Indirect adjusted comparison of 6-month clinical outcomes between esketamine nasal spray and other real-world polypharmacy treatment strategies for treatment resistant depression: results from the ICEBERG study

BackgroundThe efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known.MethodICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling.ResultsEsketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6–53.9]) and remission (33.6% [95% CI 29.7–37.6]) versus RW polypharmacy (26.8% [95% CI 21.0–32.5] and 19.4%, [95% CI 14.2–24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474–2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297–2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust.ConclusionICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video

ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry

BackgroundTreatment resistant depression (TRD) affects 10–30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking.MethodsICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were.ResultsPatients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6–53.9]) and remission (33.6% [95% CI 29.7–37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5–31.4] and 18.2% [95% CI 13.9–22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034–3.733], p < 0.0001; RR 1.882 [95% CI 1.534–2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621–3.196], p < 0.0001; RR 1.847 [95% CI 1.418–2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses.ConclusionICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video

Persistence of and changes in neuropsychiatric symptoms in Alzheimer disease over 6 months: the LASER-AD study

Neuropsychiatric symptoms ( NPS) are common in Alzheimer disease ( AD). It is important in terms of management to know their natural history and their effects on service use. The authors aimed to determine the persistence and change in severity of NPS over 6 months in participants with AD, and the relationship to initial severity, drug management, use of services, and cost of care. Methods: NPS scores and data on cognition, psychotropic medication, service use, and costs of care were collected on 224 participants at baseline and on 198 at 6-month follow-up. Results: Of 224 patients, 210 (93.8%)had NPS at baseline; 168 ( 75.0%) had at least one clinically significant symptom, 118 (80.4%) of whom had persistent significant symptoms at 6-month follow-up. There was no significant change in mean NPS score for any symptom over 6 months, but many individuals became better or worse; 61.2% of those with at least one significant baseline symptom in any domain improved. Those with persistent symptoms had more severe baseline symptoms. Deterioration in NPS was predicted by deterioration in MMSE. Those with at least one clinically significant symptom had higher care costs than those without. Conclusions: NPS were highly persistent overall, but many individuals became better or worse. Persistence was predicted by having more severe symptoms at baseline. Clinically significant levels of NPS were associated with greater costs of care. The relatively few associations found between specific psychiatric treatments and changes in NPS reflect both undertreatmen

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

Background: Loss of independence becomes more marked as Alzheimer's 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 community-based Alzheimer’s disease patients: an adaptation in Spain

Memantine, Moderately severe to severe Alzheimer’s disease, Cost-effectiveness, Markov model, Spain,