Exploring humanistic burden of fatigue in adults with multiple sclerosis: an analysis of US National Health and Wellness Survey data.

BACKGROUND: This retrospective study examined the humanistic burden of fatigue in patients with relapsing-remitting multiple sclerosis (RRMS), compared with adults without MS, using data from the 2017 and 2019 US National Health and Wellness Survey. METHODS: The 5-item Modified Fatigue Impact Scale (MFIS-5) was used to assess level of fatigue (MFIS-5 score <15: low fatigue [LF]; MFIS-5 score ≥15: high fatigue [HF]) in patients with RRMS. Health-related quality of life (HRQoL) measures (Short Form 36-Item Health Survey version 2, Euroqol-5 Dimensions-5 Levels [EQ-5D-5L], Patient Health Questionnaire-9 [PHQ-9], Generalized Anxiety Disorder-7 [GAD-7], Perceived Deficits Questionnaire-5) and treatment-related characteristics were assessed. RESULTS: In total, 498 respondents were identified as RRMS (n=375 RRMS+LF, n=123 RRMS+HF) and compared with 1,494 matched non-MS controls. RRMS+LF and RRMS+HF had significantly lower Short Form 6 Dimensions health utility, Mental and Physical Component Summary, and EQ-5D-5L scores and higher PHQ-9 and GAD-7 scores, compared with matched non-MS controls (all p<0.001); scores were worse for RRMS+HF than RRMS+LF across all measures (all p<0.001). A higher proportion of RRMS+HF reported moderate-to-severe depression and moderate-to-severe anxiety, compared with RRMS+LF and matched non-MS controls (both p<0.001). Fatigue was a significant predictor of poor HRQoL across all measures (all p<0.001). CONCLUSIONS: Patients with RRMS experienced lower HRQoL with higher levels of fatigue, highlighting an unmet need. Results may help to inform physician-patient communication and shared decision-making to address fatigue and its associated impact on patients' HRQoL.

Budget Impact of Increasing Market Share of Patient Self-Testing and Patient Self-Management in Anticoagulation.

BACKGROUND: Patient self-testing (PST) and/or patient self-management (PSM) might provide better coagulation care than monitoring at specialized anticoagulation centers. Yet, it remains an underused strategy in the Netherlands. METHODS: Budget-impact analyses of current and new market-share scenarios of PST and/or PSM compared with monitoring at specialized centers were performed for a national cohort of 260,338 patients requiring long-term anticoagulation testing. A health care payer perspective and 1- to 5-year time horizons were applied. The occurrence of thromboembolic and hemorrhagic complications in the aforementioned patient population was assessed in a Markov model. Dutch-specific costs were applied, next to effectiveness data derived from a meta-analysis on PST and/or PSM. Sensitivity and scenario analyses were performed to assess uncertainty on budget-impact analysis results. RESULTS: Increasing PST and/or PSM usage in the national cohort from the current 15.4% to 50% resulted in savings ranging from €8 million after the first year to €184 million after 5 years. Further increases in the use of PST and/or PSM produced greater savings. Sensitivity analyses revealed budget-impact model sensitivity to the baseline and relative risks of thromboembolic complications. Unfavorable budget impact was found in scenarios exploring an increase in the use of PST alone as well as an increase in the market share of PST and PSM in patients with atrial fibrillation. CONCLUSIONS: Overall study findings indicated that PST and PSM are more favorable alternatives to monitoring at specialized centers in patients without atrial fibrillation.

Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review.

