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A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression. A comparison of paroxetine, imipramine and placebo in depressed out-patients. Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder A double‐blind comparison of paroxetine and placebo in the treatment of depressed patients in a psychiatric outpatient clinic Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. Escitalopram in the acute treatment of depressed patients aged 60 years or older. Fluoxetine treatment of cocaine-dependent patients with major depressive disorder. The functional neuroanatomy of the placebo effect. 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Double-blind comparison of citalopram and placebo in depressed outpatients with melancholia. Analysis of the Hamilton Depression Rating Scale factors from a double‐blind, placebo‐controlled trial of fluoxetine in geriatric major depression Sexual dysfunction associated with the treatment of depression: A placebo-controlled comparison of bupropion sustained release and sertraline treatment Clinical Features and Efficacy of Escitalopram Treatment for Geriatric Depression Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group. Fluoxetine treatment of depressive disorders in methadone-maintained opioid addicts. Fluvoxamine in the treatment of the older depressed patient; double-blind, placebo-controlled data. Fluvoxamine maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients. A double-blind study of paroxetine, fluoxetine, and placebo in outpatients with major depression. Combining escitalopram with gaboxadol provides no additional benefit in the treatment of patients with severe major depressive disorder. Multicenter, placebo-controlled, fixed-dose study of citalopram in moderate-to-severe depression. What does the HAMD mean? Effect of fluoxetine on noradrenergic mediated growth hormone release: A double blind, placebo-controlled study Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Efficacy of controlled-release paroxetine in the treatment of late-life depression. Low doses of controlled-release paroxetine in the treatment of late-life depression: a randomized, placebo-controlled trial. Results From 2 Randomized, Double-Blind, Placebo-Controlled Studies of the Novel NK1 Receptor Antagonist Casopitant in Patients With Major Depressive Disorder A comparison of fluoxetine, imipramine, and placebo in patients with major depressive disorder. Short-term dynamic psychotherapy versus pharmacotherapy for major depressive disorder: a randomized, placebo-controlled trial. Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. Exercise fails to improve neurocognition in depressed middle-aged and older adults. 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A placebo-controlled inpatient comparison of fluvoxamine maleate and imipramine in major depression. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. A Randomized Trial of Combined Citalopram and Naltrexone for Nonabstinent Outpatients With Co-Occurring Alcohol Dependence and Major Depression A placebo-controlled trial of paroxetine in the treatment of major depression. Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. Paroxetine in major depression: a double-blind trial with imipramine and placebo. A double-blind, placebo-controlled study of paroxetine in depressed outpatients. The predictive value of the dexamethasone suppression test. A placebo-controlled study. A double‐blind, placebo‐controlled comparison of sertraline and dothiepin in the treatment of major depression in general practice A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. Placebo-controlled study of sertraline in depressed recently abstinent alcoholics A double-blind, placebo-controlled trial of fluvoxamine versus imipramine in outpatients with major depression. Clinical Efficacy of Sertraline Alone and Augmented With Gabapentin in Recently Abstinent Cocaine-Dependent Patients With Depressive Symptoms A fixed-dose clinical trial of fluoxetine in outpatients with major depression. A 6-week, double-blind trial of paroxetine, imipramine, and placebo in depressed outpatients. A double-blind comparison of paroxetine, imipramine, and placebo in major depression. Flibanserin: initial evidence of efficacy on sexual dysfunction, in patients with major depressive disorder. Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences. Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia A double-blind comparison of fluoxetine, imipramine and placebo in outpatients with major depression. The efficacy and safety of paroxetine compared with placebo in outpatients with major depression. Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder Placebo-controlled inpatient comparison of venlafaxine and fluoxetine for the treatment of major depression with melancholic features Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials
abstract: The current study sought to test the efficacy and safety of the novel selective norepinephrine reuptake inhibitor LY2216684 compared to placebo in patients with major depressive disorder ( MDD ) .  Escitalopram was used as a control for assay sensitivity . Adult out patients with MDD , confirmed at screening by the Mini International Neuropsychiatric Interview , a Self-Rated Quick Inventory of Depressive Symptomatology ( QIDS-SR ) score of at least 12 and a Clinical Global Impression-Severity Score of at least 4 , were r and omly assigned to LY2216684 ( N=269 ) , placebo ( N=138 ) , or escitalopram ( N=62 ) .  Efficacy , safety , and tolerability outcomes were compared during 8 weeks of double-blind treatment . LY2216684 plasma concentrations were measured . LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale ( HAM-D(17 ) ) total score . Escitalopram demonstrated significant improvement compared to placebo on the HAM-D(17 ) total score , suggesting adequate assay sensitivity . Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo .  Headache , nausea , constipation , dry mouth , and insomnia were the most frequently reported adverse events in the LY2216684 group . A 3 - 6 beats per minute mean increase from baseline in pulse rate was observed in the LY2216684 group .  LY2216684 plasma concentrations increased as the dose increased from 3 mg to 12 mg . The results of this initial investigation of LY2216684 's efficacy suggest that it may have antidepressant potential . More definitive data to confirm this is necessary . Its safety profile does not preclude further clinical development Objectives To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate ( quetiapine XR ) monotherapy in patients with major depressive disorder ( MDD ) . Patients and methods This was a 10-week ( 8-week active treatment/2-week post-treatment ) r and omized , double-blind , placebo- and active-controlled study ( D1448C00004 ) . Patients received quetiapine XR 150 mg/day , escitalopram 10 mg/day , or placebo ; patients with an inadequate response ( < 20 % improvement in Montgomery – Åsberg Depression Rating Scale [ MADRS ] total score ) at week two received double-dose treatment . The primary end point was week eight change from r and omization in MADRS total score . Secondary end points included MADRS response ( ≥50 % improvement ) and remission ( score ≤8 ) ; Hamilton Rating Scale for Depression total and item 1 ; Hamilton Rating Scale for Anxiety total , psychic , and somatic ; Clinical Global Impressions – Severity of Illness total ; Pittsburgh Sleep Quality Index ( PSQI ) global ; and Quality of Life Enjoyment and Satisfaction Question naire – Short Form percentage maximum total scores . Tolerability was assessed throughout . Results A total of 471 patients was r and omized . No significant improvements in MADRS total score were observed at week eight ( last observation carried forward ) with either active treatment ( quetiapine XR , −17.21 [ P=0.174 ] ; escitalopram , −16.73 [ P=0.346 ] ) versus placebo ( −15.61 ) . There were no significant differences in secondary end points versus placebo , with the exception of week-eight change in PSQI global score  ( quetiapine XR , −4.96 [ P<0.01 ] versus placebo , −3.37 ) . Mixed-model repeated- measures analysis of observed-case data suggested that the primary analysis may not be robust . Most commonly reported adverse events included dry mouth , somnolence , and dizziness for quetiapine XR , and headache and nausea for escitalopram . Conclusion In this study , neither quetiapine XR ( 150/300 mg/day ) nor escitalopram ( 10/20 mg/day ) showed significant separation from placebo . Both compounds have been shown previously to be effective in the treatment of MDD ; possible reasons for this failed study are discussed . Quetiapine XR was generally well tolerated , with a profile similar to that reported previously This study was aim ed at resolving the time course of clinical action of antidepressants ( ADs ) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients . The first goal was to identify , during the first 2 weeks of treatment , the onset of clinical actions of the selective serotonin reuptake inhibitor ( SSRI ) , paroxetine , and the selective noradrenergic reuptake inhibitor , desipramine ( DMI ) . The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients . The design was a r and omized , parallel group , placebo-controlled , double-blind study for 6 weeks of treatment following a 1-week washout period . The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity . The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days , averaged 13 days for paroxetine , and was 16–42 days for placebo . Furthermore , as hypothesized , the different types of ADs initially impacted different behavioral aspects of the disorder . After 1 week of treatment , DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo , and this difference persisted at the second week of treatment . Early improvement in depressed mood – motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not . Paroxetine initially reduced anxiety more in responders than in nonresponders , and by the second week , significantly improved depressed mood and distressed expression in responders to a greater extent . Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement . Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs , results that could eventually be applied directly to clinical practice OBJECTIVE Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and safety in the treatment of major depressive disorder ( MDD ) . METHODS In this r and omized , double-blind trial , patients age > or = 18 meeting DSM-IV criteria for MDD were r and omized to placebo ( N=99 ) , duloxetine 80 mg/day ( N=93 ) , duloxetine 120 mg/day ( N=103 ) , or paroxetine 20 mg/day ( N=97 ) . The primary outcome measure was mean change from baseline in the 17-item Hamilton rating scale for depression ( HAMD(17 ) ) total score after 8 weeks of treatment ; a number of secondary efficacy measures also were assessed . Safety and tolerability were assessed via collection and analysis of treatment-emergent adverse events ( TEAEs ) , vital signs , and weight . The Arizona sexual experiences scale was used to assess sexual functioning . Patients who had a > or = 30 % reduction from baseline in the HAMD(17 ) total score  at the end of the acute phase entered a 6-month continuation phase where they remained on the same treatment as they had taken during the acute phase ; efficacy and safety/tolerability outcomes were assessed during continuation treatment . RESULTS More than 87 % of patients completed the acute phase in each treatment group . Duloxetine-treated patients ( both doses ) showed significantly greater improvement ( P<0.05 ) in the HAMD(17 ) total score at week 8 compared with placebo . Paroxetine was not significantly different from placebo ( P=0.089 ) on mean change on the HAMD(17 ) .  Duloxetine 120 mg/day also showed significant improvement on most secondary efficacy measures ( six of nine ) compared with placebo while duloxetine 80 mg/day ( three of nine ) and paroxetine ( three of nine ) were significantly superior to placebo on fewer secondary measures . HAMD(17 ) mean change data from this study and an identical sister study were pooled as defined a priori for the purpose s of performing a non-inferiority test versus paroxetine . Both duloxetine doses met statistical criteria for non-inferiority to paroxetine .  TEAE reporting rates were low in all treatment groups and no deaths occurred in the acute or continuation phases . CONCLUSIONS The efficacy of duloxetine at doses of 80 and 120 mg/day in the treatment of MDD was demonstrated . Tolerability , as measured by TEAEs , and safety were similar to paroxetine 20 mg/day and consistent with previous published data on duloxetine in the treatment of MDD 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 Previous studies indicate that selective serotonin reuptake inhibitors ( SSRIs ) , including fluoxetine , fluvoxamine , citalopram and paroxetine , suppress rapid eye movement sleep , and increased nocturnal arousals . There has been no published report of the impact of sertraline on the sleep of depressed patients . This study examines such effects . Forty-seven patients with major depressive disorder , r and omized to double-blind treatment with sertraline or placebo , completed sleep studies before and after 12 weeks of pharmacotherapy . Groups were compared using multivariate analyses of covariance and /or analyses of covariance to examine 4 empirically defined sets of sleep measures . Compared to the placebo-treated group , patients who received sertraline experienced an increase in delta wave sleep in the first sleep cycle and prolonged rapid eye movement ( REM ) sleep latency . Although , sertraline therapy decreased the average number of REM periods ( from 3.86 to 2.40 ) , the activity of both REM period 1 and REM period 2 was significantly increased . Aside from an increase in sleep latency , sertraline therapy was not associated with a worsening of measures of sleep continuity . There was also no significant difference between the groups on a measure of subjective sleepiness . These findings are both similar and different from those observed in previous studies of other SSRIs . The increase in delta sleep ratio and consolidation of REM sleep may have some other clinical implication s. However , the generalizability of these findings is limited because of a number of reasons . Further studies are needed to examine the effects of SSRIs in acute treatment of depressed patients with severe insomnia , and the relationship of acute changes and relapse prevention of recurrent depression BACKGROUND Previous comparative studies of the selective serotonin reuptake inhibitors ( SSRIs ) have rarely included a placebo control group and have rarely demonstrated significant between-group differences . The study reported on here was a placebo-controlled comparison of the antidepressant effects of two SSRIs , citalopram and sertraline . METHODS Three hundred twenty-three patients with DSM-IV-defined major depressive disorder were r and omized to 24 weeks of double-blind treatment with citalopram ( 20 - 60 mg/day ) , sertraline ( 50 - 150 mg/day ) , or a placebo . The primary efficacy measure was the Hamilton Depression Rating Scale ( HAMD ) and the primary statistical analysis was an analysis of variance comparing the change from baseline to the last observation carried forward in each treatment group . RESULTS Both citalopram and sertraline produced significantly greater improvement than placebo on the HAMD , the Montgomery-Asberg Depression Rating Scale , and the Clinical Global Impression Scale . Significant improvement was observed at earlier timepoints in the citalopram group than the sertraline group ; however , sertraline treatment was associated with increased gastrointestinal side effects and a tendency toward early discontinuation , and analyses that excluded early dropouts revealed similar acute efficacy for the two active treatments . The Hamilton Anxiety Scale demonstrated a significant anxiolytic effect of citalopram , but not sertraline , relative to placebo . CONCLUSIONS This study confirms the antidepressant efficacy of two SSRIs , citalopram and sertraline . It is hypothesized that the more consistent evidence of antidepressant activity that was observed early in treatment in the citalopram group was related to more pronounced antianxiety effects and better tolerability upon initiation of therapy In a placebo-controlled , double-blind study of 91 out-patient depressives , the anti-depressant effect of fluvoxamine , a selective serotonin uptake inhibitor was compared to that of imipramine . Overall drug effects were relatively weak but analyses in selected sub-groups showed both active drugs superior to placebo .  Effects of fluvoxamine were more marked in non-situational depressives and it did not improve sleep while effects of imipramine were more marked in retarded depressives and on retardation ratings , suggesting that fluvoxamine may have a different pattern of clinical effects . Side effects of Fluvoxamine were predominantly gastrointestinal and it did not produce postural hypotension or anticholinergic side-effects 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 To compare the safety and antidepressant efficacy of paroxetine , imipramine , and placebo , data from six centres using the same protocol were pooled . A double-blind parallel-group design was used , with therapy lasting six weeks . From week 2 onwards , both the 240 paroxetine-treated and the 237 imipramine-treated patients were significantly different from the 240 placebo-treated patients , but no different from each other . Side-effects with paroxetine were less likely to lead to drop-out than with imipramine . Paroxetine had a possible earlier antidepressant effect than imipramine , and a possible earlier beneficial effect on anxiety symptoms associated with depression Objective : To assess whether patients receiving aerobic exercise training  performed either at home or in a supervised group setting achieve reductions in depression comparable to st and ard antidepressant medication ( sertraline ) and greater reductions in depression compared to placebo controls . Methods : Between October 2000 and November 2005 , we performed a prospect i ve , r and omized controlled trial ( SMILE study ) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital . A total of 202 adults ( 153 women ; 49 men ) diagnosed with major depression were assigned r and omly to one of four conditions : supervised exercise in a group setting ; home-based exercise ; antidepressant medication ( sertraline , 50–200 mg daily ) ; or placebo pill for 16 weeks . Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale ( HAM-D ) . Results : After 4 months of treatment , 41 % of the participants achieved remission , defined as no longer meeting the criteria for major depressive disorder ( MDD ) and a HAM-D score of < 8 . Patients receiving active treatments tended to have higher remission rates than the placebo controls : supervised exercise = 45 % ; home-based exercise = 40 % ; medication = 47 % ; placebo = 31 % ( p = .057 ) . All treatment groups had lower HAM-D scores after treatment ; scores for the active treatment groups were not significantly different from the placebo group ( p = .23 ) . Conclusions : The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD . Placebo response rates were high , suggesting that a considerable portion of the therapeutic response is determined by patient expectations , ongoing symptom monitoring , attention , and other nonspecific factors . BDI = Beck Depression Inventory ; CI = confidence interval ; HAM-D = Hamilton Depression Rating Scale ; ITT = intention-to-treat ; MDD = major depressive disorder ; SD = st and ard deviation ; SSRIs = selective serotonin reuptake inhibitors ; TSH = thyroid stimulating hormone Methods After initial screening and a seven-day washout period , in the case of patients who had received previous antidepressant medication , 47 adult patients who fulfiIled Feighner ’s criteria for the diagnosis of depression ( 1 ) and had a Hamilton Depression Rating Scale ( HAMD ) total score ( 21-item ) of 18 or more were r and omized to treatment with either paroxetine or placebo . The intended duration of double-blind treatment was four weeks . Paroxetine at a single daily dose of 30 mg or matched placebo was administered at night . No concomitant psychotropic medication other than triazolam or flunitrazepam as a hypnotic was permitted . Patients attended for review on days 7,14 , and 28 . The measures of severity of depression were the HAMD scale total score ( 21-item ) , the Beck Depression Inventory ( BDI ) , the Visual Analogue Scale ( VAS ) , and the Clinical Global Impression ( CGI ) of severity of illness . Assessment of tolerability was based on reports of adverse experiences , both spontaneously reported and elicited in response to asideeffect symptom checklist , physical examination , vital signs , and laboratory investigations CONTEXT Extracts of Hypericum perforatum ( St John 's wort ) are widely used for the treatment of depression of varying severity . Their efficacy in major depressive disorder , however , has not been conclusively demonstrated . OBJECTIVE To test the efficacy and safety of a well-characterized H perforatum extract ( LI-160 ) in major depressive disorder . DESIGN AND SETTING Double-blind , r and omized , placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States . PARTICIPANTS Adult out patients ( n = 340 ) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale ( HAM-D ) of at least 20 . INTERVENTIONS Patients were r and omly assigned to receive H perforatum , placebo , or sertraline ( as an active comparator ) for 8 weeks . Based on clinical response , the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg . Responders at week 8 could continue blinded treatment for another 18 weeks . MAIN OUTCOME MEASURES Change in the HAM-D total score from baseline to 8 weeks ; rates of full response , determined by the HAM-D and Clinical Global Impressions ( CGI ) scores . RESULTS On the 2 primary outcome measures , neither sertraline nor H perforatum was significantly different from placebo . The r and om regression parameter estimate for mean ( SE ) change in HAM-D total score from baseline to week 8 ( with a greater decline indicating more improvement ) was -9.20 ( 0.67 ) ( 95 % confidence interval [ CI ] , -10.51 to -7.89 ) for placebo vs -8.68 ( 0.68 ) ( 95 % CI , -10.01 to -7.35 ) for H perforatum ( P = .59 ) and -10.53 ( 0.72 ) ( 95 % CI , -11.94 to -9.12 ) for sertraline ( P = .18 ) . Full response occurred in 31.9 % of the placebo-treated patients vs 23.9 % of the H perforatum-treated patients ( P = .21 ) and 24.8 % of sertraline-treated patients ( P = .26 ) . Sertraline was better than placebo on the CGI improvement scale ( P = .02 ) , which was a secondary measure in this study . Adverse-effect profiles for H perforatum and sertraline differed relative to placebo . CONCLUSION This study fails to support the efficacy of H perforatum in moderately severe major depression . The result may be due to low assay sensitivity of the trial , but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy OBJECTIVE The present study examined the efficacy and tolerability of acute escitalopram treatment in depressed patients aged 60 years or older . METHODS Patients aged > or = 60 years with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition major depressive disorder were r and omized to 12 weeks of double-blind , flexible-dose treatment with escitalopram ( 10 - 20 mg/day ; N = 130 ) or placebo ( N = 134 ) . The prospect ively defined primary efficacy end point was change from baseline to week 12 in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score using the last observation carried forward approach . RESULTS A total of 109 ( 81 % ) patients in the placebo group and 96 ( 74 % ) patients in the escitalopram group completed treatment . Mean age in both groups was approximately 68 years . Mean baseline MADRS scores were 28.4 and 29.4 for the placebo and escitalopram treatment groups , respectively . Escitalopram did not achieve statistical significance compared with placebo in change from baseline on the MADRS ( least square mean difference : -1.34 ; last observation carried forward ) . Discontinuation rates result ing from adverse events were 6 % for placebo and 11 % for escitalopram . Treatment-emergent adverse events reported by > 10 % of patients in the escitalopram group were headache , nausea , diarrhea , and dry mouth . CONCLUSIONS Escitalopram treatment was not significantly different from placebo treatment on the primary efficacy measure , change from baseline to week 12 in MADRS . In patients aged 60 years or older with major depression , acute escitalopram treatment appeared to be well tolerated Sixty-eight male and female individuals with both DSM-IV diagnoses of cocaine dependence and major depressive disorder were r and omly assigned to one of two medication conditions ( placebo vs. 40 mg per day ) as part of a double-blind , placebo-controlled clinical efficacy trial of fluoxetine for the treatment of this dual diagnosis . During the 12-week outpatient treatment phase all participants also received individual cognitive-behavioral psychotherapy targeting both cocaine use and depression . Depressive symptoms remitted as a function of time in treatment , with no significant medication effects found . Fewer cocaine positive urines were found during the first 6 weeks of treatment in the placebo group compared with the 40-mg group . Cocaine use and depressive symptoms during treatment were significantly correlated . The findings fail to support the role of fluoxetine for treatment of cocaine use and depression in dually-diagnosed patients OBJECTIVE Administration of placebo can result in a clinical response indistinguishable from that seen with active antidepressant treatment . Functional brain correlates of this phenomenon have not been fully characterized . METHOD Changes in brain glucose metabolism were measured by using positron emission tomography in hospitalized men with unipolar depression who were administered placebo  as part of an inpatient imaging study of fluoxetine . Common and unique response effects to administration of placebo or fluoxetine were assessed after a 6-week , double-blind trial . RESULTS Placebo response was associated with regional metabolic increases involving the prefrontal , anterior cingulate , premotor , parietal , posterior insula , and posterior cingulate and metabolic decreases involving the subgenual cingulate , parahippocampus , and thalamus . Regions of change overlapped those seen in responders administered active fluoxetine . Fluoxetine response , however , was associated with additional subcortical and limbic changes in the brainstem , striatum , anterior insula , and hippocampus , sources of efferent input to the response-specific regions identified with both agents . CONCLUSIONS The common pattern of cortical glucose metabolism increases and limbic-paralimbic metabolism decreases in placebo and fluoxetine responders suggests that facilitation of these changes may be necessary for depression remission , regardless of treatment modality . Clinical improvement in the group receiving placebo as part of an inpatient study is consistent with the well-recognized effect that altering the therapeutic environment may significantly contribute to reducing clinical symptoms . The additional subcortical and limbic metabolism decreases seen uniquely in fluoxetine responders may convey additional advantage in maintaining long-term clinical response and in relapse prevention Background Antidepressant drugs such as selective serotonin re-uptake inhibitors ( SSRIs ) remediate negative biases in emotional processing in depressed patients in both behavioural and neural outcome measures . However , it is not clear if these effects occur before , or as a consequence of , changes in clinical state . Method In the present study , we investigated the effects of short-term SSRI treatment in depressed patients on the neural response to fearful faces prior to clinical improvement in mood . Altogether , 42 unmedicated depressed patients received SSRI treatment ( 10 mg escitalopram daily ) or placebo in a r and omised , parallel-group design . The neural response to fearful and happy faces was measured on day 7 of treatment using functional magnetic resonance imaging .  A group of healthy controls was imaged in the same way . Results Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls . However , this response was normalised in patients receiving 7 days treatment with escitalopram . There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo-treated patients . Conclusions Our results suggest that short-term SSRI treatment in depressed patients remediates amygdala hyperactivity in response to negative emotional stimuli prior to clinical improvement in depressed mood . This supports the hypothesis that the clinical effects of antidepressant treatment may be mediated in part through early changes in emotional processing . Further studies will be needed to show if these early effects of antidepressant medication predict eventual clinical outcome Rationale High placebo response rates are a confound in treatment trials for major depressive disorder ( MDD ) . A method for prospect i ve identification of placebo responders could enhance the efficiency of clinical trials . Objective The objective was to identify the neurophysiological , symptomatic , and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD . Methods Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24 ) or venlafaxine ( n=27 ) versus placebo . All subjects underwent pretreatment assessment with  quantitative electroencephalographic  ( QEEG ) power and cordance , as well as symptom ratings and  neuropsychological testing . After a 1-week single-blind placebo lead-in , subjects were r and omized to double-blind placebo controlled treatment with a medication or placebo . At the end of 8 weeks , the blind was broken and treatment response assessed . Response was defined by a final Hamilton Depression Rating Scale score of ≤10 . Results Of the medication-treated and placebo-treated subjects , 52 % ( 13/25 ) and 38 % ( 10/26 ) responded . Placebo responders had lower pretreatment fronto central cordance in the theta frequency b and than all other subjects ( P<0.006 ) and medication responders in particular ( P<0.004 ) . Placebo responders also had faster cognitive processing time , as assessed by neuropsychological testing , and lower reporting of late insomnia ( P<0.03 ) . Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression , in which these three pretreatment measures accurately identified 97.6 % of eventual placebo responders . Conclusions These findings suggest that combined clinical , neurophysiological , and cognitive assessment s of prospect i ve subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response  to  placebo . Prospect i ve validation of these results in a larger , independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospect i ve identification of placebo responders Escitalopram , a selective serotonin reuptake inhibitor ( SSRI ) , was compared to placebo in a study of patients with major depressive disorder ( DSM-IV ) who had baseline Montgomery – Åsberg Depression Rating Scale ( MADRS ) total scores ≥22 and ≤40 . After a 1-week , single-blind placebo period , patients were r and omized to receive escitalopram 10 mg/day  ( n = 191 ) or placebo  ( n = 189 ) in an 8-week , double-blind period . The primary efficacy analysis of adjusted mean change in MADRS total score from baseline showed a statistically significantly larger effect for escitalopram than for placebo with a treatment difference at week 8 ( last observation carried forward , LOCF ) of 2.7 points ( SE 0.85;P = 0.002 ) . In further by-week efficacy analyses , the effect of escitalopram was consistently larger than that of placebo ( P < 0.05 ) beginning at week 1 ( Clinical Global Impression – Improvement score ) , week 2 ( MADRS score ) or week 3 ( Clinical Global Impression – Severity score ) . Escitalopram was very well tolerated with a low overall withdrawal rate similar to that for placebo . Nausea was the only adverse event reported significantly more in escitalopram-treated patients than in placebo-treated patients , although it was infrequent and transient . Escitalopram 10 mg/day had a statistically significantly better antidepressant effect than placebo as early as week 1 , and was safe and very well tolerated GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin , norepinephrine , and dopamine transporters . Two r and omized , placebo- and active-controlled , double-blind studies examined the efficacy and safety of GSK372475 in out patients ( aged 18–64 years ) with a diagnosis of major depressive episode associated with major depressive disorder ( MDD ) . Patients were r and omized 1:1:1 to placebo , GSK372475 ( 1–2 mg/d ) , or active control ( Study 1 :  venlafaxine XR 150–225 mg/d ; Study 2 : paroxetine 20–30 mg/d ) .  GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints ( six-item Bech scale , IDS-Clinician Rated , MADRS ) in either study . Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints . The most common adverse effects ( AEs ) with GSK372475  were dry mouth , headache , insomnia , and nausea . AEs were more frequent for GSK372475 versus placebo for sleep , anxiety-related , gastrointestinal , and tachycardia events . Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups . Completion rates were lower for GSK372475 ( 49 % , 58 % ) compared with placebo ( 67 % , 74 % ) , venlafaxine XR ( 63 % ) , or paroxetine ( 77 % ) . GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies BACKGROUND There is substantial evidence that antidepressant medications treat moderate to severe depression effectively , but there is less data on cognitive therapy 's effects in this population . OBJECTIVE To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial . DESIGN R and om assignment to one of the following : 16 weeks of medications ( n = 120 ) , 16 weeks of cognitive therapy ( n = 60 ) , or 8 weeks of pill placebo ( n = 60 ) . SETTING Research clinics at the University of Pennsylvania , Philadelphia , and V and erbilt University , Nashville , Tenn. PATIENTS Two hundred forty out patients , aged 18 to 70 years , with moderate to severe major depressive disorder . INTERVENTIONS Some study subjects received paroxetine , up to 50 mg daily , augmented by lithium carbonate or desipramine hydrochloride if necessary ; others received individual cognitive therapy . MAIN OUTCOME MEASURE The Hamilton Depression Rating Scale provided continuous severity scores and allowed for design ations of response and remission . RESULTS At 8 weeks , response rates in medications ( 50 % ) and cognitive therapy ( 43 % ) groups were both superior to the placebo ( 25 % ) group . Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo , each with a medium effect size . The advantage was significant for medication relative to placebo , and at the level of a nonsignificant trend for cognitive therapy relative to placebo . At 16 weeks , response rates were 58 % in each of the active conditions ; remission rates were 46 % for medication , 40 % for cognitive therapy . Follow-up tests of a site x treatment interaction indicated a significant difference only at V and erbilt University , where medications were superior to cognitive therapy . Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction . CONCLUSION Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression , but this degree of effectiveness may depend on a high level of therapist experience or expertise Background : Major depressive disorder occurs commonly in association with alcohol dependence , both in clinical sample s and in the community . Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results . This multicenter , double-blind , placebo-controlled trial of sertraline was design ed to address many of the potential method ological shortcomings of studies of co-occurring disorders . Method : Following a 1-week , single-blind , placebo lead-in period , 328 patients with co-occurring major depressive disorder and alcohol dependence were r and omly assigned to receive 10 weeks of treatment with sertraline ( at a maximum dose of 200 mg/d ) or matching placebo . R and omization was stratified , based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking , result ing in a sample of 189 patients with Hamilton Depression Rating Scale scores ≥17 ( group A ) and 139 patients with Hamilton Depression Rating Scale scores ≤16 ( group B ) . Results : Both depressive symptoms and alcohol consumption decreased substantially over time in both groups . There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients . Conclusion : Despite careful attention to method ological considerations , this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence . The high rate of response among placebo-treated patients may help to explain these findings . Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders The outcome of antidepressant therapy in terms of social functioning was evaluated in a r and omized , placebo-controlled , double-blind study comparing the selective noradrenaline reuptake inhibitor ( NARI ) , reboxetine , with the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine . Of the 381 patients with major depression participating in the study , 302 patients were assessed using the new self-rating Social Adaptation Self-evaluation Scale ( SASS ) . Mean SASS total score at last assessment was superior ( p < 0.05 ) to placebo for both reboxetine and fluoxetine . Moreover , reboxetine was superior ( p < 0.05 ) to fluoxetine . Evaluation of the sensitivity to change in individual items by point-biserial correlation analysis showed a significant correlation between improvement in item score and reboxetine treatment in all but one item for the reboxetine-placebo comparison . In the fluoxetine-placebo comparison , a significant correlation was evident for only 12 of the 21 items . Direct comparison of reboxetine with fluoxetine revealed a significant correlation between change in item score and treatment for nine items , in favour of reboxetine . The association was maximal for six items , mainly related to negative self-perception and to active social behaviour . In the subset of patients in remission at last assessment ( n = 91 ) , the mean SASS total score for reboxetine was superior to that of both fluoxetine and placebo ( p < 0.05 ) . Point-biserial correlation analysis revealed that most items sensitive to change under active treatment in the total population did so with reboxetine ( 17 items ) or fluoxetine ( nine items ) in patients in remission . In the reboxetine-fluoxetine comparison , 14 items showed a significant association with reboxetine treatment . In conclusion , while social motivation and behaviour in depression are significantly affected by both noradrenergic and serotonergic antidepressant treatment , noradrenergic therapy seems particularly effective in improving negative self-perception and motivation towards action , result ing in a better quality of remission in terms of social functioning The clinical profile of reboxetine , a selective noradrenaline reuptake inhibitor , was compared with that of the selective serotonin reuptake inhibitor fluoxetine and placebo in a double-blind , multicenter , parallel-group clinical trial of patients with major depression . Among the 381 patients treated with reboxetine 8 to 10 mg/day , fluoxetine 20 to 40 mg/day , or placebo for up to 8 weeks , a statistically significant greater reduction in the mean Hamilton Rating Scale for Depression ( 21-item HAM-D ) total score ( the primary efficacy variable ) was seen for both active treatment groups compared with placebo ( p < 0.024 ) . A significantly greater proportion of patients treated with either reboxetine or fluoxetine also achieved a response ( ≥50 % reduction in HAM-D ) or remission ( HAM-D ≤10 points ) than those who received placebo ( p < 0.01 for both analyses ) . Similar findings were recorded in a sub population of severely ill patients , with statistically significantly greater decreases in the mean HAM-D total score between both active treatment groups compared with placebo ( p < 0.024 ) . Additional efficacy assessment s ( Montgomery-Åsberg Depression Rating Scale , Clinical Global Impression ) reflected the primary efficacy analysis , with both active treatments offering comparable efficacy that was superior to that of placebo . Reboxetine and fluoxetine are more effective  than placebo in the treatment of major depression . Futhermore , both antidepressants are well tolerated but possess different adverse event profiles OBJECTIVE These studies were design ed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b ) receptor antagonist , SSR149415 , in the treatment of major depressive disorder ( MDD ) and generalized anxiety disorder ( GAD ) . METHOD Studies were r and omized 8-week , double-blind , placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415 , placebo , and escitalopram 10 mg/day or paroxetine 20 mg/day , conducted from August 2006 through February 2008 . Participants met the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , Text Revision criteria for MDD or GAD .  Baseline Montgomery-Asberg Depression Rating Scale ( MADRS ) and Hamilton Depression Rating Scale ( HDRS ) total scores were ≥ 24 and 18 , respectively , and in the GAD trial baseline Hamilton Anxiety Rating Scale ( HARS ) score was ≥ 22 . Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS , and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score ( CGI-S ) . A 4-week , double-blind , placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal ( HPA ) axis in MDD patients was also conducted . RESULTS In the GAD trial , SSR149415 did not separate from placebo on the primary ( HARS-100 mg : P = .29 ; 250 mg : P = .21 ) and secondary ( CGI-S-100 mg : P = .18 ; 250 mg : P = .24 ) outcome measures , while paroxetine  demonstrated efficacy ( HARS : P = .003 ; CGI-S : P = .01 ) . In 2 MDD trials , SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients ( HDRS-100 mg : P = .21 and .48 , respectively ; 250 mg : P = .22 and P = .46 , respectively ; CGI-S-100 mg : P = .64 and P = .82 , respectively ; 250 mg : P = .33 and P = .08 , respectively ) . In the third MDD study , SSR149415 250 mg ( P = .04 ) , but not escitalopram ( P = .15 ) , demonstrated significant improvement compared to placebo on the HDRS total score at week 8 . SSR149415 had no deleterious effects on the HPA axis . CONCLUSIONS These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00374166 ( Sanofi ID number : DFI5880 ) , NCT00361491 ( Sanofi ID number : DFI5879 ) , NCT00358631 ( Sanofi ID number : DFI5878 ) , NCT01606384 ( Sanofi ID number : PDY5467 ) BACKGROUND Many patients with depression take benzodiazepine drugs long term despite the absence of continuing therapeutic value . AIMS To evaluate a treatment programme involving gradual discontinuation with or without simultaneous selective serotonin reuptake inhibitor ( SSRI ) prescribing and to determine the long-term outcome after benzodiazepine withdrawal . METHOD Patients went through three phases - change to an equivalent dose of diazepam ; subsequent r and omisation to either 20 mg of paroxetine or placebo ; and gradual reduction of diazepam in depression-free patients - with a follow-up after 2 or 3 years . RESULTS A total of 230 patients were recruited and 75 % in the paroxetine group and 61 % in the placebo group were successfully treated after 6 weeks ( P:=0.067 ) . After 2 or 3 years 13 % of patients were still benzodiazepine free : 26 % of those who had successfully tapered off benzodiazepine and 6 % of the total group . CONCLUSIONS Transfer to diazepam followed by gradual withdrawal is an effective way of discontinuing chronic benzodiazepine use . The addition of SSRI treatment is of limited value Objective : This study looks to compare the antidepressant efficacy and safety of a st and ardized extract of St John 's wort with both placebo and fluoxetine . Method : After a 1-week single-blind washout , patients with major depressive disorder diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition were r and omized to 12 weeks of double-blind treatment with LI-160 St John 's wort extract ( 900 mg/d ) , fluoxetine ( 20 mg/d ) , or placebo . The 17-item Hamilton Rating Scale for Depression ( HAMD-17 ) was the primary efficacy measure , and analysis of covariance was used to compare differences in end point HAMD-17 scores across the 3 treatment groups , treating the baseline HAMD-17 as the covariate . Results : One hundred thirty-five patients ( 57 % women ; mean age , 37.3 ± 11.0 ; mean HAMD-17 , 19.7 ± 3.2 ) were r and omized to double-blind treatment and were included in the intent-to-treat analyses . Analysis of covariance analyses showed lower mean HAMD-17 scores at end point in the St John 's wort group ( n = 45 ; mean ± SD , 10.2 ± 6.6 ) compared with the fluoxetine group ( n = 47 ; 13.3 ± 7.3 ; P < 0.03 ) and a trend toward a similar finding relative to the placebo group ( n = 43 ; 12.6 ± 6.4 ; P = 0.096 ) . There was also a trend toward higher rates of remission ( HAMD-17 < 8) in the St John 's wort group ( 38 % ) compared with the fluoxetine group ( 30 % ) and the placebo group ( 21 % ) . Overall , St John 's wort appeared to be safe and well tolerated . Conclusion : St John 's wort was significantly more effective than fluoxetine and showed a trend toward superiority over placebo . A ( 25 % ) smaller than planned sample size is likely to account for the lack of statistical significance for the advantage ( indicating a moderate effect size , d = 0.45 ) of St John 's wort over placebo Background Thresholds for statistical significance are insufficiently demonstrated by 95 % confidence intervals or P-values when assessing results from r and omised clinical trials . First , a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true . Second , a confidence interval or a P-value showing significance may be caused by multiplicity . Third , statistical significance does not necessarily result in clinical significance . Therefore , assessment of intervention effects in r and omised clinical trials deserves more rigour in order to become more valid . Methods Several method ologies for assessing the statistical and clinical  significance of intervention effects in r and omised clinical trials were considered . Balancing simplicity and comprehensiveness , a simple five-step procedure was developed . Results For a more valid assessment of results from a r and omised clinical trial we propose the following five-steps : ( 1 ) report the confidence intervals and the exact P-values ; ( 2 ) report Bayes factor for the primary outcome , being the ratio of the probability that a given trial result is compatible with a ‘ null ’ effect ( corresponding to the P-value ) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation ; ( 3 ) adjust the confidence intervals and the statistical significance threshold if the trial is stopped early or if interim analyses have been conducted ; ( 4 ) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons ; and ( 5 ) assess clinical significance of the trial results . Conclusions If the proposed five-step procedure is followed , this may increase the validity of assessment s of intervention effects in r and omised clinical trials CONTEXT Paroxetine controlled release ( CR ) is approved for the treatment of major depressive disorder ( MDD ) in the dosage range of 25 to 62.5 mg daily . However , lower daily doses ( 12.5 mg and 25 mg ) of this formulation have not been investigated in the treatment of MDD . If the 12.5-mg and 25-mg doses are found to be efficacious , these lower doses may well convey a superior tolerability profile for paroxetine CR in the treatment of MDD . OBJECTIVE To evaluate the antidepressant efficacy and tolerability profile of daily doses of paroxetine CR 12.5 mg and 25 mg versus placebo in the treatment of MDD . DESIGN AND SETTING R and omized , double-blind , placebo-controlled clinical trial conducted in 40 clinical investigation centers in the United States . PARTICIPANTS 447 adult ( > or = 18 years of age ) out patients who met DSM-IV criteria for MDD and with a baseline 17-item Hamilton Rating Scale for Depression ( HAM-D ) score of at least 20 comprised the intent-to-treat study population ( mean age = 38.8 years ; 58.4 % female ; 75.6 % white ) . INTERVENTION Eligible patients completing a 1-week single-blind placebo run-in period were r and omly assigned to receive once-a-day study medication ( paroxetine CR 12.5 mg [ N = 156 ] , paroxetine CR 25 mg [ N = 154 ] , or placebo [ N = 149 ] ) in an 8-week , double-blind , parallel cell comparison . MAIN OUTCOME MEASURES The primary efficacy measure was the change from baseline to study endpoint ( week 8) as measured by the HAM-D. Secondary efficacy measures included change from baseline to study endpoint as assessed by both the depressed mood item on the HAM-D and the Clinical Global Impressions ( CGI ) Severity of Illness scale ( CGI-S ) . The proportion of patients considered at study endpoint to be in response ( CGI-Improvement score of 1 or 2 ) or in remission ( HAM-D < or = 7 ) in the 3 treatment groups was also compared . Quality of life was assessed by the change from baseline in total score of the short form of the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) . Safety observations were made by assessing the proportion of patients who had adverse experiences , including laboratory and electrocardiographic abnormalities , during the treatment period . RESULTS The primary efficacy analysis revealed that both the 12.5-mg and the 25-mg paroxetine CR treatment groups were associated with significant therapeutic effects ( change in HAM-D score ) from baseline to study endpoint ( LOCF : p = .038 , 95 % CI = -3.38 to -0.09 and p = .005 , 95 % CI = -4.06 to -0.74 , respectively ) . Results from the Wilcoxon rank sum test of the depressed mood item of the HAM-D ( p = .011 , 95 % CI = -0.57 to -0.07 ) demonstrated significant efficacy in the 25-mg treatment group but not in the 12.5-mg group . However , LOCF analysis of the CGI-S revealed significant therapeutic effects for both the 12.5-mg ( p = .018 , 95 % CI = -0.61 to -0.06 ) and 25-mg ( p < .001 , 95 % CI = -0.78 to -0.22 ) treatment groups . Significantly more patients in the 25-mg paroxetine CR-treated group than in the placebo-treated group met criteria for response ( CGI-Improvement score of 1 or 2 , p = .035 , OR = 1.68 , 95 % CI = 1.04 to 2.73 ) as well as for remission ( HAM-D score < /= 7 , p = .013 , OR = 1.96 , 95 % CI = 1.15 to 3.33 ) . Neither HAM-D remission analysis nor CGI responder analysis showed statistical separation from placebo for paroxetine CR 12.5-mg treatment . Quality of life improvements were statistically significant for the 25-mg treatment ( p = .041 , 95 % CI = 0.17 to 8.03 ) on the Q-LES-Q total score . Post hoc LOCF analyses of HAM-D sleep disturbance , psychic anxiety , and anxiety/somatization factors revealed significant improvements from baseline in the paroxetine CR 25-mg and 12.5-mg treatment groups . The types of adverse events reported in the 12.5-mg and 25-mg groups were similar to those reported with paroxetine CR at the customary 25-mg to 62.5-mg range ; however , the lower doses of paroxetine CR were associated with a relatively reduced incident rate of these adverse events and an overall improved tolerability compared with the incident rate and tolerability profile associated with the customary dose range of paroxetine CR ( 25 to 62.5 mg ) . CONCLUSION Paroxetine CR , at 12.5 mg/day and 25 mg/day , demonstrated significant antidepressant effects OBJECTIVE Authors tested the hypothesis that one night of total sleep deprivation ( TSD ) would accelerate antidepressant response to paroxetine , as compared with TSD+placebo ( PBO ) and paroxetine-alone , in late-life major depression . METHODS Eighty elderly out patients with current episodes of non-psychotic , non-bipolar major depression were r and omly assigned to one of three treatment conditions : TSD+paroxetine ( N = 27 ) , TSD + PBO ( N = 27 ) , and paroxetine-only ( N = 26 ) . Primary outcome was percentage of subjects in each condition who demonstrated early response ( Hamilton Rating Scale for Depression scores [ Ham-D : 17-item ] of < or = 10 ) or remission ( score of < or = 7 ) on Day 14 . RESULTS Response rates after 14 days were 22 % in subjects r and omly assigned to the TSD + paroxetine condition , 41 % in TSD + PBO , and 46 % in paroxetine alone . Remission rates after 14 days were 11 % in TSD+paroxetine , 22 % in TSD + PBO , and 38 % in paroxetine . After adjusting for baseline depression severity , there were no statistically significant differences in response or remission rates . CONCLUSION Contrary to the study hypothesis , one night of total sleep deprivation did not accelerate onset of antidepressant response to paroxetine pharmacotherapy of late-life depression . The data suggest , rather , that the two interventions might have counteracted each other & NA ; Approximately 20 million patients suffer from major depressive disorder each year , indicating a need for antidepressant agents that are synonymous with effectiveness , tolerability and patient compliance . The authors examined the effects of fluvoxamine , a selective serotonin reuptake inhibitor , in the treatment of out patients meeting DSM‐III‐R criteria for major depressive disorder . A r and omized , double‐blind , parallel group , placebo‐ and imipramine‐controlled  single center study was conducted in 150 out patients . Patients were r and omized to receive up to 150 mg/day of fluvoxamine as a single bedtime dose , 240 mg/day of imipramine on a twice‐daily ( BID ) schedule , or placebo for six weeks  . Efficacy measurements included HAM‐D , MADRS , CGI , Raskin‐Covi and SCL‐56 scales . The HAM‐D total score indicated that both active treatment groups showed significantly ( p ≤ 0.05 ) greater therapeutic benefit than did placebo . Severely depressed patients ( HAM‐D ≥ 30 ) responded better to fluvoxamine in five of six measures . Side‐effects from fluvoxamine were similar to those reported for other selective serotonin reuptake inhibitors ( nausea , somnolence ) and were well tolerated . Imipramine was associated with anticholinergic effects such as dry mouth and dizziness . The pharmacokinetic properties of fluvoxamine which allow the drug to be administered as a single daily dose should aid in the maintenance of patient compliance , while offering significant clinical benefit in the improvement of depressive symptoms Summary Recent research aims at developing a biomarker to predict antidepressant treatment outcomes in major depressive disorder . The Antidepressant Treatment Response ( ATR ) index has been correlated with response to antidepressant medication ( Leuchter et al. , 2009a , 2009b ) but has not been assessed in a placebo-controlled trial . EEGs recorded at pretreatment baseline and after 1 week of r and omized treatment were used to calculate ATR index for 23 subjects with major depressive disorder who were treated for 8 weeks with fluoxetine ( FLX ) 20 mg  ( n = 12 ) or placebo  ( n = 11 ) . The 17-item Hamilton Depression Rating Scale ( HamD17 ) assessed symptom severity ; ATR index was assessed as a predictor of percent change in HamD17 score , endpoint response ( ≥ 50 % improvement ) and remission ( HamD17 score ⩽ 7 ) . The ATR index was significantly associated with improvement on FLX ( r = 0.64 , P = 0.01 ) , with a higher mean ATR index for FLX responders than for nonresponders ( t(10 ) = −2.07 , P = 0.03 ) . Receiver operating characteristic analysis found a 0.83 area under the curve ( P = 0.03 ) , for ATR index as a predictor for FLX , while an optimized ATR index cutoff of 47.3 yielded 100 % sensitivity , 66.7 % specificity , 75 % positive predictive value , and 100 % negative predictive value . Importantly , ATR index did not correlate significantly with placebo outcomes . Results extend ATR index findings to include predictive validity with fluoxetine , suggesting that this biomarker has specificity for drug effects 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 Considerable research shows that serotonin dysfunction is implicated in major depression .  