Trajectory and magnitude of response in adults with anxiety disorders: a Bayesian hierarchical modeling meta-analysis of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and benzodiazepines.

BACKGROUND: How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models. RESULTS: Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p < 0.001). By week 8, the response for benzodiazepines and SSRIs (p = 0.103) and SNRIs (p = 0.911) did not differ nor did SSRIs and SNRIs differ (p = 0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference - 12.42, CrI: -25.05 to -0.78, p = 0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4 weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders. CONCLUSIONS: Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

Pharmacologic predictors of benzodiazepine response trajectory in anxiety disorders: a Bayesian hierarchical modeling meta-analysis.

BACKGROUND: Despite frequent benzodiazepine use in anxiety disorders, the trajectory and magnitude of benzodiazepine response and the effects of benzodiazepine potency, lipophilicity, and dose on improvement are unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel group, placebo-controlled trials of benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in anxiety was evaluated as a function of medication, disorder, time, potency, lipophilicity, and standardized dose and compared among benzodiazepines. RESULTS: Data from 65 trials (73 arms, 7 medications, 7110 patients) were included. In the logarithmic model of response, treatment effects emerged within 1 week of beginning treatment (standardized benzodiazepine-placebo difference = -0.235 ± 0.024, CrI: -0.283 to -0.186, P < .001) and placebo response plateaued at week 4. Doses <6 mg per day (lorazepam equivalents) produced faster and larger improvement than higher doses (P = .039 for low vs medium dose and P = .005 for high vs medium dose) and less lipophilic benzodiazepines (beta = 0.028 ± 0.013, P = .030) produced a greater response over time. Relative to the reference benzodiazepine (lorazepam), clonazepam (beta = -0.217 ± 0.95, P = .021) had a greater trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam). CONCLUSIONS: In adults with anxiety disorders, benzodiazepine-related improvement emerges early, and the trajectory and magnitude of improvement is related to dose and lipophilicity. Lower doses and less lipophilic benzodiazepines produce greater improvement.

Magentic Resonance Imaging Evaluation of Regional Lung Vts in Severe Neonatal Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia is a heterogeneous lung disease characterized by regions of cysts and fibrosis, but methods for evaluating lung function are limited to whole lung rather than specific regions of interest.Objectives: Respiratory-gated, ultrashort echo time magnetic resonance imaging was used to test the hypothesis that cystic regions of the lung will exhibit a quantifiable Vt that will correlate with ventilator settings and clinical outcomes.Methods: Magnetic resonance images of 17 nonsedated, quiet-breathing infants with severe bronchopulmonary dysplasia were reconstructed into end-inspiration and end-expiration images. Cysts were identified and measured by using density threshold combined with manual identification and segmentation. Regional Vts were calculated by subtracting end-expiration from end-inspiration volumes in total lung, noncystic lung, total-cystic lung, and individual large cysts.Measurements and Main Results: Cystic lung areas averaged larger Vts than noncystic lung when normalized by volume (0.8 ml Vt/ml lung vs. 0.1 ml Vt/ml lung, P < 0.002). Cyst Vt correlates with cyst size (P = 0.012 for total lung cyst and P < 0.002 for large cysts), although there was variability between individual cyst Vt, with 22% of cysts demonstrating negative Vt. Peak inspiratory pressure positively correlated with total lung Vt (P = 0.027) and noncystic Vt (P = 0.015) but not total lung cyst Vt (P = 0.8). Inspiratory time and respiratory rate did not improve Vt of any analyzed lung region.Conclusions: Cystic lung has greater normalized Vt when compared with noncystic lung. Ventilator pressure increases noncystic lung Vt, but inspiratory time does not correlate with Vt of normal or cystic lung.

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments.

