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Adult outpatients with a nonpsychotic major depressive disorder received sustained-release bupropion, sertraline, or extended-release venlafaxine after a lack of response to or an inability to tolerate the selective serotonin-reuptake inhibitor (SSRI) citalopram. Approximately one in four patients had a remission of symptoms after switching to another antidepressant. All these medications provided a reasonable second-step choice for depressed outpatients who did not have a remission with or could not tolerate the SSRI. Adult outpatients with a nonpsychotic major depressive disorder received bupropion, sertraline, or venlafaxine after a lack of response to or an inability to tolerate citalopram. Approximately one in four patients had a remission of symptoms after switching to another antidepressant. Major depressive disorder is associated with substantial morbidity, mortality, family burden, and health care costs. 1 Since no single treatment is uniformly effective, 2 – 4 subsequent interventions are often needed. Second-step treatments include augmenting the first agent with a second or discontinuing the first agent and beginning a second (switching). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial used an equipoise, stratified, randomized design to evaluate the relative efficacy and tolerability of various antidepressant treatments for outpatients with nonpsychotic major depressive disorder who had a lack of remission or could not tolerate the selective serotonin-reuptake inhibitor (SSRI) citalopram (Celexa, Forest Pharmaceuticals) . . .

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ⩾30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD.

Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression. To examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers. In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers. A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline. More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.

Background Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators. Methods/Design The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm. Discussion First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide. Trial registration International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849 URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1

Background The clinical effects of mucolytics in patients with chronic obstructive pulmonary disease (COPD) are discussed controversially. Cineole is the main constituent of eucalyptus oil and mainly used in inflammatory airway diseases as a mucolytic agent. We hypothesised that its known mucolytic, bronchodilating and anti-inflammatory effects as concomitant therapy would reduce the exacerbation rate and show benefits on pulmonary function tests as well as quality of life in patients with COPD. Methods In this double-blind, placebo-controlled multi-center-study we randomly assigned 242 patients with stable COPD to receive 200 mg of cineole or placebo 3 times daily as concomitant therapy for 6 months during winter-time. The frequency, duration and severity of exacerbations were combined as primary outcome measures for testing as multiple criteria. Secondary outcome measures included changes of lung function, respiratory symptoms and quality of life as well as the single parameters of the exacerbations. Results Baseline demographics, lung function and standard medication of both groups were comparable. During the treatment period of 6 months the multiple criteria frequency, severity and duration of exacerbations were significantly lower in the group treated with cineole in comparison to placebo. Secondary outcome measures validated these findings. Improvement of lung function, dyspnea and quality of life as multiple criteria were statistically significant relative to placebo. Adverse events were comparable in both groups. Conclusion Concomitant therapy with cineole reduces exacerbations as well as dyspnea and improves lung function and health status. This study further suggests cineole as an active controller of airway inflammation in COPD by intervening in the pathophysiology of airway inflammation of the mucus membrane. Trial registration ISRCTN07600011

ABSTRACT Objective: To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD). Research design and methods: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D17) scores ≥20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks. The primary efficacy measure was the HAM-D17. Changes from baseline in HAM-D17 scores were analyzed using analysis of covariance. The final on-therapy evaluation was the primary endpoint for efficacy analyses, using last-observation-carried-forward data. Main outcomes measures and results: The intent-to-treat population included 447 patients. Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D17 (−11.5) compared with placebo (−9.5, p = 0.018); the 100-mg dose group (−11.0) did not achieve statistical significance (p = 0.065). The 100-mg dose group experienced significant improvements compared with placebo on several secondary efficacy measures, including the 6-item Hamilton Depression Rating Scale (p = 0.038) and the Visual Analog Scale–Pain Intensity total score (p = 0.041). Both desvenlafaxine doses were generally well-tolerated. The most common adverse events (incidence ≥10% in either desvenlafaxine group and twice the rate of placebo) were dry mouth, constipation, insomnia, decreased appetite, hyperhidrosis, and dizziness. Conclusions: These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. The significant findings on secondary measures support the efficacy of desvenlafaxine 100 mg, as seen in other trials. Conclusions may be limited by the exclusion of MDD patients with comorbid conditions and the short-term desvenlafaxine treatment duration.

