Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

A Perioperative Mental Health Intervention for Depressed and Anxious Older Surgical Patients: Results From a Feasibility Study.

OBJECTIVES: The perioperative period is challenging and stressful for older adults. Those with depression and/or anxiety have an increased risk of adverse surgical outcomes. We assessed the feasibility of a perioperative mental health intervention composed of medication optimization and a wellness program following principles of behavioral activation and care coordination for older surgical patients. METHODS: We included orthopedic, oncologic, and cardiac surgical patients aged 60 and older. Feasibility outcomes included study reach, the number of patients who agreed to participate out of the total eligible; and intervention reach, the number of patients who completed the intervention out of patients who agreed to participate. Intervention efficacy was assessed using the Patient Health Questionnaire for Anxiety and Depression (PHQ-ADS). Implementation potential and experiences were collected using patient surveys and qualitative interviews. Complementary caregiver feedback was also collected. RESULTS: Twenty-three out of 28 eligible older adults participated in this study (mean age 68.0 years, 65% women), achieving study reach of 82% and intervention reach of 83%. In qualitative interviews, patients (n = 15) and caregivers (complementary data, n = 5) described overwhelmingly positive experiences with both the intervention components and the interventionist, and reported improvement in managing depression and/or anxiety. Preliminary efficacy analysis indicated improvement in PHQ-ADS scores (F = 12.13, p <0.001). CONCLUSIONS: The study procedures were reported by participants as feasible and the perioperative mental health intervention to reduce anxiety and depression in older surgical patients showed strong implementation potential. Preliminary data suggest its efficacy for improving depression and/or anxiety symptoms. A randomized controlled trial assessing the intervention and implementation effectiveness is currently ongoing.

Sleep and circadian rhythms during pregnancy, social disadvantage, and alterations in brain development in neonates.

Pregnant women in poverty may be especially likely to experience sleep and circadian rhythm disturbances, which may have downstream effects on fetal neurodevelopment. However, the associations between sleep and circadian rhythm disturbances, social disadvantage during pregnancy, and neonatal brain structure remains poorly understood. The current study explored the association between maternal sleep and circadian rhythm disturbances during pregnancy and neonatal brain outcomes, examining sleep and circadian rhythm disturbances as a mediator of the effect of social disadvantage during pregnancy on infant structural brain outcomes. The study included 148 mother-infant dyads, recruited during early pregnancy, who had both actigraphy and neuroimaging data. Mothers' sleep was assessed throughout their pregnancy using actigraphy, and neonates underwent brain magnetic resonance imaging in the first weeks of life. Neonatal structural brain outcomes included cortical gray matter, subcortical gray matter, and white matter volumes along with a measure of the total surface area of the cortex. Neonates of mothers who experienced greater inter-daily deviations in sleep duration had smaller total cortical gray and white matter volumes and reduced cortical surface areas. Neonates of mothers who had higher levels of circadian misalignment and later sleep timing during pregnancy showed smaller subcortical gray matter volumes. Inter-daily deviations in sleep duration during pregnancy mediated the association between maternal social disadvantage and neonatal structural brain outcomes. Findings highlight the importance of regularity and rhythmicity in sleep schedules during pregnancy and bring to light the role of chronodisruption as a potential mechanism underlying the deleterious neurodevelopmental effects of prenatal adversity. RESEARCH HIGHLIGHTS: Social disadvantage was associated with sleep and circadian rhythm disturbances during pregnancy, including later sleep schedules, increased variability in sleep duration, circadian misalignment, and a higher proportion of the sleep period spent awake. Maternal sleep and circadian rhythm disturbances during pregnancy were associated with decreased brain volume and reduced cortical surface area in neonates. Maternal inter-daily deviations in sleep duration during pregnancy mediated the association between social disadvantage and neonatal brain volume and cortical surface area.

Healthcare center clustering for Cox's proportional hazards model by fusion penalty.

There has been growing research interest in developing methodology to evaluate healthcare centers' performance with respect to patient outcomes. Conventional assessments can be conducted using fixed or random effects models, as seen in provider profiling. We propose a new method, using fusion penalty to cluster healthcare centers with respect to a survival outcome. Without any prior knowledge of the grouping information, the new method provides a desirable data-driven approach for automatically clustering healthcare centers into distinct groups based on their performance. An efficient alternating direction method of multipliers algorithm is developed to implement the proposed method. The validity of our approach is demonstrated through simulation studies, and its practical application is illustrated by analyzing data from the national kidney transplant registry.

