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To evaluate the costs and benefits associated with the use of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for lower limb spasticity in children, upper and lower limb spasticity in adults, and cervical dystonia in adults.This pharmacoeconomic analysis compared aboBoNT-A with onaBoNT-A. A decision tree model with a 1-year time horizon was conducted from a UK National Health Service (NHS) perspective using data from a variety of sources: randomized controlled trials (RCTs), network meta-analyses (NMAs), observational studies, and a physician survey investigating treatment patterns and resource utilization. Four patient populations were included: pediatric patients with lower limb spasticity (PLL), and adults with upper limb spasticity (AUL), lower limb spasticity (ALL), and cervical dystonia (CD). Outcomes included costs, quality-adjusted life years (QALYs) gained, cost per responder, and incremental cost per QALY gained. The effectiveness of each treatment was evaluated as a response to treatment. The base case assumption was that all patients in the model continued to receive botulinum toxin type A (BoNT-A) treatments at regular intervals regardless of treatment response status. Scenario analysis evaluated the impact of discontinuing BoNT-A for patients without a response to the first injection.The model found that aboBoNT-A resulted in greater quality-of-life and lower costs compared with onaBoNT-A for the management of spasticity and CD in all included indications. Across populations, cost savings ranged from £304 to £3,963 and QALYs gained ranged from 0.010 to 0.02 over a 1-year time horizon. Results were robust to scenario analyses and were driven by the impact of treatment response on health-related quality-of-life.AboBoNT-A was associated with higher treatment response, improved quality-of-life, and reduced costs in spasticity and CD versus onaBoNT-A. These findings could help deliver more effective and efficient healthcare in the NHS.The objective of this study was to compare the costs and health outcomes associated with abobotulinumtoxinA (aboBoNT-A; Dysport) and onabotulinumtoxinA (onaBoNT-A; Botox) for treating children and adults with a variety of conditions related to limb spasticity and cervical dystonia. Therapies such as aboBoNT-A and onaBoNT-A have been shown to reduce spasticity, deformity, pain, and cervical dystonia symptoms. They can also improve function, movement, and self-care abilities. We estimated the treatment costs for patients with spasticity and patients with cervical dystonia receiving aboBoNT-A and onaBoNT-A in the UK. We also estimated other health-related costs that patients were expected to incur while receiving these treatments, as well as their quality of life.For each indication (spasticity in the upper and lower limbs in adults and children, cervical dystonia in adults), research studies were identified to estimate the likelihood of patient response for aboBoNT-A and onaBoNT-A. Survey studies were assessed to understand use of health services and costs for patients who respond to therapy vs. those who do not. We estimated total costs over one year and expected quality of life for patients. Costs included the costs of aboBoNT-A and onaBoNT-A treatments, as well as other health services.In all identified studies, the likelihood of response was higher for aboBoNT-A than for onaBoNT-A. This was associated with reduced need for other health services (and therefore lower costs), and better quality of life for patients receiving aboBoNT-A. In addition, the cost per year of aboBoNT-A treatment was lower than onaBoNT-A treatment for all indications. Therefore, treatment with aboBoNT-A was consistently associated with lower costs and better quality of life. This outcome is referred to as “economically dominant,” meaning that from a health economic perspective, aboBoNT-A would be preferred to onaBoNT-A for treating patients with spasticity or cervical dystonia.

To compare the efficacy and safety of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for the treatment of refractory neurogenic detrusor overactivity (NDO), using an indirect treatment comparison (ITC). A systematic literature review was used to identify randomized controlled trials (RCTs) that evaluated botulinum toxin type A for the treatment of refractory NDO. Treatments were compared using a Bucher ITC approach. Efficacy outcomes were reduction in number of weekly urinary incontinence (UI) episodes at 6, 12, and 24 weeks of follow-up. The safety outcome was the proportion of patients with treatment-emergent urinary tract infections (TE-UTIs) during follow-up. Subgroup/sensitivity analyses were performed to investigate the impact of heterogeneity. Fifteen studies of botulinum toxin type A were identified. Among these, onaBoNT-A 200 U was the only botulinum toxin type A considered an appropriate comparator for aboBoNT-A 600 U and 800 U. As such, six RCTs that evaluated onaBoNT-A or aboBoNT-A were included in the ITC. In base-case analyses, there were no statistically significant differences between aboBoNT-A and onaBoNT-A in terms of UI episodes or TE-UTIs. Numerically, the trend favored aboBoNT-A (either dose) for all endpoints and time points. At 12 and 24 weeks, the difference in reduction of UI episodes per week was considered clinically relevant when comparing aboBoNT-A 800 U with onaBoNT-A 200 U, but not when comparing the lower dose of aboBoNT-A (600 U) with onaBoNT-A 200 U. Results from subgroup/sensitivity analyses were consistent with the base case. Heterogeneity across studies was observed; however, strong consistency of trends across analyses suggests the impact of heterogeneity is low. There may be potential advantages of aboBoNT-A over onaBoNT-A, in terms of UI reduction, in patients with refractory NDO. More confirmatory studies are needed owing to the sparsity of current evidence. Neurogenic detrusor overactivity (NDO) is a condition in which the bladder muscle wall is overactive and does not function normally. This can lead to urinary incontinence (i.e. accidental leakage of urine). NDO may also cause urinary tract infections and upper urinary tract damage if it is left untreated or if treatment does not work (i.e. refractory NDO). Botulinum toxin is a treatment that relaxes muscles in patients with refractory NDO, so they have less chance of experiencing urinary incontinence. This study used results from clinical trials to compare two types of botulinum toxin – abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) – to see if one works better than the other. Clinical trials are experiments to assess how well treatments work by giving different treatments to different patients and observing the results. When there is no clinical trial that compares the two treatments you are interested in, it is possible to combine results from a number of different clinical trials instead. This is known as an indirect treatment comparison. We used an indirect treatment comparison to compare aboBoNT-A and onaBoNT-A for the treatment of refractory NDO. Results showed that aboBoNT-A may be more effective than onaBoNT-A in reducing the frequency of urinary incontinence episodes. On average, patients treated with aboBoNT-A had at least three fewer episodes of urinary incontinence per week than those treated with onaBoNT-A. These results suggest that patients treated with aboBoNT-A could have a better quality of life than those treated with onaBoNT-A.

