Benoît Rive

Comparison of escitalopram and citalopram efficacy: A meta-analysis

OBJECTIVE Escitalopram is a new selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) and panic disorder. Escitalopram is the therapeutically active enantiomer of citalopram. Its efficacy in the treatment of MDD was compared to that of citalopram. METHODS A quantitative meta-analysis was applied to 1262 patients in four randomised clinical trials; the comparison was based on response rate and mean change from baseline in the Montgomery–Åsberg depression rating scale (MADRS) total score at week 8. Complementary analyses were performed on early MADRS change from baseline (week 1), in very severely depressed patients (baseline MADRS total score ≥35) and on the influence of the level of severity at baseline. RESULTS Compared with citalopram, escitalopram-treated patients showed significantly higher response rates and increased mean change from baseline in MADRS at weeks 1 and 8. The superiority of escitalopram over citalopram was more pronounced in very severely depressed patients. This superiority was further shown to increase with degree of severity of the depression. The robustness of meta-analysis results was supported by sensitivity analyses. The clinical superiority of escitalopram versus citalopram is consistent with the results of preclinical pharmacological studies. CONCLUSION Escitalopram was shown to be an effective therapeutic treatment for MDD, presenting significant advantages over citalopram.

A dependency model for patients with Alzheimer's disease: its validation and relationship to the costs of care – the LASER-AD Study

SUMMARY Background: Loss of independence becomes more marked as Alzheimers disease (AD) progresses and contributes significantly to its societal and economic burden. Existing measures of functional disability focus either on basic or on instrumental activities of daily living (ADL). It would be more appropriate to combine these but, using existing assessment tools, this would involve considerable quantitative analysis. Recently, a qualitative and pragmatic system of classifying AD patients according to levels of dependency has been developed in a Belgian cohort. Objectives: To validate independently, in a UK community setting, a functional classification model of AD patients and to explore the relationship between dependency and costs of care using this model. Research design and methods: Longitudinal epidemiological study of 224 AD patients. Data were collected at baseline and at 6 months on ADL, global state, cognition, behavioural dimensions, depression, quality of life and resource utilisation using validated instruments. An automatic classification algorithm was performed to allow identification of dependency clusters. The scheme was tested for validity against other simultaneously collected data including health and social care costs. The relationship between dependency and costs of care was explored using ANOVA models. Results: Analysis of the ADL assessment instruments produced three ADL sub-scores by which patients could be classified into one of three disability clusters: (‘non-dependent’, ‘non-dependent with instrumental functional disability’, and ‘dependent’). Good external validity of the classification scheme was demonstrated by correlation with simultaneously collected data. After a backward selection process on ANOVA model (at a 5% level), institutionalisation and the most dependent status were the most significant cost drivers. Conclusions: Qualitative classification of AD patients using dependency levels is a simple and validated approach. Applying this approach showed that institutionalisation and the most ‘dependent’ status were independently and significantly associated with high care cost.

Cost effectiveness of memantine in moderately severe to severe Alzheimer's disease : a markov model in Finland.

BackgroundIn patients with moderately severe to severe Alzheimer’s disease, the N-methyl-D-aspartate (NMDA) antagonist memantine has been shown to improve outcomes and to be associated with reductions in resource utilisation and total healthcare costs relative to no pharmacological intervention after 28 weeks in phase III clinical and pharmacoeconomic studies. However, the longer term cost implications of treatment with memantine are not known.ObjectiveTo evaluate the effect of treatment with memantine in patients with moderately severe to severe Alzheimer’s disease on resource use and on cost and patient outcomes in Finland over a 5-year time horizon.MethodsA Markov model was constructed to simulate a patient’s progression through a finite series of health states with a time horizon of 5 years. The states were defined in terms of physical dependency, place of residency (community or institution), and cognitive function. Each 6-month Markov cycle was repeated ten times. A 5% rate was used to discount costs. Inputs for the model were derived from epidemiological data collected during the Kuopio 75+ Study, a Finnish population-based health survey of dementia and functional capacity among individuals aged ≥75 years. Costs were considered from a societal perspective. Probabilities used in the model, together with cost and resource use differences between treatment with memantine (Ebixa®, Namenda®, Axura®) and no pharmacological intervention, were derived from a randomised, double-blind, placebo-controlled clinical trial that included an economic assessment. This study enrolled 252 patients with moderately severe to severe Alzheimer’s disease. We took a conservative approach that assumed that the effectiveness of treatment with memantine was limited to 12 months’ duration. Monte Carlo simulations were performed to evaluate the effect of treatment with memantine on duration of independence and time to institutionalisation. Sensitivity analyses included memantine efficacy best- (5 years) and worst- (6 months) case scenarios, and an analysis in which 5% discounting was not applied.ResultsMemantine therapy was associated with approximately 4 extra months of independence, 1 additional month of residence in the community, and a cost reduction relative to placebo of approximately €1700 per patient over 5 years, despite the limiting of persistence of efficacy to 12 months (year of costing, 2001). Monte Carlo simulations and sensitivity analyses supported the findings. Conclusion: According to the model, over 5 years the additional drug costs of treating patients with moderately severe to severe Alzheimer’s disease with memantine were amply offset by cost savings related chiefly to increased independence and delayed institutionalisation.

