Clinical Outcome Assessment Instruments in Schizophrenia: A Scoping Literature Review with a Focus on the Potential of Patient-reported Outcomes.

Objective: The complexity inherent in the treatment of schizophrenia results in a multitude of outcome assessments being employed when conducting clinical trials. Subjective outcome assessments and minimal clinically important differences (MCIDs) to evaluate clinical meaningfulness have gained traction; however, the extent of application in evaluation of treatments for schizophrenia is unknown. A scoping review was conducted to assess the availability of published psychometric evaluations, including MCIDs, for clinical outcome assessments used to evaluate treatments for schizophrenia. Method of Research: Key databases (PubMed®, Embase®, APA PsycINFO®, International Society for Pharmacoeconomics and Outcomes Research) were searched for studies on schizophrenia published from 2010 to 2020. Secondary sources (ClinicalTrials.gov, PROLABELS™, FDA.gov) were also reviewed. Clinical outcome assessments were organized by type (patient-reported outcomes [PROs], clinician-reported outcomes [ClinROs], observer-reported outcomes [ObsROs]) and further classified by intended use (generic, mental health, schizophrenia). Reliability and internal consistency were evaluated using Cronbach's α. External validity was evaluated by intraclass correlation coefficient (ICC). Results: Across 140 studies, 66 clinical outcome assessments were identified. MCIDs were reported for eight of the 66 studies. Of these, two were PROs (generic) and six were ClinROs/ObsROs (three mental health-specific, three schizophrenia-specific). Reliability was good across generic, mental health-specific, and schizophrenia-specific categories, whereas external validity was strong mainly for schizophrenia-specific PROs. Overall, ClinROs/ObsROs that focused on mental health had good reliability and strong external validity. Conclusion: This review provides a comprehensive overview of the clinical outcome assessments used in schizophrenia research during the past ten years. Results highlight the heterogeneity of existing outcomes and a growing interest in PROs for schizophrenia.

Treatment Journey From Diagnosis to the Successful Implementation of a Long-Acting Injectable Antipsychotic Agent in Young Adults With Schizophrenia.

Objective: Long-acting injectable antipsychotic agents (LAIs) are effective in schizophrenia relapse prevention but are often underutilized. This study aims to understand treatment patterns leading to a successful LAI implementation following schizophrenia diagnosis in a large dataset that included commercially insured patients in the United States.Methods: Patients aged 18-40 years with a first schizophrenia diagnosis (per ICD-9 or ICD-10 criteria), successful second-generation LAI implementation (defined a priori as ≥ 90 consecutive days of use), and ≥ 1 second-generation oral antipsychotic agent (OA) were identified from IBM MarketScan Commercial and Medicare Supplemental databases from January 1, 2012, to December 31, 2019. Outcomes were measured descriptively.Results: Of 41,391 patients with newly diagnosed schizophrenia, 1,836 (4%) received ≥ 1 LAI; 202 (< 1%) met eligibility criteria of successful LAI implementation following ≥ 1 second-generation OA. Median (range) time between diagnosis and first LAI was 289.5 (0-2,171) days, time between LAI initiation and successful implementation was 90.0 (90-1,061) days, and time to LAI discontinuation after successful implementation was 166.5 (91-799) days. Before LAI initiation, 58% received ≥ 2 OAs. For 86% with successful LAI implementation, the implementation was accomplished with the first LAI.Conclusions: In this dataset of mainly commercially insured patients, LAI use in early-phase schizophrenia was very low (4%). For the majority for whom a LAI was successfully implemented per a priori definition, the implementation was accomplished with the first LAI and in a short period of time (90 days). However, even when LAIs were used in early-phase schizophrenia, they were generally not the first therapy, as most patients had several prior OA treatments.

Early versus late administration of long-acting injectable antipsychotic agents among patients with newly diagnosed schizophrenia: an analysis of a commercial claims database.

