Video-Based Kinematic Analysis of Movement Quality in a Phase 3 Clinical Trial of Troriluzole in Adults with Spinocerebellar Ataxia: A Post Hoc Analysis.

INTRODUCTION: Traditional methods for assessing movement quality rely on subjective standardized scales and clinical expertise. This limitation creates challenges for assessing patients with spinocerebellar ataxia (SCA), in whom changes in mobility can be subtle and varied. We hypothesized that a machine learning analytic system might complement traditional clinician-rated measures of gait. Our objective was to use a video-based assessment of gait dispersion to compare the effects of troriluzole with placebo on gait quality in adults with SCA. METHODS: Participants with SCA underwent gait assessment in a phase 3, double-blind, placebo-controlled trial of troriluzole (NCT03701399). Videos were processed through a deep learning pose extraction algorithm, followed by the estimation of a novel gait stability measure, the Pose Dispersion Index, quantifying the frame-by-frame symmetry, balance, and stability during natural and tandem walk tasks. The effects of troriluzole treatment were assessed in mixed linear models, participant-level grouping, and treatment group-by-visit week interaction adjusted for age, sex, baseline modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA), and time since diagnosis. RESULTS: From 218 randomized participants, 67 and 56 participants had interpretable videos of a tandem and natural walk attempt, respectively. At Week 48, individuals assigned to troriluzole exhibited significant (p = 0.010) improvement in tandem walk Pose Dispersion Index versus placebo {adjusted interaction coefficient: 0.584 [95% confidence interval (CI) 0.137 to 1.031]}. A similar, nonsignificant trend was observed in the natural walk assessment [coefficient: 1.198 (95% CI - 1.067 to 3.462)]. Further, lower baseline Pose Dispersion Index during the natural walk was significantly (p = 0.041) associated with a higher risk of subsequent falls [adjusted Poisson coefficient: - 0.356 [95% CI - 0.697 to - 0.014)]. CONCLUSION: Using this novel approach, troriluzole-treated subjects demonstrated improvement in gait as compared to placebo for the tandem walk. Machine learning applied to video-captured gait parameters can complement clinician-reported motor assessment in adults with SCA. The Pose Dispersion Index may enhance assessment in future research. TRIAL REGISTRATION-CLINICALTRIALS. GOV IDENTIFIER: NCT03701399.

Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression.

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

Development and Validation of a Patient-Reported Outcome Measure of Ataxia.

BACKGROUND: Assessment of cerebellar ataxia has been confined to rating scales, gait laboratories, and wearable sensors agnostic to patient input. OBJECTIVES: The objective of this study was to develop a Patient-Reported Outcome Measure of Ataxia. METHODS: (1) The conceptual framework, item pool development, and domain selection were developed using online surveys completed by 147 ataxia patients. Responses generated the 70-item Patient-Reported Outcome Measure of Ataxia, scored on a 0-4 Likert scale. (2) Cognitive debrief in 17 patients grouped by ataxia severity assessed content validity, readability, and comprehension. (3) Psychometric validation by 78 anonymized ataxia patients included test-retest reliability, responsiveness to ataxia severity, internal consistency (Cronbach's alpha), and item-total score correlations. (4) Validation was tested against measures of ataxia and quality of life in 20 patients. (5) Items were rank-ordered to develop the Patient-Reported Outcome Measure of Ataxia Short Form. RESULTS: Three thousand eight hundred fifty-five symptoms were grouped into 3 domains (physical, activities of daily living, mental health) and 14 subdomains. The Patient-Reported Outcome Measure of Ataxia was comprehensible, important, and relevant. Internal consistency, reliability, and test-retest reliability were high. Scores were responsive to ataxia severity stages 1, 2, and 3: mean ± standard deviation 81.0 ± 37.0, 129.6 ± 32.0, and 151.1 ± 41.3, respectively (r = 0.58, P < 0.0001). The Patient-Reported Outcome Measure of Ataxia was validated against measures of motor ataxia, quality of life, and mental health. It had an R2 of 0.82 (P < 0.0001) with the preliminary Patient-Reported Outcome Measure of Ataxia Short Form. CONCLUSIONS: The Patient-Reported Outcome Measure of Ataxia is valid and reliable in cerebellar ataxia patients. It has the potential to improve patient care and natural history studies and quantify the efficacy of novel therapeutics in clinical trials. © 2021 International Parkinson and Movement Disorder Society.