Paroxetine is an investigational antidepressant that appears to act by selectively blocking neuronal serotonin uptake . Seventy-two out patients with moderate-to-severe major depression entered this 6-week , double-blind comparison of paroxetine and placebo . The results showed clear and significant superiority of paroxetine on all of the major outcome variables . These included physician-rated measures such as the Hamilton Rating Scale for Depression and its four factor scores , the Clinical Global Impressions scale , the Montgomery and Asberg Depression Rating Scale , and the Raskin Depression Scale . Results on these agreed well with patient-rated measures like the Hopkins Symptom Checklist and Patient Global Evaluation Scale .  Paroxetine was also very well tolerated . Nausea and constipation occurred significantly more often with paroxetine , but only 9 % of paroxetine patients dropped out of the study due either in whole or in part to an adverse effect . This compares to 8 % of the placebo patients who were discontinued for the same reason . This study suggests that paroxetine is a safe and effective medication for the treatment of major depression 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 Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for major depressive disorder ( MDD ) treatment in adults . This was a 10-week , multicenter , double-blind , placebo-controlled and active-controlled , fixed-dose trial ( NCT01473381 ) . Adult patients with MDD ( Diagnostic and Statistical Manual of Mental Disorders , 4th ed . , text revision criteria ) were r and omized 1 : 1 : 1 : 1 to vilazodone 20 or 40 mg/day , citalopram 40 mg/day , or placebo . Primary efficacy : Montgomery – Åsberg Depression Rating Scale ( MADRS ) ; secondary efficacy : Clinical Global Impressions-Severity and sustained response ( MADRS total score⩽12 for at least the last two consecutive double-blind visits ) . The intent-to-treat population comprised 1133 patients , ( placebo=281 ; vilazodone 20 mg/day=288 ; vilazodone 40 mg/day=284 ; citalopram=280  ) . MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20 mg/day , vilazodone 40 mg/day , and citalopram versus  placebo . Sustained response rates were numerically higher , but not significantly different , in all active treatment groups versus placebo . The most common adverse events ( ≥5 % of vilazodone patients , twice the rate of placebo ) were diarrhea , nausea , vomiting  ( vilazodone 40 mg/day only ) , and insomnia . Improved sexual function ( Changes in Sexual Functioning Question naire scores ) was seen in all groups ; between-group differences were not significant . Vilazodone 20 and 40 mg/day demonstrated efficacy and tolerability in the treatment of MDD AIM The main purpose of this study was to evaluate the efficacy of paroxetine controlled-release ( CR ) formulation compared to placebo . A secondary objective was to test the hypothesis that the CR decreases selective-serotonin-reuptake-inhibitors-induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate-release ( IR ) formulation . METHODS We conducted this study in Japanese and Korean patients with major depressive disorder ( MDD ) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo . The primary efficacy end-point was the adjusted mean change from baseline in the 17-item Hamilton Rating Scale for Depression total score at Week 8 . RESULTS A total of 416 patients with MDD were r and omly assigned to the CR , IR and placebo groups . The mean change from baseline in the 17-item Hamilton Rating Scale for Depression was -12.8 in the CR group , -12.5 in the IR group , and -10.4 in the placebo group , which showed a statistically significant difference compared to placebo in CR ( P < 0.001 ) and IR ( P = 0.015 ) . The incidence of adverse events was 65 % in CR , 69 % in IR and 55 % in placebo . The adverse events were mostly mild or moderate in severity . In the early treatment period , when initiated from 12.5 mg , the incidence of nausea in the CR group was 6 % , which was comparable with that of placebo ( 5 % ) . CONCLUSION Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period This multicenter study compared the efficacy and safety of citalopram and placebo in a population of moderately to severely depressed patients with melancholia . This r and omized , double-blind , parallel-group study compared citalopram ( flexible dose ; 20 - 80 mg/day ) with placebo in 180 psychiatric out patients with a DSM-III diagnosis of major depression or bipolar disorder , depressed , who also met DSM-III criteria for melancholia . Following a 1-week placebo washout period , patients meeting study entry criteria were r and omized to 4 weeks of double-blind treatment with either citalopram or placebo .  Efficacy measures included the Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI ) Scale , and the Zung Self-Rating Depression Scale . Patients treated with citalopram showed significantly greater improvement at endpoint than placebo patients on the HAM-D , CGI , and Zung scales . On the HAM-D , citalopram patients exhibited significantly greater improvement than placebo patients after 1 week of double-blind treatment and at all subsequent study visits . Endpoint analyses of the HAM-D subscales demonstrated that citalopram produced significant improvement of the psychomotor retardation , cognitive disturbance , sleep disturbance , and melancholia symptom clusters . Nausea , dry mouth , somnolence , dizziness , and increased sweating were reported at higher rates by citalopram-treated patients than by placebo-treated patients , but there were no significant citalopram-placebo differences in the incidence of activation ( e.g. , anxiety , nervousness , insomnia ) or sexual dysfunction . Analysis of electrocardiograms , vital signs , and laboratory tests did not reveal any clinical ly significant effects of citalopram treatment . The results of this study indicate that citalopram is safe and effective in the treatment of depressed patients with melancholia , and is associated with a favorable side effect profile and a potentially rapid onset of action Major depression during later life represents a clinical challenge . Conventional antidepressant pharmacotherapy is relatively less well tolerated in geriatric patients compared with younger patients . Despite the striking impairments associated with this disorder , clinical investigations into the relative risk-benefit ratio of various depression treatment strategies have been limited . In this multicentre , placebo-controlled , double-blind trial with fluoxetine , 671 major depressed ( DSM-III-R-compatible ) out patients aged 60 years or older were evaluated . The 21-item Hamilton Depression Rating le ( HAMD21 ) response ( p = 0.014 ) and remission ( p = 0.008 ) criteria favoured fluoxetine over placebo . Analysis of the treatment effect on change in the HAMD21 factors ( anxiety/somatization , cognitive disturbance , psychomotor retardation , and sleep disturbance ) revealed advantages for fluoxetine within the cognitive disturbance and psychomotor retardation factors . Overall , the rate of discontinuation for an adverse event between fluoxetine ( 11.6 % ) and placebo ( 8.6 % ) was not statistically significant . Baseline HAMD21 factor scores were not predictive of adverse events leading to premature treatment discontinuation . Fluoxetine , 20 mg/day , is a well-tolerated and effective treatment option in the management of geriatric major depression This study compared the sexual functioning effects as well as the safety and efficacy of bupropion sustained release ( bupropion SR ) and sertraline .  Three hundred sixty-four patients with normal sexual functioning and recurrent major depression were treated with bupropion SR ( 150 - 400 mg/day ) , sertraline ( 50 - 200 mg/day ) , or placebo for 8 weeks in this r and omized , double-blind , multicenter study . Patients ' depression , sexual functioning , and overall safety were assessed at regular clinic visits . Significantly ( P < 0.05 ) more patients treated with sertraline experienced orgasm dysfunction compared with patients treated with bupropion SR or placebo . Bupropion SR , but not sertraline , was statistically significantly superior to placebo in improving scores on all depression scales by the end of the study . Headache occurred with similar frequency in all groups . Gastrointestinal disturbances occurred more frequently with sertraline ;  insomnia and agitation occurred more frequently with bupropion SR . Small decreases in mean weight were seen with both active treatments ; the placebo group experienced a minor increase in mean weight . Both bupropion SR and sertraline were generally well tolerated , although sertraline was more often associated with sexual dysfunction .  Bupropion SR , but not sertraline , was statistically superior to placebo in relieving depression by the end of the study . Bupropion SR may offer advantages over sertraline in treating depressed patients concerned with sexual functioning This study investigated the psychological characteristics and clinical features of 55 patients with geriatric depression , and evaluated the efficacy and safety of escitalopram in the treatment of geriatric depression , in a r and omized controlled trial . Fifty-five patients with geriatric depression were r and omly assigned to receive 8 weeks of escitalopram 10 mg , daily , orally ( n = 29 ) or placebo ( n = 26 ) . At baseline , these patients had significantly higher neuroticism and psychoticism scores on the Eysenck Personality Question naire - Adult scale than Chinese population norms . General Severity Index scores and the mean values of the nine subscales of the Symptom Checklist-90- Revised scale were also significantly higher in these patients than in Chinese population norms . The response rate to escitalopram after 8 weeks ' treatment was 74.1 % ( 20/27 patients ) . Adverse reactions included nausea , dry mouth and dizziness . In conclusion , depressed geriatric patients were found to have abnormal personality traits , and escitalopram was efficacious and had a good safety profile in the treatment of geriatric depression 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 This study tested the effectiveness of fluoxetine as a treatment for depression in a population of methadone-maintained opioid addicts . Methadone-maintained opioid addicts ( 44 ) with depression received fluoxetine or placebo in addition to their methadone , in a double-blind r and omized trial , for 12 weeks . Depressive symptoms decreased significantly overall with no significant differences between the groups treated with fluoxetine versus placebo . In addition , drug use outcomes , including cocaine and heroin self-reported use and urine toxicology were measured . There was a significant decrease in heroin use in treatment , but no medication effect . Cocaine use , was unchanged from pre-treatment to endpoint . In separately analyzing data for the sub sample of subjects with the most severe depression , there was a significant decrease in depression during treatment and a significant decrease in self-reported cocaine use , but no medication effect on either depressive symptoms or on cocaine use . This study suggests that fluoxetine is not an effective agent in treating depression or cocaine use in this population Fluvoxamine was given in placebo-controlled trials to 33 severely depressed patients of between 60 and 71 years , 29 received imipramine and 14 placebo .  At week 4 of treatment fluvoxamine and imipramine were superior to placebo on the HAMD and CGI scales ( P less than 0.05 ) . There was indication of an earlier onset of antidepressant activity in the fluvoxamine group . There was no evidence of systematic changes in laboratory variables in any treatment group . Fluvoxamine and placebo had similar effects on heart rate and blood pressure . Imipramine was associated with significant postural falls in mean systolic pressure . The most frequent unwanted symptom with fluvoxamine was mild nausea , with imipramine , dry mouth . Toxic confusion was the major reason for dropout in the imipramine ( n = 4 ) and nausea ( n = 3 ) in the fluvoxamine-treated group The efficacy and safety of fluvoxamine maleate , a selective serotonin reuptake inhibitor , was compared with placebo and imipramine in patients with major depressive disorder . Previous literature has cited a dose range of 100 to 300 mg/day of fluvoxamine maleate for the treatment of major depression ; however , this study demonstrates that a dose range of 50 to 150 mg/day is as effective as imipramine ( 80 - 240 mg/day ) . After a 1- to 2-week , single-blind , placebo washout phase , 150 depressed out patients were r and omized to double-blind treatment with fluvoxamine maleate ( 50 - 150 mg/day ) , imipramine ( 80 - 240 mg/day ) , or placebo for 6 weeks . Fluvoxamine produced a significant therapeutic benefit over placebo ( p < or = 0.05 ) as assessed by the total score on the Hamilton Rating Scale for Depression ; imipramine ( 80 - 240 mg/day ) produced similar results . The secondary outcome variables ( i.e. , Clinical Global Impression severity of illness item and 56-Item Hopkins Symptom Checklist depression factor ) also showed significant differences between fluvoxamine maleate and placebo during three of the four final weeks of the study . Both fluvoxamine maleate and imipramine appeared to be safe and well tolerated by the majority of patients . As expected from the pharmacology of these agents , the imipramine groups reported more anticholinergic effects ( dry mouth , dizziness , and urinary retention ) and electrocardiographic effects , whereas the fluvoxamine group reported more nausea , somnolence , and abnormal ejaculation . The majority of these adverse events were mild to moderate and , with the exception of dry mouth ( imipramine ) and abnormal ejaculation ( fluvoxamine ) , were transient . The data clearly demonstrate the antidepressant activity and tolerability of fluvoxamine maleate ( 50 - 150 mg/day ) as compared with placebo ; it is also as effective as the tricyclic antidepressant imipramine ( 80 - 240 mg/day ) in patients with major depressive disorder 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 The aim of this proof-of-concept study was to compare the efficacy of escitalopram ( 20 mg/d ) in combination with fixed doses of gaboxadol to escitalopram ( 20 mg ) in the treatment of patients with severe major depressive disorder ( MDD ) . Adult patients were r and omized to 8 wk of double-blind treatment with fixed doses of placebo ( n=71 ) , escitalopram ( 20 mg , n=140 ) , escitalopram ( 20 mg)+gaboxadol ( 5 mg ) ( n=139 ) , or escitalopram ( 20 mg)+gaboxadol ( 10 mg ) ( n=140 ) . The pre-defined primary analysis of efficacy was an analysis of covariance ( ANCOVA ) of change from baseline to endpoint ( week 8) in Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score using last observation carried forward ( LOCF ) . There was no statistically significant difference in the mean change from baseline in MADRS total score between the 20 mg escitalopram+10 mg gaboxadol group and the 20 mg escitalopram group [ difference=-0.45 MADRS points ( 95 % CI -2.5 to 1.6 , p=0.6619 , full analysis set ( FAS ) , LOCF , ANCOVA ) ] at week 8 . The mean treatment differences to placebo at week 8 were -5.6 ( 95 % CI -8.0 to -3.1 , p<0.0001 ) ( 20 mg escitalopram ) , -5.1 ( 95 % CI -7.5 to -2.7 , p<0.0001 ) ( 20 mg escitalopram+5 mg gaboxadol ) , and -6.0 ( 95 % CI -8.4 to -3.6 , p<0.0001 ) ( 20 mg escitalopram+10 mg gaboxadol ) . The most common adverse events reported in the active treatment groups for which the incidence was higher than that in the placebo group , comprised nausea , anxiety and insomnia . There were no clinical ly relevant efficacy differences between a combination of escitalopram and gaboxadol compared to escitalopram alone in the treatment of severe MDD . All active treatment groups were superior in efficacy to placebo and were well tolerated BACKGROUND Citalopram , the most selective serotonin reuptake inhibitor ( SSRI ) , is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of other SSRIs and available antidepressants . The drug is approved for use in 69 countries . This 6-week , fixed-dose , placebo-controlled , parallel-arm , multicenter trial was performed to confirm its efficacy and safety in treatment of out patients with major depression in the United States . METHOD Six hundred and fifty adult out patients with moderate-to-severe major depression ( DSM-III-R ) were r and omly assigned to receive citalopram at doses of 10 mg ( N = 131 ) , 20 mg ( N = 130 ) , 40 mg ( N = 131 ) , or 60 mg ( N = 129 ) or placebo ( N = 129 ) once daily . Outcome assessment s were the 21-item Hamilton Rating Scale for Depression ( HAM-D ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , and the Clinical Global Impressions scale . RESULTS Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures . Patients r and omly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures , as well as on the HAM-D symptom clusters measuring depressed mood , melancholia , cognitive disturbance , and psychomotor retardation . Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings , with statistical significance demonstrated in the MADRS response rate , the HAM-D depressed mood item , and the HAM-D melancholia subscale . Citalopram was well tolerated , with only 15 % of patients discontinuing for adverse events . The side effects most commonly associated with citalopram treatment were nausea , dry mouth , somnolence , insomnia , and increased sweating . CONCLUSION Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression , especially symptoms of depressed mood and melancholia , with particularly robust effects shown at doses of 40 and 60 mg/day . Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels , with a low incidence of anxiety , agitation , and nervousness Little is known about the clinical relevance of the Hamilton Rating Scale for Depression ( HAMD-17 ) total scores . It is unclear how total scores translate into clinical severity , or what commonly used measures for response ( reduction from baseline of ≥ 50 % in the total score ) and remission ( total HAMD-17 score ≤ 7 ) mean from a clinical perspective . We therefore compared : ( a ) the percentage and absolute change in the HAMD-17 total scores with Clinical Global Impression-Improvement ( CGI-I ) ; ( b ) the absolute and percentage change in the HAMD-17 total scores with Clinical Global Impression-Severity ( CGI-S ) absolute change ; and ( c ) the percentage and absolute change in the HAMD-17 total scores with CGI-I in the subgroups of patients with ≤ median and > median HAMD-17 total scores at baseline . The method used was equipercentile linking of HAMD-17 and CGI ratings from 43 drug trials in patients with Major Depressive Disorder ( MDD ) ( n = 7131 ) . Our results confirm the validity of the commonly used measures for remission and response in MDD trials : a CGI-I score of 2 ( ' much improved ' ) corresponded to a reduction from baseline of > 50 % and < 60 % , and a CGI-I score of 1 ( ' very much improved ' ) to a reduction of > 75 % and < 85 % . The CGI-S score of 1 ( ' normal . , not at all ill ' ) corresponded to the HAMD-17 total score of < 5 and the CGI-S score of 2 ( ' borderline mentally ill ' ) to the score between 6 and 8 . An effect of baseline illness severity was observed Twelve patients with DSM-III-R major depressive illness were tested for growth hormone ( GH ) response to desipramine ( DMI ) , a noradrenergic ( NA ) reuptake inhibitor . The response is mediated by NA alpha 2 receptors . They were then r and omly assigned to treatment under double-blind conditions with either fluoxetine , the highly selective serotonin reuptake inhibitor or placebo . After 4 weeks they were retested . Fluoxetine but not placebo was effective in promoting recovery in four of the six patients treated . Patients treated with fluoxetine showed a significant decrease in DMI-mediated GH release irrespective of therapeutic outcome . This is consistent with marked alteration of NA function and raises questions as to the selectivity of fluoxetine BACKGROUND We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea ( R. rosea ) versus sertraline for mild to moderate major depressive disorder . HYPOTHESIS We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events . STUDY DESIGN Phase II r and omized placebo controlled clinical trial . METHODS 57 subjects were r and omized to 12 weeks of st and ardized R. rosea extract , sertraline , or placebo . Changes over time in Hamilton Depression Rating ( HAM-D ) , Beck Depression Inventory ( BDI ) , and Clinical Global Impression Change ( CGI/C ) scores among groups were examined using mixed-effects models . RESULTS Modest , albeit statistically non-significant , reductions were observed for HAM-D , BDI , and CGI/C scores for all treatment conditions with no significant difference between groups ( p = 0.79 , p = 0.28 , and p = 0.17 , respectively ) . The decline in HAM-D scores was greater for sertraline ( -8.2 , 95 % confidence interval [ CI ] , -12.7 to -3.6 ) versus R. rosea ( -5.1 , 95 % CI : -8.8 to -1.3 ) and placebo ( -4.6 , 95 % CI : -8.6 to -0.6 ) . While the odds of improving ( versus placebo ) were greater for sertraline ( 1.90 [ 0.44 - 8.20 ] ; odds ratio [ 95 % CI ] ) than R. rosea ( 1.39 [ 0.38 - 5.04 ] ) , more subjects on sertraline reported adverse events ( 63.2 % ) than R. rosea ( 30.0 % ) or placebo ( 16.7 % ) ( p = 0.012 ) . CONCLUSIONS Although R. rosea produced less antidepressant effect versus sertraline , it also result ed in significantly fewer adverse events and was better tolerated . These findings suggest that R. rosea , although less effective than sertraline , may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression BACKGROUND Escitalopram is the single isomer responsible for the serotonin reuptake inhibition produced by the racemic antidepressant citalopram . The present r and omized , double-blind , placebo-controlled , fixed-dose multicenter trial was design ed to evaluate the efficacy and tolerability of escitalopram in the treatment of major depressive disorder . METHOD Out patients with an ongoing DSM-IV major depressive episode ( N = 491 ) were r and omly assigned to placebo , escitalopram , 10 mg/day , escitalopram , 20 mg/day , or citalopram , 40 mg/day , and entered an 8-week double-blind treatment period following a 1-week single-blind placebo lead-in . Clinical response was evaluated by the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the 24-item Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI ) scales , the Hamilton Rating Scale for Anxiety ( HAM-A ) , and patient-rated quality -of-life scales . RESULTS Escitalopram , at both doses , produced significant improvement at study endpoint relative to placebo on all measures of depression ; significant separation of escitalopram from placebo was observed within I week of double-blind treatment . Citalopram treatment also significantly improved depressive symptomatology compared with placebo ; however , escitalopram , 10 mg/day , was at least as effective as citalopram , 40 mg/day , at endpoint . Anxiety symptoms and quality of life were also significantly improved by escitalopram compared with placebo . The incidence of discontinuations due to adverse events for the escitalopram 10 mg/day group was not different from the placebo group ( 4.2 % vs. 2.5 % ; p = .50 ) , and not different for the escitalopram 20 mg/day group and the citalopram 40 mg/day group ( 10.4 % vs. 8.8 % ; p = .83 ) . CONCLUSION Escitalopram , a single isomer SSRI , is well-tolerated and has demonstrated antidepressant efficacy at a dose of 10 mg/day BACKGROUND Despite the high prevalence of depression in elderly patients , few well- design ed , placebo-controlled studies of antidepressants have been conducted in this population . This masked , placebo-controlled trial assessed the efficacy and safety of venlafaxine and fluoxetine in depressed patients older than 65 years . METHOD Three hundred patients were r and omly assigned to treatment with venlafaxine immediate release ( [ IR ] ; N = 104 ) , fluoxetine ( N = 100 ) , or placebo ( N = 96 ) in an eight-week trial . Venlafaxine doses were titrated from 37.5 to 225 mg per day and fluoxetine doses were titrated from 20 to 60 mg per day , as necessary , over 29 days . Efficacy variables included the 21-item Hamilton Depression Rating Scale ( HAM-D21 ) total score , HAM-D21 depressed mood item score , scores on the Montgomery Asberg Depression Rating Scale ( MADRS ) , Clinical Global Impression-Severity of Illness ( CGI-S ) and Improvement ( CGI-I ) scales , and rates of response ( based on change from baseline HAM-D or MADRS score or CGI-I score ) and remission ( HAM-D17 < or = 7 ) . For the purpose s of this report , efficacy analyses are focused on the HAM-D21 total score . Safety assessment s included monitoring of adverse events ( AEs ) , physical examinations , vital signs assessment s , laboratory determinations , and electrocardiograms . RESULTS In all three of the treatment groups , there was a significant reduction at week 8 compared with the baseline HAM-D21 total score . However , there were no significant differences among the three treatment groups on the change in HAM-D21 , MADRS , or CGI scores from baseline to week 8 . There was no statistically significant difference in the proportion of remitters at the last on-therapy visit . The incidence of individual AEs was higher in the venlafaxine group ( 27 % ) compared with patients taking fluoxetine ( 19 % ) or placebo ( 9 % ) . CONCLUSION In this study , there was no significant difference in efficacy among placebo , venlafaxine , and fluoxetine for the treatment of depression OBJECTIVE Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence . While some studies have demonstrated that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence , most studies have not found antidepressant treatment helpful in reducing excessive drinking in these patients . The authors provide results from a double-blind , placebo-controlled trial that evaluated the efficacy of combining approved medications for depression ( sertraline ) and alcohol dependence ( naltrexone ) in treating patients with both disorders . METHOD A total of 170 depressed alcohol-dependent patients were r and omly assigned to receive 14 weeks of treatment with sertraline ( 200 mg/day [ N=40 ] ) , naltrexone ( 100 mg/day [ N=49 ] ) , the combination of sertraline plus naltrexone ( N=42 ) , or double placebo ( N=39 ) while receiving weekly cognitive-behavioral therapy . RESULTS The sertraline plus naltrexone combination produced a higher alcohol abstinence rate ( 53.7 % ) and demonstrated a longer delay before relapse to heavy drinking ( median delay=98 days ) than the naltrexone ( abstinence rate : 21.3 % ; delay=29 days ) , sertraline ( abstinence rate : 27.5 % ; delay=23 days ) , and placebo ( abstinence rate : 23.1 % ; delay=26 days ) groups . The number of patients in the medication combination group not depressed by the end of treatment ( 83.3 % ) approached significance when compared with patients in the other treatment groups . The serious adverse event rate was 25.9 % , with fewer reported with the medication combination ( 11.9 % ) than the other treatments . CONCLUSIONS More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol , had delayed relapse to heavy drinking , reported fewer serious adverse events , and tended to not be depressed by the end of treatment OBJECTIVE The corticotropin-releasing hormone ( CRH ) system is implicated in the pathogenesis of several psychiatric disorders , including major depressive disorder . This study was design ed to evaluate the safety and efficacy of CP-316,311 , a selective nonpeptide antagonist of corticotropin-releasing hormone type 1 ( CRH(1 ) ) receptors , in the treatment of recurrent major depressive disorder . METHOD Of a total of 167 patients with recurrent major depression who were screened , 123 were r and omly assigned to receive 400 mg of CP-316,311 twice daily , or 100 mg of sertraline daily , or placebo in a 6-week fixed-dose , double-blind , double-dummy , parallel-group , placebo- and sertraline-controlled trial . The primary efficacy analysis compared the change in score from baseline to endpoint on the 17-item Hamilton Depression Rating Scale ( HAM-D ) between the CP-316,311 and placebo groups . A group sequential design was used to support early trial termination based on efficacy or futility at a planned interim analysis . RESULTS The evaluable data set for the interim analysis included 28 patients in the CP-316,311 group , 31 patients in the placebo group , and 30 patients in the sertraline group . In the interim analysis , the change from baseline in the HAM-D score at the final visit was not significantly different between the CP-316,311 and placebo groups , while change from baseline between the sertraline and placebo groups was significantly different . Given these results , futility was declared for CP-316,311 and the trial was terminated . CONCLUSIONS Although CP-316,311 was safe and well tolerated in this study population , it failed to demonstrate efficacy in the treatment of major depression BACKGROUND Depression is the second most common neuropsychiatric disorder in older Americans , with significant clinical and public health costs . Despite advances in treatment , late-life depression remains a clinical challenge . Although the selective serotonin reuptake inhibitors ( SSRIs ) are the most common pharmacologic intervention for late-life depression , few placebo-controlled trials have assessed the efficacy of SSRIs for this condition . METHOD In this 12-week , multicenter , placebo-controlled , flexible-dose , double-blind , r and omized trial , 319 elderly patients ( mean age = 70 years ) were treated with controlled-release paroxetine ( paroxetine CR ) up to 50 mg/day ( N = 104 ) , immediate-release paroxetine ( paroxetine IR ) up to 40 mg/day ( N = 106 ) , or placebo ( N = 109 ) . Patients met DSM-IV criteria for major depressive disorder and had a total score of 18 or more on the 17-item Hamilton Rating Scale for Depression ( HAM-D ) . The primary efficacy measure was change from baseline to endpoint in HAM-D total score . RESULTS The primary efficacy analysis showed an adjusted difference between change from baseline in HAM-D score for paroxetine CR and placebo of -2.6 ( 95 % confidence interval [ CI ] = -4.47 to -0.73 , p = .007 ) at the week 12 last-observation-carried-forward ( LOCF ) endpoint . The adjusted difference between paroxetine IR and placebo was -2.8 ( 95 % CI = -4.65 to -0.99 , p = .003 ) at week 12 . Paroxetine CR and IR were more effective than placebo , with mean + /- SD endpoint HAM-D total scores of 10.0 + /- 7.41 and 10.0 + /- 7.10 , respectively , for the active treatments compared with 12.6 + /- 7.34 for placebo . Response , defined as a score of 1 or 2 on the Clinical Global Impressions-global improvement scale , was achieved by 72 % of paroxetine CR patients ( LOCF ; p < .002 vs. placebo ) , 65 % of paroxetine IR patients ( p = .06 vs. placebo ) , and 52 % of placebo patients . Remission , defined as a HAM-D total score < or = 7 , was achieved by 43 % of paroxetine CR patients ( LOCF ; p = .009 vs. placebo ) , 44 % of paroxetine IR patients ( p = .01 vs. placebo ) , and 26 % of placebo patients . In a post hoc analysis , mean HAM-D improvement for paroxetine CR and paroxetine IR was greater than for placebo in both chronically depressed patients ( duration > 2 years ) and those with short-term ( < or = 2 years ) depression .  Dropout rates due to adverse events were 12.5 % for paroxetine CR , 16.0 % for paroxetine IR , and 8.3 % for placebo . CONCLUSION Paroxetine CR and paroxetine IR are effective and well tolerated treatments for major depressive disorder in elderly patients , including those with chronic depression OBJECTIVE To evaluate the efficacy and tolerability of low daily doses of controlled-release ( CR ) paroxetine in patients with late-life depression . METHOD This was a 10-week , multicenter , placebo-controlled , double-blind , fixed-dose trial r and omly assigning patients > or= 60 years old to daily doses of paroxetine CR  12.5 mg ( N = 168 ) , paroxetine CR 25 mg ( N = 177 ) , or placebo ( N = 180 ) . Patients had major depressive disorder ( DSM-IV criteria ) and 17-item Hamilton Rating Scale for Depression ( HAM-D ) total scores of > or= 18 . The primary efficacy variable was the change from baseline to study endpoint in total HAM-D scores . The study was conducted from June 2003 to October 2004 . RESULTS The drug/placebo difference in HAM-D change from baseline at study endpoint was -1.8 ( 95 % CI = -3.41 to -0.19 , p = .029 ) for paroxetine CR 12.5 mg , and -3.3 ( 95 % CI = -4.84 to -1.68 , p < .001 ) for paroxetine CR 25 mg . A significantly larger percentage of patients achieved remission ( HAM-D total score < or= 7 at endpoint ) with paroxetine CR 25 mg ( 41 % ) , but not with 12.5 mg ( 31 % ) , as compared with placebo ( 28 % ) ( p = .008 ) . Both doses of paroxetine CR also achieved statistical significance compared to placebo for the Clinical Global Impressions-Severity of Illness scale ( p < .01 ) and the patient-rated measures of depression severity ( p < .05 ) and quality of life ( p < or= .001 ) . Both active treatments were generally well tolerated , with adverse event withdrawal rates of 6 % , 8 % , and 7 % for paroxetine CR 12.5 mg , paroxetine CR 25 mg , and placebo , respectively . CONCLUSION These data demonstrate that paroxetine CR 12.5 mg and 25 mg daily are efficacious and well tolerated in the treatment of major depressive disorder in patients > or= 60 years of age , although effect sizes are relatively smaller with the 12.5 mg/day dose Clinical study results for neurokinin ( NK ) receptor antagonists in the treatment of depression have been mixed , with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies . Casopitant , a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 r and omized , placebo-controlled , double-blind , Phase II trials in depressed out patients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy . Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression ( 17-item , HAMD17 ) total scores higher than 24 who were r and omized to fixed-dose casopitant 30 mg/d , 80 mg/d , or placebo for 8 weeks ( n = 356 ) . Study 096 required Carroll Depression Scale-Revised self- assessment scores of higher than 24 for r and omization to casopitant 120 mg/d , paroxetine 30 mg/d ( both reached via forced titration ) , or placebo for 8 weeks ( n = 362 ) . In study 092 , casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure , week 8 last observation carried forward change from baseline HAMD17 ( difference = −2.7 ; 95 % confidence interval , −5.1 to −0.4 , P = 0.023 ) . In study 096 , neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 ( casopitant difference = −1.7 ; 95 % CI , −3.8 to 0.4 , P = 0.282 ) . Casopitant and paroxetine were generally well tolerated in most patients . These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression 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 OBJECTIVE To determine whether supportive-expressive psychotherapy ( SET ) , a form of dynamic psychotherapy , and pharmacotherapy + clinical management ( MED ) for major depressive disorder ( MDD ) are more effective than pill-placebo + clinical management ( PBO ) . METHOD This National Institute of Mental Health (NIMH)-sponsored r and omized controlled trial was conducted ( from November 2001 through June 2007 ) at the University of Pennsylvania Medical School . The sample included 156 patients diagnosed with MDD ( DSM-IV ) and having a 17-item Hamilton Rating Scale for Depression ( HRSD(17 ) ) score ≥ 14 for at least 2 consecutive weeks . This was an underserved sample in which 41 % were male , 52 % were self- design ated minorities , and 76 % had an annual income under $ 30,000 . Treatment lasted 16 weeks . Medication patients not responsive by week 8 ( maximum dose 200 mg/d of sertraline ) were switched to venlafaxine ( maximum dose 375 mg/d ) . Nonresponsive placebo patients at week 8 were switched to a different placebo . RESULTS Patients ' depression improved over the 16 weeks ( P < .0001 ) , with no between-group differences ( P = .95 ) , even among severely ( HRSD(17 ) score ≥ 20 ) depressed patients ( P = .45 ) . Response rates did not differ between groups ( P = .73 ) . Gender and minority status moderated outcome ( P = .014 ) , with psychotherapy more efficacious for minority men than MED ( P = .027 , Cohen d = 1.02 ) and PBO ( P = .019 , d = 1.09 ) . PBO was more efficacious for white men than MED ( P = .03 , d = 0.62 ) and SET ( P = .003 , d = 1.07 ) . For white women , MED ( P = .005 , d = 0.77 ) and SET ( P = .033 , d = 0.71 ) were more efficacious than placebo . No differences among treatments were found for minority women . CONCLUSIONS This trial of urban MDD patients failed to confirm that either active treatment was better than placebo . Minority status and gender had significant and differential effects on outcome that warrant replication in future studies . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00043550 OBJECTIVE This study determined the efficacy of antidepressant medication for the treatment of depression in the " old-old . " METHOD This r and omized 8-week medication trial compared citalopram , 10 - 40 mg/day , to placebo in the treatment of patients 75 and older with unipolar depression . RESULTS A total of 174 patients who were 58 % women with a mean age of 79.6 years ( SD=4.4 ) and a mean baseline Hamilton Depression Rating Scale score of 24.3 ( SD=4.1 ) were r and omly assigned to treatment at 15 sites . There was a main effect for site but not for treatment condition . The remission rate , defined as a final Hamilton depression scale score < 10 , was 35 % for the citalopram and 33 % for the placebo groups . However , patients with severe depression ( baseline Hamilton depression scale score > 24 ) tended to have a higher remission rate with medication than with placebo ( 35 % versus 19 % ) . CONCLUSIONS In the oldest group of community-dwelling patients to be studied to date , medication was not more effective than placebo for the treatment of depression . However , given the considerable psychosocial support received by all patients , the placebo condition represents more than the ingestion of an inactive pill . Across sites , there was considerable range in response to medication , 18 % to 82 % , and to placebo , 16 % to 80 % PURPOSE Although cross-sectional studies have demonstrated an association between higher levels of aerobic fitness and improved neurocognitive function , there have been relatively few interventional studies investigating this relationship , and results have been inconsistent . We assessed the effects of aerobic exercise on neurocognitive function in a r and omized controlled trial of patients with major depressive disorder ( MDD ) . METHODS Two-hundred and two sedentary men ( n = 49 ) and women ( n = 153 ) , aged 40 yr and over and who met diagnostic criteria for MDD , were r and omly assigned to the following : a ) supervised exercise , b ) home-based exercise , c ) sertraline , or d ) placebo pill . Before and after 4 months of treatment , participants completed measures of : Executive Function ( Trail Making Test B-A difference score , Stroop Color-Word , Ruff 2 & 7 Test , Digit Symbol ) , Verbal Memory ( Logical Memory , Verbal Paired Associates ) , and Verbal Fluency/Working Memory ( Animal Naming , Controlled Oral Word Association Test , Digit Span ) . Multivariate analyses of covariance were performed to test the effects of treatment on posttreatment neuropsychological test scores , with baseline neuropsychological test scores , age , education , and change in depression scores entered as covariates . RESULTS The performance of exercise participants was no better than participants receiving placebo across all neuropsychological tests . Exercise participants performed better than participants receiving sertraline on tests of executive function but not on tests of verbal memory or verbal fluency/working memory . CONCLUSIONS We found little evidence to support the benefits of an aerobic exercise intervention on neurocognitive performance in patients with MDD OBJECTIVE There have been few placebo-controlled trials of selective serotonin reuptake inhibitors for depressed elderly patients . This placebo-controlled study of sertraline was design ed to confirm the results of non-placebo-controlled trials . METHOD The subjects were out patients age 60 years or older who had a DSM-IV diagnosis of major depressive disorder and a total score on the 17-item Hamilton Depression Rating Scale of 18 or higher . The patients were r and omly assigned to 8 weeks of double-blind treatment with placebo or a flexible daily dose of 50 or 100 mg of sertraline . The primary outcome variables were the Hamilton scale and Clinical Global Impression ( CGI ) scales for severity and improvement . RESULTS A total of 371 patients assigned to sertraline and 376 assigned to placebo  took at least one dose . At endpoint , the patients receiving sertraline evidence d significantly greater improvements than those receiving placebo on the Hamilton depression scale and CGI severity and improvement scales . The mean changes from baseline to endpoint in Hamilton score were -7.4 points ( SD=6.3 ) for sertraline and -6.6 points ( SD=6.4 ) for placebo . The rate of CGI-defined response at endpoint was significantly higher for sertraline ( 45 % ) than for placebo ( 35 % ) , and the time to sustained response was significantly shorter for sertraline ( median , 57 versus 61 days ) . There were few discontinuations due to treatment-related adverse events , 8 % for sertraline and 2 % for placebo . CONCLUSIONS Sertraline was effective and well tolerated by older adults with major depression , although the drug-placebo difference was not large in this 8-week trial 1 A double-blind placebo-controlled study of fluvoxamine and imipramine was performed in a group of depressed patients . Twenty-two patients received fluvoxamine ( mean dose 101 mg/day ) , 25 received imipramine ( mean dose 127 mg/day ) and 22 received placebo . 2 Apart from an increase in the SGOT and SGPT values of four imipramine patients , no statistically significant changes in haematology or urinalysis were judged to be medically relevant . Fluvoxamine exhibited fewer anticholinergic side effects than imipramine . 3 Both fluvoxamine treated patients and imipramine-treated patients exhibited a statistically significant improvement at the end of the 28-day treatment period with respect to the placebo patients , as measured using the Hamilton Rating Scale for Depression , and the Clinical Global Impression Scale . Evaluations of the results of the Beck Depression Inventory and the Profile of Mood States revealed a statistically significant improvement for imipramine patients with respect to placebo at week 4 , but not for fluvoxamine patients . It is postulated on the basis of quantitative pharmaco-EEG findings , that the slight superiority of imipramine over fluvoxamine was due to underdosing of the latter BACKGROUND This study was design ed to compare the efficacy , safety , tolerability profiles , and effects on quality of life of the serotonin selective reuptake inhibitor antidepressant sertraline versus the nonselective tricyclic antidepressant amitriptyline and placebo in patients with major depression . METHOD Out patients with DSM-III-R major depression were r and omly assigned to double-blind treatment for 8 weeks with sertraline ( 50 - 200 mg daily ) , amitriptyline ( 50 - 150 mg daily ) , or matching placebo . Assessment s included the Hamilton Rating Scale for Depression , Montgomery-Asberg Depression Rating Scale , Clinical Global Impressions-Severity of Illness scale , Clinical Global Impressions-Improvement scale , Global Assessment Scale , Profile of Mood States , Beck Depression Inventory , Quality of Life Enjoyment and Satisfaction Question naire , and Health-Related Quality of Life battery . RESULTS All treatment groups demonstrated statistically significant improvement from baseline in depression ratings by Week 1 and thereafter . The antidepressant effects of amitriptyline and sertraline were significantly ( p < .05 ) greater than placebo and did not differ significantly from each other . Sertraline was associated with significantly ( p < .05 ) greater subjective ( i.e. , patient-rated ) improvement in mood than amitriptyline or placebo . Both active drugs were associated with greater improvements than placebo on most quality of life measurements . On several items , sertraline , but not amitriptyline , was superior to placebo . There was a discernible effect of sertraline earlier than amitriptyline on most quality of life scales .  Amitriptyline therapy was associated with significantly more treatment-related adverse events , and discontinuations due to treatment-related adverse events , in comparison to both sertraline and placebo therapy . CONCLUSION Sertraline and amitriptyline each were effective treatments for major depression as assessed by both physician- and patient-rated scales . These results show that sertraline therapy is better tolerated than amitriptyline therapy . Quality of life was also improved by effective antidepressant treatment , with sertraline showing a tendency to produce greater improvements on quality of life measures OBJECTIVE The atypical subtype of depression appears to be both well vali date d and common . Although monoamine oxidase inhibitors are effective in treating atypical depression , their side effects and prescription-associated dietary restrictions reduce their suitability as a first-line treatment . The objective of this study was to estimate the efficacy of the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine in the treatment of major depression with atypical features . METHOD One hundred fifty-four subjects with DSM-IV major depression who met the Columbia criteria for atypical depression were r and omly assigned to receive fluoxetine , imipramine , or placebo for a 10-week clinical trial . Imipramine was included because its known efficacy for treatment of atypical depression helped to calibrate the appropriateness of the study group . RESULTS In both intention-to-treat and completer groups , the effectiveness of both fluoxetine and imipramine was significantly better than that of placebo . The two medications did not differ from each other in effectiveness . Significantly more patients dropped out of treatment with imipramine than with fluoxetine . Before treatment , patients on average rated themselves as very impaired on psychological dimensions of general health and moderately impaired on physical dimensions , compared with population norms . The self-ratings of patients who responded to treatment essentially normalized on these measures . CONCLUSIONS Despite earlier data that SSRIs might be the treatment of choice , fluoxetine appeared to be no better than imipramine in the treatment of atypical depression , although fluoxetine was better tolerated than imipramine 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 In a 6-week , r and omized , double-blind , multicenter trial , sertraline 50 mg , 100 mg , or 200 mg , or placebo , was administered once daily to 369 patients with DSM-III-defined major depression . Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression ( HAMD ) , HAMD Bech Depression Cluster , Clinical Global Impressions ( CGI ) Severity , CGI Improvement , and Profile of Mood States Depression/Dejection Factor . For the evaluable- patients analysis , all sertraline groups showed significantly ( p < 0.05 or better ) greater improvements in all efficacy variables except one when compared with the placebo group . For the all- patients analysis , all efficacy variables in the 50 mg group were statistically significantly ( p < 0.05 ) better than placebo .  Side effects increased with increasing dosage but were usually mild and well tolerated . The results of this study show that sertraline 50 mg once daily is as effective as higher dosages for the treatment of major depression with fewer side effects and therapy discontinuations This 7- to 8-week , multicenter , r and omized , double-blind , placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder . Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects . The study enrolled 600 out patients , male and female , age 18 - 65 , meeting DSM-III-R criteria for major depressive disorder . A 13-item subscore of the st and ard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score . Secondary efficacy assessment s included the HAM-D retardation factor , HAM-D depressed mood item , CGI-severity of illness item , and SCL depression factor .  Fluvoxamine ( 50 - 150 mg/day ) was therapeutically effective and well tolerated during 6 weeks of therapy . Based on the HAM-D depressed mood item , efficacy was dose dependent . The minimum effective dose was 50 mg/day . Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder IMPORTANCE Transcranial direct current stimulation ( tDCS ) trials for major depressive disorder ( MDD ) have shown positive but mixed results . OBJECTIVE To assess the combined safety and efficacy of tDCS vs a common pharmacological treatment ( sertraline hydrochloride , 50 mg/d ) . DESIGN Double-blind , controlled trial . Participants were r and omized using a 2 × 2 factorial design to sertraline/placebo and active/sham tDCS . SETTING Outpatient , single-center academic setting in São Paulo , Brazil . PARTICIPANTS One hundred twenty antidepressant-free patients with moderate to severe , nonpsychotic , unipolar MDD . INTERVENTIONS Six-week treatment of 2-mA anodal left/cathodal right prefrontal tDCS ( twelve 30-minute sessions : 10 consecutive sessions once daily from Monday to Friday plus 2 extra sessions every other week ) and sertraline hydrochloride ( 50 mg/d ) . MAIN OUTCOME MEASURES In this intention-to-treat analysis , the primary outcome measure was the change in Montgomery-Asberg depression rating scale score at 6 weeks ( end point ) . We considered a difference of at least 3 points to be clinical ly relevant . The analysis plan was previously published . Safety was measured with an adverse effects question naire , the young mania rating scale , and cognitive assessment . Secondary measures were rates of clinical response and remission and scores on other scales . RESULTS At the main end point , there was a significant difference in Montgomery-Asberg depression rating scale scores when comparing the combined treatment group ( sertraline/active tDCS ) vs sertraline only ( mean difference , 8.5 points ; 95 % CI , 2.96 to 14.03 ; P = .002 ) , tDCS only ( mean difference , 5.9 points ; 95 % CI , 0.36 to 11.43 ; P = .03 ) , and placebo/sham tDCS ( mean difference , 11.5 points ; 95 % CI , 6.03 to 17.10 ; P < .001 ) . Analysis of tDCS only vs sertraline only presented comparable efficacies ( mean difference , 2.6 points ; 95 % CI , -2.90 to 8.13 ; P = .35 ) . Use of tDCS only ( but not sertraline only ) was superior to placebo/sham tDCS . Common adverse effects did not differ between interventions , except for skin redness on the scalp in active tDCS ( P = .03 ) . There were 7 episodes of treatment-emergent mania or hypomania , 5 occurring in the combined treatment group . CONCLUSIONS AND RELEVANCE In MDD , the combination of tDCS and sertraline increases the efficacy of each treatment . The efficacy and safety of tDCS and sertraline did not differ . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01033084 BACKGROUND Recent publications have raised questions over the efficacy and clinical ly relevant effects of antidepressants that have been approved for the treatment of major depression . In this context , the European Commission requested that the European Medicines Agency ( EMEA ) and its scientific committee ( CHMP ) issue an opinion on these data under Article 5(3 ) of Regulation ( EC ) No 726/2004 . FINDINGS Results from a recent meta- analysis [ Kirsch , I. , Deacon , B.J. et al. , ( 2008 ) Initial severity and antidepressant benefits : a meta- analysis of data su bmi tted to the Food and Drug Administration . PLoS Med . 5(2 ) , e45 . ] have question ed the clinical relevance of the use of some antidepressants in treating major depression . This analysis focused only on statistically significant mean differences versus placebo in changes in a rating scale ( such as the Hamilton Depression Rating Scale ) . This , however , would not be an adequate basis for the evaluation of clinical relevance and , from a regulatory perspective , would not be sufficient to grant an antidepressant the approval needed to allow it onto the market . Improvements that are both statistically significant ( based on improvements in vali date d rating scales between baseline and study end ) and clinical ly relevant ( based on responder rates ) need to be shown in short-term studies . In addition , these short-term results need to be confirmed in a r and omised withdrawal study to demonstrate the maintenance of an antidepressant 's effects . CONCLUSIONS The CHMP concluded that the approval of antidepressants for the treatment of patients with major depression is based on data that provide robust and sufficient evidence of clinical ly meaningful benefits for patients with major depression . Therefore , the CHMP is of the opinion that , as no public health concerns have been identified , no regulatory action is necessary on the basis of Kirsch et al. 's findings This double-blind , placebo-controlled study compared venlafaxine ( immediate release ) , the first modern serotonin-norepinephrine reuptake inhibitor , with the selective serotonin reuptake inhibitor fluoxetine .  Out patients were r and omly assigned to 6 weeks of treatment with venlafaxine  ( 75 - 225mg/day ; n=102 ) , fluoxetine ( 20 - 60mg/day ; n=104 ) , or placebo ( n=102 ) . Efficacy was assessed using the 21-item Hamilton Depression Rating Scale ( HAM-D(21 ) ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Clinical Global Impression-Severity of Illness ( CGI-S ) scale , response and remission rates , and several other measures . Intent-to-treat analyses utilized both the last observation carried forward and ETRANK methods to account for missing data . At week 6 or study endpoint , venlafaxine ( mean dose : 142mg/day ) was superior to placebo on most outcomes measures , whereas the differences between fluoxetine ( mean dose : 41mg/day ) and placebo were less consistent . Final remission ( defined as HAM-D < or = 7 ) rates were 32 % , 28 % , and 22 % for venlafaxine , fluoxetine , and placebo , respectively . Few differences between the active treatments attained statistical significance . Both active therapies were generally well tolerated ; however , attrition due to adverse events , incidence of selected side effects , and increases in pulse and blood pressure favored fluoxetine over venlafaxine . This study provides further evidence that venlafaxine is effective after 6 weeks of treatment compared with placebo . The efficacy profile of fluoxetine was somewhat less consistent . It is strongly recommended that future studies of comparative antidepressant efficacy be adequately powered to detect modest between-drug differences in efficacy 1 . The efficacy of fluvoxamine is compared to that of desipramine in a multicenter double blind placebo controlled six-week flexible dose trial of 90 out patients with major depressive disorder . 2 . Although overall drug effects were relatively weak , there were trends suggesting separation of both active drugs from placebo at week six . Both drugs were well tolerated . 