Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer. A preliminary report.

Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A(2)) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A(2) (11.9, 25, 35 or 50 IU/kg) or placebo in a 4:1 ratio. Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5-7. The primary end-point was incidence and severity of adverse events. Thirty-five patients were randomised to rFXIII-A(2) and eight to placebo. Eighteen serious adverse events were reported. These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/kg rFXIII-A(2) was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25-50 IU/kg rFXIII-A(2) restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A(2), in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For post-operative FXIII replenishment, 35 IU/kg of rFXIII-A(2) may be the most appropriate dose.

Escitalopram versus SNRI antidepressants in the acute treatment of major depressive disorder: integrative analysis of four double-blind, randomized clinical trials.

INTRODUCTION: Recent data suggest that escitalopram may be more effective in severe depression than other selective serotonin reuptake inhibitors. METHODS: Individual patient data from four randomized, double-blind comparative trials of escitalopram versus a serotonin/norepinephrine reuptake inhibitor (SNRI) (two trials with duloxetine and two with venlafaxine extended release) in outpatients (18-85 years of age) with moderate-to-severe major depressive disorder were pooled. The primary efficacy parameter in all four trials was mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. RESULTS: Significantly fewer escitalopram (82/524) than SNRI (114/527) patients prematurely withdrew from treatment due to all causes (15.6% vs. 21.6%, Fisher Exact: P=.014) and adverse events (5.3% vs. 12.0%, Fisher Exact: P<.0001). Mean reduction in MADRS score from baseline to Week 8 was significantly greater for the escitalopram group versus the SNRI group using the last observation carried forward (LOCF) approach [mean treatment difference at Week 8 of 1.7 points (P<.01)]. Similar results were observed in the severely depressed (baseline MADRS score >or= 30) patient subset (mean treatment difference at Week 8 of 2.9 points [P<.001, LOCF]). Observed cases analyses yielded no significant differences in efficacy parameters. CONCLUSION: This pooled analysis indicates that escitalopram is at least as effective as the SNRIs (venlafaxine XR and duloxetine), even in severe depression, and escitalopram treatment was better tolerated.

Anxiety symptom severity and functional recovery or relapse.

BACKGROUND: Anxiety disorders are associated with significant disability. There is growing interest in the question of whether pharmacotherapy that effectively reduces symptoms can also restore function. Recovery could potentially be defined as a lack of disability, with an associated reduction in symptom severity. Conversely, relapse could potentially be defined in terms of either increased disability or increased symptoms. METHODS: We analyzed a database of randomized controlled trials of escitalopram in generalized anxiety disorder (GAD) and social anxiety disorder (SAD), focusing on the relationship between disorder-specific severity scales, and the Sheehan Disability Scale (SDS). In short-term studies, cut-points on symptom scales were derived for recovered function. In relapse prevention studies, the effects of defining relapse in terms of increased disability scores were examined. RESULTS: In GAD and SAD, there is a close correlation between primary symptom severity scales and the SDS, both in the short term and during relapse prevention. Thus, functional recovery is associated with relatively low symptom severity scores, and rates of relapse-defined in terms of increased disability-are significantly lower on escitalopram than on placebo. CONCLUSIONS: These data indicate that recovery and relapse can potentially be defined either in terms of symptom severity or functioning. Thus, the concept of functional recovery and relapse may be useful in defining treatment outcomes. Longer-term treatment of anxiety disorders is needed to ensure functional recovery.

Baseline severity of depression predicts antidepressant drug response relative to escitalopram.

OBJECTIVE: The intent of this pooled analysis was to determine the relationship between baseline depression symptom severity and treatment response for escitalopram compared to that for other pooled antidepressant medications (citalopram, duloxetine, fluoxetine, paroxetine, sertraline and venlafaxine). METHODS: Data were pooled from controlled clinical trials comparing escitalopram with other antidepressants for the treatment of major depression. The 15 trials meeting the inclusion criteria comprised 2,216 patients treated with escitalopram and 2,085 treated with one of the other antidepressants. The primary outcome measure of change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was analyzed by an analysis of covariance, using the method of last-observation-carried-forward for missing values and adjusting for baseline and center values. RESULTS: There was a significant interaction between baseline MADRS total score and treatment group (p = 0.0208). Response to escitalopram was stable regardless of baseline severity. For the pooled active comparators, response decreased with increasing baseline symptom severity. This differential efficacy of escitalopram with increasing symptom severity was confirmed by the analyses of the pooled 24-item Hamilton Depression Rating Scale (HAMD-24) results. A HAMD-24 single item analysis indicated that the sum of the baseline psychomotor retardation and hopelessness item scores significantly predicted which patients would benefit from treatment with escitalopram versus a comparator. CONCLUSION: Newer generation antidepressant medications clearly differ in their efficacy as a function of baseline symptom severity. The selective serotonin reuptake inhibitor escitalopram had superior efficacy in the treatment of more severe depression, perhaps attributable to differential efficacy related to symptoms of negativistic thinking.

Escitalopram in the treatment of major depressive disorder: a meta-analysis.