A network meta-analysis of the efficacy of belatacept, cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients.

Belatacept is a first in-class co-stimulation blocker developed for primary maintenance immunosuppression following renal transplantation. The objective of this study was to estimate the efficacy of belatacept relative to tacrolimus and cyclosporine among adults receiving a single kidney transplant. A systematic review was conducted of randomized clinical trials (RCTs) published between January 1990 and December 2013 using EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and unpublished study reports from two belatacept RCTs. Bayesian network meta-analysis (NMA) methods were used to compare the efficacy measures, mortality, graft loss, acute rejection and glomerular filtration rate (GFR). Heterogeneity was quantified using statistical metrics and potential sources were evaluated using meta-regression and subgroup analysis. A total of 28 RCTs comparing tacrolimus with cyclosporine, and three comparing belatacept with cyclosporine, were identified. All three agents provided comparable graft and patient survival, despite a higher risk of acute rejection associated with belatacept and cyclosporine. Belatacept was associated with significant improvement in GFR versus cyclosporine. Compared with tacrolimus, this difference was clinically meaningful yet statistically non-significant. The probability of being the best treatment was highest for belatacept for graft survival (68%), patient survival (97%) and renal function (89%), and highest for tacrolimus for acute rejection (99%).Variability in donor, recipient, and trial characteristics was present in the included RCTs; however, minimal statistical heterogeneity was detected in the analysis of acute rejection, graft or patient survival, and none of the characteristics were found to be significantly associated with relative effect. Although the direction of effect of immunosuppressants on GFR was consistent across RCTs, precise estimation of its magnitude was limited by a small number of RCTs and heterogeneity in relative effect sizes. Clinicians often seek an alternative to CNIs due to their nephrotoxic effects. The results of this indirect comparison indicate that belatacept is an effective immunosuppressive agent in renal transplantation among adults.

Projecting long-term graft and patient survival after transplantation.

OBJECTIVE: In spite of increases in short-term kidney transplant survival rates and reductions in acute rejection rates, increasing long-term graft survival rates remains a major challenge. The objective here was to project long-term graft- and survival-related outcomes occurring among renal transplant recipients based on short-term outcomes including acute rejection and estimated glomerular filtration rates observed in randomized trials. METHODS: We developed a two-phase decision model including a trial phase and a Markov state transition phase to project long-term outcomes over the lifetimes of hypothetical renal graft recipients who survived the trial period with a functioning graft. Health states included functioning graft stratified by level of renal function, failed graft, functioning regraft, and death. Transitions between health states were predicted using statistical models that accounted for renal function, acute rejection, and new-onset diabetes after transplant and for donor and recipient predictors of long-term graft and patient survival. Models were estimated using data from 38,015 renal transplant recipients from the United States Renal Data System. The model was populated with data from a 3-year, randomized phase III trial comparing belatacept to cyclosporine. RESULTS: The decision model was well calibrated with data from the United States Renal Data System. Long-term extrapolation of Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial was projected to yield a 1.9-year increase in time alive with a functioning graft and a 1.2 life-year increase over a 20-year time horizon. CONCLUSIONS: This is the first long-term follow-up model of renal transplant patients to be based on renal function, acute rejection, and new-onset diabetes. It is a useful tool for undertaking comparative effectiveness and cost-effectiveness studies of immunosuppressive medications.

The external validation of the cardiovascular risk equation for renal transplant recipients: applications to BENEFIT and BENEFIT-EXT trials.