Cost-effectiveness of memantine compared with standard care in moderate-to-severe Alzheimer disease in Canada

Objective: To conduct a cost-effectiveness analysis comparing the addition of memantine to standard care (that is, without acetylcholinesterase inhibitors) with standard care alone in moderate-to-severe Alzheimer disease (AD) in Canada. Methods: A 2-year Markov model estimated clinical effects in terms of quality-adjusted life years (QALYs) and time in complete dependence as well as societal costs in four 6-month cycles. Health states were defined by AD severity assessed with the Mini-Mental State Examination (moderate = 10 to 19; severe < 10), by level of dependence in activities of daily living, and by death. Transition probabilities were estimated by combining data of patients with moderate-to-severe AD from all relevant clinical trials. QALYs were estimated from a UK epidemiologic study. The initial distribution and use of medical and support services for each health state was obtained from the Canadian Study on Health and Aging with current estimates of frequency of use and unit prices applied. Results: Compared with standard care, the memantine strategy saved more than 1 month of complete dependence and produced 0.03 additional QALYs, with no additional cost. Probabilistic sensitivity analyses give an 83.3% chance that memantine treatment is cost-neutral, an 89.5% chance of its being cost-effective if the decision maker is willing to pay

New assessment of dependency in demented patients: impact on the quality of life in informal caregivers.

20 000 for a QALY, and a 96.2% chance with a willingness to pay

Relative efficacy and tolerability of vortioxetine versus selected antidepressants by indirect comparisons of similar clinical studies

100 000 per QALY. Robustness of results was confirmed through 1-way and scenario-based sensitivity analyses. Conclusions: Our evaluation found that memantine monotherapy produced relevant health benefit, compared with standard care alone, with no additional costs. Results are consistent with other economic evaluations of memantine conducted in Europe and the United States.

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

Abstract  A qualitative tool was recently developed for evaluation of dependency in a demented population. This tool assesses the impact of cognitive impairment on functional status, taking into account disability in both the basic and the instrumental activities of daily living. The purpose of the present paper was to study the impact of dependency on informal caregivers who assist demented patients at home, with this new useful tool. Methods: A cross‐sectional analysis was undertaken of the subgroup of 145 demented patients of the National Dementia Economic Study, aged ≥65 years, living in the community, with an available caregiver. A neuropsychological assessment of patients (Mini‐Mental State Examination) and a comprehensive evaluation of caregivers (quality of life, Short Form Health Survey‐36, depression, Sense of Competence) were recorded. A total of 32.4% were dependent, disabled in both basic and instrumental functions, 42.1% were non‐dependent but with instrumental functional disabilities and 25.5% were non‐dependent. Impact of dependency on the caregivers experience was significant for different aspects (satisfaction with caregiving, subjective burden, quality of life, depression). Medical and non‐medical costs increased with the severity of functional disability. Findings indicate that this tool is also useful to assess the impact of progression of functional disability in patients with dementia, on the caregiver issues. The consequences appeared both on personal feelings and on quality of life and financial involvement in management of the patient. Cognitive impairment appears to have more moderate repercussions in these areas.