OBJECTIVE: To assess the relative antidepressant efficacy of escitalopram and comparator antidepressants. RESEARCH DESIGN AND METHODS: A meta-analysis was performed using studies in major depressive disorder (MDD) comparing escitalopram with active controls, including selective serotonin reuptake inhibitors [SSRIs] (citalopram, fluoxetine, paroxetine, sertraline) and serotonin/noradrenaline reuptake inhibitors [SNRIs] (venlafaxine, duloxetine). Adult patients had to meet DSM-IV criteria for MDD. MAIN OUTCOME MEASURES: The primary outcome measure was the treatment difference in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 8. Secondary outcome measures were response and remission (MADRS total score < or = 12) rates. RESULTS: Individual patient data (N = 4549) from 16 randomized controlled trials were included in the analyses (escitalopram n = 2272, SSRIs n = 1750, SNRIs n = 527). Escitalopram was significantly more effective than comparators in overall treatment effect, with an estimated mean treatment difference of 1.1 points on the MADRS (p < 0.0001), and in responder (63.7 vs. 58.3%, p < 0.0001) and remitter (53.1 vs. 49.4%, p < 0.0059) analyses. Escitalopram was significantly superior to SSRIs, with an estimated difference in response of 62.1 vs. 58.4% and remission of 51.6 vs. 49.0%. In comparison to SNRIs, the estimated difference in response was 68.3 vs. 59.0% (p = 0.0007) and for remission the difference was 57.8 vs. 50.5% (p = 0.0088). These results were similar for severely depressed patients (baseline MADRS > or = 30). Sensitivity analyses were performed with data from articles reporting Hamilton Rating Scale for Depression (HAMD) scores. The 8-week withdrawal rate due to adverse events was 5.4% for escitalopram and 7.9% for the comparators (p < 0.01). This difference was accounted for by statistically significant higher attrition rates in the SNRI comparisons. This work may be limited by the clinical methodology underlying meta-analytic studies, in particular, the exclusion of trials that fail to meet predetermined criteria for inclusion. CONCLUSIONS: In this meta-analysis, superior efficacy of escitalopram compared to SSRIs and SNRIs was confirmed, although the superiority over SSRIs was largely explained by differences between escitalopram and citalopram.

Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials.

Pooled analyses have shown that escitalopram has superior effectiveness versus all comparators, including selective serotonin reuptake inhibitors and venlafaxine. Recent studies have compared escitalopram with duloxetine. Data from two randomized, double-blind studies that compared escitalopram (10-20 mg/day) and duloxetine (60 mg/day) were pooled and analysed for all patients and for the subsample of severely depressed patients [baseline Montgomery-Asberg Depression Rating Scale (MADRS) score > or =30]. Escitalopram (n=280) was superior to duloxetine (n=284) with respect to mean change from baseline in MADRS score at weeks 1, 2, 4 and 8 with a mean treatment difference at week 8 of 2.6 points (P<0.01). Similar results were seen for severely depressed patients, with a mean treatment difference of 3.7 points (P<0.01). Response and remission rates at week 8 were significantly higher for patients treated with escitalopram [response 67.1% for escitalopram compared with 53.2% for duloxetine, P<0.001; remission (MADRS< or =12) 54.3% for escitalopram compared with 44.4% for duloxetine, P<0.05]. The numbers needed to treat based on response and remission rates, in favour of escitalopram, were 8 and 11, respectively, for all patients (6 and 7, respectively, for severely depressed patients). Significantly fewer (P<0.001) patients (all cause and owing to adverse events) withdrew from the escitalopram group. This pooled analysis shows that over an 8-week treatment period, escitalopram (10-20 mg/day) is superior in both effectiveness and tolerability compared with duloxetine (60 mg/day).

Qualitative changes in symptomatology as an effect of treatment with escitalopram in generalized anxiety disorder and major depressive disorder.

The purpose of this article is to examine the similarities and differences between patients with Major Depressive Disorder (MDD) versus Generalized Anxiety Disorder (GAD) versus MDD with anxiety symptoms. Data were analysed from all randomized double-blind clinical studies with escitalopram that measured symptoms using either Hamilton Anxiety Scale (HAMA) or Montgomery-Asberg Depression Rating Scale (MADRS). The contribution of each item of a scale to the total score was calculated before and after treatment, in remitters. Most single items of the HAMA contribute nearly equally in patients with GAD. In patients with MDD, four symptoms (i.e. anxious mood, tension, insomnia and concentration) contribute to most to the HAMA total score. In patients with GAD, three symptoms (tension, sleep and concentration) contribute two-thirds of the MADRS total score. In contrast, most MADRS items contribute equally to the total score in patients with MDD. After treatment to remission, the profile of residual symptoms MDD or GAD was similar to the symptom profile before treatment. Anxiety symptoms are very common in patients with MDD or GAD, and the symptomatic pattern is similar. In both disorders, the symptomatic pattern of residual symptoms is similar to the pattern of symptoms before treatment.

Escitalopram in the treatment of anxiety symptoms associated with depression.