BACKGROUND: Renal transplant recipients (RTRs) have increased cardiovascular disease risk. Recently, major adverse cardiac event (MACE) and mortality risk calculators for prevalent RTRs were developed. We aimed to externally validate these risk equations in an international transplant database and subsequently demonstrate application to 2 clinical trials: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT). METHODS: The 7-year risk calculators were developed using data from the ALERT trial and validated for discrimination and calibration in the Patient Outcomes in Renal Transplantation (PORT) study cohort. The outlier laboratory readings were trimmed to the 99th percentile observed in the PORT database. Diabetes mellitus, LDL-cholesterol, and serum creatinine values 3 years posttransplantation were used when applying the calculators to BENEFIT and BENEFIT-EXT trial treatment arms. RESULTS: MACE could be predicted using a 7-variable model. The area under the ROC curve was 0.738 in ALERT and 0.740 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 5 and 9. Total mortality could be predicted using a 6-variable model. The area under the ROC curve was 0.734 in ALERT and 0.721 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 7 and significant overestimation in the highest risk decile. In BENEFIT and BENEFIT-EXT trial, the calculator estimated that belatacept use may result in reduction in MACE (>20%) and mortality (∼18%-30%). CONCLUSION: The MACE and mortality risk calculators for prevalent RTRs have been externally validated and found suitable for generic risk stratification.

The burden of viral hepatitis C in Europe: a propensity analysis of patient outcomes.

OBJECTIVE: Hepatitis C virus (HCV) affects 170 million patients worldwide and is the leading cause of liver cirrhosis and hepatocellular carcinoma. The aim of the current study is to examine the burden of HCV in the European Union (EU) from a patient perspective. METHODS: Using data from the 2010 EU National Health and Wellness Survey, patients who reported a diagnosis of HCV (n=332) were compared with a propensity-score-matched non-HCV control group (n=332) on measures of quality of life (using the SF-12v2), work productivity, and healthcare resource utilization in the past 6 months. All analyses applied sampling weights to project to the respective country populations. RESULTS: Projected prevalence estimates of HCV were 0.59% in France, 0.44% in Germany, 1.42% in Italy, 0.82% in Spain, and 0.35% in the UK. HCV patients reported significantly lower levels of emotional role limitations (means=66.4 vs. 70.6, P=0.040), physical functioning (means=63.8 vs. 71.9, P=0.001), general health (means=48.3 vs. 54.4, P=0.004), bodily pain (means=64.3 vs. 70.8, P=0.002), and physical component summary scores (means=42.9 vs. 45.3, P=0.002) than the matched controls. Patients with HCV also reported significantly higher levels of presenteeism (means=27.1 vs. 21.0%, P=0.044) and a greater number of physician visits in the past 6 months (means=9.9 vs. 6.7, P<0.001). CONCLUSION: Using a population-based survey methodology and a propensity-score matching analysis, these results add to the literature by documenting the significant effect that HCV has on a variety of both humanistic and economic outcomes in the EU.

The burden of illness for patients with viral hepatitis C: evidence from a national survey in Japan.

OBJECTIVE: Viral hepatitis C (HCV) affects 170 million patients worldwide and 2 million patients in Japan. The objective of the current study was to examine the burden of HCV in Japan from a patient's perspective. METHODS: Using data from the 2008 and 2009 Japan National Health and Wellness Surveys, patients who reported an HCV diagnosis (n = 306) were compared with a propensity-score-matched control group (n = 306) on measures of quality of life (using the Medical Outcomes Study 12-Item Short Form Survey Instrument version 2), work productivity (using the Work Productivity and Activity Impairment questionnaire), and health-care resource use. All analyses applied sampling weights to project to the population. RESULTS: Prior to matching, patients with HCV had higher rates of hepatocellular carcinoma (4.88% vs. 0.02%) and cirrhosis (12.20% vs. 0.11%) than did subjects without HCV. The propensity-matching process eliminated differences between the two groups on demographics and patient characteristics. The postmatching analysis found significantly lower levels of quality of life for patients with HCV as measured by bodily pain (72.07 vs. 76.28), general health (44.64 vs. 48.61), and mental health (66.50 vs. 70.32) (all Ps < 0.05). Furthermore, compared with the matched group, the HCV group had significantly higher workplace absenteeism (8.59% vs. 4.12%), overall work impairment (26.08% vs. 17.32%), and health-care provider visits in the past 6 months (14.80 vs. 9.74). CONCLUSIONS: The results of this study suggest that HCV can be a substantial burden on patients in terms of quality of life in both physical and mental health measures. In addition, HCV can be a significant cost driver in terms of health-care use and lost productivity.

Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose?

BACKGROUND: The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose. METHODS: Patients were ≥18 years of age from three US healthcare systems and exposed to an SGA for ≥45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference. RESULTS: Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile. CONCLUSIONS: In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers.

A real-world data analysis of dose effect of second-generation antipsychotic therapy on hemoglobin A1C level.

Previous studies have demonstrated an association between certain second-generation antipsychotics (SGAs) and diabetes mellitus. The study assessed the impact of SGA dose on hemoglobin A1C (HbA(1c) >6.0) levels in a real-world setting. Patients aged ≥ 18 years during 2002-2006 in Ingenix LabRx claims database were included. The database collects medical and prescription claims and a subset of laboratory results for an employed, commercially insured population distributed throughout the United States. Patients with previously diagnosed diabetes, identified by the ICD-9-CM code of 250.x or use of antidiabetic agents, were excluded. The main exposure measure was the cumulative dose over a 30 day period before the HbA(1c) test, calculated as [sum of (number of pills per day×strength)]/100. A logistic regression was used to examine the relation with HbA(1c) >6.0 by tertile of the cumulative dose and average daily dose, adjusted for the covariates. The study included 391 patients on olanzapine, 467 on quetiapine, and 262 on risperidone. Patients treated with aripiprazole or ziprasidone (n=212) were included as a secondary reference because of their minimal metabolic risk. Compared to lower (Tertiles 1 and 2) cumulative doses of risperidone, patients with a high cumulative dose of risperidone (Tertile 3) had a significantly higher odds ratio (OR) for HbA(1c) >6.0 (adjusted OR=2.45; 95% confidence interval=1.13-5.32; P=0.023). A similar increase in OR was seen in patients with high cumulative dose of olanzapine (2.41; 1.19-4.89; P=0.015). Analyses of average daily dose revealed that quetiapine ≥ 400 mg/day and risperidone ≥ 2 mg/day had an OR of 2.29 (1.04-5.06; P=0.041) and 2.28 (1.08-4.83; P=0.032), respectively, compared to aripiprazole/ziprasidone. Both olanzapine groups (≥ 10 and <10mg/day) were associated with a significantly increased OR. All results remained similar after further adjustment for the predicated probability of having an HbA(1c) test and additional medication covariates. In this claims data study, use of olanzapine was associated with elevated HbA(1c) and risperidone and quetiapine appeared to have dose-related association with elevated HbA(1c). One of the limitations of a claims data analysis is the lack of information on potential confounders such as ethnicity and weight.

UK cost-consequence analysis of aripiprazole in schizophrenia: diabetes and coronary heart disease risk projections (STAR study).

Patients with schizophrenia experience elevated rates of morbidity and mortality, largely due to an increased incidence of cardiovascular disease and diabetes. There is increasing concern that some atypical antipsychotic therapies are associated with adverse metabolic symptoms, such as weight gain, dyslipidaemia and glucose dysregulation. These metabolic symptoms may further increase the risk of coronary heart disease (CHD) and diabetes in this population and, subsequently, the cost of treating these patients' physical health. The STAR study showed that the metabolic side effects of aripiprazole treatment are less than that experienced by those receiving standard-of-care (SOC). In a follow-up study the projected risks for diabetes or CHD, calculated using the Stern and Framingham models, were lower in the aripiprazole treatment group. Assuming the risk of diabetes onset/CHD events remained linear over 10 years, these risks were used to estimate the difference in direct and indirect cost consequences of diabetes and CHD in schizophrenia patients treated with aripiprazole or SOC over a 10-year period. Diabetes costs were estimated from the UKPDS and UK T(2)ARDIS studies, respectively, and CHD costs were estimated using prevalence data from the Health Survey of England and the published literature. All costs were inflated to 2007 costs using the NHS pay and prices index. The number of avoided diabetes cases (23.4 cases per 1,000 treated patients) in patients treated with aripiprazole compared with SOC was associated with estimated total (direct and indirect) cost savings of 37,261,293 pounds over 10 years for the UK population. Similarly, the number of avoided CHD events (3.7 events per 1,000 treated patients) was associated with estimated total cost savings of 7,506,770 pounds over 10 years. Compared with SOC, aripiprazole treatment may provide reductions in the health and economic burden to schizophrenia patients and health care services in the UK as a result of its favourable metabolic profile.