Background In an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder. Methods Adult outpatients with DSM-IV–defined major depressive disorder and a 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) total score ≥20 were randomly assigned to receive placebo or desvenlafaxine (10 or 50 mg/day) after a 6- to 14-day single-blind placebo lead-in period in an 8-week, phase 3, fixed-dose trial. The primary efficacy measure was change from baseline in the HAM-D 17 score analyzed using analysis of covariance. Efficacy analyses were conducted with the intent-to-treat population, using the last observation carried forward. Results The intent-to-treat population included 673 patients. Change from baseline to final evaluation in adjusted HAM-D 17 total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42). There were no differences among treatment groups in the rates of treatment response or remission. Discontinuations due to adverse events occurred in 1.8%, 0.9%, and 1.8% of patients in the placebo and desvenlafaxine 10- and 50-mg/day groups, respectively. Overall rates of treatment-emergent adverse events with both doses were similar to placebo. Conclusions Both doses of desvenlafaxine failed to separate from placebo. However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. ClinicalTrials.gov Identifier NCT00863798 http://clinicaltrials.gov/ct2/show/NCT00863798?term=00863798&rank=1 .

This study investigated clinical and genetic predictors of increasing suicidal ideation during antidepressant treatment. A total of 131 depressed outpatients were allocated to four antidepressants (paroxetine, venlafaxine, clomipramine or nefazodone) in a sequential step procedure until remission. Suicidality was assessed using the 10th item of the Montgomery-–Asberg Depression Rating Scale (MADRS). A total of 11 candidate genes involved in different mechanisms of antidepressant action were selected for association with increasing suicidality. Increasing suicidality correlated with depression severity and higher antidepressant blood levels. Risk of increasing suicidal ideation was higher in subjects taking antidepressants other than paroxetine (odds ratio: 1.11). The strongest genetic predictor was found to be rs1360780 within the gene (p = 2.9 ×× 10 ), followed by 2677G>T in the gene. The rs130058 SNP within the gene demonstrated a differential association with increasing suicidal ideation depending on antidepressant type. Increasing suicidal ideation might be an adverse effect of antidepressants. The involvement of indicates that dysregulation of the hypothalamic-–pituitary-–adrenal axis is involved in treatment increasing suicidal ideation. Original submitted 12 October 2010; Revision submitted 18 November 2010.