Neonatal Intensive Care Unit Network Neurobehavioral Scale Profiles in Full-Term Infants: Associations with Maternal Adversity, Medical Risk, and Neonatal Outcomes.

OBJECTIVES: To examine healthy, full-term neonatal behavior using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) in relation to measures of maternal adversity, maternal medical risk, and infant brain volumes. STUDY DESIGN: This was a prospective, longitudinal, observational cohort study of pregnant mothers followed from the first trimester and their healthy, full-term infants. Infants underwent an NNNS assessment and high-quality magnetic resonance imaging 2-5 weeks after birth. A latent profile analysis of NNNS scores categorized infants into neurobehavioral profiles. Univariate and multivariate analyses compared differences in maternal factors (social advantage, psychosocial stress, and medical risk) and neonatal characteristics between profiles. RESULTS: The latent profile analysis of NNNS summary scales of 296 infants generated 3 profiles: regulated (46.6%), hypotonic (16.6%), and fussy (36.8%). Infants with a hypotonic profile were more likely to be male (χ2 = 8.601; P = .014). Fussy infants had smaller head circumferences (F = 3.871; P = .022) and smaller total brain (F = 3.522; P = .031) and cerebral white matter (F = 3.986; P = .020) volumes compared with infants with a hypotonic profile. There were no differences between profiles in prenatal maternal health, social advantage, or psychosocial stress. CONCLUSIONS: Three distinct neurobehavioral profiles were identified in healthy, full-term infants with hypotonic and fussy neurobehavioral features related to neonatal brain volumes and head circumference, but not prenatal exposure to socioeconomic or psychosocial adversity. Follow-up beyond the neonatal period will determine if identified profiles at birth are associated with subsequent clinical or developmental outcomes.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial.

Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.

Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders.

The goal of precision medicine (individually tailored treatments) is not being achieved for neurobehavioural conditions such as psychiatric disorders. Traditional randomized clinical trial methods are insufficient for advancing precision medicine because of the dynamic complexity of these conditions. We present a pragmatic solution: the precision clinical trial framework, encompassing methods for individually tailored treatments. This framework includes the following: (1) treatment-targeted enrichment, which involves measuring patients' response after a brief bout of an intervention, and then randomizing patients to a full course of treatment, using the acute response to predict long-term outcomes; (2) adaptive treatments, which involve adjusting treatment parameters during the trial to individually optimize the treatment; and (3) precise measurement, which involves measuring predictor and outcome variables with high accuracy and reliability using techniques such as ecological momentary assessment. This review summarizes precision clinical trials and provides a research agenda, including new biomarkers such as precision neuroimaging, transcranial magnetic stimulation-electroencephalogram digital phenotyping and advances in statistical and machine-learning models. Validation of these approaches - and then widespread incorporation of the precision clinical trial framework - could help achieve the vision of precision medicine for neurobehavioural conditions.

Capturing heterogeneity in repeated measures data by fusion penalty.

In this article, we are interested in capturing heterogeneity in clustered or longitudinal data. Traditionally such heterogeneity is modeled by either fixed effects (FE) or random effects (RE). In FE models, the degree of freedom for the heterogeneity equals the number of clusters/subjects minus 1, which could result in less efficiency. In RE models, the heterogeneity across different clusters/subjects is described by, for example, a random intercept with 1 parameter (for the variance of the random intercept), which could lead to oversimplification and biases (for the estimates of subject-specific effects). Our "fused effects" model stands in between these two approaches: we assume that there are unknown number of distinct levels of heterogeneity, and use the fusion penalty approach for estimation and inference. We evaluate and compare the performance of our method to the FE and RE models by simulation studies. We apply our method to the Ocular Hypertension Treatment Study to capture the heterogeneity in the progression rate of primary open-angle glaucoma of left and right eyes of different subjects.

The Effect of Venlafaxine on Electrocardiogram Intervals During Treatment for Depression in Older Adults.

