Ioana Florea

A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients.

ABSTRACT Objective: This randomised, double-blind, fixed-dose study evaluated the efficacy of escitalopram and paroxetine in the long-term treatment of severely depressed patients with major depressive disorder (MDD). Research design and methods: Patients with a primary diagnosis of MDD and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) ≥ 30 were randomised to 24 weeks of double-blind treatment with fixed doses of either escitalopram (20 mg) (n = 232) or paroxetine (40 mg) (n = 227). The primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (Week 24) in MADRS total score (last observation carried forward, LOCF). Main outcome measures; results: At endpoint (24 weeks), the mean change from baseline in MADRS total score was –25.2 for patients treated with escitalopram (n = 228) and –23.1 for patients with paroxetine (n = 223), resulting in a difference of 2.1 points ( p < 0.05). The difference in the change in the MADRS total score (LOCF) was significantly in favour of escitalopram from Week 8 onwards. The proportion of remitters (MADRS ≤ 12) after 24 weeks was 75% for escitalopram and 67% for paroxetine ( p < 0.05). The results on the primary efficacy scale were supported by significantly greater differences in favour of escitalopram on the Hamilton Anxiety, Hamilton Depression and Clinical Global Impression-Improvement and -Severity scales. For very severely depressed patients (baseline MADRS ≥ 35), there was a difference of 3.4 points at endpoint in the MADRS total score in favour of escitalopram ( p < 0.05). The overall withdrawal rate for patients treated with escitalopram (19%) was significantly lower than with paroxetine (32%) ( p < 0.01). The withdrawal rate due to adverse events was significantly lower for escitalopram (8%) compared to paroxetine (16%) ( p < 0.05). There were no significant differences in the incidence of individual adverse events during treatment. Conclusion: Escitalopram is significantly more effective than paroxetine in the long-term treatment of severely depressed patients.

Prevention of relapse in generalized anxiety disorder by escitalopram treatment.

Escitalopram has demonstrated a robust and dose-dependent efficacy in the treatment of generalized anxiety disorder (GAD) for up to 3 months. In the present study, the efficacy and tolerability of escitalopram in the prevention of relapse in GAD was investigated. A total of 491 patients with a primary diagnosis of GAD and a Hamilton Anxiety (HAMA) total score>or=20 received 12 wk of open-label treatment with a fixed dose of escitalopram (20 mg/d). Of these, 375 patients responded (HAMA total score<or=10) and were randomized to double-blind treatment with 20 mg/d escitalopram (n=187) or placebo (n=188). Treatment was continued for 24-76 wk unless the patient relapsed or was withdrawn for other reasons. Relapse was defined as either an increase in HAMA total score to >or=15, or lack of efficacy, as judged by the investigator. The results of the primary analysis showed a clear beneficial effect of escitalopram relative to placebo on the time to relapse of GAD (log-rank test, p<0.001). The risk of relapse was 4.04 times higher for placebo-treated patients than for escitalopram-treated patients; the proportion of patients who relapsed was statistically significantly higher in the placebo group (56%) than in the escitalopram group (19%) (p<0.001). Escitalopram was well tolerated and 7% of the escitalopram-treated patients withdrew due to adverse events, vs. 8% of the placebo patients. The incidence of discontinuation symptoms with escitalopram during tapered withdrawal was low; the symptoms primarily being dizziness (10-12%), nervousness (2-6%), and insomnia (2-6%). Escitalopram 20 mg/d significantly reduced the risk of relapse and was well tolerated in patients with GAD.

A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder

ABSTRACT Objective: This study evaluated the efficacy and tolerability of escitalopram and duloxetine in the treatment of major depressive disorder (MDD). Research design and methods: Patients were randomised to 24 weeks of double-blind treatment with fixed doses of escitalopram (20 mg) (n = 143) or duloxetine (60 mg) (n = 151). The primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 24) in MADRS total score (last observation carried forward). Main outcome measures; Results: At week 8, the mean change from baseline in total MADRS score was –19.5 for patients treated with escitalopram (n = 141) and –17.4 for patients treated with duloxetine (n = 146), a difference of 2.1 points ( p < 0.05). At week 8, the proportion of responders (≥ 50% decrease in MADRS) was 69% (escitalopram) and 58% (duloxetine) ( p < 0.05) and remission (MADRS ≤ 12) rates were 56% (escitalopram) and 48% (duloxetine) (NS). For the primary endpoint, the mean change from baseline in total MADRS score at week 24 was –23.4 for patients treated with escitalopram and –21.7 for patients treated with duloxetine, a difference of 1.7 points ( p = 0.055, one-sided). The difference in mean change from baseline in MADRS total score favoured escitalopram at weeks 1, 2, 4, 8, 12 and 16 ( p < 0.05). The overall withdrawal rates were 22% (escitalopram) and 25% (duloxetine) (NS). The withdrawal rate due to adverse events was lower for escitalopram (9%) compared to duloxetine (17%) ( p < 0.05) and significantly more patients treated with duloxetine reported insomnia (12.6% vs. 4.9%) and constipation (8.6% vs. 2.8%). Conclusion: Escitalopram was superior to duloxetine in acute treatment and at least as efficacious and better tolerated in long-term treatment of MDD.

