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. Additional exploratory analyses were used to identify factors associated with trajectory group membership that could have been missed in the primary analysis. Results GBTM showed the best fit for depression symptom change was comprised of six trajectories, with some trajectories demonstrating minimal improvement and others showing a high probability of remission. High baseline depression and anxiety severity scores decreased, and early improvement increased, the likelihood of inclusion into the most responsive trajectory in both the GBTM and exploratory analyses. Conclusion While multiple factors influence responsiveness, the probability of inclusion into a specific depression symptom trajectory is most strongly influenced by three factors: baseline depression, baseline anxiety, and the presence of early improvement.

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.Results:The end of week 2 of treatment was identified as the best time to evaluate early improvement. The presence of a ≥20% drop from the baseline QIDS-C score by the end of week 2 resulted in a PPV for remission of 38% and an NPV of 93% by week 12. Extending the observational window to week 6 minimally improved NPV (97%). This association did not differ across treatment groups.Conclusions:A lack of early improvement at the end of week 2 of antidepressant therapy can be used to inform clinical decisions on the likelihood of nonremission of depression during the subsequent 10 weeks, even when dosage optimization is incomplete.

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.METHODS:The authors used data from the U.S. Department of Veterans Affairs (VA) Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, a multisite, randomized, single-blind trial of 1,522 Veterans Health Administration patients who did not have an adequate response to at least one course of antidepressant treatment meeting minimal standards for dosage and duration. For 12 weeks, participants received one of three possible next-step treatments: switch to another antidepressant-sustained-release bupropion; combination with another antidepressant-sustained-release bupropion; or augmentation with an antipsychotic-aripiprazole. Life table regression models were used to identify baseline characteristics associated with remission overall (general predictors) and their interaction with remission among the three treatment groups (moderators).RESULTS:Remission was more likely for individuals who were employed, less severely and chronically depressed, less anxious, not experiencing complicated grief symptoms, did not experience childhood adversity, and had better quality of life and positive mental health. Two features suggested specific next-step treatment selections: age ≥65 years (for whom augmentation with aripiprazole was more effective than switch to bupropion) and severe mixed hypomanic symptoms (for which augmentation with aripiprazole and combination with bupropion were more effective than switch to bupropion).CONCLUSIONS:If replicated, these preliminary findings could help clinicians determine which patients with depression requiring next-step treatment will benefit most from a specific augmentation, combination, or switching strategy.

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. Overall, there was no difference in the rate of functional decline between APOE ε4 allele carriers and noncarriers. A significant interaction was observed between treatment and the APOE genotype on AD progression: ε4 carriers declined faster than noncarriers in the vitamin E plus memantine treatment arm.DISCUSSION:APOE genotypes may modulate AD treatment response and should be included in the design of future randomized controlled trials.

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.RESULTS:A total of 87% of patients displayed at least 1 NPS; 70% displayed clinically meaningful NPS. The most common symptoms were apathy (47%), irritability (44%), agitation (42%), and depression (40%). Those with moderate AD had more severe NPS than those with mild AD ( P = .03). Neuropsychiatric symptoms were significantly associated with caregiver time after adjusting for age, education, cognitive function, and comorbidity ( P-value < .0001) with every point increase in NPS associated with a 10-minute increase in caregiver time.CONCLUSION:Neuropsychiatric symptoms were prevalent in both mild and moderate AD, even in patients receiving treatment with an acetylcholinesterase inhibitors, and were more severe in moderate AD and associated with greater caregiver time.

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. These frameworks were selected for applicability to Center processes and systems, consistency and reinforcement of complimentary approaches, and international acceptance. External validations include the MBNQA, the highest quality award in the US, continued registration and conformance to ISO standards and guidelines, and multiple VA and state awards. With a focus on a holistic approach to quality involving processes, systems and personnel, this paper presents activities and lessons that were critical to building TIPES and establishing the quality environment for conducting clinical research in support of Veterans and national health care.