Cost-effectiveness of atypical antipsychotics for the management of schizophrenia in the UK .

OBJECTIVE: To evaluate the cost-effectiveness of atypical antipsychotic treatment sequences for the management of stable schizophrenia in the UK. RESEARCH DESIGN AND METHODS: A Markov model was developed to assess the cost per quality-adjusted life year (QALY) gained from 12 alternative treatment sequences each containing two of four atypical antipsychotics (aripiprazole, olanzapine, quetiapine and risperidone), followed by clozapine. The main model parameters were populated with data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and a recent trial comparing aripiprazole with olanzapine. Patients enter the model with stable schizophrenia and may relapse, discontinue or continue and experience adverse events (AEs), or develop diabetes. Population mortality was adjusted for schizophrenia and diabetes. Utility decrements applied to stable schizophrenia, relapse, diabetes and treatment-related AEs were taken from a direct UK utility elicitation study. Resource use and unit costs were taken from published sources. A time horizon of 10 years was adopted. Results are based on 10,000 probabilistic iterations of the model. RESULTS: Aripiprazole followed by risperidone produced the greatest number of QALYs, an additional 0.03 compared with risperidone followed by olanzapine, at an incremental cost of £257 (incremental cost/QALY: £9,440). Aripiprazole followed by risperidone had the greatest probability among evaluated sequences of being cost-effective at a threshold of >£10,000/QALY. All other strategies were dominated by at least one of these strategies. The impact of lower pricing for risperidone (based on generic availability) did not impact results. CONCLUSIONS: Modelling the cost-effectiveness of different treatment sequences for stable schizophrenia is appropriate given that patients rarely remain on one treatment for long periods. The treatment sequence aripiprazole followed by risperidone was the most cost-effective option for patients with stable schizophrenia in the UK.

A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine.

OBJECTIVE: Major mental disorders are associated with an increased risk for obesity-related cardiovascular mortality, leading to interest in risk-reduction approaches that target weight and risk-related plasma lipids, including use of antipsychotic agents with low metabolic risk. This multicenter, randomized, double-blind study compared the metabolic effects of aripiprazole versus olanzapine in overweight persons with schizophrenia or schizoaffective disorder who were previously on olanzapine treatment. METHOD: In total, 173 subjects with DSM-IV-TR-defined schizophrenia or schizoaffective disorder were randomly assigned to receive aripiprazole (N = 88) or olanzapine (N = 85) for 16 weeks in a study conducted from March 30, 2004, to August 8, 2006. Primary and secondary endpoints were mean weight change from baseline and percentage change from baseline in fasting triglyceride levels, respectively. RESULTS: At week 16, weight decreased significantly with aripiprazole versus olanzapine (-1.8 vs. +1.41 kg; p < .001). Significant differences in percentage change in triglyceride levels were observed with aripiprazole (decreases) versus olanzapine (increases) at all time-points. In addition, significantly more subjects receiving aripiprazole had clinically relevant (> or = 7%) weight loss versus olanzapine (11.1% vs. 2.6%; p = .038), and a lower percentage of subjects receiving aripiprazole had clinically relevant weight gain (2.5% vs. 9.1%; p = .082). Mean percentage changes in fasting total cholesterol and high-density lipoprotein cholesterol at week 16 were significantly different with aripiprazole versus olanzapine, with no significant effects on glycemic laboratory measures. Mean Clinical Global Impressions-Improvement (CGI-I) scores for both groups were in the range of "no change" to "minimal improvement." CGI-I endpoint scores were statistically significantly better with olanzapine (mean +/- SE = 3.09 +/- 0.16) versus aripiprazole (mean +/- SE = 3.74 +/- 0.15; p < .001), and more subjects discontinued aripiprazole (N = 32/88; 36%) than olanzapine (N = 22/85; 26%). CONCLUSION: Significant improvements in weight and lipids observed during discontinuation of olanzapine and switch to aripiprazole treatment occurred with limited evidence of negative psychiatric effects, relative to uninterrupted continuation of olanzapine treatment. The results suggest that the potential value of therapeutic substitutions involving specific antipsychotic medications should be considered in overall efforts to reduce cardiovascular risk in this population.