This study was designed to assess healthcare resource utilization (HCRU) and costs in patients with newly diagnosed schizophrenia based on timing and context of long-acting injectable antipsychotic agent (LAI) initiation. Using claims data, patients (aged 18-40 years) with first schizophrenia diagnosis January 2013-September 2019 (index date), no LAI or oral antipsychotic agent claims during 12-month preindex period, and continuous benefit enrollment from 12 months before index date to 12 months after first LAI administration were identified. Patients were grouped based on timing [early (≤1 year after index date) vs. late] and circumstances [reactive (after schizophrenia-related event) vs. proactive] of LAI initiation. Of 1290 patients with at least one LAI claim, 306 met criteria for early ( n = 204; reactive, n = 107; proactive, n = 97) and late ( n = 102; n = 75; n = 27) initiation. HCRU and costs were numerically lower in early versus late groups, and significantly lower for proactive initiation in both groups. Comparing worst-case (late-reactive) and best-case (early-proactive) scenarios, the average annual cost difference was $7195.13 ( P = 0.0233), with major drivers being emergency department ($171.28; P < 0.05) and other outpatient ($2845.73; P < 0.00001) visits. In addition to the clinical advantages previously described in the literature, the proactive use of LAIs in early-phase schizophrenia is associated with lower healthcare costs.

Predictors for Initiation of Atypical Long-Acting Injectable Antipsychotic Agents in a Commercial Claims Cohort of Individuals With Early-Phase Schizophrenia.

Objective: Long-acting injectable antipsychotic agents (LAIs) have improved clinical effectiveness and adherence versus oral antipsychotic agents (OAs); however, a minority of individuals with schizophrenia are treated with LAIs compared with OAs. This cohort study aimed to evaluate predictors of initiation of atypical LAIs among patients with newly diagnosed schizophrenia in the United States.Methods: Using claims data from IBM MarketScan Commercial and Medicare Supplemental databases between January 1, 2013, and March 31, 2020, adults with first diagnosis of schizophrenia, ≥ 1 OA claim following diagnosis, and continuous benefits were identified. To evaluate predictors of LAI initiation, a Cox proportional hazard regression model per independent predictors and main outcome (ie, LAI initiation) was performed.Results: Of 3,639 patients with early-phase schizophrenia, 369 (10%) had ≥ 1 LAI claim(s) after ≥ 1 OA claim(s). Several factors present prior to LAI initiation were significantly (P < .0001) predictive of LAI initiation: greater monthly OA switches (hazard ratio [95% CI]: 11.39 [7.01-18.51]), unsuccessful OA implementation (3.09 [2.39-3.98]), greater monthly schizophrenia-related hospitalizations (20.83 [14.22-30.51]), and greater monthly schizophrenia-related emergency department visits (4.13 [2.07-8.22]).Conclusions: In this analysis of pharmacy claims records for patients with early-phase schizophrenia, results suggest that LAIs are used less frequently in the early phase than reported in later stages. Their initiation is often reactive to relapse or disease exacerbation, rather than proactive as a relapse-prevention tool for early-phase schizophrenia. These data highlight the underuse of LAIs, particularly in the early phase when they could make the most difference.

Incremental health care resource utilization and expenditures associated with autosomal-dominant polycystic kidney disease.

PURPOSE: Incremental health care resource utilization and expenditures associated with autosomal dominant polycystic kidney disease (ADPKD) were estimated. METHODS: Study data were from a large administrative claims database. Individuals aged 18 years or older enrolled in tracked health plans for 12 months from April 1, 2011 through March 31, 2012, and with an International Classification of Disease, Ninth Revision, Clinical Modification diagnosis code for "polycystic kidney, autosomal dominant" (753.13) or for "polycystic kidney, unspecified type" (753.12) were identified as having ADPKD, and linked one-to-one with individuals without ADPKD based on age and gender. Zero-inflated negative binomial models estimated incremental health care resource utilization and expenditures, adjusting for risk factors. RESULTS: A total of 3,844 individuals with ADPKD who satisfied selection criteria were linked one-to-one with 3,844 individuals without ADPKD. Multivariate, regression models adjusting for risk factors revealed incremental mean (standard error) resource use associated with ADPKD of 0.68 (0.090) hospital days, equal to 68 additional hospital days per 100 ADPKD patients, and 6.9 (0.28) outpatient visits, equal to 690 additional visits per 100 ADPKD patients. Mean (standard error) incremental total expenditures associated with ADPKD were US$8,639 ($470). Mean incremental expenditures were largest for outpatient expenditures at US$4,918 ($198), followed by mean incremental hospital expenditures of US$2,603 ($263), and mean incremental medication expenditures of US$1,589 ($77). Based on sub-group analysis, mean incremental total expenditures were US$2,944 ($417) among ADPKD patients without end-stage renal disease and US$38,962 ($6,181) for those with end-stage renal disease. CONCLUSION: ADPKD was associated with considerable incremental health care resource utilization and expenditures. Significant illness burden was found even before patients reached end-stage renal disease.