OBJECTIVES: Patients receiving therapy for haematological malignancies have a higher risk of invasive fungal infections (IFIs). Antifungal prophylaxis is an effective strategy against IFIs, but relative effectiveness estimates across agents are inconclusive. A mixed treatment comparison (MTC) was conducted to estimate the relative effectiveness of all agents for a number of outcomes of interest. METHODS: A systematic review was performed to collect evidence from randomized controlled trials (RCTs) on the risk of IFIs and on mortality after antifungal prophylaxis. The agents analysed were no prophylaxis/placebo, fluconazole, itraconazole, micafungin, caspofungin, liposomal amphotericin B and posaconazole. Meta-analyses and MTCs were used to synthesize the evidence. The primary outcome was the risk of proven or probable IFI. Secondary outcomes were risk of candidiasis/aspergillosis, risk of IFI mortality and risk of all-cause mortality. RESULTS: Antifungal prophylaxis was more effective than no prophylaxis/placebo in reducing IFI risk. The IFI risk after voriconazole or posaconazole was lower than after fluconazole [relative risk (RR) 0.38, 95% CI 0.14-0.83 and RR 0.34, 95% CI 0.14-0.83] or itraconazole tablets (RR 0.22 95% CI 0.06-0.72 and RR 0.20 95% CI 0.05-0.72). Posaconazole was also found to be more effective than no prophylaxis/placebo in reducing all-cause mortality (RR 0.56, 95% CI 0.30-0.98). Posaconazole had the highest probability of being the most effective agent in reducing IFI risk and all-cause mortality. CONCLUSIONS: IFI prophylaxis has a positive effect on IFI risk reduction. However, its effect on all-cause mortality is not as pronounced. The analysis has additionally pinpointed posaconazole as potentially the most effective IFI prophylaxis in neutropenic patients.

Direct costs of hypertensive patients admitted to hospital in Vietnam- a bottom-up micro-costing analysis.

BACKGROUND: There is an economic burden associated with hypertension both worldwide and in Vietnam. In Vietnam, patients with uncontrolled high blood pressure are hospitalized for further diagnosis and initiation of treatment. Because there is no evidence on costs of inpatient care for hypertensive patients available yet to inform policy makers, health insurance and hospitals, this study aims to quantify direct costs of inpatient care for these patients in Vietnam. METHODS: A retrospective study was conducted in a hospital in Vietnam. Direct costs were analyzed from the health-care provider's perspective. Hospital-based costing was performed using both bottom-up and micro-costing methods. Patients with sole essential or primary hypertension (ICD-code I10) and those comorbid with sphingolipid metabolism or other lipid storage disorders (ICD-code E75) were selected. Costs were quantified based on financial and other records of the hospital. Total cost per patient resulted from an aggregation of laboratory test costs, drug costs, inpatient-days' costs and other remaining costs, including appropriate allocation of overheads. Both mean and medians, as well as interquartile ranges (IQRs) were calculated. In addition to a base-case analysis, specific scenarios were analyzed. RESULTS: 230 patients were included in the study (147 cases with I10 code only and 83 cases with I10 combined with E75). Median length of hospital stay was 6 days. Median total direct costs per patient were US$65 (IQR: 37 -95). Total costs per patient were higher in the combined hypertensive and lipid population than in the sole hypertensive population at US$78 and US$53, respectively. In all scenarios, hospital inpatient days' costs were identified as the major cost driver in the total costs. CONCLUSIONS: Costs of hospitalization of hypertensive patients is relatively high compared to annual medication treatment at a community health station for hypertension as well as to the total health expenditure per capita in Vietnam. Given that untreated/undetected hypertension likely leads to more expensive treatments of complications, these findings may justify investments by the Vietnamese health-care sector to control high blood pressure in order to save downstream health care budgets.