Predicted risk of diabetes and coronary heart disease in patients with schizophrenia: aripiprazole versus standard of care.

OBJECTIVE: Patients with schizophrenia are at increased risk of developing diabetes mellitus and cardiovascular disease. Furthermore, some atypical antipsychotics are associated with metabolic disturbances, which augment the risk for these comorbid conditions. In clinical trials, effects on metabolic parameters with aripiprazole are similar to those with placebo and superior to those with olanzapine, and the Schizophrenia Trial of Aripiprazole (STAR) demonstrated comparable efficacy of aripiprazole versus standard of care (SoC; physicians' selection of quetiapine, olanzapine, or risperidone). METHOD: In this post hoc analysis, data from STAR were used to assess the risks of diabetes and coronary heart disease (CHD) in patients with schizophrenia. The Stern (San Antonio Heart Disease Study) and Framingham models, with modifications, were used to predict the risk of diabetes at 7.5 years and CHD at 10 years, respectively. RESULTS: Aripiprazole-treated patients had more favorable changes in lipids, glucose, and body weight versus SoC. In a subsample of patients who had fasting lipid and glucose test results, the Stern model predicted 23.4 fewer incidences of new-onset diabetes with aripiprazole versus SoC in a hypothetical 1000-patient cohort. The number needed to treat with aripiprazole to avoid 1 adverse outcome expected with SoC was 43. In the same population, the Framingham model predicted 3.9 fewer CHD events, with a number needed to treat with aripiprazole of 256. CONCLUSION: Aripiprazole-treated patients had more favorable changes in metabolic parameters compared with SoC, leading to a reduced risk of diabetes and CHD, based on validated models.

Impact of obesity on health-related quality of life in schizophrenia and bipolar disorder.

OBJECTIVE: Studies have reported that up to 60% of individuals with schizophrenia and 68% of those with bipolar disorder are overweight/obese. This paper explores the health-related quality of life (HRQOL) of individuals with schizophrenia or bipolar disorder as a function of obesity status. METHODS AND PROCEDURES: Two hundred and eleven participants were recruited from four psychiatric programs (outpatient, day treatment, case management, and psychosocial rehabilitation). HRQOL was assessed using both a general measure (Medical Outcomes Study Short-Form-36 (SF-36)) and a weight-related measure (Impact of Weight on Quality of Life-Lite (IWQOL-Lite)). To interpret HRQOL scores obtained by the obese group, we compared scores to those obtained by reference groups from the weight-loss literature. RESULTS: Sixty-three percent of participants with schizophrenia and 68% of those with bipolar disorder were obese. Obese participants were more likely to be women, on mood stabilizers, taking a greater number of psychiatric medications, and to have poorer weight-related and general HRQOL. Weight-related HRQOL in the obese psychiatric sample was more impaired than in outpatient and day treatment samples seeking weight loss but less impaired than in gastric-bypass patients. Several of the physical domains of general HRQOL were more impaired for the obese psychiatric sample than for the outpatient weight-loss sample. However, physical functioning was less impaired for the obese psychiatric sample than for gastric-bypass patients. DISCUSSION: The presence of obesity among individuals with schizophrenia or bipolar disorder is associated with decreased HRQOL. These results have implications for prevention and management of weight gain in individuals with schizophrenia or bipolar disorder.