Background Patients frequently require several lines of therapy for treatment of major depressive episodes. This economic analysis details the management of patients who responded inadequately due to lack of efficacy or intolerability to two previous antidepressants in the UK. Methods The model included a decision tree and a Markov component. Health states considered in the decision tree were remission, response, no response, withdrawal due to adverse events, relapse, recovery, and recurrence. The time horizon was 24 months. Patients were on third-line treatment for up to a 3-month acute phase and a 6-month maintenance phase. As third-line efficacy data were not available, inputs were calculated by adjusting original second-line data to third-line based on proportionate reductions observed in STAR*D. Equivalent efficacy was assumed for all comparators. Healthcare resource use and utilities were based on UK estimates. Results Vortioxetine was a cost-effective treatment option at a threshold of £20,000/QALY vs. escitalopram, citalopram, sertraline, and was associated with more health benefits, less costs (was dominant) versus relevant third-line comparators venlafaxine and duloxetine. Agomelatine was found not to be a cost-effective option. The 22-month maintenance phase treatment scenario results were similar to the 6-month base case. Limitations Third-line efficacy data were not available. This highlights the need for studies in patients receiving third-line treatment. Conclusion This model provides an overview for the management of patients receiving third-line treatment where limited evidence currently exists. Vortioxetine, with its novel mechanism of action, is expected to be a dominant treatment option versus relevant comparators in the UK.

There is limited research on the impact of antidepressant treatment on family functioning. This study examines the impact of vortioxetine and agomelatine on family functioning using the Depression and Family Functioning Scale (DFFS).The DFFS was included in REVIVE, a randomized, double-blind study of adults with major depressive disorder with inadequate response to antidepressant treatment who switched to vortioxetine or agomelatine. The prespecified DFFS analyses were performed using change from baseline to weeks 8 and 12, analyzed by mixed models for repeated measurements by treatment groups. Post hoc analyses compared DFFS scores for remitters and nonremitters. Patients were stratified into quartiles using DFFS scores, and scores on other clinical outcome assessments were compared.Sizeable improvements in DFFS scores were observed from baseline to week 8 (-10.8, -7.9 for vortioxetine and agomelatine, respectively), with further improvements at week 12 (-13.5, -11.0). Vortioxetine (n = 189) was superior to agomelatine (n = 187) by 2.9 DFFS points at week 8 (p .01) and 2.5 points at week 12 (p .05), and DFFS item-level improvements were also significantly greater for vortioxetine for 8 of 15 DFFS items at week 8 and 7 items at week 12. At week 8, remitters (n = 142) and nonremitters (n = 233) differed by 11 DFFS points; at week 12, remitters (n = 183) and nonremitters (n = 121) differed by almost 12 DFFS points. Patients stratified into baseline DFFS quartiles showed trends on clinical outcomes such that better family functioning was associated with better functional status and depressive symptoms.Vortioxetine was significantly superior to agomelatine in terms of family functioning and partner relationships, as well as social functioning, health status, and depression symptoms at weeks 8 and 12. Depressed patients with impaired family functioning showed worse overall functioning, health status, and depression symptoms, suggesting that more attention should be given to family functioning of depressed patients.

Raymond W Lam,1 François-Xavier Lamy,2 Natalya Danchenko,2 Aaron Yarlas,3 Michelle K White,3 Benoît Rive,2 Delphine Saragoussi2 1Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; 2Global Outcomes Research, Lundbeck SAS, Issy-les-Moulineaux, France; 3Optum Patient Insights, Optum, Inc., Lincoln, RI, USA Background: Although depression and cognitive dysfunction are connected, limited tools exist to capture the patient’s perspective on cognitive dysfunction and its impact on major depressive disorder (MDD). We report results of a psychometric validation of the Perceived Deficits Questionnaire-Depression (PDQ-D), a self-report measure of cognitive dysfunction for use in MDD.Methods: A non-interventional, prospective, panel-recruited, online survey was conducted using the PDQ-D in adults with and without MDD in the US and UK. Respondents were assessed at baseline and after 6 weeks (MDD only) (baseline: US n=418, UK n=437, 49% MDD; follow-up: US n=169, UK n=153, all MDD). The criterion measures included: Medical Outcomes Study Cognitive Functioning Scale-Revised-acute form (MOS COG-R), Patient Health Questionnaire-9 (PHQ-9), Patient Global Impression of Severity scale (PGI-Severity), Sheehan Disability Scale (SDS), Work Productivity and Activity Impairment Questionnaire: Specific-Health Problem (WPAI:SHP), and modified Lam Employment Absence and Productivity Scale (LEAPS). US and UK data were analyzed separately.Results: Internal consistency was high for PDQ-D total scale and four subscales (Cronbach’s alpha 0.81–0.96). Convergent validity was good, with strong concordance with MOS COG-R and moderate/small correlations with PHQ-9, SDS, WPAI:SHP, LEAPS, and PGI-Severity. Significant differences (all P

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.

