Association of Bowel Urgency With Quality-of-Life Measures in Patients With Moderately-to-Severely Active Ulcerative Colitis: Results From Phase 3 LUCENT-1 (Induction) and LUCENT-2 (Maintenance) Studies.

Background: Improvement in bowel urgency (BU) was associated with better clinical outcomes in phase 3 LUCENT-1 (induction) and LUCENT-2 (maintenance) studies in moderately-to-severely active ulcerative colitis (UC). We assessed association of BU with quality-of-life (QoL) outcomes. Methods: LUCENT-1: 1162 patients randomized 3:1 to intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W) for 12 weeks. LUCENT-2: 544 mirikizumab induction responders re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo Q4W through Week (W) 40 (W52 of continuous treatment). Patients reported BU severity in the past 24 hours using a validated Urgency Numeric Rating Scale (NRS). In patients with baseline Urgency NRS ≥3, the association between BU Clinically Meaningful Improvement (CMI; ≥3-point decrease) and remission (score 0 or 1) with patient-reported outcomes was assessed at W12 and W52. Results: A significantly greater proportion of patients with versus without BU Remission achieved IBDQ remission (W12: 87.3% vs 42.7%, P < .0001; W52: 91.4% vs 45.5%, p < .0001). Similarly, BU Remission was associated with more patients achieving CMI in SF-36 Physical Component Summary (W12: 69.0% vs 44.4%, P < .0001; W52: 77.5% vs 42.1%, P < .0001) and Mental Component Summary (W12: 53.5% vs 41.0%, P = .0019; W52: 62.0% vs 38.3%, P < .0001) scores. At W12 and W52, patients with BU CMI or Remission showed significant improvements in EQ-5D-5L and Work Productivity and Activity Impairment:UC scores. Significant improvements were also seen in fatigue, abdominal pain, and nocturnal stool. Conclusions: In patients with moderately-to-severely active UC, improvement in BU was associated with improved QoL in phase 3 LUCENT-1 and LUCENT-2 studies. Clinical Studies: LUCENT-1: NCT03518086; LUCENT-2: NCT03524092.

Extended Induction and Prognostic Indicators of Response in Patients Treated with Mirikizumab with Moderately to Severely Active Ulcerative Colitis in the LUCENT Trials.

BACKGROUND: Efficacy and safety of mirikizumab, a p19-targeted anti-interleukin-23 monoclonal antibody, for moderately to severely active ulcerative colitis was demonstrated previously. We evaluated clinical response, baseline characteristics, and clinical status in patients not responding by 12 weeks (W) of induction who then received extended induction treatment. METHOD: Patients unresponsive to 300 mg of intravenous (IV) mirikizumab every 4 weeks by W12 received 3 additional 300 mg IV doses every 4 weeks. Week-4 responders received 200 mg mirikizumab every 4 weeks subcutaneously until W52. Patients responding by W12 but subsequently losing response received rescue therapy with 300 mg IV for 3 doses every 4 weeks. Logistic regression modelling was performed for patients not achieving W12 clinical response to assess baseline characteristics and W12 efficacy parameters and potential prognostic factors of clinical response at W24. RESULTS: Of patients not achieving clinical response during induction, 53.7% achieved response following extended induction. After 52W, 72.2%, 43.1%, and 36.1% of patients achieved clinical response, endoscopic, and clinical remission, respectively. Of induction responders who subsequently lost response, 63.2% and 36.8% achieved symptomatic response and remission, respectively, after receiving rescue therapy No prior biologic or tofacitinib treatment, no immunomodulators at baseline, age older than 40 years, and W12 modified Mayo Score improvement were positively associated with a response to extended induction. The safety profile was similar to initial induction, with 38.3% treatment emergent adverse events, mostly mild. CONCLUSION: With "extended induction," total of 80.3% mirikizumab-treated patients achieved clinical response by W24. Potential prognostic factors determining response include disease severity, disease phenotype, C-reactive protein, and previous biologic therapy.