Cigarette smoking (CS) can impact the immune system and induce pulmonary disorders such as chronic obstructive pulmonary disease (COPD), which is currently the fourth leading cause of chronic morbidity and mortality worldwide. Accordingly, the most significant risk factor associated with COPD is exposure to cigarette smoke. The purpose of the present study is to provide an updated overview of the literature regarding the effect of CS on the immune system and lungs, the mechanism of CS-induced COPD and oxidative stress, as well as the available and potential treatment options for CS-induced COPD. An extensive literature search was conducted on the PubMed/Medline databases to review current COPD treatment research, available in the English language, dating from 1976 to 2014. Studies have investigated the mechanism by which CS elicits detrimental effects on the immune system and pulmonary function through the use of human and animal subjects. A strong relationship among continued tobacco use, oxidative stress, and exacerbation of COPD symptoms is frequently observed in COPD subjects. In addition, therapeutic approaches emphasizing smoking cessation have been developed, incorporating counseling and nicotine replacement therapy. However, the inability to reverse COPD progression establishes the need for improved preventative and therapeutic strategies, such as a combination of intensive smoking cessation treatment and pharmaceutical therapy, focusing on immune homeostasis and redox balance. CS initiates a complex interplay between oxidative stress and the immune response in COPD. Therefore, multiple approaches such as smoking cessation, counseling, and pharmaceutical therapies targeting inflammation and oxidative stress are recommended for COPD treatment.

Molecular characterization of redox mechanisms in allergic asthma.

OBJECTIVE: To investigate the molecular redox mechanisms in allergic asthma and to examine current studies of the disease to provide a basis for further investigation of oxidative stress in allergic asthma and the signaling cascades involved in its pathogenesis. DATA SOURCES: Through the use of PubMed, a broad biomedical literature review was conducted in the following areas related to the physiology and pathobiology of asthma: redox therapy, reactive oxygen species (ROS), oxidative stress, allergic asthma, and antioxidants. STUDY SELECTIONS: Studies pertaining to oxidative stress and redox signaling in the molecular pathways of inflammation and hypersensitivity in the pathogenesis of allergic asthma were reviewed. RESULTS: Allergic asthma is associated with an increase in endogenous ROS formation, leading to oxidative stress-induced damage to the respiratory system and mitigated antioxidant defenses. Exposure to environmental antigens has been shown to stimulate overproduction of ROS, resulting in abnormal physiologic function of DNA, proteins, and lipids that clinically can augment bronchial hyperresponsiveness and inflammation. Through the use of animal and human studies, oxidative stress has been determined to be important in the pathogenesis of allergic asthma. Thus, recent research suggests that the assessment of oxidative stress byproducts represents a novel method by which disease severity can be monitored. In addition, the use of redox-based therapy to attenuate levels of ROS presents a potential strategy to alleviate oxidative stress-induced airway inflammation in patients with asthma. CONCLUSION: Redox mechanisms of oxidative stress in allergic asthma appear to play a key role in the pathogenesis of the disease and represent a promising therapeutic target.

Transdermal Asenapine for Agitation and Irritability in a Child With Complete Intravenous Dependence.

Atypical antipsychotics are often effective for managing behavioral disturbances in children with neurodevelopmental disabilities; however, limited evidence-based pharmacologic therapies exist for those dependent upon intravenous and transdermal routes. Transdermal asenapine is US Food and Drug Administration (FDA) approved for adult schizophrenia, but lacks data regarding pediatric use and tolerability. To our knowledge, there are no reports of transdermal asenapine use in children.1,2 Sublingual asenapine is FDA approved for pediatric bipolar mania monotherapy (ages 10-17 years), but was found to lack efficacy for schizophrenia in adolescents.1,3-5 Reportedly, its pediatric tolerability profile resembles those of other second-generation antipsychotics, with pharmacokinetic and safety data comparable to those in adults.3,6,7 We present the case of a 5-year-old child for whom transdermal asenapine effectively and safely managed agitation and improved tolerance of medical therapies and quality of life. Our case suggests that this may be an effective, well-tolerated pharmacologic option for agitation management in a subset of children. Guardian informed consent was obtained prior to publication.