Noam Y. Kirson

INTRODUCTION: This study estimated the minimal clinically important difference (MCID) for Mini Mental State Examination, Clinical Dementia Rating Scale sum of boxes, and Functional Activities Questionnaire across the Alzheimer's disease (AD) spectrum. METHODS: Retrospective analysis of the National Alzheimer's Coordinating Center Uniform Data Set (9/2005-9/2016) and MCID for clinical outcomes were estimated using anchor-based (clinician's assessment of meaningful decline) and distribution-based (1/2 baseline standard deviation) approaches, stratified by severity of cognitive impairment. RESULTS: On average, a 1-3 point decrease in Mini Mental State Examination, 1-2 point increase in Clinical Dementia Scale sum of boxes, and 3-5 point increase in Functional Activities Questionnaire were indicative of a meaningful decline. The MCID values generally increased by disease severity; the effect size and standardized response mean for those with meaningful decline were consistently in the acceptable ranges for MCID. DISCUSSION: These findings can inform design and interpretation of future clinical trials.

Aim: The economic burden of schizophrenia in the United States (US) was estimated at $155.7 billion in 2013. Since 2013, the US experienced significant health care reforms and treatment advances. This study analyzed recent data and literature to update the US economic burden estimate for schizophrenia. Methods: Direct and indirect costs associated with schizophrenia were estimated using a prevalence-based approach. Direct health care costs were assessed retrospectively using an exact matched cohort design in the IBM Watson Health MarketScan databases from October 1, 2015, through December 31, 2019. Patients with schizophrenia (identified using ICD-10-CM codes F20 and F25) were exactly matched to controls on demographics, insurance type, and index year. Direct non–health care costs were estimated using published literature and government data. Indirect costs were estimated using a human capital approach and the value of quality-adjusted life-years lost. Cost offsets were estimated to account for basic living costs avoided. Excess costs, comparing costs for individuals with and without schizophrenia, were reported in 2019 USD. Results: The estimated excess economic burden of schizophrenia in the US in 2019 was $343.2 billion, including $251.9 billion in indirect costs (73.4%), $62.3 billion in direct health care costs (18.2%), and $35.0 billion in direct non–health care costs (10.2%). The largest drivers of indirect costs were caregiving ($112.3 billion), premature mortality ($77.9 billion), and unemployment ($54.2 billion). Cost offsets, representing $6.0 billion (1.7%), were subtracted from direct non–health care costs. Conclusions: The estimated burden of schizophrenia in the US doubled between 2013 and 2019 and was $343.2 billion in 2019, highlighting the importance of effective strategies and treatment options to improve the management of this difficult-to-treat patient population.

OBJECTIVE: Nonadherence is a major challenge in schizophrenia treatment. While long-acting (depot) antipsychotic medications are often recommended to address adherence problems, evidence on the comparative effectiveness of depot versus oral antipsychotics is inconsistent. We hypothesize that this inconsistency could be due to systematic differences in study design. This review evaluates the effect of study design on the comparative effectiveness of antipsychotic formulations. The optimal use of different antipsychotic formulations in a general clinical setting depends on better understanding of the underlying reasons for differences in effectiveness across research designs. DATA SOURCES: A PubMed literature review targeted English-language studies (2000-2011) with information on relapse, hospitalization, or all-cause discontinuation for depot and oral antipsychotic treatment arms in schizophrenia. The time frame was chosen to reflect research focused on the newer generation of antipsychotic agents. The search required at least 1 term from each of the following categories: (1) schizophrenia; (2) inject, injection, injectable, injectables, injected, depot, long-acting; and (3) iloperidone, fluphenazine, haloperidol, paliperidone, risperidone, olanzapine, asenapine, flupentixol, flupenthixol, lurasidone, clopenthixol, fluspirilene, zuclopentixol, zuclopenthixol. STUDY SELECTION: Thirteen relevant studies were identified by 2 independent reviewers; these studies included information on 19 depot-oral comparisons. DATA EXTRACTION: Age- and gender-adjusted risk ratios (RRs) (depot/oral) were calculated for the identified endpoints and pooled by study design (randomized controlled trial [RCT], prospective observational, and retrospective observational). Meta-analysis with random effects was used to estimate the pooled RRs, by study design. Average conversion factors between study designs were calculated as the ratios of pooled RRs. RESULTS: Meta-analysis of adjusted endpoints showed no apparent benefit of depot over oral formulations in RCTs, with an RR of 0.89 (P = .416). In contrast, there was a significant advantage for depot formulations in other study designs (prospective RR = 0.62 [P < .001]; retrospective RR = 0.56 [P < .001]). These imply conversion factors of 1.43 and 1.59 between RCTs and prospective and retrospective designs, respectively. CONCLUSIONS: The comparative effectiveness of antipsychotic formulations is sensitive to research design. Depot formulations displayed significant advantages in nonrandomized observational studies, whereas in RCTs no difference was observed. The estimated conversion factors may facilitate comparison across studies.

