Attentiveness and mental health in adolescents with moderate-to-severe atopic dermatitis without ADHD.

Patients with moderate-to-severe atopic dermatitis (AD) experience intense chronic itch and impaired sleep. Reports from parents and teachers suggest that AD patients may also have attention problems. However, attention has not yet been directly assessed in AD patients. We utilized an objective, computer-based continuous performance test (CPT) validated for use in attention-deficit/hyperactivity disorder (ADHD) diagnosis to formally evaluate attention in adolescent AD subjects. This was a single-visit, cross-sectional, non-interventional study of moderate-to-severe (Investigator's Global Assessment [IGA] ≥ 3) AD subjects aged 12-17 years without clinician-diagnosed ADHD. Attention was evaluated using two performance-based measures: Conners, CPT-3 and the Stroop Color and Word Test. The primary parameter was CPT-3 detectability (d') measure. Lesional severity measures included Eczema Area and Severity Index (EASI) and body surface area (BSA) involvement. Subjects completed self-report rating scales assessing sensory responsiveness patterns (Adult/Adolescent Sensory Profile [AASP]), itch (Peak Pruritus Numerical Rating Scale [PP-NRS]), skin pain, quality of life, sleep, anxiety, and depressive symptoms. A total of 44 subjects were included in the study (61.4% female; mean age 15.0 [SD 1.78] years; mean EASI 20.4 [SD 7.8]; mean PP-NRS 7.0 [SD 1.8]). Results indicated substantial disease impact on sleep, quality of life, and comorbid anxiety and depressive symptoms. The mean (SD) Conners, CPT-3 d' T-score was 48.7 (SD 10.7), similar to the expected mean from a randomly selected age/gender-matched sample of the general population (50 [SD 10], by definition). Overall, 13.6% of subjects exhibited a d' T-score ≥ 60 (clinically significant poor performance), which was not greater than the expected general population value (15.9%). Subject-level data review by two psychologists determined that only 2 subjects demonstrated an overall response pattern that clearly indicated attention deficit. Many subjects had atypical sensory responsiveness profiles: sensory hypersensitivity (38.6%), sensory avoidance (50%), and low registration (hypo-sensitivity, 36.4%). Adolescents with moderate-to-severe AD without existing ADHD diagnosis did not demonstrate greater attention problems on performance-based measures than would be expected in age/gender-matched peers.Trial registration NCT05203380.

Atopic dermatitis (often shortened to AD) is a long-term skin disease that causes intense itching. It affects patients' lives in many ways, including interrupting their sleep. Parents and teachers of young people with AD have sometimes suggested that AD may also cause attention problems. But this has never been tested properly.We measured the attention of 44 adolescents aged between 12 and 17 years who all had moderate-to-severe AD. We used computerized tests of attention that were developed for young people with ADHD (attention deficit hyperactivity disorder). Also, we made sure that none of the 44 patients had also been diagnosed with ADHD. The severity and extent of the patients' AD was measured by doctors. We also used some measures that allowed the patients to report how AD affected their lives, including things like itch, skin pain, quality of life, sleep, anxiety, and depression.The adolescent patients reported that AD had a negative effect on various areas of their lives, including sleep and quality of life, and that it resulted in anxiety and symptoms of depression. However, the results of the attention tests in adolescents with AD were similar to what would usually be expected in adolescents without AD. Only 2 of the 44 patients with AD were found to have clear evidence of attention problems.The study concluded that adolescents with moderate-to-severe AD did not have any greater attention problems than would usually be expected in adolescents without AD.

Real-World Effectiveness of Dupilumab in Adult and Adolescent Patients with Atopic Dermatitis: 2-Year Interim Data from the PROSE Registry.