Comparison of metabolic syndrome incidence among schizophrenia patients treated with aripiprazole versus olanzapine or placebo.

BACKGROUND: Metabolic syndrome is a strong determinant of new-onset diabetes and coronary heart disease in general populations. Given the higher prevalence of metabolic syndrome among mentally ill patients, the syndrome poses a greater health risk to this population. Atypical antipsychotic treatment may exacerbate this condition. We compared both the rate and incidence of metabolic syndrome among schizophrenia patients (DSM-IV criteria) treated with the atypical antipsychotics aripiprazole or olanzapine or placebo from 4 double-blind, randomized, controlled clinical trials. METHOD: Metabolic syndrome was defined according to the Third Adult Treatment Panel (ATP III) Guidelines as the presence on follow-up of 3 of the following abnormalities: waist circumference > 102 cm if male and > 88 cm if female, high density lipoprotein (HDL) < 40 mg/dL if male and < 50 mg/dL if female, diastolic blood pressure >or= 85 mm Hg or systolic blood pressure >or= 130 mm Hg, fasting triglycerides >or= 150 mg/dL, fasting plasma glucose >or= 110 mg/dL. Both the rate of metabolic syndrome and the person-time incidence were computed from the on-treatment follow-up. RESULTS: In the placebo-controlled trials, the rate of metabolic syndrome was 25.8% among 155 placebo patients and 19.9% for 267 aripiprazole patients (p = .466 by stratified log rank). The incidence of metabolic syndrome was 14.3% for 91 placebo patients versus 5.3% for 151 aripiprazole patients (p < .001). In the active comparator trials, patients treated with olanzapine (N = 373) versus aripiprazole (N = 380) exhibited rates of 41.6% and 27.9%, respectively (p = .0002). Incidence rates were 27.4% for 212 olanzapine patients versus 15.7% for 198 aripiprazole patients (p = .0055). CONCLUSION: Both the rate and incidence of clinically relevant metabolic syndrome differ according to the choice of antipsychotic agent. The association between metabolic syndrome and treatment warrants careful consideration in the choice of antipsychotic agents.

Influence of medication choice and comorbid diabetes: the cost of bipolar disorder in a privately insured US population.

BACKGROUND: Bipolar disorder is the most expensive mental disorder for US employer health plans. No published studies have examined the impact of comorbid diabetes on the cost of treating bipolar disorder. The objectives of this work were to determine the direct costs incurred by patients with bipolar disorder in a US managed care plan, and to examine the influence (1) of drug therapy regimen on bipolar-related costs, and (2) of diabetes on bipolar-related and all-cause costs. METHODS: A retrospective analysis of claims in a US private insurance database from January 1, 1999 through December 31, 2002 was performed. The database included at least 4.7 million enrollees each year. Diagnosis codes were used to identify patients with bipolar disorder; patients with diabetes were identified using diagnosis codes and medication use. RESULTS: From 1999-2002, treated bipolar disorder was identified in 262 (33.9) [mean (standard deviation)] cases per 100,000 enrollees. Among patients with bipolar disorder in this cohort, between 6.3 and 7.4% were treated for diabetes each year. Among patients with newly treated bipolar disorder, 61.8% received initial therapy with only mood stabilizers, 24.3% received only atypical antipsychotics, and 13.9% received both. Mean all-cause cost for patients with bipolar disorder was US$2,690 in the 6 months before the first bipolar-related claim, and US$6,826 in the following year. Of the latter cost, bipolar-related cost was US$1,272. Patients with comorbid diabetes had much higher all-cause cost (US$11,317) than those without diabetes in the year following the first bipolar-related claim, but only slightly higher bipolar-related cost (US$1,349). Among newly treated bipolar disorder patients, all-cause and bipolar-related cost in the year after diagnosis was lowest in patients receiving only mood stabilizers. Ordinary least squares regression analysis found that treatment with mood stabilizers only was associated with 41% lower bipolar-related cost than treatment with atypical antipsychotics only (P < .001). Significant individual associations were also found between bipolar-related cost and bipolar disorder I diagnosis, severe bipolar disorder and comorbid personality disorders (P < .001 for each) but not comorbid diabetes (P = .27). CONCLUSIONS: These results suggest that patients with bipolar disorder who receive only mood stabilizer therapy incur lower bipolar-related and all-cause cost than those receiving only atypical antipsychotics. In contrast to that for all-cause cost, comorbid diabetes had little impact on direct costs related to treating bipolar disorder itself.