A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder

The efficacy and tolerability of Lu AA21004 in the prevention of relapse of major depressive disorder (MDD) in patients in remission after acute treatment was evaluated. Patients (n=639) aged 18–75 years with a primary diagnosis of MDD with a current major depressive episode (MDE) ≥4 weeks’ duration, at least one prior MDE and a MADRS total score ≥26 received 12-week, open-label Lu AA21004 at 5 or 10mg/day. Patients in remission (MADRS ≤10) at both weeks 10 and 12 were assigned to double-blind treatment with either placebo or Lu AA21004 (fixed dose from Week 8).Patients (n=396) were treated, after random assignment to placebo (n=192) or Lu AA21004 (n=204). The primary analysis of time to relapse (full-analysis set, Cox proportional hazard model) showed a statistically significant difference in favour of Lu AA21004 versus placebo with a hazard ratio of 2.01 (95% confidence interval: 1.26–3.21; p=0.0035). The proportion of patients who relapsed was 13% in the Lu AA21004 group (n=27) and 26% in the placebo group (n=50). The withdrawal rates due to adverse events were 8% (open-label), and 3% (placebo) and 8% (Lu AA21004) (double-blind). Thus, Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment.

Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder

Abstract Objective: The primary objective of this study was to evaluate the safety and tolerability of the investigational drug vortioxetine (Lu AA21004) in the long-term treatment of patients with major depressive disorder. Methods: Patients entered this 52-week, open-label extension study after completing an 8-week lead-in study. Safety and tolerability were evaluated at regular intervals on the basis of spontaneously reported adverse events (AEs), clinical safety laboratory tests, vital signs, ECG and physical examination. Effectiveness of treatment was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) total score. Results: A total of 535 patients were treated and 61.3% (n = 328) completed the study, resulting in 393 patient years of exposure to vortioxetine. AEs reported by ≥10% of patients were nausea, headache, and nasopharyngitis. Taken together, six patients had eight AEs related to sexual dysfunction. There were no clinically significant safety findings with respect to mean changes of vital signs, weight, ECG parameters, or clinical laboratory values. Patients entered the extension study with a mean MADRS total score of 13.5 ± 8.7. The mean MADRS total score decreased (improved) by approximately 8 points to 5.5 ± 6.0 at Week 52 (OC). By the end of the study, the proportion of responders had increased from 63% to 94% (OC), as had the proportion in remission (MADRS ≤10), increasing from 42% to 83% (OC). Patients in remission (n = 226) at the start of this study had a relapse rate (MADRS ≥22) of 9.7%. Conclusions: As with all open-label studies, the conclusions that can be drawn are limited by the lack of a placebo control, making it difficult to assess causality of any changes in outcome measures. However, on the basis of these findings, vortioxetine (2.5, 5, 10 mg/day) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment. Trial Registration: ClinicalTrials.gov identifier: NCT00694304.

Lu AA21004, a multimodal psychotropic agent, in the prevention of relapse in adult patients with generalized anxiety disorder

The purpose of this study was to investigate the long-term maintenance of the efficacy of Lu AA21004 5 or 10 mg/day in the prevention of relapse in patients with generalized anxiety disorder (GAD). Patients (n=687) with a primary diagnosis of GAD (DSM-IV criteria) and a baseline Hamilton Anxiety (HAM-A) total score of at least 20 underwent a 20-week, open-label Lu AA21004 treatment. In all, 459 patients responded and were randomized to 24–56 weeks of a double-blind treatment with Lu AA21004 (n=229) or placebo (n=230). The predefined primary efficacy endpoint was time to relapse (HAM-A total score ≥15) using a Cox model; the key secondary efficacy endpoint under multiplicity control was time to relapse for patients responding to treatment for at least 12 weeks. The primary analysis showed a statistically significant effect of Lu AA21004 relative to the placebo on the time to relapse of GAD, with a hazard ratio of 2.71 (P<0.001). There was a statistically significant effect of Lu AA21004 in the stable responders (hazard ratio=3.06, P<0.001). Lu AA21004 was well tolerated, with withdrawal rates due to adverse events of 9% (open-label) and 3% (placebo) and 4% (Lu AA21004) in the double-blind period. In this study, Lu AA21004 5 or 10 mg/day was efficacious in preventing relapse and was well tolerated in the maintenance treatment of GAD.

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5–20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5–20mg/day) was 4.5–7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5–20mg/day) were nausea (20.9–31.2%) and vomiting (2.9–6.5%). For vortioxetine (5–20mg/day), the incidence of TEAEs associated with insomnia was 2.0–5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6–1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7–0.8kg. Thus, vortioxetine (5–20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder.