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. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.INTERVENTIONS Switch to a different antidepressant, bupropion (switch group, n=511); augment current treatment with bupropion (augment-bupropion group, n=506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n=505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).MAIN OUTCOMES AND MEASURES The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C-16] score <= 5 at 2 consecutive visits). Secondary outcomes included response (>= 50% reduction in QIDS-C-16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.RESULTS Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n=114) for the switch group, 26.9% (n=136)for the augment-bupropion group, and 28.9% (n=146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P=.02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n=124] vs 16.6% in the augment-aripiprazole group [n=84]; and 22.5% in augment-bupropion group [n=114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.CONCLUSIONS and Relevance Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.

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.Methods: 1522 Veteran outpatients with nonpsychotic MDD completed assessments prior to being randomized to study treatment. Data is summarized and presented in terms of demographic, social, historical and clinical features and compared to a similar, non-Veteran sample.Results: Participants were largely male and white, with about half unmarried and half unemployed. They were moderately severely depressed, with about one-third reporting recent suicidal ideation. More than half had chronic and/or recurrent depression. General medical and psychiatric comorbidities were highly prevalent, particularly PTSD. Many had histories of childhood adversity and bereavement. Participants were impaired in multiple domains of their lives and had negative self-worth.Limitations: These results may not be generalizable to females, and some characteristics may be specific to Veterans of US military service. There was insufficient data on age of clinical onset and depression subtypes, and three novel measures were not psychometrically validated.Conclusions: Characterizing VAST-D participants provides important information to help clinicians understand features that may optimize "next-step" MDD treatments. Published by Elsevier B.V.

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 study was conducted between February 2007 and February 2010. DSM-IV PTSD diagnoses were made by using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Nonpatient Edition. Sleep disturbances were assessed principally by using the Pittsburgh Sleep Quality Index (PSQI) (primary outcome measure). Analyses were conducted using bivariate correlations and longitudinal mixed model regressions.RESULTS:Eighty-eight percent of the patients in this study had clinically significantly impaired sleep on the PSQI. Severity of sleep disturbances correlated with PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS) and reductions in multiple measures of quality of life (Veterans RAND 36-item Health Survey [SF-36 V] subscales, Boston Life Satisfaction Index). Risperidone produced small but statistically significant effects on total PSQI scores (main effect of drug: F1,228 = 4.57, P = .034; drug-by-time interaction: F2,421 = 4.32, P = .014) and severity of nightmares as assessed by the CAPS (main effect of drug: F1,248 = 4.60, P = .033). The improvements in sleep quality produced by risperidone correlated with reductions in PTSD symptom severity and improvement in the mental health subscale of the SF-36 V.CONCLUSIONS:This study highlighted the near universality and significant negative impact of severe disturbances in sleep quality in veterans with chronic military-related PTSD who were partial responders to standard pharmacotherapies. The modest improvements in sleep quality produced by adjunctive risperidone were correlated with limited reductions in PTSD severity and improvements in quality of life.TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00099983.

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).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.A total of 453 (74%) participants were determined to have capacity to consent by clinical judgment. ICQ perceived understanding, race, measures of cognitive function, and caregiver time were all significantly associated with the determination of capacity in multivariate analyses.We found a significant association between capacity and disease severity level, caregiver time, race, and ICQ perceived understanding.

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.

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.INTERVENTIONS:Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152).MAIN OUTCOMES AND MEASURES:Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures.RESULTS:Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).CONCLUSIONS AND RELEVANCE:Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00235716.

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. Participants with mild-to-moderate AD who were taking an acetylcholinesterase inhibitor were assigned randomly to 2000 IU/day of alpha-tocopherol, 20 mg/day memantine, 2000 IU/day alpha-tocopherol plus 20 mg/day memantine, or placebo. The primary outcome for the study is the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory. Secondary outcome measures include the Mini-Mental State Examination; the Alzheimer's Disease Assessment Scale, cognitive portion; the Dependence Scale; the Neuropsychiatric Inventory; and the Caregiver Activity Survey. Patient follow-up ranged from 6 months to 4 years.Results: A total of 613 participants were randomized. The majority of the patients were male (97%) and white (86%), with a mean age of 79 years. The mean Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory score at entry was 57 and the mean Mini-Mental State Examination score at entry was 21.Conclusion: This large multicenter trial will address the unanswered question of the long-term safety and effectiveness of alpha-tocopherol, memantine, and their combination in patients with mild-to-moderate AD taking an acetylcholinesterase inhibitor. The results are expected in early 2013. (C) 2014 The Alzheimer's Association. All rights reserved.