ObjectiveTo identify and explore concepts important to patients with cognitive symptoms of major depressive disorder (MDD) and adapt an existing patient-reported outcome (PRO) measure to assess these symptoms.MethodsFour focus groups were conducted with MDD patients (n = 33) to elicit relevant concepts and determine whether one of several PRO scales could be used to assess cognitive symptoms of depression. Following selection and minor modification of the Perceived Deficits Questionnaire (PDQ), cognitive debriefing interviews were conducted with additional patients (n = 17) to further refine and adapt this measure for use in MDD. Minor revisions based on patient input yielded the PDQ for Depression (PDQ-D).ResultsFocus group participants reported a variety of cognitive symptoms that were classified into 7 general categories: lack of focus and clear thought, memory problems, difficulty with lexical access, difficulty with divided attention, difficulty with decision making, difficulty thinking quickly, and difficulty learning new things. Limitations in work productivity were the most commonly reported impacts of cognitive symptoms. While suggesting a few modifications, focus group participants reacted positively to the PDQ based on the breadth, specificity, and relevance of the items. Cognitive debriefing participants indicated that the modified PDQ items were generally easy to understand and relevant to their experiences with MDD.ConclusionBecause cognitive symptoms are burdensome to patients with MDD, their assessment is important to optimize treatment outcomes. The PDQ-D has the potential to supplement existing assessment methods, providing unique information important for both comprehensive evaluation of individuals with MDD and evaluation of new treatments.

To assess the cost-utility of vortioxetine versus relevant comparators (agomelatine, bupropion SR, sertraline, and venlafaxine XR) in the finnish setting in major depressive disorder (MDD) patients with inadequate response to selective serotonin- /serotonin-norepinephrine reuptake inhibitors.A one-year analysis was conducted using a decision tree with a Markov state transition component. The health states were remission, relapse and recovery. A Finnish healthcare payer perspective was adopted.Vortioxetine was less costly and more effective versus all comparators in both direct and societal perspectives. Vortioxetine reduced the average annual direct costs by 4% versus venlafaxine XR and 8% versus sertraline. The greater efficacy associated with vortioxetine was translated into a higher percentage of patients in remission and recovery. The model was most sensitive to changes in remission rates at 8 weeks.This cost-utility analysis showed vortioxetine to be a good alternative for MDD patients switching therapy in Finland.

Background: Anxiety and irritability often coexist in patients with major depressive disorder (MDD). The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) added criteria for an anxious distress specifier for MDD. This study aimed at understanding the various components of anxiety and irritability, their impact, and relationships among them in MDD; and the association of anxious distress and irritability with treatment response. Methods: Focus groups were conducted with patients with MDD reporting symptoms of anxiety, irritability, agitation, and/or aggression. Clinical study data were pooled from open-label antidepressant treatment (ADT) phases of seven studies in patients with MDD and a history of inadequate response for the current depressive episode to one to three ADTs (N = 5,182). Post hoc criteria using study measures were applied to identify patients with symptoms of anxious distress and irritability. ADT response rates were compared for patients with and without anxious distress and irritability. Results: Symptoms of anxiety and irritability frequently coexisted for the focus group participants who often described symptoms of anxious distress (e.g., nervous, tense, restless, worry, fear, out of control, acting out). In the clinical studies, approximately 50% of patients with inadequate response to ADTs presented with symptoms of anxious distress and irritability. The presence of anxious distress was associated with lower ADT response rates. Conclusions: Various anxiety symptoms, including those comprising anxious distress, are prevalent and meaningful in depression, and frequently associated with irritability. Symptoms of anxious distress are associated with a decreased likelihood of ADT response.

Objective: Obtaining patient and caregiver perspectives may be critical for informing disease management, particularly with conditions like schizophrenia. The primary objective of the current study was to obtain and assess patient and caregiver perspectives on associated symptoms and behaviors of schizophrenia and their impact or burden on patients and their caregivers through patient interviews and caregiver focus groups. Research design and methods: Seven in-depth individual interviews were conducted with individuals with schizophrenia, and four focus groups were conducted with caregivers of adults with schizophrenia (n = 21) in two different locations in the United States. Following a discussion guide, interviewers asked open-ended questions to ascertain specific definitions and experiences related to five associated symptoms and behaviors (anxiety, irritability, agitation, impulsivity, and aggression), the impact of these symptoms, and how they were associated with schizophrenia. Additionally, patients completed the 8-item Birchwood Insight Scale developed to assess insight in patients with schizophrenia. Results: The impacts of anxiety were the most widespread and persistent for the patients, primarily relating to social and family interactions and relationships. For both patients and caregivers, patients’ anxiety comprised a mental and a physical component and contributed to escalation of other emotions and behaviors. Other significant or debilitating impacts, such as emotional functioning, legal issues, and financial distress, were attributed to aggression and impulsivity for both the patients and the caregivers. Conclusion: This study provides evidence of the impact of anxiety in the lives of patients with schizophrenia and their caregivers, and the potential relationship of and escalation from anxiety to aggression. Additionally, the study reinforces the importance of ensuring that treatment is taking into account the highly prevalent anxiety symptoms and behavioral disturbances in patients with schizophrenia as well as the implications of these symptoms and disturbances on the caregivers.

