r and omly assigned to 6 weeks of treatment with placebo or 20 mg , 40 mg , or 60 mg/day of fluoxetine . Patients were rated weekly for improvement and the appearance of side effects . Pattern analysis of treatment response showed more patients in the active drug treatment groups having a persistent or a delayed persistent response , the types of response specifically associated with active treatment . Analyses of mean changes in treatment measures showed little difference among treatment groups . This may be explained in part by different distributions in outcome , placebo patients having had a higher frequency of mild improvement with fewer negative and very positive outcomes . Response rate analyses favor the active treatments numerically , but only one of the comparisons is statistically significant . These findings suggest a specific role for fluoxetine treatment in mildly depressed patients who do not respond promptly or who respond inconsistently to nonspecific treatment 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 This paper aims to explore the potential usefulness and limitations of indirect comparisons in evaluating the relative efficacy of interventions . From a systematic review of antimicrobial prophylaxis in colorectal surgery , we identified 11 sets of r and omized trials that can be used to compare antibiotics both directly and indirectly . The discrepancy between the direct and the indirect comparison is defined as the absolute value of difference in log odds ratio . The adjusted indirect comparison has the advantages that the prognostic factors of participants in different trials can be partially taken into account and more uncertainty be incorporated into its result by providing a wider confidence interval . However , considerable discrepancies exist between the direct and the adjusted indirect comparisons . When there is no direct comparison , the adjusted indirect method may be used to obtain some evidence about the relative efficacy of competing interventions , although such indirect results should be interpreted with great caution . Further empirical and method ologic research is needed to explore the validity and generalizability of the adjusted indirect comparison for evaluating different interventions Fixed daily doses of 20 mg , 40 mg , or 60 mg of fluoxetine , a highly specific serotonin reuptake inhibitor , were given to 84 depressed out patients in a double-blind , placebo-controlled , r and omized 6-week trial . The 20-mg dose produced improvement of depression in the moderate-severe depression group as expressed in significant reductions of scores on the Hamilton Rating Scale for Depression ( p greater than or equal to .007 ) and the Patient Global Impressions scale ( p greater than or equal to .011 ) , and the 20-mg dose caused fewer side effects than did the higher doses . A mildly depressed group of patients showed no improvement at any dose level of fluoxetine BACKGROUND Venlafaxine is a new phenylethylamine antidepressant that exhibits monoamine reuptake inhibition . The current study evaluates the efficacy of venlafaxine compared to that of imipramine in out patients suffering from major depression of moderate-to-marked severity . METHOD We conducted a double-blind , placebo-controlled , 6-week treatment study of 224 out patients who met DSM-III-R criteria for major depression , and who had a score of at least 20 on the 21-item Hamilton Rating Scale for Depression ( HAM-D ) .  Dosage was flexible and administered on a three-times-a-day schedule , with a mean maximum daily dose of 182 mg for venlafaxine and 176 mg for imipramine . RESULTS For patients completing 6 weeks of treatment with venlafaxine , the HAM-D total score improved by 16.6 + /- 4.9 points . Improvement at 6 weeks was 13.6 + /- 6.3 points for patients treated with imipramine and 10.6 + /- 7.8 points for patients treated with placebo ( p < .05 for active drug vs. placebo ) . Ninety percent of venlafaxine completers were rated as " much " or " very much " improved on the Clinical Global Impression-Improvement scale , compared to 79 % treated with imipramine and 53 % treated with placebo ( p < .05 ) . An endpoint analysis , where the last scores of patients who dropped out were carried forward to subsequent visits , showed significant efficacy only for venlafaxine and not imipramine , probably because of the higher attrition for the latter drug . Overall , both venlafaxine and imipramine were well-tolerated , with venlafaxine having a somewhat lower attrition rate due to adverse effects than imipramine ( 16 % vs. 25 % ) . CONCLUSION These results , together with those of previously reported studies , suggest that venlafaxine has antidepressant efficacy comparable to that provided by available antidepressants A double-blind , placebo-controlled trial was undertaken to compare the safety and efficacy of venlafaxine and trazodone in patients with major depression . Two hundred twenty-five patients entered an initial 6-week treatment phase , and 149 completed it . Ninety-six patients who were responders continued in a 1-year , double-blind , long-term phase during which they received the same medication and doses they had during the short-term phase . Both active treatments were significantly more effective than placebo on some measures during the short-term study , but venlafaxine produced more improvement in the cognitive disturbance and retardation factors on the Hamilton Rating Scale for Depression .  Trazodone was more effective against the sleep disturbance factor . Patients on venlafaxine were most likely to enter the long-term phase and to remain in the trial longest . The side effect profiles of the three treatment groups were compared . Venlafaxine was most likely to cause nausea , whereas trazodone was associated with the most dizziness and somnolence Venlafaxine is a structurally novel compound with a biochemical and pharmacological profile suggesting antidepressant properties . We report the results of a Phase II , double-blind , placebo-controlled clinical trial assessing the efficacy and safety of venlafaxine in a sample of 93 depressed out patients .  Venlafaxine doses of 25 mg t.i.d . , 75 mg t.i.d . , and 125 mg t.i.d . were compared to placebo . Patients receiving venlafaxine showed a significantly greater improvement in their mood symptoms compared to those receiving placebo . Venlafaxine was well tolerated and the most common side effect was nausea . There was some evidence to suggest that venlafaxine may have antidepressant activity within the first 2 weeks of treatment Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 out patients with DSM-III major depression , of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy . Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo . Both imipramine and fluoxetine were significantly superior to placebo on most measures . There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures . Fluoxetine was generally well tolerated . Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant . The results support previous studies which suggest fluoxetine 's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs
target: Conclusion Fluoxetine was not statistically different in either tolerability or efficacy when compared with duloxetine .
  Venlafaxine was significantly superior to duloxetine in all analyses except dropout rate .
  In the absence of relevant data from head-to-head comparison trials , results suggest that venlafaxine is superior compared with duloxetine and that duloxetine does not differentiate from fluoxetine
background: Background Data comparing duloxetine with existing antidepressant treatments is limited .
  A comparison of duloxetine with fluoxetine has been performed but no comparison with venlafaxine , the other antidepressant in the same therapeutic class with a significant market share , has been undertaken .
  In the absence of relevant data to assess the place that duloxetine should occupy in the therapeutic arsenal , indirect comparisons are the most rigorous way to go .
  We conducted a systematic review of the efficacy of duloxetine , fluoxetine and venlafaxine versus placebo in the treatment of Major Depressive Disorder ( MDD ) , and performed indirect comparisons through meta-regressions .