Risk of diabetes mellitus associated with atypical antipsychotic use among Medicaid patients with bipolar disorder: a nested case-control study.

STUDY OBJECTIVE: To quantify the risk of diabetes mellitus associated with atypical antipsychotics compared with conventional antipsychotics in managed care Medicaid patients with bipolar disorder. DESIGN: Retrospective nested case-control study. DATA SOURCE: Integrated seven-state Medicaid managed care claims database from January 1, 1998-December 31, 2002. PATIENTS: Two hundred eighty-three patients with diabetes (cases) and 1134 controls matched by age, sex, and the index date on which bipolar disorder was diagnosed. MEASUREMENTS AND MAIN RESULTS: Cases were defined as those having an International Classification of Diseases, Ninth Revision diagnosis of diabetes or those receiving treatment with antidiabetic drugs. Both case and control patients had at least a 3-month exposure to either conventional or atypical antipsychotic agents or three filled prescriptions related to treatment for bipolar disorder. Of the 283 cases, 139 (49%) received atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, and clozapine) and 133 (47%) were prescribed conventional antipsychotics. To compare the risk for new-onset diabetes associated with atypical versus conventional antipsychotics, we conducted a Cox proportional hazard regression, in which we controlled for age; sex; duration of bipolar disorder follow-up; use of lithium, anticonvulsants, antidepressants, and other drugs; and psychiatric and medical comorbidities. Compared with patients receiving conventional antipsychotics, the risk of diabetes was greatest among patients taking risperidone (hazard ratio [HR] 3.8, 95% confidence interval [CI] 2.7-5.3), olanzapine (3.7, 95% CI 2.5-5.3), and quetiapine (2.5, 95% CI 1.4-4.3). The risk for developing diabetes was also associated with weight gain (HR 2.5, 95% CI 1.9-3.4), hypertension (HR 1.6, 95% CI 1.2-2.2), and substance abuse (HR 1.5, 95% CI 1.0-2.2). CONCLUSION: Olanzapine, risperidone, and quetiapine are all associated with development or exacerbation of diabetes mellitus in patients with bipolar disorder. When prescribing therapy for this patient population, metabolic complications such as diabetes, weight gain, and hypertension need to be considered.

Double jeopardy for the mentally ill: higher cardiovascular risk and reduced frequency of certain interventional procedures.

Evaluation of: Kisely S, Smith M, Lawrence D et al.: Inequitable access for mentally ill patients to some medically necessary procedures. CMAJ 176[6], 779-784 [2007]. This observational database study utilized data from three administrative databases to determine the relative effect of psychiatric disease status on mortality and utilization of in-patient procedures for cardiovascular conditions. The study results indicated that psychiatric patients exhibit significantly greater mortality compared with other groups of patients, despite adjustments for relevant socioeconomic and clinical factors. Compounding the problem, the authors further determined that cardiovascular medical procedures were underutilized in this population. This important study reveals significant public health implications for a patient population already at elevated risk for cardiovascular morbidity and mortality due to lifestyle, medical comorbidities and certain antipsychotic therapies. This study now offers supportive evidence that inequities in primary care health delivery systems provide a partial explanation for the excess cardiovascular risk observed in mentally ill patients. The widespread recognition of this issue should prompt additional research and consequent remedial action by medical providers and those institutions that support them.