Economic impact of childhood/adolescent ADHD in a European setting: the Netherlands as a reference case.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder in children/adolescents. This study reviews available European-based studies of ADHD-related costs and applies the findings to the Netherlands to estimate annual national costs for children/adolescents from a societal perspective. A systematic literature search was conducted for primary studies in Europe, published January 1, 1990 through April 23, 2013. Per-person cost estimates were converted to 2012 Euros and used to estimate annual national ADHD-related costs based on the Dutch 2011 census, ADHD prevalence rates, family composition, and employment rates. Seven studies met the inclusion criteria. The average total ADHD-related costs ranged from €9,860 to 14,483 per patient and annual national costs were between €1,041 and €1,529 million (M). The largest cost category was education (€648 M), representing 62 and 42 % of the low- and high-value overall national estimates, respectively. By comparison, ADHD patient healthcare costs ranged between €84 M (8 %) and €377 M (25 %), and social services costs were €4.3 M (0.3-0.4 %). While the majority of the costs were incurred by ADHD patients themselves, €161 M (11-15 %) was healthcare costs to family members that were attributable to having an ADHD child/adolescent. In addition, productivity losses of family members were €143-€339 M (14-22 %). Despite uncertainties because of the small number of studies identified and the wide range in the national cost estimates, our results suggest that ADHD imposes a significant economic burden on multiple public sectors in Europe. The limited number of European-based studies examining the economic burden of ADHD highlights the need for more research in this area.

Shared Decision-Making in the Treatment of Multiple Sclerosis: Results of a Cross-Sectional, Real-World Survey in Europe and the United States.

Introduction: Multiple sclerosis (MS) is a neurodegenerative disease characterized by progressive deterioration of cognitive and physical functioning, reducing activities of daily living and quality of life (QoL). Several treatments are available that modify the course of the disease and reduce the frequency of relapses. Although effective, all treatment options are accompanied by adverse events, and this study aimed to assess the extent to which patients were involved in the choice of treatment. Methods: Data were drawn from the Adelphi Multiple Sclerosis Disease Specific Program (DSP)™, a cross-sectional survey of healthcare practitioners (HCP) and their patients with MS in real-world clinical settings in Europe and the United States (US) between December 2020 and July 2021. HCPs reported patient demographics, clinical characteristics, current and previous treatment, and treatment outcomes. Patients voluntarily completed questionnaires reporting the physical and psychological impact of their MS and its treatment. Regression analysis with inverse probability of treatment weighting was used to compare treatment outcomes in patients actively involved in their current treatment choice with those who were not. Results: Of a total of 692 patients, median age 40 years and 64% female, mostly diagnosed with relapsing-remitting MS, those who were involved in shared decision-making tended to choose oral therapies such as dimethyl fumarate more often than HCPs. MS had greater impact on physical and psychological functioning in patients whose HCP made treatment decisions solely. Patients involved in decision-making reported greater satisfaction with their treatment and a better QoL. Discussion: Because no single optimal therapy exists for patients with MS, treatments should be individualized with consideration of patients' preferences. Our study shows that shared decision-making is under-utilized in the management of MS and supports the benefits of patient involvement. Conclusion: Patients who have an active role in treatment decision-making show improved wellbeing and QoL, and overall treatment satisfaction.

Patients' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

BACKGROUND: Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC]). OBJECTIVES: This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC. METHODS: A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator. RESULTS: Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n = 341) and with (n = 59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points). CONCLUSIONS: When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors.

A retrospective claims analysis of fatigue in patients with multiple sclerosis on disease-modifying therapy.