Extended induction with mirikizumab led to clinical response in more than half of primary nonresponders. Intravenous reinduction therapy in patients losing response during treatment led to more than 60% achieving symptomatic response, confirming the clinical benefit of these treatment strategies for harder to treat patients.

Executive Functioning Outcomes Over 6 Months of Atomoxetine for Adults With ADHD: Relationship to Maintenance of Response and Relapse Over the Subsequent 6 Months After Treatment.

Objective: This study examines the relationship between maintenance of improved executive functioning (EF) in adults with ADHD with long-term symptom improvement with atomoxetine. Method: Data were collected from a yearlong, double-blind, placebo-controlled clinical study on adult patients with ADHD receiving atomoxetine (80-100 mg/day) for 24 weeks. Patients were then randomized to continue atomoxetine or placebo for 6 months. Executive functioning was rated with Behavior Rating Inventory of Executive Function-Adult Version: Self-Report™ (BRIEF-A: Self-Report™), and the T-scores were determined. Results: Postrandomization T-scores for atomoxetine patients were significantly better than those of placebo patients (3 and 6 months postrandomization). Patients with greater improvements in EF were more likely to show worsening of EF and to relapse after atomoxetine discontinuation. The maintenance of improved EF was significantly associated with improved ADHD symptoms (Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version [CAARS-Inv:SV] with adult prompts). Conclusion: Treatment with atomoxetine improved EF during the treatment phases. Improved EF was maintained up to 6 months after discontinuation of atomoxetine.

Analysis of HAM-D scores and working ability in an observational study of Japanese patients with major depressive disorder and painful physical symptoms treated with duloxetine or SSRI monotherapy.

OBJECTIVE: To investigate the relationship between Hamilton Depression Rating Scale (HAM-D) score and psychiatrists' judgment of working ability in patients with major depressive disorder (MDD) and painful physical symptoms. METHODS: This was a prospective, observational, 12-week study in patients who received duloxetine or a selective serotonin reuptake inhibitor. Patients were ≥20 years old, resided in Japan, and had at least moderate depression (Quick Inventory of Depressive Symptomatology ≥16) and at least moderate painful physical symptoms (Brief Pain Inventory-Short Form average pain ≥3). The main outcome in this post-hoc analysis was the HAM-D17 cutoff best corresponding with patients' working ability according to the investigator's judgment. Area under the receiver-operator curve was used to determine the time point with the strongest relationship between HAM-D17 and working ability. The optimal HAM-D17 cutoff was determined based on the maximum of sensitivity (true positive rate) minus ([1 minus specificity] [true negative rate]). For the evaluation of binary data, a mixed effects model with repeated measures analysis was used. RESULTS: For the estimation of the HAM-D17 cutoff, the area under the receiver-operator curve was maximal at 12 weeks, when a HAM-D17 score of 6 resulted in the best correspondence with working ability in the combined study population. At 12 weeks, a HAM-D17 score of 6 also resulted in the maximum predictive ability in each of the two treatment groups separately. For predicted working ability at 12 weeks, 52.7% of duloxetine-treated patients achieved the HAM-D17 cutoff of ≤6, whereas 48.5% of SSRIs-treated patients achieved HAM-D17 ≤6 (P=0.477). CONCLUSION: In this study of patients with major depressive disorder and painful physical symptoms, a HAM-D17 score ≤6 corresponded best with patients' working ability. This finding is consistent with previous studies showing that a HAM-D17 cutoff of ≤7 may overestimate functional recovery from MDD.

An observational study of duloxetine versus SSRI monotherapy in Japanese patients with major depressive disorder: subgroup analyses of treatment effectiveness for pain, depressive symptoms, and quality of life.