Objective Mood disorders are associated with a high societal cost, mainly due to presenteeism. The objective of this study was to review the use of 10 instruments that rate presenteeism in mood disorders and to provide recommendations regarding the appropriateness of instruments in different study settings. Methods A systematic review of the literature was conducted to identify scales used to measure presenteeism, including the World Health Organization Health and Work Performance Questionnaire, the Lam Employment Absence and Productivity Scale, the Sheehan Disability Scale, the Work Limitation Questionnaire, and Work Productivity and Activity Impairment questionnaire. Study characteristics and major results (by symptom level, by treatment arm, correlation to other scales, and use of monetization) were data extracted. Results Twenty-nine studies were identified. The Sheehan Disability Scale, the Work Limitation Questionnaire, and Health and Work Performance Questionnaire were the most commonly used instruments. The majority (60%) of scales demonstrated higher presenteeism in individuals with mood disorders than in individuals without. The Lam Employment Absence and Productivity Scale, the Sheehan Disability Scale, and the Work Limitation Questionnaire showed that presenteeism increased with increasing severity of disease. Few studies reported results on presenteeism by treatment, with only small between-treatment differences observed. Good correlations between presenteeism instruments and clinical or quality-of-life scales were reported. Three studies converted results from presenteeism scales into monetary units. Conclusions Limited experiential evidence exists comparing the performance of presenteeism scales in mood disorders. Therefore, recommendations for inclusion of a presenteeism tool must be driven by instrument properties (ease of administration, amenability to monetization) and the study type. Future research should focus on the responsiveness of the instrument and on how mood disorders impact self-reported assessment.

Objectives Major depressive disorder (MDD) is a major public health concern associated with a high burden to society, the health-care system, and patients and an estimated cost of €3.5 billion in Sweden. The objective of this study was to assess the cost-effectiveness of escitalopram versus generic venlafaxine extended-release (XR) in MDD, accounting for the full clinical profile of each, adopting the Swedish societal perspective, and identifying major cost drivers. Methods Cost-effectiveness of escitalopram versus venlafaxine XR was analyzed over a 6-month time frame, on the basis of a decision tree, for patients with MDD seeking primary care treatment in Sweden. Effectiveness outcomes for the model were quality-adjusted life-years and probability of sustained remission after acute treatment (first 8 weeks) and sustained for 6 months. Cost outcomes included direct treatment costs and indirect costs associated with sick leave. Results Compared with generic venlafaxine XR, escitalopram was less costly and more effective in terms of quality-adjusted life-years (expected gain 0.00865) and expected 6-month sustained remission probability (incremental gain 0.0374). The better tolerability profile of escitalopram contributed to higher expected quality-adjusted life-years and lower health-care resource utilization in terms of pharmacological treatment of adverse events (though only a minor component of treatment costs). Expected per-patient saving was €169.15 for escitalopram versus venlafaxine. Cost from sick leave constituted about 85% of total costs. Conclusions Escitalopram was estimated as more effective and cost saving than generic venlafaxine XR in first-line MDD treatment in Sweden, driven by the effectiveness and tolerability advantages of escitalopram. The study findings are robust and in line with similar pharmacoeconomic analyses.