BACKGROUND: Fatigue, one of the most common symptoms in patients with multiple sclerosis (MS), severely impairs quality of life and the ability to work or perform activities of daily living. Real-world data on fatigue in MS can help inform healthcare decisions and identify care gaps. We identified fatigue in patients with MS, using existing codes for fatigue and proxies of fatigue in healthcare claims database records and characterized cohorts with and without markers of fatigue who had been prescribed disease-modifying therapies for MS (MS-DMTs). METHODS: In this cohort study, we retrospectively analyzed Optum's de-identified Clinformatics® Data Mart database from 1 January 2015 to 31 December 2019. The index date was defined as the first prescription record date for any MS-DMT during the study identification period. Included patient records were from adults (≥18 years) with ≥2 MS diagnosis claims listed within 12 months prior to the index date. Patients had ≥1 claim for any MS-DMT during the identification period (1 January 2016-31 December 2018), continuous enrollment in a health plan with medical and pharmacy benefits for 12 months before the index date (assessment one), and 12 months following the index date or to end of data availability (assessment two). After exploratory analyses, we applied the following definition to sort patient records into two cohorts according to presence or absence of markers of fatigue: ≥1 diagnosis (International Classification of Diseases, Ninth/Tenth Revisions code) claim for fatigue or ≥2 claims for stimulant drugs or ≥2 procedure claims for a sleep study or ≥2 pharmacy claims for sleep aid drugs; we used the broadest definition of fatigue so meeting any of these criteria qualified patients with MS as having fatigue. To minimize assessment one differences in selected patient characteristics between cohorts, we applied 1:1 propensity score matching with age, sex, US geographic region, and Charlson Comorbidity Index score as covariates. We analyzed demographic data, markers of fatigue, comorbidities at assessment one, and physical disabilities and neurologic impairment at assessment two. RESULTS: Of 4077 patient records that met the eligibility criteria, 1976 had markers of fatigue. The propensity score-matched cohorts included 1519 patients each with and without fatigue. Assessment one comorbidities including anxiety (25.3% vs 10.5%; P<0.0001), arthritis (17.6% vs 12.9%; P = 0.0003), depression (15.0% vs 3.5%; P<0.0001), and gastrointestinal disorders (20.3% vs 14.2%; P<0.0001) were significantly more prevalent in the cohort with markers of fatigue at assessment one compared with those without fatigue. At assessment two, the cohort with baseline fatigue upon initial assessment was more likely to have indication of physical impairments (spasticity [63.5% vs 35.8%; P<0.0001], bladder dysfunction [37.8% vs 24.0%; P<0.0001], cognitive/behavioral dysfunction [27.0% vs 18.6%; P<0.0001]), neurologic impairments (pain [59.1% vs 44.0%; P<0.0001], depression [29.2% vs 9.9%; P<0.0001], and sensory disturbances [54.2% vs 36.7%; P<0.0001]), compared with the cohort without markers of fatigue at assessment one. CONCLUSIONS: In our analysis, patients with MS and fatigue were more likely to have comorbidities at assessment one and to develop physical disabilities and neurologic impairments at assessment two. Appropriate identification of patients with MS and fatigue may facilitate targeted care interventions to a group of patients at higher risk for disease progression and disability.

Severity and worsening of fatigue among individuals with multiple sclerosis.

Background: Fatigue is associated with reduced quality of life and social participation, and poor employment outcomes. However, most studies examining fatigue are limited by small sample sizes or short follow-up periods. Objective: To characterize the natural history of fatigue. Methods: The North American Research Committee on Multiple Sclerosis Registry participants with ≥7 years of longitudinal data between 2004 and 2019 and a relapsing disease course were included. A subset of participants enrolled within 5 years of diagnosis was identified. The Fatigue Performance Scale assessed fatigue and ≥1-point increase in Fatigue Performance Scale sustained at the next survey defined fatigue worsening. Results: Of 3057 participants with longitudinal data, 944 were within 5 years of multiple sclerosis diagnosis. Most participants (52%) reported fatigue worsening during follow-up. Median time to fatigue worsening ranged from 3.5 to 5 years at lower levels of index fatigue. Fatigue worsening was associated with lower annual income, increasing disability, lower initial fatigue level, taking injectable disease-modifying therapies and increasing depression levels in the relapsing multiple sclerosis participants. Conclusion: Most multiple sclerosis participants early in their disease suffer from fatigue and at least half reported fatigue worsening over time. Understanding factors associated with fatigue may help to identify populations most at risk of fatigue worsening will be informative for the overall management of patients with multiple sclerosis.

US budget impact analysis of esketamine nasal spray in major depressive disorder with acute suicidal ideation/behavior.