INTRODUCTION: There is a scarcity of data beyond 1 year for the use of dupilumab to treat atopic dermatitis (AD) in a real-world setting. This study aimed to evaluate the 2-year effectiveness of dupilumab among adult and pediatric patients with moderate-to-severe AD included in a real-world, longitudinal database study. METHODS: PROSE is an ongoing, prospective, observational, multi-center registry in the USA and Canada, designed to collect real-world data from patients aged ≥ 12 years with moderate-to-severe AD who initiate dupilumab in accordance with country-specific prescribing information. Assessments include body surface area affected by AD (BSA), Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Pruritus Numerical Rating Scale (P-NRS), Patient-Oriented Eczema Measure (POEM), Patient Global Assessment of Disease (PGAD) questionnaire score, and occurrence of adverse events (AEs). RESULTS: Of 764 patients who enrolled in PROSE, 632 (83%) remained in the study at the time of this interim analysis. Improvements were observed at the first post-baseline clinic visit (approximately 3 months) in the clinician-assessed measures (mean BSA and EASI scores); improvements were sustained throughout the 2-year period covered in the present study. Consistent and sustained improvements were also observed over the 2-year period in the patient-reported measures of P-NRS, POEM, and DLQI, and in the proportion of patients reporting "very good/excellent" in answer to the question in the PGAD questionnaire: "Considering all the ways in which your eczema affects you, indicate how well you are doing". Dupilumab treatment was well tolerated, with safety findings consistent with those previously reported in studies of dupilumab for the treatment of AD. CONCLUSIONS: In the real-world PROSE registry, patients with moderate-to-severe AD experienced sustained improvement in disease control, symptoms, and quality of life up to 2 years after initiating dupilumab treatment. Safety data were consistent with the known safety profile of dupilumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03428646. Video abstract (MP4 20,717 kb).

Atopic dermatitis (AD) is a long-term disease that affects the skin of patients, causing rash, inflammation, and intense itching, all leading to profound negative effects on their quality of life. In short-term studies, dupilumab has been shown to improve the signs and symptoms of AD, and to improve patients' quality of life. However, there is currently little information about the effectiveness of dupilumab when patients use it over the long term in the real world. This study used data from the ongoing PROSE registry, which is collecting information on 764 adults and adolescents (aged ≥ 12 years) with moderate-to-severe AD who are using dupilumab in the real world; patients were allowed to use other AD treatments and could even stop using dupilumab. Most patients (83%) were evaluated after 2 years of treatment. The study looked at how physicians judged changes over time in the severity of patients' AD. Importantly, it also used measures to allow patients themselves to report how they felt treatment affected their AD, the amount of itch they experienced, and their quality of life. Improvements in the severity of AD were already seen at 3 months, and they were maintained over the 2-year period. Patients also reported consistent and sustained improvements in their AD symptoms and quality of life during the 2 years of treatment. This analysis shows that patients with AD who began dupilumab treatment can have sustained long-term improvements.

Type 2 cytokines sensitize human sensory neurons to itch-associated stimuli.

Introduction: Chronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Methods: We measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing. Results: Type 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and non-type 2 inflammatory stimuli. Discussion: This study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons.

Baseline Demographics and Severity and Burden of Atopic Dermatitis in Adult Patients Initiating Dupilumab Treatment in a Real-World Registry (PROSE).

INTRODUCTION: Dupilumab was initially approved in 2017 as the first biologic therapy for atopic dermatitis (AD). We characterized adults with AD initiating dupilumab in a real-world setting in the USA/Canada. METHODS: PROSE is an ongoing, longitudinal, prospective, observational, multicenter registry of patients with AD initiating dupilumab per country-specific prescribing information. We report baseline data (day of first dupilumab injection) for patients enrolled from April 2018 through July 2019. RESULTS: Among 315 patients (mean age 42.5 years, 55.2% female), the median AD duration was 17.0 years; 65.4% reported a history of type 2 inflammatory comorbidities (e.g., allergic rhinitis, asthma), and 93.3% reported treatment(s) for AD in the previous year, including topical corticosteroids (90.8%), systemic corticosteroids (36.2%), and nonsteroidal systemic therapies (14.0%). In total, 89.2% had an Overall Disease Severity score of 3 (moderate) or 4 (severe). Other mean disease severity scores included the following: Eczema Area and Severity Index 16.9 (range 0-72), body surface area affected 26.8%, Patient-Oriented Eczema Measure 18.5 (range 0-28), Dermatology Life Quality Index 12.7 (range 0-30), and pruritus Numerical Rating Scale score 6.9 (range 0-10). CONCLUSION: Patients initiating dupilumab have longstanding moderate-to-severe AD with significant disease burden and frequent type 2 comorbidities. GOV IDENTIFIER: NCT03428646.

The Use of Real-World Data to Evaluate the Association Between Atopic Dermatitis and Cardiovascular Disease: A Retrospective Claims Analysis.