To better understand depression's impact on family functioning from the perspectives of patients with major depressive disorder (MDD) and their partners; to develop and test patient and partner versions of a new self-reported measure, the Depression and Family Functioning Scale (DFFS), for use in clinical trials.Concept elicitation interviews were conducted with 32 adults with clinician-diagnosed moderate-to-severe MDD and their respective partners. Twenty-six items were drafted to address relevant aspects of family functioning and were then tested and refined through two iterative sets of cognitive debriefing interviews, each conducted by the same pair of highly experienced researchers, including a licensed clinical psychologist.Depression negatively affects family functioning through poorer communication, increased conflicts, decreased family interaction, and decreased intimacy. No existing instrument measured all domains of interest, or had been rigorously developed and psychometrically validated in the target populations. The draft DFFS items generally tested well and only minor modifications were made to the items after the second set of interviews. Both patients and partners indicated that the final set of 15 DFFS items addresses all concepts of importance.The DFFS evaluates the impact of depression on family functioning and has the potential to provide important information that can facilitate a more comprehensive evaluation of new treatments in clinical trial settings. Although MDD severity was not confirmed with a standardized interview, in clinical practice in the US, MDD is generally not diagnosed with the use of a structured clinical interview or clinician-administered tool. In the current study, depression severity had little (if any) impact on the specific concepts elicited as being important to family functioning. In fact, patients with milder depression had more insight and were able to better articulate changes in family functioning with treatment.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with polymorphic clinical manifestations that range from mild symptoms to life-threatening multiorgan dysfunction. The combination of heterogeneous clinical presentations at the time of diagnosis and unpredictable disease courses represents an immense medical and scientific challenge to biomarker development. Despite our advancing knowledge of the pathogenesis of SLE, few lupus biomarkers have been validated and widely accepted, and those in routine clinical use have been in place for decades (1,2). The dearth of lupus biomarkers is a major contributing factor to challenges in the clinical care of patients with lupus, in the accurate and thorough interpretation of clinical lupus research, in randomized controlled clinical trials, and in the development of new therapeutic agents for lupus. The US Food and Drug Administration has not approved a new drug for lupus in >50 years. In lieu of more useful lupus biomarkers, numerous indices have been developed in an attempt to measure disease activity in patients with lupus; the most widely used indices are the Systemic Lupus Activity Measure (SLAM) (3), the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (4), and the British Isles Lupus Assessment Group index (5). All of these indices have been validated and have excellent reliability, validity, and responsiveness to change. However, these indices are used almost exclusively by lupus research specialists; intense training is required to accurately complete these indices, and they may be too complex, cumbersome, and time-consuming to be used in routine clinical practice. Numerous studies have documented abnormalities in complement activation and clearance of immune complexes by erythrocytes as central pathogenic mechanisms in SLE (6,7). Measurement of serum C3 and serum C4 has traditionally been the gold standard for monitoring disease activity in patients with SLE; however, several major weaknesses in this approach have been previously identified. First, there is a wide range of variation of serum C3 and serum C4 levels among healthy individuals, and this range overlaps with the range observed in patients with SLE. Second, these are measurements of precursors rather than products of complement activation. Systemic inflammation resulting in an acute-phase response can increase synthesis of C3 and C4 that balances the increased catabolism of these proteins. Third, hereditary deficiencies and partial deficiencies of C4-null alleles may result in persistently lower-than-normal serum C4 levels because of decreased synthesis rather than because of increased complement activation and/or active SLE. Although the value of using serum C3 and serum C4 levels as biomarkers for SLE remains controversial, these markers are widely used in clinical practice (8–17). The recognition that complement and SLE are intimately associated, together with the questionable value of using serum C3 and serum C4 levels as biomarkers of lupus disease activity (8–17), led us to consider alternative measures of complement activation for monitoring patients with SLE (18–20). Proteolytic fragments of complement component C4, particularly C4d, are present on the surface of normal erythrocytes (21,22). Our group previously demonstrated that patients with SLE had significantly higher levels of erythrocyte-bound C4d (E-C4d) and lower levels of erythrocyte-expressing complement receptor 1 than did patients with other diseases and healthy control subjects (19). In addition, we observed that lupus disease activity correlated with reticulocyte C4d in a cross-sectional analysis and correlated serial measurements of E-C4d and reticulocyte C4d with disease activity in individual patients with SLE (20). In this longitudinal study, we assessed the utility of assays with E-C3d and E-C4d, as compared with the serum C3 and C4 assays in routine clinical use, as measures of lupus disease activity.

Racial differences exist in disease rates and mortality in both cardiovascular disease (CVD) and systemic lupus erythematosus (SLE). The objective of this cross-sectional study was to compare the frequency and risk factors for subclinical CVD in African American (AA) and Caucasian women with SLE and no prior CVD events. Traditional CVD risk factors and SLE-related factors were assessed in 309 SLE women. Subclinical CVD was assessed by carotid ultrasound to measure intimamedial thickness (IMT) and plaque, and electron beam computed tomography (EBCT) was used to measure coronary artery calcium (CAC). AA women had less education and higher levels of body mass index, blood pressure, lipoprotein(a), C-reactive protein (CRP), fibrinogen, and erythrocyte sedimentation rate (ESR). However, AA women had lower albumin, more and longer duration of corticosteroid use, higher SLE disease activity and damage, and more dsDNA antibodies compared with Caucasian women after adjustment for age and study site. More AA women had carotid plaque (adjusted odds ratio [OR], 1.94; 95% confidence interval [CI], 1.03–3.65) and higher carotid IMT (0.620 vs 0.605 mm, P = 0.07) but similar CAC compared with Caucasians. A multivariate analysis revealed that the following risk factor variables were significantly different between the racial groups and associated with plaque: blood pressure, current corticosteroid use, SLE disease activity, and SLE damage. All factors contributed to the result, but no individual risk factor fully accounted for the association between race and plaque. In conclusion, the presence of carotid plaque was higher in AA compared with Caucasian women with SLE, in contrast to studies of non-SLE subjects, in which AA have similar or less plaque than Caucasians. A combination of SLE-related and traditional CVD risk factors explained the racial difference in plaque burden.

Background/Aims Despite the rising prevalence of hepatocellular carcinoma (HCC), data on its economic consequences are limited. This study was undertaken to estimate the aggregate annual financial burden associated with HCC in the United States, including healthcare costs and the value of lost productivity. Methods Annual prevalence of HCC and incidence and survival were estimated using SEER data. The linked SEER-Medicare database was used to estimate distributions of healthcare utilization, quantities of treatment, and unit costs among 392 HCC patients. An age- and sex-matched cohort of non-cancer controls was used to estimate background non-cancer-related resource use and costs. Results We determined the annual cost of HCC in the United States to be $454.9 million, with per-patient costs of $32,907. Healthcare costs and lost productivity accounted for 89.2% and 10.8% of total cost, respectively. Costs associated with localized HCC accounted for the highest portion (44.5%) of the total cost of illness, at $202.5 million. Regional, distant, and unstaged HCC accounted for 31.0%, 13.9%, and 10.6%, respectively. Conclusions Our results exhibit a considerable economic impact of HCC and substantial national spending on this disease.