Background: Esketamine nasal spray plus an oral antidepressant is approved in adults with major depressive disorder with acute suicidal ideation or behavior (MDSI). Methods: A budget impact analysis from a US payer perspective was performed with a hypothetical 1-million-member plan, using pharmacy and medical costs associated with adding esketamine plus an oral antidepressant to usual care. Results: Estimated annual total healthcare costs of managing patients with MDSI increased from $32,988,247 without esketamine to $34,161,188 in Year 3 with esketamine (primarily due to medical costs). The per-member-per-month incremental costs were $0.02, $0.06 and $0.10 in Years 1, 2 and 3, respectively. Conclusion: Incorporation of esketamine results in a modest estimated impact on the annual budget over a 3-year time horizon.

Assessment of economic burden of fatigue in adults with multiple sclerosis: An analysis of US National Health and Wellness Survey data.

BACKGROUND: Fatigue, a common disabling symptom in multiple sclerosis (MS), is reported by the majority of patients. However, evidence on the economic burden of fatigue in MS by fatigue status is limited. This study aimed to evaluate the economic burden of fatigue, including healthcare resource utilization (HCRU), labor force participation, and Work Productivity and Activity Impairment (WPAI), among adults with relapsing-remitting MS (RRMS) by low fatigue (LF) vs high fatigue (HF) and compared with adults without MS. METHODS: This cross-sectional, retrospective, observational study included pooled data from the 2017 and 2019 US National Health and Wellness Survey. The RRMS sample included respondents aged ≥18 years who reported being diagnosed with MS by a healthcare provider (HCP) and reported having RRMS. Non-MS controls included respondents aged ≥18 years who did not report being diagnosed with MS by an HCP. Fatigue was measured using the Modified Fatigue Impact Scale-5 (MFIS-5). Outcomes included HCRU (HCP visits, emergency department visits, and hospitalizations in the past 12 months), labor force participation (yes vs no), WPAI (absenteeism, presenteeism, total work productivity impairment, and activity impairment), and annualized costs (direct medical, indirect, and total). Respondents with RRMS were propensity-score matched to non-MS controls (ratio 1:3). RRMS respondents were categorized as having LF (MFIS-5<15; RRMS+LF) and HF (MFIS-5≥15; RRMS+HF). Bivariate analysis compared matched non-MS controls, RRMS+LF, and RRMS+HF. Multivariable analyses were conducted among RRMS to evaluate associations between fatigue (continuous variable) and outcomes. RESULTS: Overall, 498 respondents with RRMS (RRMS+LF, n=375; RRMS+HF, n=123) and 1494 matched non-MS controls were included. RRMS+HF and RRMS+LF had more HCRU in the past 12 months than non-MS controls, whereas RRMS+HF had greater HCRU than RRMS+LF (all p<0.05). WPAI was also higher among RRMS+HF and RRMS+LF, compared with non-MS controls, as well as higher in RRMS+HF vs RRMS+LF (all p<0.001). RRMS+HF had significantly higher annualized direct medical costs than RRMS+LF and matched non-MS controls ($19,978 vs $10,656, p=0.007; vs $8,048, p<0.001). Among employed respondents, RRMS+HF and RRMS+LF had higher annualized indirect costs than non-MS controls, with RRMS+HF also having higher annualized indirect costs than RRMS+LF ($23,647 vs $13,738 vs $8,001; all p<0.01); total annualized costs were higher in RRMS+HF and RRMS+LF, compared with non-MS controls, as well as RRMS+HF vs RRMS+LF (all p<0.01). In multivariable models, fatigue was significantly and positively associated with the number of HCP visits in the past 12 months (p=0.002); not participating in the labor force (p<0.001); and absenteeism, presenteeism, total work productivity impairment, and activity impairment (all p<0.001). CONCLUSION: RRMS poses a substantial economic burden on patients and society, and this burden is disproportionately associated with HF.

A novel disease specific scale to characterize the symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis: A real-world study.

BACKGROUND: Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE: To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS: This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS: 300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION: Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

Cost-per-remitter with esketamine nasal spray versus standard of care for treatment-resistant depression.