Most patients with depression have symptoms of anxiety associated with their illness. Our aim in this study was to investigate the efficacy of escitalopram, a proven antidepressant, on symptoms of anxiety in patients with major depressive disorder (MDD). Data from five placebo-controlled escitalopram studies in MDD were analyzed. Three of the studies also included a comparison with citalopram. In all studies, anxiety was assessed using the Inner Tension item (item 3) of the Montgomery-Asberg Depression Rating Scale (MADRS). In three studies, anxiety symptoms were also specifically assessed, either continuously over time or at baseline and end point, by using the Hamilton Rating Scale for Anxiety (HAM-A), the Anxious Mood item of the HAM-A (item 1), the Psychic Anxiety subscale of the HAM-A (items 1-6 and 14), the Anxiety Psychic item (item 10) of the Hamilton Rating Scale for Depression (HAM-D-24), and the Anxiety/Somatization subfactor (items 10-13, 15, and 17) of the HAM-D-24. Escitalopram was significantly superior to placebo in all comparisons. Citalopram was also consistently better than placebo in all comparisons, except in the HAM-D-24 Anxiety/Somatization subfactor. In some comparisons with placebo, escitalopram showed a significantly earlier onset of action or an earlier separation. Escitalopram was significantly more effective compared to placebo in treating both anxiety symptoms and the entire depression in the total depressive population, as well as in depressive patients with a high degree of anxiety.

Escitalopram versus venlafaxine XR in the treatment of depression.

This article reanalyses and reviews data from the two published randomized clinical trials comparing escitalopram and venlafaxine XR in the treatment of patients with major depressive disorder. The aim was to further compare the efficacy and tolerability of escitalopram and venlafaxine XR and to assess the impact of the two treatments on the patient's quality of life, as well as the benefit/risk of treatment. A total of 243 escitalopram-treated patients and 240 venlafaxine XR-treated patients were included in this analysis. Comparable treatment efficacy was achieved with respect to the prospectively defined primary efficacy endpoint (mean change from baseline in Montgomery Asberg Depression Rating Scale (MADRS) total score at week 8). An analysis of the outcome at the end of study by baseline severity showed that the treatment difference became greater the more severely depressed the patients were at baseline. At the highest permitted doses, in the subgroup of patients who were severely depressed (baseline MADRS > or =30), patients treated with escitalopram had a statistically significantly greater improvement (P<0.05) in mean MADRS total scores than patients treated with venlafaxine XR at endpoint. For these patients, treatment with 20 mg/day escitalopram resulted in a statistically significantly (P<0.05) higher remission rate at week 8 (47%) than treatment with venlafaxine XR (29%). This difference was confirmed by the analysis of the pooled data, which showed that patients in the escitalopram group had a significantly (P<0.05) higher mean number of depression-free days (30.4 days) than those in the venlafaxine XR group (26.2 days) over the 8-week period. The relative benefit of escitalopram versus venlafaxine XR was 1.46, indicating that a patient was more likely to benefit from treatment with escitalopram. The proportions of patients who withdrew owing to adverse events were 7.5% in the escitalopram group and 11.2% in the venlafaxine XR group. The mean number of discontinuation emergent signs and symptoms in the venlafaxine XR group (mean: 5.0) was significantly (P<0.001) higher than for the escitalopram group (mean: 2.4).

Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis.

OBJECTIVE: Escitalopram is the most selective of the selective serotonin reuptake inhibitor (SSRI) antidepressants. Previous studies have suggested that escitalopram is superior to citalopram in efficacy. We conducted a meta-analysis of studies in which escitalopram was compared with other antidepressants to assess the relative efficacy of these agents. METHODS: Data from all randomized, double-blind studies in major depression in which escitalopram was compared with active controls (citalopram, fluoxetine, paroxetine, sertraline and venlafaxine XR [extended release]) were pooled. The 10 studies were conducted in both specialist settings and general practice. Patients met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), for major depressive disorder and were at least 18 years old. In all but 2 studies, patients were required to have a score of 22 or more on the Montgomery-Asberg Depression Rating Scale (MADRS). The primary outcome measure was the estimated difference in treatment effect in MADRS total score at the end of the study. Secondary outcome measures were the response to treatment (defined as a > or = 50% reduction in baseline MADRS total score) and remission rate (defined as MADRS total score < or = 12 at end of study). RESULTS: A total of 2687 patients were included in the analyses (escitalopram n = 1345, conventional SSRIs n = 1102, venlafaxine XR n = 240). Escitalopram was superior to all comparators in overall treatment effect, with an estimated difference in treatment effect of 1.07 points (95% confidence interval [CI] 0.42-1.73, p < 0.01), and in response (odds ratio [OR] 1.29, 95% CI 1.07-1.56, p < 0.01) and remission (OR 1.21, 95% CI 1.01-1.46, p < 0.05) rates. In analysis by medication class, escitalopram was significantly superior to the SSRIs and comparable to venlafaxine, although the overall results do not necessarily reflect a significant difference between escitalopram and individual SSRIs. These results were similar in the severely depressed population (patients with baseline MADRS > or = 30). The withdrawal rate due to adverse events was 6.7% for escitalopram compared with 9.1% for the comparators (p < 0.05). CONCLUSIONS: In this meta-analysis, escitalopram showed significant superiority in efficacy compared with the active controls.