Associations Between Sildenafil Use and Changes in Days of Hospitalization in a Population With Pulmonary Arterial Hypertension Associated With Connective Tissue Disease.

PURPOSE: Pulmonary arterial hypertension (PAH) can be a complication in patients with connective tissue disease (CTD). Although the phosphodiesterase-5 inhibitor sildenafil shows evidence of efficacy and tolerability among patients with PAH associated with CTD in clinical trials, no studies have examined the association between its use and health care resource utilization in clinical practice. The objective of this study was to assess the associations between the use of sildenafil and health care resource utilization, specifically days of hospitalization, in a population with PAH associated with CTD. METHODS: A retrospective, matched, case-control analysis was conducted using data from a commercial claims database. Patients with a claim dated between 2003 and 2009 were selected. Cases and controls were matched on age, sex, and baseline total days of hospitalization. A longitudinal, zero-inflated, negative binomial model was used for analyzing the data after control for age, sex, region, Charlson comorbidity score, and use of PAH-specific medication other than sildenafil. FINDINGS: A total of 420 individuals, 210 cases and 210 controls, were included in the sample. The sample was 85.71% women, and the mean age was 57.6 years. Estimates for variances of an intercept random effect (5.08 × 10(-13)) and for a time-variable random effect (2.84 × 10(-16)) were both essentially zero. Thus a zero-inflated negative binomial model without random effects was used. When individuals were not using sildenafil, each 1-month interval was associated with a 2.8% increase in the mean number of days of hospitalization. In contrast, when individuals were using sildenafil, each 1-month interval was associated with a decrease of 3.3% in days of hospitalization. IMPLICATIONS: In this data analysis of the association between sildenafil use and days of hospitalization among individuals with PAH associated with CTD in a large-scale population, sildenafil use in the treatment of PAH associated with CTD was associated with reduced days of hospitalization during the year after the initiation of treatment.

Use of Sildenafil in Pulmonary Arterial Hypertension: Findings from a U.S. Healthcare Claims Database.

Background: Pulmonary arterial hypertension (PAH) is a disease characterized by dyspnea, fatigue, chest pain and syncope. As there is no known cure for PAH, the goal of treatment is to control symptoms and slow disease progression. Sildenafil, a phosphodiesterase-5 inhibitor, has been indicated to improve exercise capacity in PAH in both the United States and the European Union since 2005; since 2009, it also has been indicated in the United States to delay clinical worsening. Patterns of sildenafil use in PAH patients have not been reported. Objectives: To describe patterns of treatment with sildenafil among commercially insured patients in the United States with PAH. Methods: Using a large U.S. healthcare claims database, we identified all patients with evidence of PAH (International Classification of Disease, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis codes 416.0, 416.8) and receipt of sildenafil between January 1, 2005 and September 30, 2008. The date of each patient's earliest pharmacy claim for sildenafil was designated as his or her "index date"; patients with <6 months of data prior to this date were excluded. Post-index use of sildenafil was then examined in terms of the numbers of pharmacy claims and therapy-days, the medication possession ratio (MPR), and the incidence of therapy switching. Results: We identified a total of 855 PAH patients who began sildenafil therapy and met all other entry criteria. Mean (standard deviation [SD]) follow-up was 423.4 (313.0) days. Over this period, these patients averaged 7.1 (6.8) (median, 5) pharmacy dispensings for sildenafil, representing 273.4 (254.8) therapy-days (median, 180). Mean MPR was 71% (median, 83%). Fourteen percent of sildenafil patients switched to another agent during follow-up. Conclusions: In "real-world" clinical practice, many PAH patients beginning treatment with sildenafil remain on therapy for extended periods and are relatively compliant with treatment.