Aim: Estimate the cost-per-remitter with esketamine nasal spray plus an oral antidepressant (ESK + oral AD) versus oral AD plus nasal placebo (oral AD + PBO) among patients with treatment-resistant depression. Patients & methods: An Excel-based model was developed to estimate the cost-per-remitter for ESK + oral AD versus oral AD + PBO over 52 weeks from multiple US payer perspectives. Clinical end points and cost inputs were derived from clinical trials and the literature, respectively. Results: Under the base-case scenario, the cost-per-remitter for ESK + oral AD and oral AD + PBO were as follows: Commercial: US$85,808 versus US$100,198; Medicaid: US$76,236 versus US$96,067; Veteran's Affairs: US$77,765 versus US$104,519; and Integrated Delivery Network: US$103,924 versus US$142,766. Conclusion: The findings suggest that ESK + oral AD is a cost-efficient alternative treatment for treatment-resistant depression compared with oral AD + PBO.

Lay abstract The US FDA recently approved esketamine nasal spray plus an oral antidepressant (AD) as a new treatment for adults with treatment-resistant depression. We developed an Excel-based model to understand whether esketamine + oral AD treatment offers better value for the money spent, compared with treatment with oral AD alone. We find that the higher annual costs of esketamine + oral AD treatment are more than offset by the better clinical outcomes achieved with this treatment. Specifically, in a given year, more people treated with esketamine + oral AD versus oral AD alone achieved and remained in remission, and as a result, they incurred fewer other medical costs.

A retrospective chart review study to quantify the monthly medical resource use and costs of treating patients with treatment resistant depression in the United Kingdom.

INTRODUCTION: Major depressive disorder (MDD) is a globally prevalent chronic psychiatric illness with a significant disease impact. As many as 30% of patients with MDD do not adequately respond to two therapies and are considered to be treatment resistant. This study aimed to quantify healthcare costs associated with treatment resistant depression (TRD) in the UK. METHODS: A retrospective chart review of patients with TRD was conducted in primary and secondary care settings over a 2 year period. Data abstracted from medical records of patients included demographics, clinical characteristics and healthcare resource utilization (HCRU; number of consultations, use of Crisis Resolution and Home Treatment Teams [CRHTTs], non-drug and drug interventions, and hospitalizations). HCRU per patient per month (28 days) was calculated for three health states: major depressive episode (MDE), remission and recovery. Unit costs were from the British National Formulary (BNF) and the Personal Social Services Research Unit (PSSRU). RESULTS: A total of 295 patients with TRD were recruited between January 2016 and May 2018. The mean age of the total sample was 43.3 years; 60.3% were female. Costs per patient, per 28 days, were highest in the MDE state, with the average cost (£992) mainly driven by consultations, non-drug treatment, hospitalizations and CRHTT, with a considerable fall in costs as patients moved into remission and subsequent recovery. CONCLUSION: The results suggest that antidepressant treatments for TRD that are more effective in reducing the time spent in an MDE health state, and helping patients achieve remission and recovery, are essential for reducing the overall HCRU and costs in patients with TRD. Cost of TRD in the UK Strengths and limitations of this study This observational study of TRD is the first to assess the HCRU impact associated with different predefined health states. Using retrospective data from both primary and secondary care physicians from regions across the UK ensures a representative real-world patient population. One limitation is that the selection of patients is based on criteria that define TRD that rely on physician judgement. Although the study captures direct HCRU costs, the indirect costs of lost productivity and care are not included in the overall burden. This study has defined the current clinical management of patients with TRD in the UK and provides an estimate of the associated HCRU and associated costs.

Defining hormesis: evaluation of a complex concentration response phenomenon.