INTRODUCTION: Atopic dermatitis (AD) is a systemic inflammatory condition that may increase the risk of cardiovascular disease (CVD); however, ongoing debate exists surrounding its direct association. We aimed to elucidate whether AD contributes to a higher incidence of CVD and major adverse cardiovascular events (MACE) in adult patients with AD, independent of metabolic disorders. METHODS: We retrospectively analyzed a large US-based population of patients with AD (≥ 18 years of age). Logistic regression estimated the risk of CVD and MACE in adult patients with AD, independent of metabolic disorders (including diabetes, hypertension, and obesity). RESULTS: The odds ratio (OR; 95% confidence interval [CI]) for patients without metabolic disorders was 1.25 (1.13, 1.39) for CVD and 1.22 (1.01, 1.47) for MACE. The OR (95% CI) for AD patients with metabolic disorders was 1.09 (1.07, 1.12) for CVD and 1.14 (1.09, 1.18) for MACE. This trend was even more pronounced after long-term follow-up (≥ 3 years). Lifestyle and health behavioral factors of the subjects were not available in the dataset. The lack of control for these factors could potentially confound our results. CONCLUSIONS: Atopic dermatitis may contribute to the risk of developing CVD and MACE in adults, independent of metabolic disorders.

Real-world persistence with dupilumab among adults with atopic dermatitis.

BACKGROUND: The real-world persistence with dupilumab therapy for atopic dermatitis (AD) is unknown. OBJECTIVE: To characterize adults with AD who initiated dupilumab and evaluate persistence with dupilumab therapy. METHODS: This retrospective cohort study used the IBM MarketScan Commercial and Medicare database. Adults with AD who initiated dupilumab (first dispensation = index date) between March 28, 2017, and March 31, 2018, were identified and followed up until September 30, 2018, or disenrollment. Twelve months of continuous preindex enrollment were required to characterize baseline treatment history and comorbidities. Kaplan-Meier analysis was used to estimate dupilumab persistence at 6 and 12 months, assuming a 14-day injection frequency and a 30-day grace period. RESULTS: A total of 1963 adults were identified who initiated dupilumab (mean [SD] age 42.1 [15.7] years; 50.7% women; 49.8% with ≥1 atopic comorbidity). Baseline AD treatments included topical corticosteroids (81.6%), systemic corticosteroids (72.5%), and systemic immunosuppressants (22.8%). Dupilumab persistence (95% confidence interval) at 6 and 12 months was 91.9% (90.7%-93.2%) and 77.3% (75.0%-79.7%), respectively. Among 329 patients who discontinued dupilumab, the risk of reinitiation was 78.8% (95% confidence interval: 75.8%-81.7%) within an average of 4 months. CONCLUSION: Dupilumab persistence at 12 months was high, suggesting patient satisfaction with effectiveness, tolerability, and treatment regimen.

Topical Treatment of Onychomycosis and Clinically Meaningful Outcomes.

BACKGROUND: Although a completely normal nail would be the ideal outcome when treating onychomycosis, this is not always achievable and long treatment courses or patient expectations can impact patient adherence. METHODS: We analyzed cure rates from a number of subpopulations derived from the two pivotal phase III studies with efinaconazole topical solution (10%) to provide some insights into clinically meaningful treatment outcomes and support for effective long-term management programs. RESULTS: Efinaconazole affords greater efficacy in milder disease, female patients, and those patients whose disease is relatively recent and confined to the great toenail, following 48 weeks' treatment. With longer treatment courses, similar results may be achieved in other subpopulations. Clinically meaningful results (a 40% improvement in the involvement of the diseased nail) were achieved with efinaconazole within six months in half the patients treated, and in over 90% of patients by study end. A greater proportion of female patients achieved clinically meaningful results at six months, although treatment success did not seem to be influenced by baseline disease severity. CONCLUSIONS: The majority of patients treated with efinaconazole could expect to see clinically meaningful results within six months.

J Drugs Dermatol. 2016;15(10):1260-1266.

Topical Treatment for Onychomycosis: Is it More Effective than the Clinical Data Suggests?