A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety symptoms

BACKGROUND Coexisting anxiety is common in major depressive disorder (MDD) and more difficult to treat than depression without anxiety. This analysis assessed the efficacy, safety, and tolerability of vortioxetine in MDD patients with high levels of anxiety (baseline Hamilton Anxiety Rating Scale [HAM-A] total score ≥20). METHODS Efficacy was assessed using an aggregated, study-level meta-analysis of 10 randomized, placebo-controlled, 6/8-week trials of vortioxetine 5-20mg/day in adults (18-75 years), with a study in elderly patients (≥65 years) analyzed separately. Outcome measures included mean differences from placebo in change from baseline to endpoint (Δ) in the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A total, and HAM-A subscales. Safety and tolerability were assessed by treatment-emergent adverse events (TEAEs). RESULTS A total of 1497 (48.6%) vortioxetine-treated and 860 (49.1%) placebo-treated patients had baseline HAM-A≥20. There were significant differences from placebo in MADRS (vortioxetine 5mg/day, n=415, Δ-2.68, P=0.005; 10mg/day, n=373, Δ-3.59, P<0.001; 20mg/day, n=207, Δ-4.30, P=0.005) and HAM-A total (5mg/day, n=419, Δ-1.64, P=0.022; 10mg/day, n=373, Δ-2.04, P=0.003; 20mg/day, n=207, Δ-2.19, P=0.027). There were significantly greater improvements versus placebo on the HAM-A psychic subscale for all doses. The most common TEAEs (≥5.0%) were nausea, headache, dizziness, dry mouth, diarrhea, nasopharyngitis, constipation, and vomiting. Incidence of serious TEAEs was 1.3% (placebo) and ≤1.3% (vortioxetine, across doses). LIMITATIONS Study heterogeneity limits this analysis. Patients with baseline HAM-A≥20 were not directly compared to baseline HAM-A<20 or total MDD population. CONCLUSIONS Vortioxetine was efficacious in reducing depressive and anxiety symptoms in patients with MDD and high levels of anxiety.

Factors associated with failure to achieve remission and with relapse after remission in patients with major depressive disorder in the PERFORM study

Background The Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder (PERFORM) study has been initiated to better understand the course of a depressive episode and its impact on patient functioning. This analysis aimed to identify sociodemographic and clinical factors associated with failure to achieve remission at month 2 after initiating or switching antidepressant monotherapy and with subsequent relapse at month 6 for patients in remission at month 2. Materials and methods This was a 2-year observational cohort study in 1,159 outpatients aged 18–65 years with major depressive disorder initiating or undergoing the first switch of antidepressant monotherapy. Factors with P<0.20 in univariate logistic regression analyses were combined in a multiple logistic regression model to which backward variable selection was applied (ie, sequential removal of the least significant variable from the model and recomputation of the model until all remaining variables have P<0.05). Results Baseline factors significantly associated with lower odds of remission at month 2 were body-mass index ≥30 kg/m2 (OR 0.51), depressive episode >8 weeks (OR 0.51), being in psychotherapy (OR 0.51), sexual dysfunction (OR 0.62), and severity of depression (OR 0.87). Factors significantly associated with relapse at month 6 were male sex (OR 2.47), being married or living as a couple (OR 2.73), residual patient-reported cognitive symptoms at 2 months (OR 1.12 per additional unit of Perceived Deficit Questionnaire-5 score) and residual depressive symptoms at 2 months (OR 1.27 per additional unit of Patient Health Questionnaire-9 score). Conclusion Different factors appear to be associated with failure to achieve remission in patients with major depressive disorder and with subsequent relapse in patients who do achieve remission. Patient-reported cognitive dysfunction is an easily measurable and treatable characteristic that may be associated with an increased likelihood of relapse at 6 months in patients who have achieved remission.

Comparative evaluation of vortioxetine as a switch therapy in patients with major depressive disorder

Switching antidepressant therapy is a recommended strategy for depressed patients who neither respond to nor tolerate an initial pharmacotherapy course. This paper reviews the efficacy and tolerability of switching to vortioxetine. All three published studies of patients with major depressive disorder (MDD) switched from SSRI/SNRI therapy to vortioxetine due to lack of efficacy or tolerability were selected. Vortioxetine was evaluated versus agomelatine directly (REVIVE) and versus sertraline, venlafaxine, bupropion, and citalopram in an indirect treatment comparison (ITC) from switch studies retrieved in a literature review. Vortioxetine׳s impact on SSRI-induced treatment-emergent sexual dysfunction (TESD) was assessed directly versus escitalopram (NCT01364649) in stable patients with MDD. Vortioxetine׳s tolerability in the switch population was compared to the overall MDD population. Vortioxetine showed significant benefits over agomelatine on efficacy, functioning, and quality-of-life outcomes, with fewer withdrawals due to adverse events (AEs) (REVIVE). Vortioxetine had numerically higher remission rates versus all therapies included (ITC). Withdrawal rates due to AEs were significantly lower for vortioxetine versus sertraline, venlafaxine, and bupropion, and numerically lower versus citalopram. Switching to vortioxetine was statistically superior to escitalopram in improving TESD (NCT01364649). Tolerability was similar in the switch and overall MDD populations. These findings suggest that vortioxetine is an effective switch therapy for patients with MDD whose response to SSRI/SNRI therapy is inadequate. Vortioxetine was well tolerated and, for patients with a history of TESD, showed significant advantages versus escitalopram. Vortioxetine appears to be a valid option for patients with MDD who have not been effectively treated with first-line pharmacotherapies.