Objective. To compare the costs and effectiveness of escitalopram with venlafaxine and fluvoxamine for treatment of major depressive disorder (MDD) from the societal perspective in Singapore. Methods. The decision analytical model consisted of two pathways, one for primary care and the other for secondary care over a time horizon of 6 months. The parameters in the model were derived from clinical trials and results of a survey on local general practitioners and psychiatrists. The proportion of patients successfully treated was the main effectiveness measurement. Both direct and indirect costs were estimated and reported in 2007 Singapore dollars. Deterministic and probabilistic sensitivity analyses were performed. Results. The overall success rate for the 6-month treatment was 68.1% for escitalopram compared to 66.0% for venlafaxine. The total costs per patient treated were $2845 for escitalopram compared to $3176 for venlafaxine. The overall success rate was 64.7% for escitalopram and 60.0% for fluvoxamine. The total costs per patient treated were $3133 for escitalopram compared to $3297 for fluvoxamine. Probability sensitivity analysis demonstrated that escitalopram was dominant to venlafaxine and fluvoxamine in more than 95% of the random samples. Conclusion. Escitalopram is a cost-effective pharmacotherapy for MDD compared to venlafaxine and fluvoxamine.

Objectives. To determine the associations between depression, cardiovascular risk factors and coronary artery calcification (CAC) in women with SLE and controls. Methods. CAC was measured using electron-beam CT (EBCT). Traditional, inflammatory and lupus-related risk factors as well as depressive symptoms (Center for Epidemiologic Studies Depression Scale—CES-D) were measured at a single study visit in 161 women with SLE and 161 age- and race frequency-matched female healthy controls. Results. Women with SLE reported more depressive symptoms than controls, with 27% of SLE and 15% of controls having CES-D scores suggestive of clinical depression. SLE women were more likely to have CAC, as well as more severe CAC compared with controls. Among the SLE women, depression was associated with greater than 2-fold odds of having any CAC [odds ratio (OR) 2.48; 95% CI 1.05, 5.87; P ¼ 0.04], independent of traditional risk factors (age, hypertension and triglycerides) and inflammatory markers. However, when BMI was included among the covariates, the association between depression and CAC was attenuated, indicating the potential mediating role of BMI. Depression was not a risk factor for CAC in controls. Conclusions. In women with SLE, depression was associated with CAC. This association was mediated by BMI. Depression and adiposity may add to the inflammatory burden of SLE, thus contributing to cardiovascular disease risk.

Background: Selective serotonin reuptake inhibitors (SSRIs) and serotoninnoradrenaline reuptake inhibitors (SNRIs) are approved for the treatment of major depressive disorder (MDD). The allosteric SSRI escitalopram has been shown to be at least as clinically effective as the SNRIs venlafaxine and duloxetine in MDD, with a better tolerability profile. In addition, escitalopram has been shown to be cost saving compared with venlafaxine. Objective: To evaluate the cost effectiveness of escitalopram versus duloxetine in the treatment of MDD, and to identify key cost drivers. Methods: The pharmacoeconomic evaluation was conducted alongside a 24-week, double-blind, multinational randomized study (escitalopram 20 mg/day and duloxetine 60 mg/day) in outpatients with MDD, aged 18–65 years, with Montgomery-Asberg Depression Rating Scale (MADRS) score ≥26 and Clinical Global Impression Severity (CGI-S) score ≥4, and baseline duration of the current depressive episode of 12 weeks to 1 year. The analysis was conducted on the full analysis set (FAS), which included all patients with ≥1 valid post-baseline health economic assessment. Effectiveness outcomes of the cost-effectiveness analyses (CEA) included the change in Sheehan Disability Scale (SDS) score (primary CEA), treatment response (MADRS score decrease ≥50%) and remission (MADRS score ≤12) rates at week 24. Cost outcomes were assessed from the societal perspective. Healthcare resource use and sick leave were evaluated using a health economic assessment questionnaire. Unit costs of healthcare services were obtained from standard UK sources (£, year 2006 values). Results: Over the total 24-week study period, escitalopram was associated with significant cost savings compared with duloxetine (total per-patient monthly cost £188 vs £334, respectively). In the primary CEA, escitalopram dominated duloxetine (i.e. was more effective on the disability scale and less costly). Treatment with escitalopram resulted in significantly lower mean sick leave duration per patient over 24 weeks than duloxetine (30.7 days vs 62.2 days). In multivariate analyses, escitalopram as a treatment choice was associated with a 54% reduction in sick leave duration (p < 0.001). Treatment with escitalopram also resulted in 49% lower total costs than treatment with duloxetine (p = 0.002). Absenteeism accounted for about two-thirds of the overall cost. Early clinical improvement (mean change in MADRS total score, response and remission) had an independent significant impact on the sick leave duration, after controlling for key co-variates. Conclusions: Escitalopram was associated with significantly lower duration of sick leave and significant savings in the total cost compared with duloxetine; it dominated duloxetine when effectiveness was assessed on the SDS scale. Indirect costs due to sick leave accounted for the most substantial portion of the total cost and should, therefore, be an important consideration when pharmacoeconomic comparisons between treatments are made from the societal perspective. The link between decrease in absenteeism and early (8-week) clinical improvement suggested in the additional analyses may explain the reduced sick leave observed with escitalopram, given its superior short-term efficacy compared with duloxetine (demonstrated in the underlying clinical trial).