Prevalence of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review of the literature.

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Understanding of PAH prevalence remains limited, but PAH has been reported as a frequent complication in connective tissue diseases. This study estimated prevalence of PAH in patients with connective tissue diseases and prevalence of idiopathic PAH using a systematic review of the literature. We searched PubMed through May 19, 2012 for all studies on prevalence of PAH in patients with connective tissue diseases or prevalence of idiopathic PAH. To be included, studies had to be in English, have humans as subjects, and determine prevalence within a time interval of up to 2 years. Studies only investigating pediatric patients were excluded. Pooled prevalence estimates were calculated. Twenty studies were identified in the review. Seventeen of the 20 studies reported prevalence of PAH in connective tissue diseases and three reported prevalence of idiopathic PAH. The pooled prevalence estimate of idiopathic PAH was 12 cases per million population (95 % CI 5 cases per million to 22 cases per million) with estimates ranging from 5.9 cases per million population to 25 cases per million population. The pooled prevalence estimate of PAH in patients with connective tissue diseases was 13 % (95 % CI, 9.18 % to 18.16 %) with reported estimates ranging from 2.8 % to 32 %. Prevalence of PAH in patients with connective tissue diseases was substantially higher than that of idiopathic PAH based on pooled prevalence estimates. Comparisons of PAH prevalence in persons with connective tissue disease and idiopathic PAH using a large observational study would be helpful in better assessing relative prevalence.

Changes in healthcare utilization and costs associated with sildenafil therapy for pulmonary arterial hypertension: a retrospective cohort study.

BACKGROUND: Little is known concerning the degree to which initiation of sildenafil for pulmonary arterial hypertension (PAH) impacts patterns of healthcare utilization and costs. METHODS: Using a large US health insurance claims database, we identified all patients with evidence of PAH (ICD-9-CM diagnosis codes 416.0, 416.8) who received sildenafil between 1/1/2005 and 9/30/2008. Date of the first-noted prescription for sildenafil was designated the "index date," and claims data were compiled for all study subjects for 6 months prior to their index date ("pretreatment") and 6 months thereafter ("follow-up"); patients with incomplete data during either of these periods were excluded. Healthcare utilization and costs were then compared between pretreatment and follow-up for all study subjects. RESULTS: A total of 567 PAH patients were identified who began therapy with sildenafil and met all other study entry criteria. Mean (SD) age was 52 (10) years; 73% were women. Healthcare utilization was largely unchanged between pretreatment and follow-up, the only exceptions being decreases in the mean number of emergency department visits (from 0.7 to 0.5 per patient; p<0.01) and the percentage of patients hospitalized (from 35% to 29%; p=0.01). The mean cost of all PAH-related medication was $7139 during pretreatment and $14,095 during follow-up (sildenafil cost during follow-up= $5236); exclusive of PAH-related medications, however, total healthcare costs decreased modestly (from $30,104 to $27,605) (p<0.01 for all comparisons). CONCLUSIONS: The cost of sildenafil therapy may be partially offset by reductions in other healthcare costs.

Assessment of measurement properties of peak VO(2) in children with pulmonary arterial hypertension.

