Henning Friis Andersen

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

ABSTRACT 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–Åsberg Depression Rating Scale (MADRS) total score at week 8. Secondary outcome measures were response and remission (MADRS total score ≤ 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 ≥ 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.

Do equivalent doses of escitalopram and citalopram have similar efficacy? A pooled analysis of two positive placebo-controlled studies in major depressive disorder.

Escitalopram is the S-enantiomer of citalopram. In this study, we compared the efficacy of equivalent dosages of escitalopram and citalopram in the treatment of moderate to severe major depressive disorder (MDD), based on data from two, pooled, randomized, double-blind, placebo-controlled studies of escitalopram in which citalopram was the active reference. The primary efficacy parameter was the mean change from baseline in the Montgomery Åsberg Depression Rating Scale (MADRS) total score. Significant differences in favour of escitalopram were observed for the MADRS [P<0.05, observed cases (OC)/last observation carried forward (LOCF)] and Clinical Global Improvement–Severity of Illness scores (CGI-S; P<0.05, OC/LOCF). Escitalopram separated from placebo at week 1 on the primary efficacy parameter, whereas citalopram first separated from placebo at week 6. An analysis of time to response showed that escitalopram-treated patients responded significantly faster to treatment than citalopram-treated patients (P<0.01). More patients responded to and achieved remission with escitalopram than to citalopram (P<0.05, OC). The HAMD scale was only used in the fixed-dose study, where escitalopram-treated patients had a significant reduction in HAMD-17 total score at week 8 compared to citalopram-treated patients (P<0.05, OC/LOCF). In the pooled subpopulation of severely ill patients (MADRS≥30), escitalopram-treated patients showed greater improvement than citalopram-treated patients (P<0.05, LOCF/OC). Escitalopram showed consistently superior efficacy compared to citalopram in the treatment of moderate to severe MDD on all efficacy parameters, and was similarly well tolerated.

A randomized, double-blind, 24-week study of escitalopram (10 mg/day) versus citalopram (20 mg/day) in primary care patients with major depressive disorder.

ABSTRACT Objective: A randomized, double-blind, 24‐week fixed-dose study comparing the efficacy and safety of escitalopram to that of citalopram was conducted in primary care patients with moderate to severe major depressive disorder (MDD). Research design and methods: This was a randomized, double-blind, 24‐week fixed-dose study. Patients were randomly assigned to treatment with escitalopram 10 mg/day (n = 175) or citalopram 20 mg/day (n = 182). Clinical response was evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression-Severity (CGI‐S) scale. The prospectively defined primary parameter of antidepressant efficacy was the change from baseline in the mean MADRS total score during the 24 weeks of double-blind treatment, using a repeated measures analysis of variance to compare the treatment groups over all assessment points simultaneously. Results: Based on the primary parameter, escitalopram was at least as efficacious as citalopram. Based on the prospectively defined secondary parameter, mean change from baseline in the CGI‐S score, escitalopram was statistically significantly superior to citalopram at Week 24. The importance of long-term treatment could be demonstrated, in that more than half (55% and 51%) of the patients who had not responded by Week 8 achieved remission by Week 24. Both escitalopram and citalopram were safe and well tolerated in acute and long-term treatment, and the overall adverse event profiles for the two drugs were similar. For the intent-to-treat population, there were statistically significantly fewer withdrawals in the escitalopram group than in the citalopram group, particularly after Week 8. Conclusion: Patients with MDD responded well to long-term treatment with either escitalopram or citalopram. This study demonstrated the importance of extending treatment of depression beyond 8 weeks.

Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer's disease

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and delaying disease worsening is a relevant treatment outcome. Methods: Data from 6 randomized, double-blind, placebo-controlled, 6-month studies were pooled and a subgroup of patients (867 on placebo, 959 on memantine) with moderate to severe AD (Mini- Mental State Examination <20) was analyzed. ‘Any clinical worsening’ was defined as a decline on the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog) or the Severe Impairment Battery (SIB) and on the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (ADCS-ADL), and ‘marked clinical worsening’ as ≧4 points decline on the ADAS-cog or ≧5 points on the SIB and decline on the CIBIC-plus and the ADCS-ADL. Results: More placebo-treated than memantine-treated patients showed any clinical worsening (28 vs. 18%; p < 0.001), and 21% placebo-treated patients compared to 11% memantine-treated patients had marked clinical worsening (p < 0.001). Conclusion: In this population of moderate and severe AD patients, treatment with memantine was associated with reducing worsening of clinical symptoms in AD during the 6-month study period.

Treatment intensification with stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy (FullSTEP Study): a randomised, treat-to-target clinical trial

BACKGROUND We compared stepwise addition of bolus insulin with a full basal-bolus regimen in patients with type 2 diabetes inadequately controlled on basal insulin plus oral antidiabetic drugs. METHODS The FullSTEP study was a phase 4, 32-week, randomised, open-label, two-arm, parallel-group, multinational, treat-to-target, non-inferiority trial done at 150 sites across seven countries to assess the effectiveness of a stepwise dosing approach versus a basal-bolus regimen. In this trial, 401 patients (mean age 59·8 years [SD 9·3]; HbA1c 7·9% [63 mmol/mol]; mean diabetes duration 12·6 years [SD 8·0]) were block randomised (ratio 1:1) to receive either stepwise treatment or full basal-bolus treatment. Patients in the basal-bolus group received insulin aspart before every meal throughout the trial. Patients in the stepwise group received one bolus dose with the largest meal, with additional insulin aspart doses before the next largest meal added to their regimen at 11 weeks and 22 weeks if HbA1c remained at 7% or higher. The primary outcome was non-inferiority of stepwise addition of bolus insulin versus complete basal-bolus therapy, as assessed by change in HbA1c from baseline to 32 weeks (non-inferiority margin of 0·4%). This trial is registered with ClinicalTrials.gov, number NCT01165684. FINDINGS The study was started on Oct 27, 2010, and completed on April 25, 2012. After 32 weeks, HbA1c change from baseline was -0·98% (95% CI -1·09 to -0·87) for the stepwise group and -1·12% (-1·23 to -1·00) for the basal-bolus group; mean treatment difference 0·14 (95% CI -0·02 to 0·30), non-significant (p=0·0876). Fewer hypoglycaemic episodes occurred in the stepwise group than in the basal-bolus group (rate ratio 0·58 [95% CI 0·45 to 0·75]; p<0·0001). Treatment-emergent adverse events did not differ between the two treatment groups. The most frequently reported treatment-emergent adverse event were nasopharyngitis, influenza, diarrhoea, headache, peripheral oedema, and wrong drug given. Three participants died: two before randomisation and one in the basal-bolus group (due to severe acute myocardial infarction and respiratory tract inflammation). INTERPRETATION Stepwise prandial insulin intensification provides glycaemic control non-inferior to a full basal-bolus regimen after 32 weeks, with significantly lower hypoglycaemia risk and better patient satisfaction. FUNDING Novo Nordisk.

The onset of effect for escitalopram and its relevance for the clinical management of depression.