Background: The current definition of complete cure is considered too stringent to reflect the true benefit of onychomycosis treatment seen in general practice and may limit the use of newer topical agents in mild-to-moderate disease. In addition, outcomes reported in clinical trials do not consistently report secondary endpoints, making data comparison difficult. Methods: The authors review the clinical data reported on two new topical antifungals, efinaconazole and tavaborole, in light of the latest thinking of more practical approaches to assess improvement and treatment success. Results: Almost 20 percent (19.7%) of patients treated with efinaconazole had absence of clinical signs, and almost a third (31.6%) had ≤10 percent affected toenail and mycologic cure at Week 52. Cure rates for tavaborole (<10% affected toenail and mycologic cure) were 15.3 percent and 17.9 percent at week 52. With both topical treatments, cure rates were higher when only negative culture was considered. Conclusion: These clinical cure rates likely better reflect the efficacy we see in practice. It is probable that efficacy would be further improved with longer treatment courses and/or longer follow-up periods and appropriate prophylactic strategies. This clinical judgment is predicated by any risk of nonadherence or disease recurrence.

Sub-group Analyses from a Trial of a Fixed Combination of Clindamycin Phosphate 1.2% and Benzoyl Peroxide 3.75% Gel for the Treatment of Moderate-to-severe Acne Vulgaris.

BACKGROUND: Acne vulgaris is commonplace and can be difficult to manage. Providing an effective and well-tolerated treatment may lead to improved adherence, increased patient satisfaction, and improved clinical outcomes. METHODS: A review of efficacy, safety, and cutaneous tolerability of clindamycin phosphate 1.2%-benzoyl peroxide 3.75% gel in 498 patients with moderate-to-severe acne vulgaris enrolled in a multicenter Phase III study randomized to receive active or vehicle once daily for 12 weeks, including the most recent post-hoc analyses. RESULTS: Significantly superior reductions in lesion counts were observed with clindamycin phosphate 1.2%-benzoyl peroxide 3.75% gel from Week 4, with median percent reductions in inflammatory and noninflammatory lesions from baseline of 68.4 and 57.9 percent, respectively (bothp<0.001 versus vehicle). More than half (55.1%) of the severe acne vulgaris patients treated with clindamycin phosphate 1.2%-benzoyl peroxide 3.75% gel achieved ≥2-grade improvement from baseline in their Evaluator's Global Severity Score, and almost a third of the adolescent acne vulgaris patients (32.4%) achieved at least a marked improvement in their acne vulgaris as early as Week 2. In adult female acne overall treatments success was achieved in 52.7 percent of patients treated with clindamycin phosphate 1.2%-benzoyl peroxide 3.75% gel. Overall, and in the specific subpopulations, clindamycin phosphate 1.2%-benzoyl peroxide 3.75% gel was well-tolerated with a similar adverse event profile to vehicle. LIMITATIONS: Post-hoc analyses from a single clinical trial with demographic imbalances that could potentially confound the results. CONCLUSION: Clindamycin phosphate 1.2%-benzoyl peroxide 3.75% gel appears to be effective in treating acne across various clinically relevant sub-groups.

Prognostic Factors for Complete Cure Following Treatment of Mild and Moderate Toenail Onychomycosis With Efinaconazole Topical Solution 10.

OBJECTIVE: To identify those patients who are more likely to achieve treatment success with efinaconazole topical solution 10% based on clinical improvement and mycological status during treatment. METHODS: A subgroup analysis of patients, aged 18 to 70 years, randomized to receive efinaconazole topical solution 10% or vehicle from 2 identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point, complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52 was evaluated based on mycologic cure at week 24, and the degree of clinical improvement in nail involvement at week 12. RESULTS: Over a quarter (25.1%) of patients treated with efinaconazole topical solution 10% who could demonstrate at least 10% improvement in affected nail involvement by week 12 progressed to complete cures at week 52. Similarly, 21.7% of patients who demonstrated mycologic cure at week 24 achieved complete cures at week 52. CONCLUSIONS: Early clinical improvement and mycologic clearance may help to predict treatment success with efinaconazole topical solution 10%.

More money, fewer lives: the cost effectiveness of welfare reform in the United States.