BACKGROUND: The 6-minute walk test evaluates the effect of pharmacologic intervention in adults with pulmonary arterial hypertension (PAH) but, for reasons of compliance or reliability, may not be appropriate for children at all ages. Thus, peak oxygen consumption (VO2, maximal exercise test) was used instead in a pediatric PAH trial (STARTS-1) to evaluate pharmacologic intervention with sildenafil. This was the first large placebo-controlled trial to use the peak VO2 endpoint in this population. Our working hypothesis was that, as with other populations, percentage changes in peak VO2 in pediatric patients with PAH are reliable and are associated with changes in other clinical endpoints. METHODS: Using data from the subpopulation of 106 patients who were developmentally and physically able to perform exercise testing, all of whom were World Health Organization Functional Class (WHO FC) I, II, or III, reliability was assessed using the intraclass correlation coefficient and Bland-Altman plot on screening and baseline data. Relationships between percentage change in peak VO2 from baseline to end of treatment and other endpoints were evaluated using correlation coefficients and regression analyses. RESULTS: The intraclass correlation was 0.79 between screening and baseline peak VO2, an agreement that was supported by the Bland-Altman plot. Percentage change in peak VO2 correlated well (r ≥0.40) and showed responsiveness to a physician global assessment of change and with change in WHO FC (for baseline classes I and III). Percentage change in peak VO2 did not correlate with change in the Family Cohesion of the Child Health Questionnaire (r = 0.04) or with a subject global assessment of change (r = 0.12). The latter may have been influenced by child and parental-proxy response and instrument administration. CONCLUSION: In pediatric PAH patients who are developmentally and physically able to perform exercise testing, peak VO2 measurements exhibited good reliability and improvements that were associated with improvements in certain other clinical endpoints, such as the WHO FC and a physician global assessment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00159913.

Medication adherence and utilization in patients with schizophrenia or bipolar disorder receiving aripiprazole, quetiapine, or ziprasidone at hospital discharge: a retrospective cohort study.

BACKGROUND: Schizophrenia and bipolar disorder are chronic debilitating disorders that are often treated with second-generation antipsychotic agents, such as aripiprazole, quetiapine, and ziprasidone. While patients who are hospitalized for schizophrenia and bipolar disorder often receive these agents at discharge, comparatively little information exists on subsequent patterns of pharmacotherapy. METHODS: Using a database linking hospital admission records to health insurance claims, we identified all patients hospitalized for schizophrenia (ICD-9-CM diagnosis code 295.XX) or bipolar disorder (296.0, 296.1, 296.4-296.89) between January 1, 2001 and September 30, 2008 who received aripiprazole, quetiapine, or ziprasidone at discharge. Patients not continuously enrolled for 6 months before and after hospitalization ("pre-admission" and "follow-up", respectively) were excluded. We examined patterns of use of these agents during follow-up, including adherence with treatment (using medication possession ratios [MPRs] and cumulative medication gaps [CMGs]) and therapy switching. Analyses were undertaken separately for patients with schizophrenia and bipolar disorder, respectively. RESULTS: We identified a total of 43 patients with schizophrenia, and 84 patients with bipolar disorder. During the 6-month period following hospitalization, patients with schizophrenia received an average of 101 therapy-days with the second-generation antipsychotic agent prescribed at discharge; for patients with bipolar disorder, the corresponding value was 68 therapy-days. Mean MPR at 6 months was 55.1% for schizophrenia patients, and 37.3% for those with bipolar disorder; approximately one-quarter of patients switched to another agent over this period. CONCLUSIONS: Medication compliance is poor in patients with schizophrenia or bipolar disorder who initiate treatment with aripiprazole, quetiapine, or ziprasidone at hospital discharge.

Association of subjective anxiety, depression, and sleep disturbance with quality-of-life ratings in adults with epilepsy.

PURPOSE: To determine the relative contributions of subjective anxiety, depression, sleep disturbance, and seizure-related variables to quality-of-life scores in adults with epilepsy, and the interrelationships among these factors. METHODS: Consecutive adult patients with epilepsy attending neurology outpatient clinics were recruited. Patients completed the following scales: Hospital Anxiety and Depression Scale (HADS), Hamilton Anxiety Rating Scale, Medical Outcomes Study (MOS) Sleep Scale, Epworth Sleepiness Scale, and Quality of Life in Epilepsy Inventory-31 (QOLIE-31). Univariate and multivariate linear regression models were used to identify variables associated with QOLIE-31 overall score. Path analysis model was constructed to test for interrelations between the variables. RESULTS: Two hundred forty-seven patients completed the questionnaires. By multivariate analysis, in order of degree of contribution, HADS anxiety subscale score, MOS Sleep Scale Sleep Problems Index score, HADS depression subscale score, number of current antiepileptic drugs used, and seizure freedom in the past 4 weeks, significantly correlated with QOLIE-31 overall score, accounting for 65.2% of the variance. Complex interrelationships were present between these factors. A general linear model to predict QOLIE-31 overall score in the presence of these factors was constructed. CONCLUSION: Subjective anxiety, depression, and sleep disturbance exerted greater effect than short-term seizure control on quality of life scores of patients with epilepsy. These factors should be considered simultaneously when evaluating effects of treatment on quality of life.