3 . Studies of major depression ought to be design ed to last 8 - 10 weeks in order to demonstrate placebo active drug differences and the stability of such a difference should it occur in the first six weeks Paroxetine is a selective serotonin uptake inhibitor , which is being investigated as an antidepressant . In this double‐blind , six‐week study 120 out patients with DSM‐I11 major depression were r and omly assigned to treatment with paroxetine , imipramine , or placebo . Results showed a statistically significant superiority of paroxetineover placebo on almost all outcome measures . Paroxetine was significantly superior to imipramine on the HAMD total score and was generally better tolerated than imipramine . The results support paroxetine 's effectiveness in the treatment of major depression and suggest that further studies with this compound are warranted The predictive value of the  dexamethasone suppression test ( DST ) was evaluated in two consecutive double-blind , placebo-controlled trials evaluating 61 depressed in patients r and omized to either one of two drugs , sertraline or oxaprotiline , or placebo over a 4-week clinical trial . For 30 patients who completed at least 3 weeks of double-blind treatment on either drug , the initial DST was not predictive of response to drug treatment . For the 17 patients who completed at least 3 weeks of double-blind treatment on placebo , the presence of a positive DST predicted a statistically significantly poorer response to placebo as opposed to a negative DST . These preliminary findings suggest that for depressed individuals who present with a positive DST , remission without active medication is less likely and somatic treatment should be considered & NA ; Escitalopram was compared to placebo in moderately to severely depressed patients in primary care with citalopram as the active reference . Patients were r and omized to receive flexible doses of 10–20 mg/day escitalopram ( n=155 ) , 20–40 mg/day citalopram ( n=160 ) , or placebo ( n=154 ) over an 8‐week double‐blind period . The primary efficacy parameter was the change from baseline to last assessment in the Montgomery – Asberg Depression Rating Scale total score . Escitalopram produced a statistically significant therapeutic difference of 2.9 points ( P=0.002 ) compared to placebo , and escitalopram was consistently and statistically significantly more efficacious than placebo from week 1 onwards . Analysis of Clinical Global Impression – Severity and Clinical Global Impression – Improvement confirmed the primary efficacy results . By week 8 , significantly more patients had responded to treatment with escitalopram than with citalopram ( P=0.021 ) or placebo ( P=0.009 ) . Escitalopram was as well tolerated as citalopram and had a similar adverse event profile . Both escitalopram‐ and citalopram‐treated patients had  placebo‐level adverse event withdrawal rates ( 3 % and 4 % , respectively ) . This study demonstrates the consistent antidepressant efficacy and excellent tolerability  of escitalopram 10–20 mg/day in primary care patients with major depressive disorder OBJECTIVE Management of depression in elderly patients presents a significant medical challenge , and there is a need for further clinical trials . The authors examined the efficacy and tolerability of escitalopram and fluoxetine versus placebo in the treatment of elderly patients with major depressive disorder ( MDD ) . METHODS This was an 8-week , r and omized , double-blind comparison of the efficacy and tolerability of escitalopram ( 10 mg/day ) and fluoxetine ( 20 mg/day ) , to placebo in elderly patients with MDD . The prospect ively defined primary efficacy parameter was the change from baseline in mean Montgomery-Asberg Depression Rating Scale ( MADRS ) total score at endpoint , using last observation carried forward . RESULTS The intent-to-treat set comprised 517 patients ; the escitalopram group included 173 patients ; fluoxetine , 164 patients ; and placebo , 180 patients . Mean age was 75 years , with a range of 65 to 93 . Formally , this was a " failed study " ( i.e. , neither active treatment was superior to placebo ) , and the efficacy results should , therefore , be interpreted with caution . On the basis of the primary efficacy parameter , fluoxetine showed significantly lower efficacy than both escitalopram and placebo , which were not significantly different from each other . Rates of withdrawal because of adverse events/lack of efficacy were : placebo ( 2.8%/4.4 % , respectively ) , escitalopram ( 9.8%/1.7 % , respectively ) , and fluoxetine ( 12.2%/1.8 % , respectively ) . No single adverse event occurred at an incidence > or = 10 % in escitalopram-treated patients . CONCLUSIONS Both escitalopram and fluoxetine were well tolerated by elderly patients with MDD . Neither demonstrated superior efficacy on primary endpoint versus placebo ABSTRACT Objective : The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment1 . The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine ( a dual serotonin and norepinephrine reuptake inhibitor ) and escitalopram ( a selective serotonin reuptake inhibitor ) . Research design and methods : This was a r and omized , double-blind , placebo- and active comparator-controlled study , in which patients ( ≥ 18 years ) meeting DSM‑IV criteria for Major Depressive Disorder ( MDD ) received duloxetine 60 mg once daily ( QD ; N = 273 ) , escitalopram 10 mg QD ( N = 274 ) , or placebo ( N = 137 ) for 8 weeks . The primary objective was to compare the onset of antidepressant efficacy , by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group . Main outcome measures : Onset of efficacy was defined as a 20 % decrease from baseline on the 17‑item Hamilton Rating Scale for Depression ( HAMD17 ) Maier subscale that was maintained or exceeded at all subsequent visits . Results : Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6 % versus 35.2 % , respectively ( treatment difference = 7.4 % ; 95 % confidence interval , –1.3 % to 16.2 % ; p = 0.097 ) . Both drugs showed significant improvement compared with placebo ( p ≤ 0.05 ) on the primary efficacy measure ( Maier subscale ) at Week 1 and endpoint ( Week 8) . No differences were found between duloxetine , escitalopram , and placebo rates of remission or response at 8 weeks . Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea , dry mouth , vomiting , yawning , and irritability . The rate of discontinuation due to adverse events did not differ significantly between treatment groups . Limitations : Given the difficulties in constructing appropriate dose comparisons , the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole . This study employed a fixed-dose design ; flexible-dose design s are more likely to find a difference between antidepressants and placebo . Conclusion : In this study , both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8‑week acute treatment period , while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks . Escitalopram at a starting dose of 10 mg QD was better tolerated  than duloxetine at a starting dose of 60 mg QD . This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram  in antidepressant onset efficacy , and the results show that duloxetine is at least as fast as ( non-inferior to ) escitalopram . Trial registration : Clinical Trials.gov identifier : NCT00073411 OBJECTIVE To examine the comparative antidepressant efficacy of S-adenosyl-L-methionine ( SAMe ) and escitalopram in a placebo-controlled , r and omized , double-blind clinical trial . METHOD One hundred eighty-nine out patients ( 49.7 % female , mean [ SD ] age = 45 [ 15 ] years ) with DSM-IV-diagnosed major depressive disorder ( MDD ) were recruited from April 13 , 2005 , to December 22 , 2009 , at the Massachusetts General Hospital and at Butler Hospital . Patients were r and omized for 12 weeks to SAMe 1,600 - 3,200 mg/d , escitalopram 10 - 20 mg/d , or placebo . Doses were escalated at 6 weeks in the event of nonresponse . The main outcome measure was the 17-item Hamilton Depression Rating Scale ( HDRS-17 ) . Tolerability was assessed by the Systematic Assessment for Treatment of Emergent Events-Specific Inquiry ( SAFTEE-SI ) . RESULTS All 3 treatment arms demonstrated a significant improvement of about 5 - 6 points in HDRS-17 scores ( P < .001 for all ) , and no significant differences were observed between the treatment arms ( P > .05 for all ) . Response rates in the intent-to-treat sample were 36 % for SAMe , 34 % for escitalopram , and 30 % for placebo .  Remission rates were 28 % for SAMe , 28 % for escitalopram , and 17 % for placebo . No comparisons between treatment groups attained significance ( P > .05 for all ) . Tolerability was good , with gastrointestinal side effects ( 19 % for stomach discomfort and 20 % for diarrhea ) as the most common in the SAMe arm . Significant differences were observed between treatment groups for dizziness , anorgasmia , diminished mental acuity , and hot flashes ( P < .05 for all ) . CONCLUSIONS The results fail to support an advantage over placebo for either the investigational treatment SAMe or the st and ard treatment escitalopram for MDD . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00101452 Fluvoxamine , a selective serotonin reuptake inhibitor , was investigated in a 6-week double-blind study among severely ill in patients with DSM-III major depression . All but 1 patient also fulfilled criteria for melancholia . Following a 3-day placebo wash-out patients were r and omly assigned to fluvoxamine , imipramine or placebo .  Sixty of 81 patients completed at least 2 weeks following wash-out and were evaluated for efficacy . Analysis of covariance ( controlling for baseline scores ) showed significant ( p less than 0.05 ) differences on CGI severity and BPRS total and a similar trend ( p = 0.08 ) on the Hamilton Depression Scale . Fluvoxamine was superior ( p less than or equal to 0.02 ) to both placebo and imipramine on these measures . Fluvoxamine 's most common adverse effects were nausea and agitation . The number of fluvoxamine patients withdrawn for side-effects was less than imipramine and not significantly different than placebo . Fluvoxamine was not associated with significant changes in vital signs , ECG or laboratory tests . The results therefore indicate that fluvoxamine is a safe and highly effective treatment for hospitalized patients with major depression BACKGROUND The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism . However , no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism , despite previous observations that both depression and alcoholism are associated with low serotonergic functioning . METHODS Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were r and omized to receive fluoxetine ( n = 25 ) or placebo ( n = 26 ) in a 12-week , double-blind , parallel-group trial . Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study . RESULTS The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group . Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group . CONCLUSIONS Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence . It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics Abstract Despite the high rate of co-occurrence of major depression and alcohol dependence , the role of pharmacotherapy in their treatment remains unclear . In the new era of naltrexone for alcohol dependence , it is notable that only 1 study to date has examined the efficacy of antidepressant medication prescribed concurrently with naltrexone . We aim ed to determine whether combining naltrexone with citalopram produced better treatment outcomes than naltrexone alone in patients with co-occurring alcohol dependence and depression , and to investigate whether either sex or depression type ( independent or substance-induced depression ) moderated treatment response . Participants were 138 depressed alcohol-dependent adults who were not required to be abstinent at the commencement of the trial . They were r and omized to 12 weeks of citalopram or placebo , plus naltrexone and clinical case management .  Treatment was well attended , and medications were reasonably well tolerated with high adherence rates . Substantial improvements in both mood and drinking occurred in both groups , with no significant differences between groups on any of the mood or drinking outcome measures , whether or not other variables were controlled for . No interaction effect was found for independent/substance-induced depression status , whereas there was a marginal effect found by sex , with greater improvement in 1 drinking outcome measure ( percent days abstinent ) in women taking citalopram . These findings suggest that citalopram is not a clinical ly useful addition to naltrexone and clinical case management in this treatment population . Independent/substance-induced depression status did not predict treatment response . Findings for sex were equivocal Paroxetine is a phenylpiperidine compound that selectively inhibits neuronal serotonin uptake in man . In this study , the efficacy of paroxetine was compared with that of placebo in the treatment of 66 out patients with the diagnosis of moderate-to-severe major depression . The research was a 6-week , prospect i ve , double-blind design after a 1-week placebo baseline phase . Paroxetine was associated with a consistent pattern of greater improvement on the primary efficacy scales , but the differences were not statistically significant . Paroxetine did produce significantly greater improvement than placebo for patients whose illness had lasted more than 1 year , and there was a significant reduction in suicidal ideation . Significantly fewer dropouts were due to lack of efficacy in those patients treated with paroxetine compared with those in the placebo group . Paroxetine was well tolerated . There was no difference between paroxetine and placebo in the rate of adverse effects or in the number of patients who dropped out because of adverse effects A double-blind , placebo- and amitriptyline-controlled comparison study was performed to evaluate the antidepressant efficacy of sertraline , a specific serotonin uptake inhibitor . Patients with DSM-III-defined major depression r and omly received either sertraline  ( N = 149 ) , amitriptyline ( N = 149 ) , or placebo ( N = 150 ) once daily for the 8-week study period . The mean final daily medication dose for the all- patients group was 145 mg and 104 mg for the sertraline- and amitriptyline-treatment groups , respectively . As measured by the Hamilton Rating Scale for Depression and the Clinical Global Impressions Scale , both the sertraline and amitriptyline treatment groups showed a significantly greater improvement from baseline ( p less than or equal to .001 ) than the placebo group . The sertraline group had a higher proportion of gastrointestinal complaints and male sexual dysfunction than either the amitriptyline or the placebo group . The amitriptyline group showed a higher proportion of anticholinergic and sedative side effects and dizziness compared with patients who received either sertraline or placebo Paroxetine is a selective serotonin reuptake inhibitor which is being developed as an antidepressant . Previous studies suggest it is effective in the treatment of depression and has a low incidence of side effects . The authors report on a 6-week , r and omized , prospect i ve trial of paroxetine , imipramine , and placebo in 120 out patients with major depression . The results showed that paroxetine was significantly superior to placebo in relieving depression . There were no significant differences in antidepressant efficacy between paroxetine and imipramine . However , paroxetine was also significantly superior to placebo on several measures of anxiety . Imipramine either was not superior on these measures or took longer to show a significant difference . Paroxetine lacked the typical anticholinergic side effects that accompanied imipramine therapy . The results show that paroxetine is an effective antidepressant that may have value especially when depression is accompanied by significant anxiety Paroxetine is an investigational antidepressant that acts through selective inhibition of serotonin reuptake at the synapse . In this study , 81 out patients with major depression according to DSM-III criteria were treated with either paroxetine or placebo in a 6-week , r and omized , double-blind study . Paroxetine was significantly superior to placebo on all major efficacy variables , including depression as well as anxiety , cognitive disturbance , insomnia , psychomotor retardation , and sleep disturbance . Significant differences in favor of paroxetine were apparent by Week 2 . Paroxetine was also well tolerated . The results support the efficacy and safety of paroxetine as a treatment for patients with major depression We evaluated the dexamethasone suppression test ( DST ) as a predictor of response to drugs and placebo in 105 patients , in a large double-blind placebo-controlled out-patient trial to determine the efficacy of paroxetine HCl , a selective serotonin reuptake inhibitor , compared with that of imipramine HCl and placebo . The presence of a positive or negative DST did not predict response to either paroxetine or imipramine . However , a positive DST predicted a poorer response to placebo :  only 3 out of 18 patients who showed DST non-suppression responded to placebo , as opposed to 11 out of 21 who exhibited DST suppression ( P less than 0.05 ) . A positive DST was associated with a 61 % response to drugs and a 16 % response to placebo . This finding suggests that the presence of a positive DST implies the need for active somatic treatment In a double-blind multi-centre study of general practice patients with DSM-III-R major depressive disorder , sertraline  ( 50 or 100 mg/day ) was compared with dothiepin ( 75 or 150 mg/day ) and with placebo . There were 83 , 96 and 90 patients evaluated in the respective treatment groups ; treatment lasted 6 weeks . Patients were assessed on the MADRS , CGI , and Leeds Self-rating Scales . Statistically significant differences ( p < 0.05 ) between sertraline and placebo were found on MADRS and CGI but not the Leeds Scales . In the mild subgroup analyses , there were no significant differences between sertraline and placebo . However , clear significant differences ( p < 0.05 ) between sertraline and placebo were present in the severe subgroup . Dothiepin failed to achieve a statistically significant difference from placebo on any analyses . Seventy-six per cent of patients were treated with 50 mg sertraline and 81 % of patients received 150 mg dothiepin . Both sertraline and dothiepin were generally well tolerated ; the most frequent side effects with sertraline were nausea , dizziness and headache ; with dothiepin the most frequent side effects were dry mouth , somnolence and headache Sexual dysfunction , a frequently reported side effect of many antidepressants , may result in patient dissatisfaction and noncompliance with treatment regimens . This paper describes the results of the first placebo-controlled comparison of the efficacy , safety , and effects on sexual functioning of sustained-release