PURPOSE/BACKGROUND: Venlafaxine is a commonly used antidepressant with both serotonergic and noradrenergic activity. There are concerns that it may prolong the corrected QT interval (QTc), and older adults may be at higher risk for this adverse effect, especially at higher dosages of the medication. METHODS/PROCEDURES: In this secondary analysis of a prospective clinical trial, we measured changes in QTc and other electrocardiogram (ECG) parameters in 169 adults 60 years or older with a major depressive disorder treated acutely with venlafaxine extended release up to 300 mg daily. We examined the relationship of venlafaxine dosage and ECG parameters, as well as the relationship between serum levels of venlafaxine and ECG parameters. FINDINGS/RESULTS: Venlafaxine exposure was not associated with an increase in QTc. Heart rate increased with venlafaxine treatment, whereas the PR interval shortened, and QRS width did not change significantly. The QTc change from baseline was not associated with venlafaxine dosages or serum concentrations. Age, sex, cardiovascular comorbidities, and depression remission status did not predict changes in QTc with venlafaxine. IMPLICATIONS/CONCLUSIONS: Venlafaxine treatment did not prolong QTc or other ECG parameters, even in high dosages in older depressed adults. These findings indicate that venlafaxine does not significantly affect cardiac conduction in most older patients.

iTBS to Relieve Depression and Executive Dysfunction in Older Adults: An Open Label Study.

BACKGROUND: Executive Function Deficits (EFD) accompany depression and are associated with poor outcomes in older adults. We examined whether Intermittent Theta Burst Stimulation (iTBS) could improve depression with EFD. METHODS: Thirteen geriatric patients with depression and EFD were enrolled. Open label iTBS was delivered bilaterally over the dorso-lateral-prefrontal-cortex for four weeks. RESULTS: Montgomery Asberg Depression Scale scores improved significantly from baseline to treatment-end, mean change in score = 11.82 points, 95% CI = 8.3, 15.4. The Flanker Inhibitory control and attention test showed significant improvement in executive function from baseline to treatment-end, mean change in score = -7.73, 95% CI ( -13.54, -1.92). Side effects included twitching in facial muscles (n = 11), headaches (n = 10) and stimulation discomfort (n = 4). LIMITATIONS: Small sample size and lack of a sham comparator. CONCLUSION: iTBS improved depression with EFD in older adults. Side effects appeared higher than in previous iTBS studies.

Experiences of American Older Adults with Pre-existing Depression During the Beginnings of the COVID-19 Pandemic: A Multicity, Mixed-Methods Study.

OBJECTIVE: To determine the effect of the COVID-19 pandemic on the mental health of older adults with pre-existing major depressive disorder (MDD). PARTICIPANTS: Participants were 73 community-living older adults with pre-existing MDD (mean age 69 [SD 6]) in Los Angeles, New York, Pittsburgh, and St Louis. DESIGN AND MEASUREMENTS: During the first 2 months of the pandemic, the authors interviewed participants with a semistructured qualitative interview evaluating access to care, mental health, quality of life, and coping. The authors also assessed depression, anxiety, and suicidality with validated scales and compared scores before and during the pandemic. RESULTS: Five themes from the interviews highlight the experience of older adults with MDD: 1) They are more concerned about the risk of contracting the virus than the risks of isolation. 2) They exhibit resilience to the stress and isolation of physical distancing. 3) Most are not isolated socially, with virtual contact with friends and family. 4) Their quality of life is lower, and they worry their mental health will suffer with continued physical distancing. 5) They are outraged by an inadequate governmental response to the pandemic. Depression, anxiety, and suicidal ideation symptom scores did not differ from scores before the pandemic. CONCLUSION: Most older adults with pre-existing MDD show resilience in the first 2 months of the COVID-19 pandemic but have concerns about the future. Policies and interventions to provide access to medical services and opportunities for social interaction are needed to help to maintain mental health and quality of life as the pandemic continues.

Does patient expectancy account for the cognitive and clinical benefits of mindfulness training in older adults?

OBJECTIVES: Patient expectations of treatment effects could influence neuropsychological and clinical outcomes in clinical trials of behavioral and lifestyle interventions, which could potentially confound the interpretation of findings. Our aim was to examine whether patient expectancy mediated effectiveness of Mindfulness-Based Stress Reduction (MBSR) for improving cognitive function and clinical outcome. METHODS: The present study uses data from a single-blind, multi-site, randomized controlled trial comparing MBSR to a health education attention control in older adults with anxiety and/or depressive disorders and subjective cognitive concerns. Using the Credibility and Expectations Questionnaire, we measured expectancy and perceived credibility of the interventions assigned to patients. Using mediational analysis, we examined the influence of expectancy and credibility on two key outcomes: memory performance and clinical global improvement. RESULTS: Neither expectancy nor perceived credibility of intervention accounted significantly for MBSR's effectiveness for memory test performance or clinical global improvement. CONCLUSION: In this clinical trial, expectancy for improvement did not account for the effectiveness of MBSR on memory performance or clinical outcomes in depressed and anxious older adults. We advise that clinical trials of behavioral and lifestyle interventions for brain health in older adults should measure and test the role of expectancy.

