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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) . . .

Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82],  < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52],  < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Severe depression can be a life-threatening disorder, especially in elderly patients. A fast-acting treatment is crucial for this group. Electroconvulsive therapy (ECT) may work faster than medication. To compare the speed of remission using ECT v. medication in elderly in-patients. The speed of remission in in-patients with a DSM-IV diagnosis of major depression (baseline MADRS score ≥20) was compared between 47 participants (mean age 74.0 years, s.d. = 7.4) from an ECT randomised controlled trial (RCT) and 81 participants (mean age 72.2 years, s.d. = 7.6) from a medication RCT (nortriptyline v. venlafaxine). Mean time to remission was 3.1 weeks (s.d. = 1.1) for the ECT group and 4.0 weeks (s.d. = 1.0) for the medication group; the adjusted hazard ratio for remission within 5 weeks (ECT v. medication) was 3.4 (95% CI 1.9-6.2). Considering the substantially higher speed of remission, ECT deserves a more prominent position in the treatment of elderly patients with severe depression.

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

Hot flushes are the most common complaints reported by men undergoing androgen suppression treatment for prostate cancer. We designed a randomised double-blind trial to compare the efficacy of three drugs, each of which has proven effective for preventing hot flushes in previous studies. Men with prostate cancer with an indication for androgen suppression were enrolled in the study at 106 urology centres in France between April 14, 2004, and April 20, 2007. All patients were treated for 6 months with leuprorelin (11·25 mg). At month 6, patients who spontaneously asked for treatment, or those who presented with 14 hot flushes or more during the week before the visit, were randomly assigned to either venlafaxine 75 mg daily, medroxyprogesterone acetate 20 mg daily, or cyproterone acetate 100 mg daily. All patients received two indistinguishable pills in the morning and one in the evening from week 1 to week 8, and one indistinguishable pill in the morning from week 9 to week 10, to comply with the double-blind design. Random assignment with a block size of three was done centrally, by fax, and each patient was given a randomisation number. The allocation sequence was stratified by centre. Assessment was done at inclusion, at randomisation, and then at 4 weeks, 8 weeks, and 12 weeks after randomisation. Participants completed a daily hot-flush diary for 1 week, and a quality of life questionnaire before each visit throughout the study. The primary outcome was the change in median daily hot-flush score between randomisation and 1 month. All patients who received at least one study treatment dose were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01011751. Of the 919 men initially enrolled, 311 were randomly assigned to one of the study treatments at 6 months: 102 to venlafaxine, 101 to cyproterone, and 108 to medroxyprogesterone. 309 patients were included in the efficacy analysis, since two were excluded for protocol deviations (one in the cyproterone and one in the medroxyprogesterone group; both were excluded because they were already undergoing treatment with serotonin reuptake inhibitor antidepressants at randomisation). The change in median daily hot-flush score between randomisation and 1 month was −47·2% (IQR −74·3 to −2·5) in the venlafaxine group, −94·5% (−100·0 to −74·5) in the cyproterone group, and −83·7% (−98·9 to −64·3) in the medroxyprogesterone group. The decrease from baseline was significant for all three groups (p<0·0001). Pairwise comparison of treatment groups adjusted by the Bonferroni method confirmed that the decreases in hot-flush score were significantly larger in the cyproterone and medroxyprogesterone groups than in the venlafaxine group, regardless of the interval considered (p<0·0001 in all cases). There was no significant difference between the cyproterone and medroxyprogesterone groups (p>0·2 in all cases). Serious side-effects occurred in four, seven, and five patients in the venlafaxine, cyproterone, and medroxyprogesterone groups, respectively, of which none, one (dyspnoea), and one (urticaria) were considered related to the drug, respectively. After 6 months of treatment with leuprorelin, venlafaxine, cyproterone, and medroxyprogesterone proved to be effective in reducing hot flushes. However, the hormonal treatments cyproterone and medroxyprogesterone were significantly more effective than venlafaxine. As cyproterone is a recognised treatment in prostate cancer, and its use could interfere with hormonal therapy, medroxyprogesterone could be considered to be the standard treatment for hot flushes in men undergoing androgen suppression for prostate cancer. Takeda Laboratories, Puteaux, France.