OBJECTIVES: We evaluated the economic benefits of Temporary Assistance to Needy Families (TANF) relative to the previous program, Aid to Families with Dependent Children (AFDC). METHODS: We used pooled mortality hazard ratios from 2 randomized controlled trials-Connecticut Jobs First and the Florida Transition Program, which had follow-up from the early and mid-1990s through December 2011-and previous estimates of health and economic benefits of TANF and AFDC. We entered them into a Markov model to evaluate TANF's economic benefits relative to AFDC and weigh them against the potential health threats of TANF. RESULTS: Over the working life of the average cash assistance recipient, AFDC would cost approximately $28000 more than TANF from the societal perspective. However, it would also bring 0.44 additional years of life. The incremental cost effectiveness of AFDC would be approximately $64000 per life-year saved relative to TANF. CONCLUSIONS: AFDC may provide more value as a health investment than TANF. Additional attention given to the neediest US families denied cash assistance could improve the value of TANF.

A Randomized, Double-blind, Vehicle-controlled Trial of Luliconazole Cream 1% in the Treatment of Interdigital Tinea Pedis.

OBJECTIVE: To evaluate the efficacy and safety of luliconazole cream 1% applied once daily for 14 days in patients with interdigital tinea pedis. DESIGN: Multicenter, randomized, double-blind, parallel-group, vehicle-controlled study. SETTING: Private dermatology clinics and clinical research centers in the United States and Central America. PARTICIPANTS: Three hundred twenty-two male and female patients ≥12 years of age diagnosed with interdigital tinea pedis. MEASUREMENTS: Complete clearance (i.e., clinical and mycological cure), effective treatment, and fungal culture and susceptibility. RESULTS: At study Day 42, complete clearance was obtained by a larger percentage (14.0% [15/107] vs. 2.8% [3/107]; p<0.001) of patients treated with luliconazole cream 1% compared with vehicle. Also at Day 42, more luliconazole-treated patients compared with vehicle-treated patients obtained effective treatment (32.7% vs. 15.0%), clinical cure (15.0% vs. 3.7%), and mycologic cure (56.1% vs. 27.1%). Erythema, scaling, and pruritus scores were lower for the luliconazole cream 1% group compared with vehicle on Day 14, Day 28, and Day 42. For all species and the same isolates, the MIC50/90 for luliconazole cream 1% was 6- to 12-fold lower than for other agents tested. No patients discontinued treatment because of a treatment-emergent adverse event. CONCLUSION: Luliconazole cream 1% was safe and well-tolerated and demonstrated significantly greater efficacy than vehicle cream in patients with interdigital tinea pedis.

Penetration of ((14)C)-Efinaconazole Topical Solution, 10%, Does Not Appear to be Influenced by Nail Polish.

Onychomycosis is a common nail disorder with significant medical impacts and aesthetic consequences. Patients seek treatment for several reasons, including the unsightliness of the nail(s). Even with successful management, it takes months for the diseased nail to appear cosmetically normal. Patients commonly apply nail polish to mask the appearance of the dystrophic nail, though it is contraindicated with the currently available topical lacquers for onychomycosis. The authors' nonclinical study using a cadaver nail model showed that penetration of efinaconazole topical solution, 10%, a new antifungal being developed for the treatment of mild-to-moderate toenail onychomycosis, was not influenced by application of nail polish. Polishes showed an increase in surface tackiness with repeated efinaconazole topical solution, 10% application. The medical and aesthetic significance of the authors' findings have yet to be assessed clinically.

An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the once-daily treatment of moderate to severe acne vulgaris.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of a fixed combination clindamycin phosphate 1.2% and benzoyl peroxide 3.75% (clindamycin-BP 3.75%) aqueous gel in moderate to severe acne vulgaris. METHODS: A total of 498 patients, 12-40 years of age, were randomized to receive clindamycin-BP 3.75% or vehicle in a double-blind, controlled 12-week, 2-arm study evaluating safety and efficacy using inflammatory and noninflammatory lesion counts, Evaluator Global Severity Scores (EGSS) and subject self-assessment (SSA). In addition, patients completed a patient satisfaction survey (PSS), acne-specific QoL questionnaire, and assessed their facial skin for shininess/oiliness. RESULTS: Clindamycin-BP 3.75% demonstrated statistical superiority to vehicle in reducing both inflammatory and noninflammatory lesions and acne severity. Clindamycin-BP 3.75% showed greater efficacy relative to vehicle in assessments of skin oiliness, SSA and PSS. No substantive differences were seen in cutaneous tolerability among treatment groups and no patients discontinued treatment with Clindamycin-BP 3.75% because of adverse events. LIMITATIONS: Data from controlled studies may differ from clinical practice. It is not possible to determine the contributions from the individual active ingredients. CONCLUSIONS: Clindamycin-BP 3.75% provides statistically significant greater efficacy than vehicle with a favorable safety and tolerability profile.

Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial.

OBJECTIVE: This article presents the results from a prospective, randomized, double-blind, placebo-controlled trial of escitalopram in adolescent patients with major depressive disorder. METHOD: Male and female adolescents (aged 12-17 years) with DSM-IV-defined major depressive disorder were randomly assigned to 8 weeks of double-blind treatment with escitalopram 10 to 20 mg/day (n = 155) or placebo (n = 157). The primary efficacy parameter was change from baseline to week 8 in Children's Depression Rating Scale-Revised (CDRS-R) score using the last observation carried forward approach. RESULTS: A total of 83% patients (259/312) completed 8 weeks of double-blind treatment. Mean CDRS-R score at baseline was 57.6 for escitalopram and 56.0 for placebo. Significant improvement was seen in the escitalopram group relative to the placebo group at endpoint in CDRS-R score (-22.1 versus -18.8, p =.022; last observation carried forward). Adverse events occurring in at least 10% of escitalopram patients were headache, menstrual cramps, insomnia, and nausea; only influenza-like symptoms occurred in at least 5% of escitalopram patients and at least twice the incidence of placebo (7.1% versus 3.2%). Discontinuation rates due to adverse events were 2.6% for escitalopram and 0.6% for placebo. Serious adverse events were reported by 2.6% and 1.3% of escitalopram and placebo patients, respectively, and incidence of suicidality was similar for both groups. CONCLUSIONS: In this study, escitalopram was effective and well tolerated in the treatment of depressed adolescents.

Randomized placebo-controlled trial of escitalopram and venlafaxine XR in the treatment of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a highly prevalent and disabling condition. Escitalopram and venlafaxine extended release (XR) both are indicated for the treatment of GAD. Outpatients (ages 18-65 years) with DSM-IV-defined GAD (Hamilton Anxiety Scale [HAMA] >or=20) were eligible to participate in this randomized, double-blind, placebo-controlled, multicenter, flexible-dose trial. Following randomization, patients received 8 weeks of double-blind treatment with escitalopram (10-20 mg/day; N=127), venlafaxine XR (75-225 mg/day; N=129), or placebo (N=136). The primary efficacy parameter was mean change from baseline at week 8 in HAMA total score, using the Last Observation Carried Forward (LOCF) approach. Secondary efficacy parameters were HAMA psychic anxiety subscale, Clinical Global Impressions of Severity (CGI-S) and Improvement (CGI-I) scales. Treatment was completed by 77% of patients. The least square mean difference for change from baseline at week 8 in HAMA total score for escitalopram and venlafaxine XR versus placebo were -1.52 (P=.09) and -2.27 (P=.01), respectively, for LOCF, and -1.92 (P=.033) and -3.02 (P=.001), respectively, for Observed Cases (OC). On all secondary parameters, both active treatments were significantly superior to placebo on the LOCF and OC analyses. Discontinuation due to adverse events was not different for escitalopram versus placebo (7 versus 5%, P=.61), but was significantly greater for venlafaxine XR (13%) versus placebo (P=.03). Venlafaxine XR, but not escitalopram, separated from placebo on the primary efficacy measure, using the LOCF approach. However, overall efficacy analyses suggest that escitalopram and venlafaxine XR are both effective treatments for GAD. Escitalopram was better tolerated.

Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study.

