Factors Affecting Antidepressant Response Trajectories: A Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes Trial Report.

Background: In this secondary analysis of the VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study we used antidepressant response trajectories to assess the association of treatment and multiple clinical/demographic factors with the probability of response.

Methods: Using data from VAST-D, a multi-site, randomized, single-blind trial with parallel-assignment to one of three treatment interventions in 1522 Veterans whose major depressive disorder was unresponsive to at least one antidepressant trial, we evaluated response patterns using group-based trajectory modeling (GBTM). A weighted multinomial logistic regression analysis with backward elimination and additional exploratory analyses were performed to evaluate the association of multiple clinical/demographic factors with the probability of inclusion into specific trajectories.

Predictability of Nonremitting Depression After First 2 Weeks of Antidepressant Treatment: A VAST-D Trial Report.

Objective: In this secondary analysis of data from the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, the authors sought to determine the effectiveness of early improvement (or lack thereof) for predicting remission from depression with antidepressant therapy.

Methods: This study used data from the VAST-D study, a multisite, randomized, single-blind trial with parallel assignment to one of three medication interventions for 1,522 veterans whose major depressive disorder was unresponsive to at least one course of antidepressant treatment meeting minimal standards for dosage and duration. The authors calculated the positive predictive value (PPV) and negative predictive value (NPV) of early improvement on remission, response, or greater than minimal improvement from depression for various degrees of improvement (10%-50%) on the Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C) at 1, 2, 4, and 6 weeks.

General Predictors and Moderators of Depression Remission: A VAST-D Report.

Objective: Almost two-thirds of patients with major depressive disorder do not achieve remission with initial treatments. Thus, identifying and providing effective, feasible, and safe "next-step" treatments are clinical imperatives. This study explores patient baseline features that might help clinicians select between commonly used next-step treatments.

Impact of apolipoprotein E genotypes on vitamin E and memantine treatment outcomes in Alzheimer's disease.

Introduction: Because apolipoprotein E (APOE) genotypes are known risk factors for Alzheimer's disease (AD), they have been measured in clinical trial participants to determine their effect on treatment outcome.

Methods: We determined APOE genotypes in a subset of subjects (N = 415) who participated in a randomized controlled trial of vitamin E and memantine in 613 veterans with mild-to-moderate AD.

Results: Similar to the primary study, substudy participants receiving vitamin E also had slower functional decline than those receiving placebo.

Neuropsychiatric Symptoms and Caregiver Burden in Individuals With Alzheimer's Disease: The TEAM-AD VA Cooperative Study.

Objectives: To assess the prevalence of neuropsychiatric symptoms (NPS) in mild-to-moderate Alzheimer disease (AD) and their association with caregiver burden.

Methods: Secondary analyses of baseline data from the Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD) (N=613). Neuropsychiatric Inventory were used to measure severity of NPS and caregiver activity survey to measure caregiver burden.

Total integrated performance excellence system (TIPES): A true north direction for a clinical trial support center.

This paper presents the quality journey taken by a Federal organization over more than 20 years. These efforts have resulted in the implementation of a Total Integrated Performance Excellence System (TIPES) that combines key principles and practices of established quality systems. The Center has progressively integrated quality system frameworks including the Malcom Baldrige National Quality Award (MBNQA) Framework and Criteria for Performance Excellence, ISO 9001, and the Organizational Project Management Maturity Model (OPM3), as well as supplemental quality systems of ISO 15378 (packaging for medicinal products) and ISO 21500 (guide to project management) to systematically improve all areas of operations.

Measuring informed consent capacity in an Alzheimer's disease clinical trial.

Introduction: Accurately and efficiently determining a participant's capacity to consent to research is critically important to protect the rights of patients with Alzheimer's disease (AD).

Methods: Understanding of the informed consent document was assessed in 613 community-dwelling patients with mild-to-moderate AD enrolled in a randomized, placebo-controlled trial. Associations were examined between clinically determined capacity to consent and (1) patient demographics and clinical characteristics and (2) the Informed Consent Questionnaire (ICQ), an objective measurement of a participant's factual understanding and perceived understanding.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

Importance: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.

Objective: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD.

Design, Setting, And Participants: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study.

Characteristics of U.S. Veteran Patients with Major Depressive Disorder who require "next-step" treatments: A VAST-D report.

Objective: Finding effective and lasting treatments for patients with Major Depressive Disorder (MDD) that fail to respond optimally to initial standard treatment is a critical public health imperative. Understanding the nature and characteristics of patients prior to initiating "next-step" treatment is an important component of identifying which specific treatments are best suited for individual patients. We describe clinical features and demographic characteristics of a sample of Veterans who enrolled in a "next-step" clinical trial after failing to achieve an optimal outcome from at least one well-delivered antidepressant trial.

How Encouraging Provider Collaboration and Financial Incentives Can Improve Outcomes for Persons With Severe Psychiatric Disorders.

This Open Forum addresses the challenging situation involving decisions about when to hospitalize patients for psychiatric care. Because the evidence base for when to hospitalize patients is incomplete, current practice is to hospitalize only patients who are in crisis. This Open Forum provides a suggested set of payment options that can provide financial incentives to change practice patterns and lead to better clinical outcomes.

Sleep disturbance in chronic military-related PTSD: clinical impact and response to adjunctive risperidone in the Veterans Affairs cooperative study #504.