Cost-effectiveness of treating ocular hypertension.

PURPOSE: To assess the cost-effectiveness of treating ocular hypertension (OHT) in the United States. DESIGN: A Markov model was constructed to perform a cost-effectiveness analysis. PARTICIPANTS: Patients with OHT. METHODS: The health states considered were stable OHT and glaucoma. Practice patterns for the model were derived from the Ocular Hypertension Treatment Study (OHTS), and transition probabilities were derived from previous literature. Specific unit costs used for medications, patient visits, and diagnostic and therapeutic procedures were obtained from Blue Cross/Blue Shield. The time horizon was 5 years. Costs were discounted at 3% per annum. MAIN OUTCOME MEASURE: Long-term cost effectiveness of treating OHT to prevent the development of glaucoma. RESULTS: The incremental cost-effectiveness ratio (ICER) for all OHT patients to prevent 1 case from progressing to primary open-angle glaucoma was $89,072. However, the minimally cost-effective ICER level after adjustment for risk factors identified by multivariate analysis in the OHTS were: 20 years above the average of 56 years, ICER of $45,155; 4 mmHg above the average pressure of 25 mmHg, ICER of $46,748; 40 microm less than the average central corneal thickness of 573 mum, ICER of $36,683; and a vertical cup-to-disc ratio of 0.2 wider than the average of 0.4, ICER of $35,633. CONCLUSIONS: Based on the results and practice patterns of the OHTS, treating all OHT patients seems not to be cost-effective. However, treating selective OHT patients with risk factors identified in the OHTS, for example, advancing age, higher pressures, thinner central corneal thickness, and wider vertical cup-to-disc ratios, does seem to be cost-effective for preventing the onset of glaucomatous damage.

Accounting for restart rates in evaluating persistence with ocular hypotensives.

PURPOSE: Persistence with ocular hypotensive medication is important as a long-term outcome, and rates of persistence typically are low. This study assessed restart rates for 3 prostaglandin analogs by determining the percentage of patients who discontinued and then restarted therapy. DESIGN: Retrospective cohort study of pharmacy claims submitted to a large national administrative claims database. PARTICIPANTS: In all, 4356 patients initiating prostaglandin therapy were identified. METHODS: Claims for 3 prostaglandin analogs (bimatoprost, latanoprost, travoprost [index prostaglandin]) submitted between 2001 and 2002 were analyzed. Patients were excluded if they did not have coverage in the plan for the preceding 180 days or had been prescribed any ocular prostaglandin in the prior 180 days. MAIN OUTCOME MEASURES: Persistence was defined as neither discontinuing nor changing the index prostaglandin. The number of current users of the index prostaglandin at day 180 was the sum of patients who persisted with the index prostaglandin plus patients who restarted the index prostaglandin after a discontinuation. RESULTS: Of the 4356 patients initiating prostaglandin therapy, 2503 (57%) were potential current users (were still plan members and had not switched ocular hypotensive therapies after 180 days). Just over half, (1356/2503 [54%]) were current users, including 879 (35%) who persisted with their index prostaglandin and 477 (19%) who restarted their index prostaglandin. Of patients discontinuing their index prostaglandin, more than half failed to restart any topical therapy (827/1624 [51%]). CONCLUSIONS: Previous studies showing low persistence rates for glaucoma therapy failed to evaluate restarts. Restart analyses are crucial for assessing long-term treatment of chronic diseases such as glaucoma. In general, persistence remains a challenge, and our findings demonstrate the importance of clinicians' identifying patients who are not persistent and encouraging them either to restart or to initiate treatment with an alternative therapy.