Escitalopram has been shown in clinical trials to improve anxiety symptoms associated with depression, panic disorder, and social anxiety disorder. This study was designed to evaluate the efficacy and tolerability of escitalopram in the treatment of generalized anxiety disorder (GAD). Outpatients (18 years or older) who met DSM-IV criteria for GAD, with baseline Hamilton Rating Scale for Anxiety (HAMA) scores > or = 18, were randomly assigned to double blind treatment with escitalopram (10 mg/day for the first 4 weeks and then flexibly dosed from 10-20 mg/day) or placebo for 8 weeks, following a 1-week, single-blind, placebo lead-in period. The primary efficacy variable was the mean change from baseline in total HAMA score at Week 8. The escitalopram group (N = 158) showed a statistically significant, and clinically relevant, greater improvement at endpoint compared with placebo (N = 157) in all prospectively defined efficacy parameters. Significant improvement in HAMA total score and HAMA psychic anxiety subscale score for the escitalopram-treated group vs. the placebo-treated group was observed beginning at Week 1 and at each study visit thereafter. Mean changes from baseline to Week 8 on the HAMA total score using a last-observation-carried-forward (LOCF) approach were -11.3 for escitalopram and -7.4 for placebo (P<.001). Response rates at Week 8 were 68% for escitalopram and 41% for placebo (P<.01) for completers, and 58% for escitalopram and 38% for placebo LOCF values (P<.01). Treatment with escitalopram was well tolerated, with low rates of reported adverse events and an incidence of discontinuation due to adverse events not statistically different from placebo (8.9% vs. 5.1%; P=.27). Escitalopram 10-20 mg/day is effective, safe, and well tolerated in the treatment of patients with GAD.

Effects of prostratin on T-cell activation and human immunodeficiency virus latency.

Human immunodeficiency virus (HIV) replication is linked to cellular gene transcription and requires target cell activation. The latent reservoir of HIV-1 in quiescent T cells is thought to be a major obstacle to clearance of infection by highly active antiretroviral therapy (HAART). Thus, identification of agents that can induce expression of latent virus may, in the presence of HAART, allow elimination of the infected cells by the immune response. We previously used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis. Latently infected mature thymocytes can be exported into the periphery, providing an efficient primary cell model to determine cellular activation signals that induce renewed expression of latent virus. Here we characterized the effects of prostratin, a non-tumor-promoting phorbol ester, on primary human peripheral blood lymphocytes (PBLs) and assessed its ability to reactivate latent HIV infection from thymocytes and PBLs in the SCID-hu (Thy/Liv) model. Prostratin stimulation alone did not induce proliferation of quiescent PBLs; however, it could provide a secondary signal in the context of T-cell receptor stimulation or a primary activation signal in the presence of CD28 stimulation to induce T-cell proliferation. While prostratin alone was not sufficient to allow de novo HIV infection, it efficiently reactivated HIV expression from latently infected cells generated in the SCID-hu mouse. Our data indicate that prostratin alone is able to specifically reactivate latent virus in the absence of cellular proliferation, making it an attractive candidate for further study as an adjunctive therapy for the elimination of the latent HIV reservoir.

Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials.

BACKGROUND: Citalopram is a racemic selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of depression. Citalopram is a racemate and its serotonin reuptake inhibitory activity resides primarily in the single S-isomer, escitalopram, which is now being evaluated for its potential usefulness in the treatment of depression and other psychiatric disorders. RESULTS from placebo-controlled studies that also included citalopram as an active control have shown that escitalopram is effective in treating depression and associated symptoms of anxiety. However, none of these studies was powered sufficiently to detect differences between active treatment groups. The goal of the present analysis is to evaluate the efficacy of escitalopram compared with citalopram in the treatment of major depressive disorder. METHOD: Data were pooled from three similarly designed, randomized, double-blind, placebo-controlled trials of escitalopram (10-20 mg/day) and citalopram (20-40 mg/day). Patients were male or female, greater than or equal to 18 years of age, who met criteria for a major depressive episode with a Montgomery Asberg Depression Rating Scale (MADRS) score greater than or equal to 22 at baseline. Efficacy measures included change from baseline in MADRS score and the Clinical Global Impression of Improvement (CGI-I) scale. Improvement in associated symptoms of anxiety was measured using the change from baseline in the MADRS inner tension item. RESULTS: Both escitalopram and citalopram significantly improved depression and anxiety symptoms compared with placebo, and there were significantly more MADRS responders (defined as >/=50% improvement in MADRS scores at end point) in the escitalopram and citalopram treatment groups. Escitalopram treatment was associated with statistically significant improvements in all efficacy measures relative to placebo after 1 week of treatment, whereas citalopram treatment statistically separated from placebo at the end of week 4 (CGI-I and MADRS inner tension) or week 6 (MADRS). Escitalopram treatment also was statistically significantly superior to citalopram treatment at a number of time points. CONCLUSION: These data support the effectiveness of escitalopram and citalopram in the treatment of major depressive disorder, and suggest escitalopram may have a faster onset and greater overall magnitude of effect than citalopram in improving symptoms of depression and anxiety in patients with major depressive disorder.