Objective: Sleep disturbances are common among veterans with chronic military-related posttraumatic stress disorder (PTSD). This article reports the results of a multicenter clinical trial that explored the clinical correlates of reported sleep impairment in these veterans and tested the impact of the second-generation antipsychotic risperidone upon these symptoms.

Method: This article reports secondary analyses of a 24-week multicenter randomized placebo-controlled trial of adjunctive risperidone in patients with chronic military-related PTSD symptoms (n = 267, 97% male) who were symptomatic despite treatment with antidepressants and other medications.

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial.

Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

Importance: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD.

Objective: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.

Design, Setting, And Participants: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers.

Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data.

Background: Alzheimer's disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha-tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N-methyl-D-aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD.

Methods: The Veterans Affairs Cooperative Studies Program initiated a multicenter, randomized, double-blind, placebo-controlled trial in August 2007, with enrollment through March 2012 and follow-up continuing through September 2012.

Bundling post-acute care services into MS-DRG payments.

Objective: A bundled hospital payment system that encompasses both acute and post-acute care has been proposed as a means of creating financial incentives in the Medicare fee-for-service system to foster care coordination and to improve the current disorganized system of post care. The objective of this study was to evaluate the statistical stability of alternative designs of a hospital payment system that includes post-acute care services to determine the feasibility of using a combined hospital and post-acute care bundle as a unit of payment.

Methods: The Medicare Severity-Diagnosis Related Groups (MS-DRGs) were subdivided into clinical subclasses that measured a patient's chronic illness burden to test whether a patient's chronic illness burden had a substantial impact on post-acute care expenditures.

Adjusting Medicaid managed care payments for changes in health status.

Risk adjustment of managed care organization (MCO) payments is essential to avoid creating financial incentives for MCOs adopting enrollee selection strategies. However, all risk-adjustment methods have an inherent structural flaw that rewards preventable deterioration in enrollee health status and improved coding of disease burden. We propose a payment adjustment to offset this flaw.

Tretinoin and the prevention of keratinocyte carcinoma (Basal and squamous cell carcinoma of the skin): a veterans affairs randomized chemoprevention trial.

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention.

Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.

Context: Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).

Objective: To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD.

Design, Setting, And Participants: A 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers.

Long-acting risperidone and oral antipsychotics in unstable schizophrenia.

Background: Long-acting injectable risperidone, a second-generation antipsychotic agent, may improve adherence to treatment and outcomes in schizophrenia, but it has not been tested in a long-term randomized trial involving patients with unstable disease.

Methods: We randomly assigned patients in the Veterans Affairs (VA) system who had schizophrenia or schizoaffective disorder and who had been hospitalized within the previous 2 years or were at imminent risk for hospitalization to 25 to 50 mg of long-acting injectable risperidone every two weeks or to a psychiatrist's choice of an oral antipsychotic. All patients were followed for up to 2 years.

Challenges in the design and conduct of controlled clinical effectiveness trials in schizophrenia.

Background: The introduction of antipsychotic medication has been a major advance in the treatment of schizophrenia and allows millions of people to live outside of institutions. It is generally believed that long-acting intramuscular antipsychotic medication is the most effective approach to increasing medication adherence and thereby reduce relapse in high-risk patients with schizophrenia, but the data are scant.

Purpose: To report the design of a study to assess the effect of long-acting injectable risperidone in unstable patients and under more realistic conditions than previously studied and to evaluate the effect of this medication on psychiatric inpatient hospitalization, schizophrenia symptoms, quality of life, medication adherence, side effects, and health care costs.

Effect of home testing of international normalized ratio on clinical events.

Background: Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes.

Methods: We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic.

An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481--The Home INR Study (THINRS).

Prior studies suggest patient self-testing (PST) of prothrombin time (PT) can improve the quality of anticoagulation (AC) and reduce complications (e.g., bleeding and thromboembolic events).

Functional characterization of the YmcB and YqeV tRNA methylthiotransferases of Bacillus subtilis.

Methylthiotransferases (MTTases) are a closely related family of proteins that perform both radical-S-adenosylmethionine (SAM) mediated sulfur insertion and SAM-dependent methylation to modify nucleic acid or protein targets with a methyl thioether group (-SCH(3)). Members of two of the four known subgroups of MTTases have been characterized, typified by MiaB, which modifies N(6)-isopentenyladenosine (i(6)A) to 2-methylthio-N(6)-isopentenyladenosine (ms(2)i(6)A) in tRNA, and RimO, which modifies a specific aspartate residue in ribosomal protein S12. In this work, we have characterized the two MTTases encoded by Bacillus subtilis 168 and find that, consistent with bioinformatic predictions, ymcB is required for ms(2)i(6)A formation (MiaB activity), and yqeV is required for modification of N(6)-threonylcarbamoyladenosine (t(6)A) to 2-methylthio-N(6)-threonylcarbamoyladenosine (ms(2)t(6)A) in tRNA.

Achieving cost control, care coordination, and quality improvement through incremental payment system reform.

The healthcare reform goal of increasing eligibility and coverage cannot be realized without simultaneously achieving control over healthcare costs. The reform of existing payment systems can provide the financial incentive for providers to deliver care in a more coordinated and efficient manner with minimal changes to existing payer and provider infrastructure. Pay for performance, best practice pricing, price discounting, alignment of incentives, the medical home, payment by episodes, and provider performance reports are a set of payment reforms that can result in lower costs, better coordination of care, improved quality of care, and increased consumer involvement.