bupropion ( bupropion SR ) and the selective serotonin reuptake inhibitor sertraline . This r and omized , double-masked , double-dummy , parallel-group , multicenter trial enrolled 360 patients with moderate-to-severe recurrent major depression . Patients were treated with bupropion SR 150 to 400 mg/d , sertraline 50 to 200 mg/d , or placebo for up to 8 weeks . Patients ' depression and sexual functioning were assessed at weekly or biweekly clinic visits ; safety was assessed by regular monitoring of adverse events , vital signs , and body weight . Treatment groups were similar at baseline in terms of age , sex , and race , and most patients had a diagnosis of moderate uncomplicated depression . Patients treated with bupropion SR or sertraline showed similar improvements on all efficacy measures ; both active treatments were superior to placebo in improving scores on all rating scales for depression at various time points . Significantly more patients treated with sertraline experienced orgasmic dysfunction throughout the study than did patients treated with bupropion SR or placebo ( P < 0.001 ) . Headache was the most frequently reported adverse event in all 3 treatment groups and occurred with similar frequency in each group ( 30 % to 40 % ) . Nausea ( 31 % ) , diarrhea ( 26 % ) , insomnia ( 18 % ) , and somnolence ( 17 % ) occurred in significantly more patients in the sertraline group than in the bupropion SR group ( 18 % , 7 % , 13 % , and 3 % , respectively ) and the placebo group ( 10 % , 11 % , 4 % , and 6 % , respectively ) . Dry mouth occurred more frequently with bupropion SR ( 19 % ) than with sertraline ( 14 % ) or placebo ( 12 % ) , although the differences were not significant . Changes in vital signs were similar in all groups . Similar ( small , but not statistically significant ) decreases in mean body weight were seen in both the bupropion SR ( -1.06 kg ) and sertraline ( -0.79 kg ) groups , whereas the placebo group experienced a minor increase ( 0.21 kg ) . Although bupropion SR and sertraline were similarly well tolerated and effective in the treatment of depression , sertraline treatment was more often associated with sexual dysfunction and certain other adverse events compared with bupropion SR and placebo . Therefore , bupropion SR may be an appropriate choice as an antidepressant for the treatment of sexually active patients 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 BACKGROUND Depression is common among recently abstinent alcoholics ; however , its treatment has been little studied . METHODS Thirty-six depressed recently abstinent alcoholics were r and omized in a 6-week double-blind placebo-controlled trial of sertraline 100 mg daily . RESULTS There was a significant group x time interaction for both the Hamilton Depression Rating Scale ( HDRS ) and the Beck Depression Inventory ( BDI ) . For the HDRS there were significant differences between the sertraline and placebo groups at weeks 3 and 6 and for the BDI at week 3 . Also , patients receiving sertraline had significantly lower mean posttreatment HDRS and BDI scores than patients receiving placebo . Furthermore , significantly more of the patients receiving sertraline obtained a Clinical Global Impression rating of " very much improved . " CONCLUSIONS Depressed recently abstinent alcoholics benefit from antidepressant medication The authors employed a double-blind , placebo-controlled design to investigate the effectiveness of fluvoxamine versus imipramine in 54 out patients with moderate major depression .  Fluvoxamine proved superior to placebo but not to imipramine on the Hamilton Rating Scale for Depression and the Montgomery and Asberg Depression Rating Scale . Nausea and hyperarousal were the most common side effects in the fluvoxamine-treated patients Background Cocaine dependence is a major public health problem with no available robustly effective pharmacotherapy . This study ’s aim was to determine if treatment with sertraline ( SERT ) or SERT plus gabapentin ( GBP ) improved treatment retention , depressive symptoms , and /or cocaine use . Methods Depressed cocaine-dependent patients ( N = 99 ) were enrolled in a 12-week , double-blind , r and omized , placebo (PLA)-controlled , clinical trial and placed in research beds at a residential treatment facility ( Recovery Centers of Arkansas ) . They were r and omized by depressive symptom severity and inducted onto 1 of the following while residing at the Recovery Centers of Arkansas : SERT ( 200 mg/d ) , SERT ( 200 mg/d ) plus GBP ( 1200 mg/d ) , or PLA . Participants transferred to outpatient treatment at the start of their third week , continued receiving study medications or PLA ( weeks 3–12 ) , and participated in weekly individual cognitive behavioral therapy . Compliance was facilitated through the use of contingency management procedures . Supervised urine sample s were obtained thrice weekly and self-reported mood weekly . At the end of 12 weeks , participants were tapered off the study medication over 5 days and referred to a local treatment program . Results Sertraline , but not SERT plus GBP , showed a significantly lower overall percentage of cocaine-positive urine sample s compared with that of PLA . A significantly greater percentage of participants experienced relapse in the PLA group ( 88.9 % ) compared with that of the SERT group ( 65.2 % ) . Hamilton depression ratings decreased significantly over time regardless of the treatment group . Retention in treatment did not differ significantly between the treatment groups . Conclusions Sertraline plus GBP may not be superior to SERT alone in delaying relapse among abstinent cocaine-dependent individuals undergoing cognitive behavioral therapy 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 Paroxetine is a novel antidepressant that selectively inhibits neuronal reuptake of serotonin . Results are reported from a 6-week , double-blind trial of paroxetine , imipramine , and placebo in 120 out patients with DSM-III major depression .  Paroxetine was significantly superior to placebo on almost all measures . This included the main outcome variable , the Hamilton Rating Scale for Depression ( HAM-D ) , and its factor scores , anxiety-somatization , cognitive disturbance , psychomotor retardation , and sleep disturbance . There were no significant differences between paroxetine and imipramine on the same scales . Imipramine-treated patients were significantly more likely than those taking placebo to report one or more adverse effects , which were predominantly anticholinergic in nature . There was no significant difference in the number of paroxetine and placebo patients who reported one or more adverse effects . The results of this and similar studies indicate that paroxetine is an effective treatment in major depression and has a favorable side effect profile Results from a single-center , 6-week , double-blind , r and omized prospect i ve study of paroxetine , a selective serotonin reuptake inhibitor ; imipramine ; and placebo are reported . One hundred twenty out patients with a moderate-to-severe DSM-III diagnosis of major depression were r and omly assigned to one of the three treatments following a 4- to 10-day single-blind placebo washout period . Significant differences favoring paroxetine over placebo were present at endpoint on most major efficacy measures .  Paroxetine was also well tolerated ; 5 ( 15 % ) paroxetine and 5 ( 14 % ) placebo patients dropped out of the study due to adverse effects .  Imipramine , however , was comparatively poorly tolerated . Forty-five percent of  imipramine-treated patients ( N = 17 ) dropped out of the study due to adverse effects . None of the efficacy measures showed a significant difference between imipramine and placebo . This finding was probably due to the high number of imipramine patients who discontinued before they could improve . These results support the efficacy of paroxetine in the treatment of major depression and underline its favorable side effect profile compared with tricyclic antidepressants INTRODUCTION Flibanserin , a novel 5-HT(1A ) agonist and 5-HT(2A ) antagonist , has the potential to treat  sexual dysfunction .  AIM Provide historical perspective on the rationale for development of flibanserin to treat sexual dysfunction , based on post hoc analyses of data . MAIN OUTCOME MEASURES The Arizona Sexual Experiences ( ASEX ) scale and the Hamilton depression rating scale ( HAMD ) Genital Symptoms item . METHODS Sexual function outcomes are presented from four double-blind , r and omized controlled studies involving a total of 369 men and 523 women diagnosed with Major Depressive Disorder . Each study had an active treatment arm to confirm assay sensitivity on the primary antidepressive endpoint . Two studies placebo , flibanserin ( 50 mg bid ) , or fluoxetine ( 20 mg qd ) for 6 weeks and two involved placebo , flibanserin ( 50 - 100 mg bid ) , or paroxetine ( 20 - 40 mg qd ) for 8 weeks . RESULTS Individual study completion rates were 77 - 80 % . At baseline , 38 % of men and 67 % of women reported sexual dysfunction . Assay sensitivity was not demonstrated in the fluoxetine trials and sexual function outcomes were inconsistent . Flibanserin and placebo were associated with low rates of treatment-emergent sexual dysfunction in women during the paroxetine studies . In one study , 70 % of flibanserin-treated women with baseline sexual dysfunction reported improvement in sexual function , compared with 30 % of placebo-treated women . Mean change from baseline on the HAMD " Genital Symptoms " item in one paroxetine study was significantly better among flibanserin- than placebo-treated women at weeks 4 , 6 , and 8 ( P<0.05 ) . Sexual function adverse events across flibanserin groups were generally comparable to placebo . CONCLUSIONS Although these studies were not design ed or powered to compare sexual function outcomes , results suggested a potential benefit of flibanserin on sexual function , particularly on female sexual desire , and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder Meta-analyses indicate that antidepressants are superior to placebos in statistical terms , but the clinical relevance of the differences has not been established . Previous suggestions of clinical ly relevant effect sizes have not been supported by empirical evidence . In the current paper we apply an empirical method that consists of comparing scores obtained on the Hamilton rating scale for depression ( HAM-D ) and scores from the Clinical Global Impressions-Improvement ( CGI-I ) scale . This method reveals that a HAM-D difference of 3 points is undetectable by clinicians using the CGI-I scale . A difference of 7 points on the HAM-D , or an effect size of 0.875 , is required to correspond to a rating of ' minimal improvement ' on the CGI-I. By these criteria differences between antidepressants and placebo in r and omised controlled trials , including trials conducted with people diagnosed with very severe depression , are not detectable by clinicians and fall far short of levels consistent with clinical ly observable minimal levels of improvement . Clinical significance should be considered alongside statistical significance when making decisions about the approval and use of medications like antidepressants BACKGROUND Antidepressant efficacy may be compromised by early discontinuation of treatment secondary to common , treatment-emergent side effects , including nausea , agitation , and somnolence .  Paroxetine controlled-release ( CR ) was developed to improve general tolerability and , in particular , gastrointestinal tolerability . OBJECTIVE To determine the antidepressant efficacy and tolerability of paroxetine CR in adult patients 18 to 65 years of age with DSM-IV major depressive disorder . METHOD Paroxetine CR ( 25 - 62.5 mg/day ; N = 212 ) and paroxetine immediate-release ( IR ; 20 - 50 mg/day ; N = 217 ) were compared with placebo ( N = 211 ) in the pooled data set from 2 identical , double-blind , 12-week clinical trials . RESULTS Both paroxetine CR and paroxetine IR exhibited efficacy in major depressive disorder as assessed by the reduction in 17-item Hamilton Rating Scale for Depression total score compared with placebo . Moreover , depressed mood and psychic anxiety symptoms improved as early as treatment week 1 in the paroxetine CR group compared with the placebo group . After 6 weeks of treatment , response and remission rates were 41.5 % and 20.5 % for placebo , 52.8 % and 29.6 % for paroxetine IR , and 58.9 % and 34.4 % for paroxetine CR , respectively . After 12 weeks of treatment , response and remission rates were 61.2 % and 44.0 % for placebo , 72.9 % and 52.5 % for paroxetine IR , and 73.7 % and 56.2 % for paroxetine CR , respectively . Rates of nausea were significantly lower for paroxetine CR ( 14 % ) than for paroxetine IR ( 23 % ; p < or = .05 ) during week 1 . Rates of dropout due to adverse events were comparable between paroxetine CR and placebo , while significantly ( p = .0008 ) more patients treated with paroxetine IR withdrew from the study prematurely compared with those treated with placebo . CONCLUSION Paroxetine CR is an effective and well-tolerated antidepressant exhibiting symptomatic improvement as early as week 1 . Paroxetine CR is associated with low rates of early-onset nausea and dropout rates due to adverse events comparable to those of placebo . The clinical improvement seen with paroxetine CR , coupled with its favorable adverse event profile , suggests a benefit for therapeutic outcome with paroxetine CR A total of 149 patients in 7 centers in Denmark , Norway and Sweden entered a 6‐week double‐blind trial intended to assess the antidepressant effect and safety of citalopram vs placebo in depressed elderly patients ( 65 years of age or older ) who might also suffer from somatic disorders and /or senile dementia . Results of ratings on the Hamilton Rating Scale for Depression , the Montgomery‐Åsberg Depression Rating Scale and the Clinical Global Impression Scale provided consistent evidence that the citalopram‐treated patients improved more than the placebo‐treated patients . Results of ratings on the Gottfries‐Bråne‐Steen dementia rating scale indicated that both cognitive and emotional functioning improved significantly more in the citalopram‐treated subgroup of patients with dementia than in the placebo‐treated subgroup 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 Paroxetine , a phenylpiperidine derivative , is an antidepressant that selectively inhibits serotonin reuptake . In this study 111 out patients with major depression diagnosed by DSM-III criteria were treated with either paroxetine or placebo in a 6-week , r and omized , double-blind study . Paroxetine was significantly superior to placebo on six of the seven major efficacy variables . Significant differences in favor of paroxetine were apparent by Week 2 . Paroxetine was also well tolerated . These results support the efficacy and safety of paroxetine as a treatment for patients with major depression Aprepitant is a neurokinin 1 receptor antagonist approved for prevention of chemotherapy‐induced and  post‐operative nausea and vomiting . Early studies demonstrated promising antidepressant activity as monotherapy , although this was unsupported by subsequent phase 3 trials . This phase 2 study evaluated whether aprepitant  potentiated the antidepressant effects of paroxetine The objective of this study was to compare venlafaxine and fluoxetine with placebo in treating major depressive disorder with melancholic features . Adult in patients with Diagnostic and Statistical Manual of Mental Disorders , fourth edition major depressive disorder with melancholia and 21-item Hamilton Depression Rating Scale ( HAM-D21 ) scores ≥24 ( n=289 ) were r and omized to receive ( double-blind ) venlafaxine 225–375 mg/day , fluoxetine 60–80 mg/day , or placebo for 6 weeks . The primary outcome measures were HAM-D21 total score , HAM-D depressed mood item , Montgomery Åsberg Depression Rating Scale total score and the Clinical Global Impressions-Severity ( CGI-S ) and Improvement ( CGI-I ) scores . Last observation carried forward ( LOCF ) was the primary analysis method . In the LOCF analysis , venlafaxine was statistically superior to placebo on the CGI-S ( venlafaxine −1.7 , placebo −1.1 ; P=0.003 ) and the HAM-D depressed mood item ( venlafaxine −1.6 , placebo −1.1 ; P=0.010 ) ; and to fluoxetine on the CGI-S ( −1.2 ; P=0.012 ) . No significant differences were observed on the other 12 LOCF primary efficacy comparisons . Increases in pulse and blood pressure , dry mouth , constipation , and lightheadedness were significantly more common with venlafaxine than fluoxetine . Venlafaxine was statistically superior to placebo on two of five primary and two of five secondary outcome measures and to fluoxetine on one primary and one secondary outcome measure ( LOCF ) . Venlafaxine was not superior to fluoxetine or placebo in providing remission Published evidence suggests that aspects of trial design lead to biased intervention effect estimates , but findings from different studies are inconsistent . This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials . Outcome measures were classified as " mortality , " " other objective , " " or subjective , " and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity . Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear ( vs. adequate ) r and om-sequence generation ( ratio of odds ratios , 0.89 [ 95 % credible interval { CrI } , 0.82 to 0.96 ] ) and with inadequate or unclear ( vs. adequate ) allocation concealment ( ratio of odds ratios , 0.93 [ CrI , 0.87 to 0.99 ] ) . Lack of or unclear double-blinding ( vs. double-blinding ) was associated with an average of 13 % exaggeration of intervention effects ( ratio of odds ratios , 0.87 [ CrI , 0.79 to 0.96 ] ) , and between-trial heterogeneity was increased for such studies ( SD increase in heterogeneity , 0.14 [ CrI , 0.02 to 0.30 ] ) . For each characteristic , average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes , with little evidence of bias in trials with objective and mortality outcomes . This study is limited by incomplete trial reporting , and findings may be confounded by other study design characteristics . Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes
target: SSRIs significantly increase the risk of both serious and non-serious adverse events .
  The potential small beneficial effects seem to be outweighed by harmful effects .
background: Background The evidence on selective serotonin reuptake inhibitors ( SSRIs ) for major depressive disorder is unclear .
  Methods Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo , ‘ active ’ placebo , or no intervention in adult participants with major depressive disorder .