Background: Major depressive disorder (MDD) is a common, chronic illness associated with substantial disability and economic burden. Although a number of effective antidepressants are available, the need for new medications that are effective and well tolerated remains. Objective: The aim of this study was to compare the efficacy and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/d with placebo for MDD. A post hoc pooled analysis was conducted to evaluate this study in the context of all similarly designed, completed studies with the 2 doses. Methods: This was an 8-week, Phase III, randomized, double-blind, duloxetine-referenced, placebo-controlled, parallel-group trial conducted in 21 centers across the United States. Duloxetine was included for assay sensitivity as a positive control; the study was not designed or powered to compare desvenlafaxine with duloxetine. Participants were outpatients aged ≥18 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition—defined MDD and a 17-item Hamilton Rating Scale for Depression (HAM-D 17) score ≥20. Patients were randomly assigned at baseline to fixed-dose desvenlafaxine (50 or 100 mg/d), fixed-dose duloxetine (60 mg/d), or placebo. The primary outcome measure was HAM-D 17 total score at the final evaluation. Additional measures included the Clinical Global Impressions-Improvement (CGI-I) score, Montgomery Åsberg Depression Rating Scale (MADRS) score, Clinical Global Impressions-Severity (CGI-S) score, and 6-item Hamilton Rating Scale for Depression, Bech version (HAM-D 6). Tolerability assessments included discontinuation rates, adverse events (AEs), vital signs, and laboratory tests. The post hoc pooled analysis was performed using data from the current study and 2 previously published, positive studies that compared the efficacy and tolerability of desvenlafaxine 50 and 100 mg/d with placebo for MDD. The design and methodologies of the 2 studies were similar to the methodology of the current trial, other than not including a reference compound. Results: Of the 925 patients who were screened, 287 did not meet entry criteria, and 638 patients enrolled in the study; the intent-to-treat (ITT) population included 615 patients who were evaluated for efficacy (mean [SD] age range, 38.8–40.7 [12.1–13.2] years; mean weight range, 83.3–87.0 [22.8–23.9] kg; female sex, 398 [64.7%]; white race, 458 [74.5%]). The primary end point did not reach significance based on the global F test for controlling multiplicity of the desvenlafaxine doses. Based on pairwise comparison, significantly greater improvements on the HAM-D 17 were observed in the desven-lafaxine 100 mg/d (−10.5; P = 0.028, unadjusted for multiple comparisons) and duloxetine 60 mg/d groups (−10.3; P = 0.047) compared with placebo (−8.7). Desvenlafaxine 100 mg/d and duloxetine 60 mg/d were associated with significantly better scores compared with placebo on the CGI-I, MADRS, CGI-S, and HAM-D 6. No significant differences were observed in any scale between the desvenlafaxine 50 mg/d and placebo groups. Discontinuation rates due to AEs were 5%, 7%, 13%, and 6% for the desvenlafaxine 50-mg/d, desvenlafaxine 100-mg/d, duloxetine 60-mg/d, and placebo groups, respectively. The ITT population from all 3 studies in the pooled analysis consisted of 1388 patients (mean [SD] age range, 38.8–45.7 [12.1–12.6] years; mean weight range, 73.1–87.0 [17.6–23.9] kg; female sex, 896 [64.6%]; white race, 1136 [81.8%]). Significantly greater improvements on the HAM-D 17 were observed for desvenlafaxine 50 mg/d (−11.5; P < 0.001) and 100 mg/d (−11.8; P < 0.001) versus placebo (−9.6). Both doses were significantly better than placebo on the CGI-I, MADRS, and HAM-D 6. Conclusions: The current study failed to meet its primary efficacy end point based on the a priori analysis plan. Desvenlafaxine was generally well tolerated. A post hoc pooled analysis of this trial and 2 previously published trials with both desvenlafaxine 50 and 100 mg/d found both doses to be effective for MDD compared with placebo. ClinicalTrials.gov Identifier: 00384033.

Few randomized, placebo-controlled trials have evaluated the comparative efficacy and tolerability of more than one pharmacological agent for panic disorder. The primary objective of this study was to compare the efficacy and tolerability of venlafaxine extended release (ER) with placebo in treating panic disorder. Secondary objectives included comparing paroxetine with venlafaxine ER and placebo. Outpatients aged > or =18 years (placebo, n = 157; venlafaxine ER 75 mg, n = 156; venlafaxine ER 225 mg, n = 160; paroxetine, n = 151), with a primary diagnosis of panic disorder (+/-agoraphobia) based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for > or =3 months were randomly assigned to receive venlafaxine ER (titrated to 75 mg/day or 225 mg/day), paroxetine (titrated to 40 mg/day), or placebo for 12 weeks. The primary efficacy measure was the percentage of patients free of full-symptom panic attacks (> or = four symptoms) at endpoint. Key secondary outcomes included the Panic Disorder Severity Scale (PDSS) mean score change and response. At endpoint, all active treatment groups showed a significantly (P < 0.01) greater proportion of patients free of full-symptom panic attacks, compared with placebo, and were superior (P < 0.05) on most secondary measures. The venlafaxine ER 225 mg group had significantly (P < 0.05) greater mean PDSS score improvement than the paroxetine group (-12.58 vs -11.87) and a significantly higher proportion of patients free of full symptom panic attacks (70.0 vs 58.3%). Both drugs were generally well tolerated. Venlafaxine ER 75 mg/days and 225 mg/days and paroxetine 40 mg/day were both well tolerated and effective for short-term treatment of panic disorder.