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

Hot flashes can be troublesome, especially when hormonal therapy is contraindicated. Preliminary data have suggested that newer antidepressants, such as venlafaxine, can diminish hot flashes. We undertook a double-blind, placebo-controlled, randomised trial to assess the efficacy of venlafaxine in women with a history of breast cancer or reluctance to take hormonal treatment because of fear of breast cancer. Participants were assigned placebo (n=56) or venlafaxine 37·5 mg daily (n=56), 75 mg daily (n=55), or 150 mg daily (n=54). After a baseline assessment week, patients took the study medication for 4 weeks. All venlafaxine treatment started at 37·5 mg daily and gradually increased in the 75 mg and 150 mg groups. Patients completed daily hot-flash questionnaire diaries. The primary endpoint was average daily hot-flash activity (number of flashes and a score combining number and severity). Analyses were based on the women who provided data throughout the baseline and study weeks. 191 patients had evaluable data for the whole study period (50 placebo, 49 venlafaxine 37·5 mg, 43 venlafaxine 75 mg, 49 venlafaxine 150 mg). After week 4 of treatment, median hot flash scores were reduced from baseline by 27% (95% CI 11–34), 37% (26–54), 61% (50–68), and 61% (48–75) in the four groups. Frequencies of some side-effects (mouth dryness, decreased appetite, nausea, and constipation) were significantly higher in the venlafaxine 75mg and 150 mg groups than in the placebo group. Venlafaxine is an effective non-hormonal treatment for hot flashes, though the efficacy must be balanced against the drug's side-effects. Confirmation of the results of this 4-week study awaits the completion of three ongoing randomised studies to assess the effects of other related antidepressants for the treatment of hot flashes.

Prior studies have suggested that major depressive disorder (MDD) with pre-adult onset represents a distinct subtype with greater symptom severity and higher rates of suicidal ideation. Whether these patients have poorer response to various types of antidepressant treatment than those with adult-onset MDD is unclear. Method A total of 665 psychiatric and primary care out-patients (aged 18-75 years) with non-psychotic chronic or recurrent MDD participated in a single-blind, randomized trial that compared the efficacy of escitalopram plus placebo, bupropion sustained-release plus escitalopram, or venlafaxine extended-release plus mirtazapine. We compared participants who self-reported MDD onset (before age 18) to those with a later onset (adult onset) with respect to baseline characteristics and treatment/outcome variables at 12 and 28 weeks. Early-onset chronic/recurrent MDD was associated with a distinct set of sociodemographic (female, younger age) and clinical correlates (longer duration of illness, greater number of prior episodes, greater likelihood of atypical features, higher rates of suicidality and psychiatric co-morbidity, fewer medical problems, poorer quality of life, greater history of child abuse/neglect). However, results from unadjusted and adjusted analyses showed no significant differences in response, remission, tolerability of medications, quality of life, or retention at 12 or 28 weeks. Although early-onset chronic/recurrent MDD is associated with a more severe clinical picture, it does not seem to be useful for predicting differential treatment response to antidepressant medication. Clinicians should remain alert to an increased risk of suicidality in this population.

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 .

It had been suggested that the antidepressant venlafaxine, which inhibits reuptake of both serotonin and (at higher doses) noradrenaline, may result in better outcomes than treatment with selective serotonin reuptake inhibitors (SSRIs). To compare remission rates during treatment with SSRIs or venlafaxine. Data from eight comparable randomised, double-blind studies of major depressive disorder were pooled to compare remission rates (Hamilton Rating Scale for Depression score < or = 7) during treatment with venlafaxine (n = 851), SSRIs (fluoxetine, paroxetine, fluvoxamine; n = 748) or placebo (four studies; n = 446). Remission rates were: venlafaxine, 45% (382/851); SSRIs, 35% (260/748); placebo, 25% (110/446) (P: < 0.001; odds ratio for remission is 1.50 (1.3-1.9), favouring venlafaxine v. SSRIs). The difference between venlafaxine and the SSRIs was significant at week 2, whereas the difference between SSRIs and placebo reached significance at week 4. Results were not dependent on any one study or the definition of remission. Remission rates were significantly higher with venlafaxine than with an SSRI.