Mindfulness, Education, and Exercise for age-related cognitive decline: Study protocol, pilot study results, and description of the baseline sample.

BACKGROUND/AIMS: Age-related cognitive decline is a pervasive problem in our aging population. To date, no pharmacological treatments to halt or reverse cognitive decline are available. Behavioral interventions, such as physical exercise and Mindfulness-Based Stress Reduction, may reduce or reverse cognitive decline, but rigorously designed randomized controlled trials are needed to test the efficacy of such interventions. METHODS: Here, we describe the design of the Mindfulness, Education, and Exercise study, an 18-month randomized controlled trial that will assess the effect of two interventions-mindfulness training plus moderate-to-vigorous intensity exercise or moderate-to-vigorous intensity exercise alone-compared with a health education control group on cognitive function in older adults. An extensive battery of biobehavioral assessments will be used to understand the mechanisms of cognitive remediation, by using structural and resting state functional magnetic resonance imaging, insulin sensitivity, inflammation, and metabolic and behavioral assessments. RESULTS: We provide the results from a preliminary study (n = 29) of non-randomized pilot participants who received both the exercise and Mindfulness-Based Stress Reduction interventions. We also provide details on the recruitment and baseline characteristics of the randomized controlled trial sample (n = 585). CONCLUSION: When complete, the Mindfulness, Education, and Exercise study will inform the research community on the efficacy of these widely available interventions improve cognitive functioning in older adults.

Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial.

Importance: Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production. Objective: To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease. Design, Setting, and Participants: Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020. Interventions: Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days. Main Outcomes and Measures: The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Results: Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events. Conclusions and Relevance: In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures. Trial Registration: ClinicalTrials.gov Identifier: NCT04342663.

Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized.

OBJECTIVE: Evidence from clinical trials comparing effectiveness and safety of pharmacological strategies in older adults unresponsive to first-line antidepressants is limited. The study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), tests three hypotheses concerning pharmacotherapy strategies for treatment-resistant late-life depression: 1) augmentation strategies will provide greater improvement than switching monotherapies; 2) augmentation strategies will have lower tolerability and more safety concerns than switching monotherapies; and 3) age will moderate the effectiveness and safety differences between treatment strategies. The authors describe the methodology, processes for stakeholder engagement, challenges, and lessons learned in the early phases of OPTIMUM. METHODS: This pragmatic randomized clinical trial located in five North American regions will enroll 1,500 participants aged 60 years and older unresponsive to two or more antidepressant trials. The authors evaluate two strategies (medication augmentation versus switch) using four medications (aripiprazole, bupropion, lithium, and nortriptyline) via a stepwise, prespecified protocol. Primary outcomes include: 1) symptom remission (Montgomery Asberg Depression scale ≤10); 2) psychological well-being, comprising positive affect, general life satisfaction, and purpose; and 3) safety (rates of serious adverse events and prevalence of falls and fall-related injuries). RESULTS: To date, 396 participants have been randomized. The authors report on four challenges: 1) engagement and recruitment; 2) increasing polypharmacy in older adults, resulting in potentially hazardous scenarios; 3) reporting adverse events and procedure standardization across sites; and 4) dissemination of results. CONCLUSION: Solutions to these challenges, including early inclusion of stake holders, will inform future pragmatic studies in older adults with depression.

Comorbid anxiety in late-life depression: Relationship with remission and suicidal ideation on venlafaxine treatment.