OBJECTIVE: Sepsis is a leading cause of mortality in noncoronary ICUs. Although immediate start of antibiotics reduces sepsis-related mortality, antibiotics are often administered for too long, leading to suboptimal treatment and, importantly, contributes to antimicrobial resistance. Prior literature suggests that procalcitonin correlates with infection and thus may help to guide the decision on when to stop antibiotic treatment. This study was conducted as part of a regulatory submission to the U.S. Food and Drug Administration and aimed to summarize the evidence of procalcitonin guidance on efficacy and safety outcomes in adult patients with sepsis. DATA SOURCES: PubMed and the Cochrane Database of Systematic Reviews. STUDY SELECTION: English-language randomized controlled trials evaluating procalcitonin use among adult patients with suspected or confirmed sepsis published between January 2004 and May 2016. DATA EXTRACTION: Inverse-variance weighting fixed and random effects meta-analyses were performed on the following efficacy and safety endpoints: antibiotic duration, all-cause mortality, and length of ICU stay. Two reviewers independently extracted data elements from identified studies and measured risk of bias with the Cochrane Risk of Bias Tool. DATA SYNTHESIS: From a total of 369 potentially eligible articles, 10 randomized controlled trials containing 3,489 patients were used for analysis. Procalcitonin-guided patients had shorter antibiotics duration compared with controls (7.35 vs. 8.85 d; weighted mean difference, -1.49 d; 95% CI, -2.27 to -0.71; p < 0.001). Procalcitonin use had no adverse impact on mortality (risk ratio, 0.90; 95% CI, 0.79-1.03; p = 0.114) and length of ICU stay (11.09 d vs. 11.91 d; weighted mean difference, -0.84 d; 95% CI, -2.52 to 0.84; p = 0.329). CONCLUSIONS: In adult patients with suspected or confirmed sepsis, procalcitonin guidance reduces antibiotics duration with no observed adverse effects on patient outcomes.

OBJECTIVE: Diversion and abuse of prescription opioids are important public health concerns in the US. This study examined possible sources of prescription opioids among patients diagnosed with opioid abuse. METHODS: Commercially insured patients aged 12-64 diagnosed with opioid abuse/dependence ('abuse') were identified in OptumHealth Reporting and Insights medical and pharmacy claims data, 2006-2012, and required to have continuous eligibility over an 18 month study period surrounding the first abuse diagnosis. We examined whether abusers had access to prescription opioids through their own prescriptions and/or to diverted prescription opioids through family members' prescriptions obtained prior to the abuser's first abuse diagnosis. For comparison, we examined access to prescription opioids of a reference population of non-abusers. Sensitivity analyses focused on patients initially diagnosed with opioid dependence and, separately, abusers not previously treated with buprenorphine. RESULTS: Of the 9291 abusers meeting the selection criteria, 79.9% had an opioid prescription prior to their first abuse diagnosis; 20.1% of abusers did not have an opioid prescription prior to their first abuse diagnosis, of whom approximately half (50.8%) had a family member who had an opioid prescription prior to the abuser's first abuse diagnosis (compared to 42.2% of non-abusers). Similar results were found among patients initially diagnosed with opioid dependence and among abusers not previously treated with buprenorphine. LIMITATIONS: The study relied on the accuracy of claims data to identify abusers, but opioid abuse is often undiagnosed. In addition, only prescription claims that were reimbursed by a health plan were included in the analysis. CONCLUSIONS: While most abusers had access to prescription opioids through their own prescriptions, many abusers without their own opioid prescriptions had access to prescription opioids through family members and may have obtained prescription opioids that way. Given the study design and data source, this is likely a conservative estimate of prescription opioid diversion.