Hormesis describes dose-response relationships characterized by a reversal of response between low and high doses of chemicals, biological molecules, physical stressors, or other initiators of a response. Acceptance of hormesis as a viable dose-response theory has been limited until recently, in part, because of poor conceptual understanding, ad hoc and inappropriate use, and lack of a defined mechanism. By examining the history of this dose-response theory, it is clear that both pharmacological and toxicological studies provide evidence for hormetic dose responses, but retrospective examination of studies can be problematic at best. Limited scientific evidence and lack of a common lexicon with which to describe these responses have left hormesis open to inappropriate application to unrelated dose-response relationships. Future studies should examine low-dose effects using unbiased, descriptive criteria to further the scientific understanding of this dose response. A clear, concise definition is required to further the limited scientific evidence for hormetic dose responses.

Pitfalls of Cost-Effectiveness Analysis in Practice: A TRD Case Example in the United States with Esketamine Versus Oral Antidepressants.

DISCLOSURES: The writing of this letter was supported by Janssen Scientific Affairs. The authors are employees of Janssen Scientific Affairs or Janssen Global Services (Johnson & Johnson).

Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons.

The impact of endocrine disrupting chemical (EDC) exposure on human health is receiving increasingly focused attention. The prototypical EDC bisphenol A (BPA) is an estrogenic high-production chemical used primarily as a monomer for the production of polycarbonate and epoxy resins. It is now well established that there is ubiquitous human exposure to BPA. In the general population, exposure to BPA occurs mainly by consumption of contaminated foods and beverages that have contacted epoxy resins or polycarbonate plastics. To test the hypothesis that bioactive BPA was released from polycarbonate bottles used for consumption of water and other beverages, we evaluated whether BPA migrated into water stored in new or used high-quality polycarbonate bottles used by consumers. Using a sensitive and quantitative competitive enzyme-linked immunosorbent assay, BPA was found to migrate from polycarbonate water bottles at rates ranging from 0.20 ng/h to 0.79 ng/h. At room temperature the migration of BPA was independent of whether or not the bottle had been previously used. Exposure to boiling water (100 degrees C) increased the rate of BPA migration by up to 55-fold. The estrogenic bioactivity of the BPA-like immunoreactivity released into the water samples was confirmed using an in vitro assay of rapid estrogen signaling and neurotoxicity in developing cerebellar neurons. The amounts of BPA found to migrate from polycarbonate drinking bottles should be considered as a contributing source to the total "EDC-burden" to which some individuals are exposed.

Clinical and economic benefits of extended treatment with apixaban for the treatment and prevention of recurrent venous thromboembolism in Canada.

Background and objective Venous thromboembolism (VTE) is associated with long-term clinical and economic burden. Clinical guidelines generally recommend at least 3 months of anticoagulation, but, in clinical practice, concerns over bleeding risk often limit extended treatment. Apixaban was studied for extended VTE treatment in the AMPLIFY-EXT trial, demonstrating superiority to placebo in VTE reduction without increasing risk of major bleeding. This study assessed the long-term clinical and economic benefits of extending treatment with apixaban when clinical equipoise exists compared to standard of care with enoxaparin/warfarin and other novel oral anti-coagulants (NOACs) for the treatment and prevention of recurrent VTE in Canada. Methods A Markov model was developed to follow patients with VTE over their lifetimes. Efficacy and safety for apixaban and enoxaparin/warfarin were based on AMPLIFY and AMPLIFY-EXT, while relative efficacy to other NOACs was synthesized by network meta-analysis (NMA). Dosages for NOACs and enoxaparin/warfarin were based on their respective trials and were given up to 18 months and up to 6 months, followed by no treatment, respectively. Patient quality adjusted life years (QALYs) were based on published studies, and costs for resource utilization were from a Ministry of Health perspective, expressed as 2014 CAD ($). Results Extended treatment with apixaban compared to enoxaparin/warfarin resulted in fewer recurrent VTEs, VTE-related deaths, and bleeding events, but at slightly increased cost. The incremental cost-effectiveness ratio was $4828 per QALY gained. Compared to other NOACs, apixaban had the fewest bleeding events, similar recurrent VTE events, and the lowest overall cost, which was driven by the strong bleeding profile. In scenario analyses of acute and lifetime treatments, apixaban was cost-effective against all strategies. Conclusions Extended treatment with apixaban can offer substantial clinical benefits and is a cost-effective alternative to enoxaparin/warfarin and other NOACs.