Pharmacotherapeutic strategies for patients treated for depression in UK primary care: a database analysis

Abstract Introduction: Vortioxetine is an antidepressant with multimodal activity which has shown efficacy in major depressive disorder (MDD) patients in six of ten short-term, randomized, placebo-controlled trials (completed end 2012). Methods: We performed meta-regression analyses to indirectly compare vortioxetine to seven marketed antidepressants with different mechanisms of action. To ensure study comparability, only experimental drug and placebo arms from placebo-controlled registration studies were included in primary analyses. The main outcomes were efficacy (standardized mean difference in change from baseline to 2 months on primary endpoint [MADRS/HAM-D]), and tolerability (withdrawal rate due to adverse events). Results: For efficacy, estimates of treatment effect (negative estimates favor vortioxetine) for vortioxetine versus comparators were: agomelatine, −0.16 (p = 0.11); desvenlafaxine, 0.03 (p = 0.80); duloxetine, 0.09 (p = 0.42); escitalopram, −0.05 (p = 0.70); sertraline, −0.04 (p = 0.83); venlafaxine IR/XR, 0.12 (p = 0.33); and vilazodone, −0.25 (p = 0.11). For tolerability, all but one combination was numerically in favor of vortioxetine (odds ratio < 1), although not all differences were statistically significant: agomelatine, 1.77 (p = 0.03); desvenlafaxine, 0.58 (p = 0.04); duloxetine, 0.75 (p = 0.26); escitalopram, 0.67 (p = 0.28); sertraline, 0.30 (p = 0.01); venlafaxine, 0.47 (p = 0.01); and vilazodone, 0.64 (p = 0.18). Sensitivity analyses did not significantly alter antidepressant effect estimates or relative ranking. Conclusion: These meta-regression data show that vortioxetine offers a comparable or favorable combination of efficacy (measured by MADRS/HAM-D) and tolerability (measured by withdrawal rate due to adverse events) versus other antidepressants in registration studies in MDD. Alternative methods like mixed-treatment comparison and inclusion of all randomized studies and active reference arms may provide complementary information to this analysis (more evidence but also more heterogeneity). Key messages: Indirect comparisons based on registration studies allow a useful comparison between a recently approved antidepressant and an approved drug. Vortioxetine offers a comparable or favorable combination of efficacy (measured by MADRS/HAM-D assessments) and tolerability (measured by withdrawal rate due to adverse events) versus other antidepressants in registration studies in MDD.

The effect of vortioxetine on overall patient functioning in patients with major depressive disorder

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.

Functional impairment in patients with major depressive disorder: the 2-year PERFORM study

Abstract Objective: To investigate long-term patterns of antidepressant treatment in patients in primary care in the UK, and to assess their healthcare resource use and disease outcomes. Research design and methods: A retrospective longitudinal cohort study was conducted using the Clinical Practice Research Datalink. The study population comprised patients aged ≥18 years with depression receiving a prescription for antidepressant monotherapy between 1 January 2006 and 31 December 2011 with no antidepressants within the preceding 6 months. Recovery was defined by timing of antidepressant prescriptions (≥6 months without treatment). Treatment lines and strategies (switching, combining, augmenting and resuming medication) were analyzed. Healthcare resource use for the different treatment strategies and periods of no therapy was assessed. Results: Data from 123,662 patients (287,564 treatment lines) were analyzed. Switching and resumption of treatment were more frequent than other strategies. Recovery was highest with first-line monotherapy (45% of patients), while as a second-line strategy switching was more successful (43%) than combination or augmentation. In subsequent lines of treatment, switching was associated with successively lower rates of recovery (31% in the third line and 24% from the fourth line onwards). Similar rates were observed for resumption. Healthcare resource use was greater during antidepressant use than treatment-free periods. Augmentation was associated with the highest proportions of patients with a psychiatrist referral, psychologist referral and psychiatric hospitalization. Conclusions: This study provides extensive real-world information on the prescribing patterns and treatment outcomes for a large cohort of patients treated for depression with antidepressants in primary care. Switching is more frequently used than augmentation or combination treatment, with decreasing effectiveness across successive lines. Key limitations of the study were: (i) risk of selection bias due to the use of inclusion criteria based on depression diagnoses recorded by the practitioner; and (ii) reliance on prescribing patterns as proxies for clinical outcomes, such as recovery.