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Citrome L.,New York Medical College | Baker R.,Otsuka Pharmaceutical Development and Commercialization Inc.
Journal of Clinical Psychiatry | Year: 2013

Objective: To examine the risk of cardiovascular outcomes and diabetes mellitus in patients prescribed second-generation antipsychotics. Method: From the MarketScan claims database, nondiabetic adults prescribed aripiprazole between July 2003 and March 2010 were propensity core- matched with patients prescribed olanzapine, quetiapine, risperidone, and ziprasidone. Patients were followed through the claims for International Classification of Diseases, Ninth Revision codes indicating myocardial infarction, stroke, heart failure, coronary bypass/angioplasty procedures, and incident diabetes. Incidence rates of each outcome were calculated and compared between aripiprazole and the other secondgeneration antipsychotics using Cox models. Results: Aripiprazole initiators were matched 1:1 to 9,917 olanzapine, 14,935 quetiapine, 10,192 risperidone, and 5,696 ziprasidone initiators. Increased risk was found with olanzapine for stroke (hazard ratio = 1.43; 95% confidence interval, 1.05-1.95) and any cardiovascular event (1.28; 1.05-1.55); with quetiapine for stroke (1.58; 1.19-2.09), heart failure (1.55; 1.15-2.11), and any cardiovascular event (1.50; 1.25-1.79); and with risperidone for stroke (1.54; 1.12-2.12), heart failure (1.43; 1.02-1.99), and any cardiovascular event (1.49; 1.21-1.83). Ziprasidone showed no significant difference in risk from aripiprazole for any outcome. Incidence of diabetes ranged from 18 to 21 events per 1,000 person-years in each cohort and did not differ significantly between second-generation drugs. Conclusions: This analysis of real-world data found lower risk of some cardiovascular events with aripiprazole than with olanzapine, quetiapine, or risperidone, but no differences were found with ziprasidone. There were no significant differences in risk of diabetes. Limitations include use of claims data and inability to adequately control for differential prescribing of second-generation antipsychotics to patients at higher risk of diabetes. © Copyright 2013 Physicians Postgraduate Press, Inc.

Meyers C.A.,University of Texas M. D. Anderson Cancer Center | Rock E.P.,Otsuka Pharmaceutical Development and Commercialization Inc. | Fine H.A.,U.S. National Cancer Institute
Journal of Neuro-Oncology | Year: 2012

As targeted therapies advance treatment for brain tumors, standard clinical trial endpoints of survival, progression free survival and radiographic response have become insufficient to capture clinical benefit. Brain cancer is a malignancy with neurodegenerative features. In this setting prolongation of life and/or radiographic stability are less clinically meaningful if neurocognitive function substantially declines. Hence evaluation of new therapeutic strategies should routinely include periodic assessment of neurocognitive function. © Springer Science+Business Media, LLC. 2012.

Findling R.L.,Johns Hopkins Hospital | McQuade R.D.,Otsuka Pharmaceutical Development and Commercialization Inc.
Journal of Clinical Psychiatry | Year: 2014

Objective: To evaluate the efficacy and safety of aripiprazole versus placebo in preventing relapse of irritability symptoms associated with autistic disorder in pediatric patients. Method: This multicenter, double-blind, randomized, placebocontrolled, relapse-prevention trial enrolled patients (6-17 years) who met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) criteria for autistic disorder and who also had serious behavioral problems (ie, tantrums, aggression, self-injurious behavior, or a combination of these behavioral problems) between March 2011 and June 2012. In phase 1, single-blind aripiprazole was flexibly dosed (2-15 mg/d) for 13-26 weeks. Patients with a stable response (≥ 25% decrease in Aberrant Behavior Checklist-irritability subscale score and a rating of "much improved" or "very much improved" on the Clinical Global Impressions-Improvement scale) for 12 consecutive weeks were randomized into phase 2 to continue aripiprazole or switch to placebo. Treatment was continued until relapse or up to 16 weeks. The primary end point was time from randomization to relapse. Results: Eighty-five patients were randomized in phase 2. The difference in time to relapse between aripiprazole and placebo was not statistically significant (P = .097). Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo (hazard ratio [HR] = 0.57; number needed to treat [NNT] = 6). The most common adverse events during phase 1 were weight increase (25.2%), somnolence (14.8%), and vomiting (14.2%); and, during phase 2 (aripiprazole vs placebo), they were upper respiratory tract infection (10.3% vs 2.3%), constipation (5.1% vs 0%), and movement disorder (5.1% vs 0%). Conclusions: In this study, there was no statistically significant difference between aripiprazole and placebo in time to relapse during maintenance therapy. However, the HR and NNT suggest some patients will benefit from maintenance treatment. Patients receiving aripiprazole should be periodically reassessed to determine the continued need for treatment. © Copyright 2014 Physicians Postgraduate Press, Inc.

Citrome L.,New York Medical College | Kalsekar I.,Bristol Myers Squibb | Baker R.A.,Otsuka Pharmaceutical Development and Commercialization Inc. | Hebden T.,Bristol Myers Squibb
Current Medical Research and Opinion | Year: 2014

Background: Metabolic abnormalities observed with atypical antipsychotic treatment may be specific to each antipsychotic medication. The association between atypical antipsychotics and risk factors for cardiovascular disease prompted the American Diabetes Association (ADA) and the American Psychiatric Association (APA) to issue a consensus statement that categorized aripiprazole and ziprasidone as atypical antipsychotics with a lower likelihood of metabolic abnormalities. Objective: The aim of the current systematic review was to evaluate real-world studies (i.e. observational/naturalistic and open-label studies) assessing the risk for weight gain, dyslipidemia, glucose abnormalities, and diabetes mellitus in adult patients receiving treatment with atypical antipsychotics, with a specific focus on aripiprazole. Methods: A systematic PubMed search for articles published between 1 January 2000 and 4 October 2011 was performed using the following search terms in the title and abstract: aripiprazole, atypical, glucose, insulin, cholesterol, triglycerides, diabetes, hemoglobin A1c, weight, body mass index, and hyperlipidemia. Results: Twenty-two peer-reviewed articles were found that assessed the metabolic effects associated with aripiprazole treatment, including studies from small observational trials to large databases (n=15 to n>1,700,000). Thirteen articles reported observational or naturalistic studies, and nine were open-label trials evaluating weight gain, dyslipidemia, glucose abnormalities, and the risk of developing diabetes in adult patients receiving treatment with aripiprazole. Compared with other atypical antipsychotics, aripiprazole was either less likely to have an impact or had a comparable impact on weight gain and dyslipidemia; the degree of effect appeared to be dependent on study design. In addition, there was less risk of diabetes mellitus with aripiprazole compared with most other atypical antipsychotic agents. Conclusions: Consistent with data from randomized controlled studies, the current review of observational/naturalistic and open-label studies suggests aripiprazole may be associated with a lower risk than other commonly used atypical antipsychotics for metabolic adverse events in adults, consistent with the ADA/APA consensus statement. © 2014 Informa UK Ltd.

Berl T.,University of Colorado at Denver | Quittnat-Pelletier F.,University of Toronto | Verbalis J.G.,Georgetown University | Schrier R.W.,University of Colorado at Denver | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2010

Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (≤30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (>145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety. Copyright © 2010 by the American Society of Nephrology.

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