Background There were over 36,000 new cases of kidney cancer reported in the United States in 2004, the most common type being renal cell carcinoma (RCC). Available treatments for localized RCC frequently lead to cure; however RCC patients with advanced disease have limited treatment options and low survival rates. Data on the economic burden of RCC are limited. Methods A prevalence-based model was used to estimate the aggregate annual societal cost burden of RCC in the U.S., including costs of treatment and lost productivity. Key parameters in the model include: the annual number of patients treated for RCC by age group and cancer stage; utilization of cancer treatments; unit costs; work-days missed; and wage rates. Multiplying stratum-specific distributions of treatment by annual quantities of treatments and unit costs yields estimates of RCC-related health-care costs. Multiplying stratum-specific estimates of annual workdays missed by average wage rates yields estimates of RCC-related lost productivity. Results The annual prevalence of RCC in the U.S. was estimated to be 109,500 cases. The associated annual burden (inflated to 2005 U.S.$) was approximately $4.4 billion ($40,176 per patient). Health-care costs and lost productivity accounted for 92.4% ($4.1 billion) and 7.6% ($334 million), respectively. Reflecting its higher prevalence, the total cost associated with localized RCC accounted for the greatest share (78.2%), followed by regional, distant, and unstaged RCC, at 18.3%, 2.8%, and 0.7%, respectively. Conclusions The economic burden of RCC in the U.S. is substantial. Interventions to reduce the prevalence of RCC have the potential to yield considerable economic benefits.

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. Activation of the complement system plays a fundamental role in the pathogenesis of SLE. For the past several decades, laboratory monitoring of SLE has focused primarily on measurement of serum C3, C4, and their activation products. However, the utility of these measures as biomarkers for diagnosis and assessment of disease activity of SLE is still debated. Over the same time span, knowledge of the complement system has advanced remarkably, with more than 30 proteins identified. In view of the urgent need for identifying reliable lupus biomarkers, it is appropriate to revisit the issue of whether the complement system is a potential source of biomarkers for SLE. This article will review historical aspects of complement measurement in SLE, and summarize recent advances that may lead to a newly rejuvenated “gold rush” to mine the complement system for biomarkers of SLE. Specifically, development and utility of a novel assay that measures cell-bound complement activation products as lupus biomarkers will be discussed.

Activation of the complement system plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). For the past several decades, quantifying this process has focused primarily on determination of serum C3 and C4, although the utility of these assays for diagnosis and monitoring disease activity is still debated. During this same timespan, knowledge of the complement system has exploded, with identification of more than 30 proteins, an abundance of newly recognized functions, and even a third pathway of activation. These advances suggest that it is appropriate to revisit the complement system as a potential source of biomarkers for SLE. This paper reviews briefly the role of complement in SLE and other inflammatory diseases, discusses conventional methods for complement measurement and their drawbacks, and focuses on recent advancements in harnessing the complement system for monitoring SLE. Specifically, novel assays that measure cell-bound complement activation products are introduced and their utility as biomarkers of SLE disease activity is discussed.

Background The objectives of this meta-analysis of data from randomized, placebo-controlled studies were to assess the effect of vortioxetine on overall functioning (primary) and functional remission (secondary) using the Sheehan Disability Scale (SDS) in adults with major depressive disorder (MDD). Methods Data from nine short-term (6/8 weeks) pivotal studies that included patient functioning assessments were included in this random-effects meta-analysis, which used aggregated study-level data for all therapeutic vortioxetine doses and a mixed-effect model for repeated measures using the full analysis set. Results A total of 4,216 patients received ≥1 dose of study treatment (1,522 placebo, 2,694 vortioxetine 5–20 mg/day). At study end, the meta-analysis showed improvement for vortioxetine versus placebo (n = 911) in SDS total score (vortioxetine 5 mg, n = 564, change from baseline versus placebo [Δ] −0.24, p = NS; 10 mg, n = 445, Δ −1.68, p ≤ .001; 15 mg, n = 204, Δ −0.91, p = NS; 20 mg, n = 340, Δ −1.94, p ≤ .01). Functional remission (SDS total score ≤6) was observed with vortioxetine 10 mg (n = 170/573; odds ratio [OR] relative to placebo 1.7, p

Objective.Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE.Methods.A cross-sectional study was conducted from 2002–2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque.Results.In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein.Conclusion.In SLE, depression is independently associated with vascular disease, along with physical factors.