ABSTRACT Objective: To analyse the significance of ‘onset of effect’ on clinical outcome in the treatment of depression and the contribution of individual Montgomery–Åsberg Depression Rating Scale (MADRS) items to improvements in the MADRS total score. Research design and method: All five published placebo-controlled clinical studies in depression as per January 1, 2005, with escitalopram, were included in this pooled analysis. Results: Of the 1636 patients who were randomised to either escitalopram (882) or placebo (754), 1333 completed 8 weeks of treatment (707 escitalopram and 626 placebo). A statistically significant difference ( p < 0.05) between the MADRS total score responses of escitalopram and placebo treatments was observed at week 1. All 10 MADRS single items showed a significant treatment effect at week 8. For items representing core symptoms of depression (apparent sadness, reported sadness, inner tension, concentration difficulties, inability to feel, pessimistic thoughts and suicidal thoughts) the effect was detected early (week 1) and for other items (reduced sleep, reduced appetite and lassitude) the effect was detected later (week 6–8). Of the patients who showed an onset of effect (≥ 20% reduction in MADRS) after 2 weeks, and who remained on escitalopram until week 8, 63% were in remission at week 8 (mean MADRS score of 6.1). Conclusion: Onset of treatment response at 2 weeks is an important indicator of subsequent remission at 8 weeks. It would therefore be a reasonable clinical recommendation that if patients fail to show a measurable clinical improvement within 2 weeks, a dose increase should be considered at this time.

Impact of escitalopram treatment on Quality of Life Enjoyment and Satisfaction Questionnaire scores in major depressive disorder and generalized anxiety disorder

Administration of the same Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) in major depressive disorder (MDD) and in generalized anxiety disorder (GAD) before and after treatment allowed us to compare quality of life enjoyment and satisfaction in these two disorders and to compare outcome based on symptoms versus functioning. Q-LES-Q and symptom-specific Montgomery–Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Scale (HAMA) data from eight randomized, 8-week, double-blind, placebo-controlled clinical trials with escitalopram were used. MDD (n=1140) or GAD (n=1045) patients report a substantial degree of quality of life enjoyment and satisfaction impairment (baseline scores 64% and 76% of community norm, respectively). Treatment resulted in statistically and clinically significant improvement in quality of life enjoyment and satisfaction. The improvement was greater in patients treated with escitalopram than with placebo. In MDD, the majority of remitters (MADRS≤12) reached ‘normal’ quality of life enjoyment and satisfaction levels, whereas in GAD, 67% of remitters (HAMA≤7) reached ‘normal’ quality of life, enjoyment, and satisfaction. A strong correlation between the symptom-specific scales and the Q-LES-Q was observed. These analyses suggest that remission with scores of 6 on the MADRS and 5 on the HAMA correspond with a quality of life enjoyment and satisfaction found in community comparison patients (Q-LES-Q score of 58±10%). Treatment with escitalopram results in a significant improvement of quality of life enjoyment and satisfaction in patients with MDD or GAD. Both response and remission in patients with GAD and remission in patients with MDD are correlated with a ‘normal’ quality of life enjoyment and satisfaction.

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–Åsberg 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 for the Treatment of GAD: Efficacy Across Different Subgroups and Outcomes.

BACKGROUND Generalized anxiety disorder (GAD) is characterized by anxiety, and also frequently associated with depressive symptoms. Benzodiazepines have commonly been used in the treatment of GAD, but are not effective antidepressant agents. In this study, we determined whether the selective serotonin reuptake inhibitor escitalopram, was effective across different subgroups and outcomes (anxious symptoms, depressive symptoms, and quality of life). METHODS Three randomized, placebo controlled studies of escitalopram in GAD have employed a similar design, allowing for pooling of the data. The primary efficacy measure was the Hamilton Anxiety Scale (HAMA). General linear models were used to determine the efficacy of escitalopram across different subgroups and outcomes. RESULTS Escitalopram was efficacious for GAD on a range of measures of both anxiety and depression, and improved the associated impairment in quality of life. There was no significant interaction of effects on the HAMA with demographic or clinical variables. Furthermore, escitalopram was efficacious on both primary and secondary scales in the subgroup of subjects with above-median severity of depressive symptoms at baseline (HAMD-17 > 12). CONCLUSIONS Escitalopram reduces anxiety and depressive symptoms in GAD, and improves quality of life. It is equally effective in GAD patients, with an above-median level of depressive symptoms. Further research is needed to determine whether these results can be extrapolated to GAD patients with comorbid major depression.

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-Åsberg Depression Rating Scale (MADRS) score ≥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≤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).