OBJECTIVE: To examine how clinical and demographic patient baseline characteristics influence effectiveness of duloxetine versus selective serotonin reuptake inhibitor (SSRI) treatment, in real-world Japanese clinical settings of patients with major depressive disorder (MDD) and associated painful physical symptoms (PPS). METHODS: This was a multicenter, 12-week, prospective, observational study in patients with MDD (Quick Inventory of Depressive Symptomatology ≥16) and at least moderate PPS (Brief Pain Inventory-Short Form [BPI-SF] average pain ≥3). Patients received duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine). Assessments were made by using BPI-SF average pain, 17-item Hamilton Rating Scale for Depression (HAM-D17), EuroQol 5-dimension questionnaire, Social Adaptation Self-Evaluation Scale, Global Assessment of Functioning, and ability to work. Predefined subgroups included the number of previous episodes of depression (0 vs ≥1), baseline BPI-SF average pain score (≤6 vs >6), baseline HAM-D17 total score (≤18 vs >18), baseline HAM-D17 retardation (≤7 vs >7) and anxiety somatic subscale scores (≤6 vs >6), and age (<65 vs ≥65 years). RESULTS: Treatment effectiveness was evaluated in 523 patients (duloxetine N=273, SSRIs N=250). Treatment with duloxetine was superior to SSRIs on most outcome measures in patients experiencing their first depressive episode, those with higher baseline PPS levels, and in patients with more severe baseline depression. This was also the case for older patients. In patients with less severe depression, SSRI treatment tended to show more improvements in depression and quality of life measures versus duloxetine treatment. CONCLUSION: These preplanned subgroup analyses of data from a prospective observational study suggest that, for Japanese MDD patients with PPS, duloxetine is more effective than SSRIs in patients with a first episode of MDD, with more severe depression, or more severe PPS.

An observational study of duloxetine versus SSRI monotherapy for the treatment of painful physical symptoms in Japanese patients with major depressive disorder: primary analysis.

OBJECTIVE: The objective of this study was to assess the effectiveness of duloxetine monotherapy, in comparison with selective serotonin reuptake inhibitor (SSRI) monotherapy, in the treatment of painful physical symptoms (PPS) in Japanese patients with major depressive disorder (MDD) in real-world clinical settings. METHODS: This was a multicenter, 12-week prospective, observational study. This study enrolled MDD patients with at least moderate PPS, defined as a Brief Pain Inventory-Short Form (BPI-SF) average pain score (item 5) ≥3. Patients were treated with duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine) for 12 weeks, and PPS were assessed by BPI-SF average pain score. The primary outcome was early improvement in the BPI-SF average pain score at 4 weeks post-baseline. RESULTS: A total of 523 patients were evaluated for treatment effectiveness (duloxetine N=273, SSRIs N=250). The difference in BPI-SF average pain score between the two groups was not statistically significant at 4 weeks post-baseline, the primary endpoint (least-squares mean change from baseline [95% confidence interval]: duloxetine, -2.8 [-3.1, -2.6]; SSRIs, -2.5 [-2.8, -2.3]; P=0.166). There was a numerical advantage for duloxetine in improvement from 4 to 12 weeks post-baseline, and the difference was statistically significant at 8 weeks post-baseline (least-squares mean change from baseline [95% confidence interval]: duloxetine, -3.6 [-3.9, -3.3]; SSRIs, -3.1 [-3.4, -2.8]; P=0.023). The 30% and 50% responder rates were significantly higher in patients treated with duloxetine at 4 and 8 weeks post-baseline. There were no serious adverse events experienced by duloxetine-treated patients. The rate of discontinuations due to adverse events was similar for duloxetine and the SSRIs (1.0% and 0.8% of patients, respectively). CONCLUSION: In this observational study, BPI-SF improvement was not significantly different at 4 weeks, the primary endpoint; however, patients treated with duloxetine tended to show better improvement in PPS compared to those treated with SSRIs.

Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine.