OBJECTIVE: The purpose of this study was to examine the influence of comorbid anxiety symptoms on antidepressant treatment remission in older adults with major depressive disorder (MDD). METHOD: In this multisite clinical trial, 468 older adults aged 60 years or older with MDD received open-label protocolized treatment with venlafaxine extended release (ER) titrated to a maximum of 300 mg daily. At baseline, anxiety was assessed with the Anxiety Sensitivity Index, the Brief Symptom Inventory (BSI) anxiety subscale, and the Penn State Worry Questionnaire. To measure treatment response, depressive symptoms and suicidality were assessed every 1-2 weeks with the Montgomery-Asberg Depression Rating Scale and the 19-item Scale for Suicide Ideation; anxiety was assessed with the BSI. Logistic regression and survival analysis were used to evaluate whether anxiety symptoms predicted depression remission. We also examined the relationships between anxiety scores and suicidality at baseline. RESULTS: Baseline anxiety symptoms did not predict remission or time to remission of depressive symptoms. Depressive, worry, and panic symptoms decreased in parallel in patients with high anxiety. Anxiety symptoms were associated with the severity of depression and with suicidality. CONCLUSION: In older adults with MDD, comorbid anxiety symptoms are associated with symptom severity but do not affect antidepressant remission or time to remission.

Crossover to Bilateral Repetitive Transcranial Magnetic Stimulation: A Potential Strategy When Patients Are Not Responding to Unilateral Left-Sided High-Frequency Repetitive Transcranial Magnetic Stimulation.

Clinical trials using left-sided repetitive transcranial magnetic stimulation (rTMS) report remission rates of 14% to 32.6%. A large percentage of patients would not achieve remission with standard rTMS treatment. The question of what clinicians should do when a patient is not responding to standard high-frequency (HF) left-sided rTMS remains unanswered. This prospective case series examines whether crossover to bilateral stimulation enhances antidepressant outcomes in patients not responding to unilateral rTMS. Patients in a major depressive episode received an rTMS clinical protocol of 4 to 6 weeks' duration. Stimulation began with HF rTMS (10 Hz) over the left dorsolateral prefrontal cortex (range, 3000-5000 pulses per session). A total of 17 patients without sufficient clinical improvement early in their rTMS course received 1-Hz rTMS (range, 600-1200 pps) over the right dorsolateral prefrontal cortex (added to the HF left-sided stimulation). Hamilton Depression Rating Scale scores decreased from 13.9 ± 3.9 (mean ± SD) from the start of augmentation to 12.2 ± 5.8 at the end of acute treatment, a 1.7-point change, Cohen d effect size = -0.35, 95% confidence interval, -1.01 to - 0.34, suggesting improvement. Remission rate in this sample was 24% (4/17). This case series indicates that crossover to bilateral stimulation is a feasible and potentially effective strategy when patients are not improving with standard rTMS. A randomized controlled trial comparing crossover versus standard rTMS is needed to determine the efficacy of this paradigm.

Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

Baseline Hemodynamic Impairment and Future Stroke Risk in Adult Idiopathic Moyamoya Phenomenon: Results of a Prospective Natural History Study.

BACKGROUND AND PURPOSE: The purpose was to test the hypothesis that increased oxygen extraction fraction (OEF), a marker of severe hemodynamic impairment measured by positron emission tomography, is an independent risk factor for subsequent ischemic stroke in this population. METHODS: Adults with idiopathic moyamoya phenomena were recruited between 2005 and 2012 for a prospective, multicenter, blindly adjudicated, longitudinal cohort study. Measurements of OEF were obtained on enrollment. Subjects were followed up for the occurrence of ipsilateral ischemic stroke at 6-month intervals. Patients were censored at the time of surgical revascularization or at last follow-up. The primary analysis was time to ischemic stroke in the territory of the occlusive vasculopathy. RESULTS: Forty-nine subjects were followed up during a median of 3.7 years. One of 16 patients with increased OEF on enrollment had an ischemic stroke and another had an intraparenchymal hemorrhage. Three of 33 patients with normal OEF had an ischemic stroke. On a per-hemisphere basis, 21 of 79 hemispheres with moyamoya vasculopathy had increased OEF at baseline. No ischemic strokes and one hemorrhage occurred in a hemisphere with increased OEF (n=21). Sixteen patients (20 hemispheres), including 5 with increased OEF at enrollment, were censored at a mean of 5.3 months after enrollment for revascularization surgery. CONCLUSIONS: The risk of new or recurrent stroke was lower than expected. The low event rate, low prevalence of increased OEF, and potential selection bias introduced by revascularization surgery limit strong conclusions about the association of increased OEF and future stroke risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00629915.