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. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P=0.3 for BCC and P=0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs.

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.METHODS:The trial was an open randomized clinical comparative effectiveness trial in patients with schizophrenia or schizo-affective disorders in which parenteral risperidone was compared to an oral antipsychotic regimen selected by each control patient's psychiatrist. Participants had unstable psychiatric disease defined by recent hospitalization or exhibition of unusual need for psychiatric services. The primary endpoint was hospitalization for psychiatric indications; the secondary endpoint was psychiatric symptoms.RESULTS:Overall, 382 patients were randomized. Determination of a persons' competency to understand the elements of informed consent was addressed. The use of a closed-circuit TV interview for psychosocial measures provided an economical, high quality, reliable means of collecting data. A unique method for insuring that usual care was optimal was incorporated in the follow-up of all subjects.LIMITATIONS:Patients with schizophrenia or schizo-affective disorders and with the common co-morbid illnesses seen in the VA are a challenging group of subjects to study in long-term trials. Some techniques unique in the VA and found useful may not be generalizable or applicable in other research or treatment settings.CONCLUSIONS:The trial tested a new antipsychotic medication early in its adoption in the Veterans Health Administration. The VA has a unique electronic medical record and database which can be used to identify the endpoint, that is, first hospitalization due to a psychiatric problem, with complete ascertainment. Several methodologic solutions addressed competency to understand elements of consent, the costs and reliability of collecting interview data gathering, and insuring usual care.

Results Change in CAPS scores from baseline to 24 weeks in the risperidone group was �16.3 (95% CI, �19.7 to �12.9) and in the placebo group, �12.5 (95% CI, �15.7 to �9.4); the mean difference was 3.74 (95% CI, �0.86 to 8.35;t=1.6;P=.11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, �0.74 to 6.20; P=.12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, �0.29 to 2.68;P=.11) or anxiety (HAMA mean difference, 1.16; 95% CI, �0.18 to 2.51; P=.09; patient-rated CGI mean difference, 0.20; 95% CI, �0.06 to 0.45;P=.14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34;P=.04), or increase quality of life (SF-36V physical component mean difference, �1.13, 95% CI, �2.58 to 0.32; P=.13; SF-36V mental component mean difference, �0.26; 95% CI, �2.13 to 1.61;P=.79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively. Conclusion Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. Trial Registration clinicaltrials.gov Identifier: NCT00099983

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. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure. INTERVENTION Risperidone (up to 4 mg once daily) or placebo. MAIN OUTCOME MEASURES The Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V). RESULTS Change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively. CONCLUSION Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00099983.

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. The primary end point was the time to a first major event (stroke, major bleeding episode, or death).Results: The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001).Conclusions: As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.)N Engl J Med 2010;363:1608-20.

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). "The Home INR Study" (THINRS) compared AC management with frequent PST using a home monitoring device to high-quality AC management (HQACM) with clinic-based monitoring on major health outcomes. A key clinical and policy question is whether and which patients can successfully use such devices. We report the results of Part 1 of THINRS in which patients and caregivers were evaluated for their ability to perform PST. Study-eligible patients (n = 3643) were trained to use the home monitoring device and evaluated after 2-4 weeks for PST competency. Information about demographics, medical history, warfarin use, medications, plus measures of numeracy, literacy, cognition, dexterity, and satisfaction with AC were collected. Approximately 80% (2931 of 3643) of patients trained on PST demonstrated competency; of these, 8% (238) required caregiver assistance. Testers who were not competent to perform PST had higher numbers of practice attempts, higher cuvette wastage, and were less able to perform a fingerstick or obtain blood for the cuvette in a timely fashion. Factors associated with failure to pass PST training included increased age, previous stroke history, poor cognition, and poor manual dexterity. A majority of patients were able to perform PST. Successful home monitoring of PT with a PST device required adequate levels of cognition and manual dexterity. Training a caregiver modestly increased the proportion of patients who can perform PST.