We identified relapse/maintenance-of-response (MOR) predictors following discontinuation of long-term atomoxetine treatment in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD) and assessed correlations between ADHD symptoms and quality of life (QoL). Post hoc analyses of data from two randomized, double-blind, placebo-controlled, phase 3 withdrawal studies in patients with ADHD meeting predefined response criteria before randomization. Study 1: patients (N = 163; 6-15 years) received atomoxetine (1.2-1.8 mg/kg/day) for 1 year, followed by randomization to atomoxetine (n = 81) or placebo (n = 82) for 6 months. Study 2: patients (N = 524; 18-50 years) received atomoxetine (80-100 mg/day) for ~6 months, followed by randomization to atomoxetine (n = 266) or placebo (n = 258) for ~6 months. Placebo patients were used for the analyses. Relapse: ≥50% worsening of prerandomization improvement in ADHD symptoms and ≥2 level severity increase on the Clinical Global Impression-Severity (CGI-S) scale at 2 consecutive visits; MOR: retaining ≥75% of prerandomization symptom improvement and CGI-S ≤ 2 at all visits (study 1); retaining ≥70% of prerandomization symptom improvement and CGI-S ≤ 3 at all visits (study 2). In adults, statistically significantly (P ≤ .05) increased likelihood of relapse was associated with prerandomization presence of Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items "difficulty awaiting turn" and "careless mistakes." In pediatric patients, less MOR was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item "does not listen"; in adults, less MOR was associated with prerandomization presence of CAARS-Inv:SV items "loses things" and "difficulty awaiting turn." Changes in patients' QoL after withdrawal from atomoxetine moderately correlated with changes in ADHD symptoms in pediatric patients and mildly in adults.

Text and Mobile Media Smoking Cessation Service for Young Adults in South Texas: Operation and Cost-Effectiveness Estimation.

To realize the promising potential of services delivered via smart phones to help young adults quit smoking at a high level of cost-efficiency, we constructed a texting and mobile media system that was promoted in South Texas via social media advertising and other recruitment channels. During the 6-month service period described here, enrollments were achieved for 798 participants with a mean age of 29.3 years. Seven-month texted follow-up found that 21% (171) of the enrollees reported abstinence at that point. This is consistent with high rates of success found in studies of telephone counseling for young adults and confirms that text and mobile media service specifically designed for young adults provide a feasible and potentially cost-effective approach to promoting cessation.

Assessment of effects of atomoxetine in adult patients with ADHD: consistency among three geographic regions in a response maintenance study.

A previous study (Upadhyaya et al. in Eur J Psychiatry 2013b; 27:185-205) reported that adults with attention-deficit/hyperactivity disorder (ADHD) demonstrated maintenance of response for up to 25 weeks after initially responding to atomoxetine treatment. In the present report, the consistency of treatment effect across three geographic regions (Europe, United States/Canada [US/Can], and Latin America [Latin Am]) was explored. Data were analyzed from a phase 3, multicenter, randomized, double-blind, maintenance-of-response (randomized withdrawal) trial of atomoxetine versus placebo in adults with ADHD. Patients were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks. Consistency assessments included the interaction test, pairwise t tests, noninferiority, and the criteria from Basic Principles on Global Clinical Trials (Ministry of Health, Labour and Welfare of Japan 2007). Atomoxetine-treated patients maintained the improved ADHD symptoms relative to placebo-treated patients on the Conners' Adult ADHD Rating Scale Investigator-Rated: Screening Version 18-Item (CAARS-Inv:SV) total score in all three regions (atomoxetine-placebo mean difference = -4.55, -3.18, and -0.07 for Europe, US/Can, and Latin Am, respectively). For the Latin Am region, the mean change in total score (0.41) was notably smaller for the placebo group than for Europe (5.87) and US/Can (4.39). Similar results were observed for the CAARS-Inv:SV hyperactivity/impulsivity and inattention subscale scores. Overall, patients maintained the response with atomoxetine treatment compared to placebo; however, the magnitude of treatment effect differed among the regions studied, being numerically higher in the EU and US/Can than Latin Am. Trial registration http://www.clinicaltrials.gov/(NCT00700427 ).