Escitalopram is the S-enantiomer of citalopram and is the most discriminating of the selective serotonin reuptake inhibitors (SSRI). The aim of the current analysis was to assess the cost effectiveness of escitalopram versus the serotonin norepinephrine reuptake inhibitors (SNRI) duloxetine and generic venlafaxine as second-step treatment of major depressive disorder.The analysis was based on a decision analytic model. Effectiveness outcomes were quality-adjusted life-years (QALYs) and remission rates; cost outcomes were direct medical costs, including impact of treating adverse events, and indirect costs associated with lost productivity. The analysis was performed from the societal perspective in Sweden over a 6-month timeframe.Estimated remission rates showed an incremental effectiveness in favour of escitalopram of 16.4 percentage points compared with both SNRI comparators. The escitalopram strategy was associated with a 0.025 increase in QALYs. Sensitivity analyses demonstrated that the model is robust and that escitalopram remains a cost-effective option when considering future predicted price reductions of generic venlafaxine.The main limitation in this study was the lack of data available for second-step treatment. The remission rates, which are a key input to the model, were obtained from a relatively small sample of patients on second-step treatment and there are no published relapse rates for second-step treatment. The model also assumed that there was no difference in the adverse event (AE) rates between treatments after the first 8 weeks.This cost-effectiveness analysis indicates that, at a willingness-to-pay threshold of £30,000, escitalopram is the most cost-effective second-step treatment option for MDD in Sweden in over 85% cases compared with both venlafaxine and with duloxetine. Benefits for escitalopram included both increased effectiveness and reduced overall costs. The major contributing costs were those associated with productivity loss. The model was shown to have internal validity and robustness through the use of stochastic simulations and sensitivity analyses, which were conducted around the key efficacy parameters.

Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule–1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.

PurposeMajor depressive disorder (MDD) has detrimental effects on health-related quality of life (HRQoL). We describe the effect of vortioxetine on HRQoL in MDD patients by using patient-reported outcome instruments.MethodsHRQoL was evaluated in 5 short-term (6–8 weeks), randomized studies of vortioxetine (5–20 mg/d; n = 2155) versus placebo (n = 1316) in adults with MDD by using the 36-item Short-Form Health Survey (SF-36), the Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form, the EuroQol 5-Dimension Questionnaire (EQ-5D), and the 12-item Health Status Questionnaire in 1 study in elderly patients. Only patients receiving the approved doses of vortioxetine 5, 10, 15, or 20 mg/d were included in the analysis. A random effects meta-analysis was performed on the 4 adult MDD studies that used the SF-36. A within-studies mixed model for repeated measures analysis based on the full analysis set (FAS) was used unless otherwise specified. Standardized effect size (SES) was calculated to reflect clinical relevance, based on a Cohen’s d of 0.2.FindingsVortioxetine produced significantly better results compared with placebo in the SF-36 mental component summary score (5 mg: 2.6, P = 0.001, SES of 0.22, n = 604; 10 mg: 4.8, P < 0.001, SES of 0.42, n = 328) and 4 domain scores (vitality, social functioning, role emotional, and mental health). Vortioxetine was also significantly better in the EuroQoL-5 Dimension Questionnaire Health State score (10 mg: 7.5, P < 0.05, SES of 0.33, n = 86) and Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form total score (15 mg: 3.3, P < 0.01, SES of 0.38, n = 127; 20 mg: 4.5, P < 0.0001, SES of 0.52, n = 134) (FAS, last-observation-carried-forward). In the study of elderly patients, vortioxetine 5 mg (n = 136) improved 12-item Health Status Questionnaire scores significantly more than placebo (n = 148) for the domains of health perception (10.4, P < 0.0001, SES of 0.54), mental health (7.9, P < 0.001, SES of 0.44), and energy (6.4, P < 0.05, SES of 0.28) (FAS, mixed model for repeated measures).ImplicationsVortioxetine yielded significant, meaningful HRQoL improvements in 6 MDD studies of 6 to 8 weeks’ duration.

Objective C4-derived activation fragments are the only complement ligands present on the surfaces of normal erythrocytes. The significance of this observation is unknown, and the role of erythrocyte-bound C4 (E-C4) in human disease has not been explored. More than any other human disease, the pathogenesis of systemic lupus erythematosus (SLE) has been characterized by defects in clearance of complement-bearing immune complexes via erythrocytes expressing complement receptor 1 (CR1). This study was undertaken to determine whether these functional defects might be reflected by abnormal patterns of E-C4 and E-CR1 expression on erythrocytes of patients with SLE. Methods We conducted a cross-sectional study of 100 patients with SLE, 133 patients with other diseases, and 84 healthy controls. Erythrocytes were characterized by indirect immunofluorescence and by flow cytometry for determination of levels of C4d and CR1. Results Patients with SLE had higher levels of E-C4d and lower levels of E-CR1 than did patients with other diseases (P ≤ 0.001) or healthy controls (P ≤ 0.001). The test was 81% sensitive and 91% specific for SLE versus healthy controls and 72% sensitive and 79% specific for SLE versus other diseases, and it had an overall negative predictive value of 92%. Conclusion This is the first report of abnormal levels of E-C4d in human disease. We found that abnormally high levels of E-C4d and low levels of E-CR1 are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus. Determination of E-C4d/E-CR1 levels may be a useful addition to current tests and criteria for SLE diagnosis.

Lost productivity is often excluded from economic evaluations, which may lead to an underestimation of the societal benefits of treatment. However, there are multiple challenges in reliably estimating and reporting productivity losses. This article explores the main challenges, ie, selecting an appropriate valuation method (ie, human capital, friction cost, or multiplier), avoiding double counting, and accounting for equity. It also discusses the use of presenteeism instruments and their application in clinical trials, with a specific focus on their relevance in individuals with mood disorders. Further research and discussion is required on the development of reliable techniques for measuring and valuing productivity changes due to presenteeism.