Estrogens and ICI182,780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase.

Estrogen influences the development and function of the nervous system through estrogen receptor-dependent changes in gene expression and by rapidly influencing diverse intracellular signaling pathways. We have investigated the influence of estradiol on developing neonatal rat cerebellar neurons in primary culture and found that low concentrations of 17beta-estradiol (17beta-E2), 17alpha-E2, 17beta-E2-BSA, and ICI182,780 stimulated phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK). Neither testosterone nor progesterone increased ERK1/2 phosphorylation. The effects of the estrogens were specific to the ERK1/2 MAPK pathway and were blocked by U0126, an inhibitor of the ERK1/2 MAPK kinase (MEK1/2). Compared with control cultures, significant MAPK-dependent decreases in viable granule cell numbers were observed in dissociated explant cultures of developing cerebellar neurons 24-96 hr after pulse treatment with 10 pm 17beta-E2 or 10 nm ICI182,780. In contrast, continuous exposure to 10 pm 17beta-E2 significantly increased granule cell numbers. Analysis of bromodeoxyuridine incorporation revealed that a 15 min pulsed treatment with 10 pm 17beta-E2 increased mitogenesis, whereas continuous exposure to the same concentration of 17beta-E2 was anti-mitotic. Estradiol did not increase caspase activity; however, significant increases in cellular permeability and lysis were observed. Cell lysis and death were independent of the pan-caspase inhibitor zVAD-fmk but were blocked fully by the irreversible calpain inhibitor PD150606. These results indicate that rapid activation of the ERK1/2 MAPK pathway by low concentrations of 17beta-E2 induces oncotic/necrotic, but not apoptotic, programmed cell death in a subpopulation of developing granule cells and increased mitogenesis of the granule cell neuroblasts refractory to estrogen-induced neurotoxicity.

Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A.

In addition to regulating estrogen receptor-dependent gene expression, 17beta-estradiol (E(2)) can directly influence intracellular signaling. In primary cultured cerebellar neurons, E(2) was previously shown to regulate growth and oncotic cell death via rapid stimulation of ERK1/2 signaling. Here we show that ERK1/2 signaling in the cerebellum of neonatal and mature rats was rapidly responsive to E(2) and during development to the environmental estrogen bisphenol A (BPA). In vivo dose-response analysis for each estrogenic compound was performed by brief (6-min) intracerebellar injection, followed by rapid fixation and phosphorylation-state-specific immunohistochemistry to quantitatively characterize changes in activated ERK1/2 (pERK) immunopositive cell numbers. Beginning on postnatal d 8, E(2) significantly influenced the number of pERK-positive cells in a cell-specific manner that was dependent on concentration and age but not sex. In cerebellar granule cells on postnatal d 10, E(2) or BPA increased pERK-positive cell numbers at low doses (10(-12) to 10(-10) M) and at higher (10(-7) to 10(-6) M) concentrations. Intermediate concentrations of either estrogenic compound did not modify basal ERK signaling. Rapid E(2)-induced increases in pERK immunoreactivity were specific to the ERK1/2 pathway as demonstrated by coinjection of the mitogen-activated, ERK-activating kinase (MEK)1/2 inhibitor U0126. Coadministration of BPA (10(-12) to 10(-10) M) with 10(-10) M E(2) dose-dependently inhibited rapid E(2)-induced ERK1/2 activation in developing cerebellar neurons. The ability of BPA to act as a highly potent E(2) mimetic and to also disrupt the rapid actions of E(2) at very low concentrations during cerebellar development highlights the potential low-dose impact of xenoestrogens on the developing brain.