Documentación filmográfica de la ventilación mecánica en un modelo animal / Filmed documentation of mechanical ventilation in an animal model

Introducción: el aprendizaje de la ventilación mecánica (VM) pediátrica requiere de tiempo y diversas estrategias educativas. En los últimos años se han utilizado los videopodcast para la educación médica. Objetivos: documentación filmográfica de los elementos básicos de la mecánica respiratoria durante la VM en un modelo animal. Creación de un videopodcast para la formación de recursos humanos especializados en VM pediátrica. Metodología: se prepararon diferentes secuencias de VM con ventilador y en forma manual. Se realizó exposición pulmonar mediante toracotomía y VM convencional en un cerdo. Se grabó simultáneamente lo monitorizado por el ventilador y la visualización in vivo del pulmón expuesto ante cada secuencia. Dos especialistas en cuidados intensivos pediátricos analizaron durante la edición las grabaciones y confeccionaron un guión explicativo de lo observado. Resultados: se editó un video con las diferentes secuencias previstas: VM basal, VM sin presión positiva teleespiratoria (PEEP), VM con niveles incrementales de PEEP, VM con bolsa autoinflable, aspiración de sonda endotraqueal con circuito cerrado y abierto durante VM con ventilador y manual con operador. Se editó un videopodcast con leyendas explicativas. Discusión: la utilización de recursos digitales para la enseñanza y divulgación de diversas especialidades médicas es cada vez más frecuente. El videopodcast se ha expandido como una nueva herramienta educativa. Se construyó un modelo para la capacitación de los recursos humanos en VM mediante este formato. La experiencia servirá para construir una videoteca universitaria dirigida a la enseñanza de cuidados críticos del niño y para la divulgación de experimentos biomédicos.

Introduction: learning about mechanical ventilation (MV) in pediatrics requires time and several educational strategies. In recent years, videopodcast has been used for medical training. Objectives: to prepare a filmed documentary of the basic elements in respiratory mechanics during MV in an animal model. To create a videopodcast to train human resources specialized in MV in pediatrics. Material: different sequences of MV with ventilator and manual ventilation were prepared. Lungs were accessed through thoracotomy and MV was started in a pig. Monitored data from the ventilator was simultaneously recorded, the same as the live visualization of the visible lung for each sequence. Two specialists in pediatrics intensive care analysed the recording while it was edited and composed a script explaining what was observed. Results: a video was edited with the different sequences expected: basal MV, MV with zero PEEP, increasing PEEP levels, MV with self-inflating bag, traqueal suction with open and closed traqueal suction systems and manual ventilation with an operator. A videopodcast with explanatory subtitles was edited. Discussion: digital resources are increasingly being used to train physicians and disseminate several medical techniques. Today, videopodcast constitutes a new educational tool. A model was designed to train human resources in MV under this format. This experience will be used to build up a new university video library to assist the training in pediatric critical care and to disseminate biomedical experiments.

Treatment discontinuation and tolerability as a function of dose and titration of duloxetine in the treatment of major depressive disorder.

PURPOSE: We sought to better understand how dose and titration with duloxetine treatment may impact tolerability and treatment discontinuation in patients with major depressive disorder. PATIENTS AND METHODS: We investigated Phase III duloxetine trials. Group 1 was a single placebo-controlled study with a 20 mg initial dose and a slow titration to 40 and 60 mg. Group 2 was a single study with a 40 mg initial dose and final "active" doses of 40 and 60 mg (5 mg control group), with 1-week titration. Group 3 consisted of eight placebo-controlled studies with starting doses of 40, 60, and 80 mg/day with minimal titration (final dose 40-120 mg/day). Tolerability was measured by rate of discontinuation due to adverse events (DCAE). RESULTS: The DCAE in Group 1 were 3.6% in the 60 mg group, 3.3% in the 40 mg group, and 3.2% in the placebo group. In Group 2, the DCAE were 15.0% in the 60 mg group, 8.1% in the 40 mg group, and 4.9% in the 5 mg group. In Group 3, the DCAE were 9.7% and 4.2% in the duloxetine and placebo groups, respectively. CONCLUSION: This study suggests that starting dose and titration may have impacted tolerability and treatment discontinuation. A lower starting dose of duloxetine and slower titration may contribute to improving treatment tolerability for patients with major depressive disorder.

Time-to-onset and -resolution of adverse events before/after atomoxetine discontinuation in adult patients with ADHD.

BACKGROUND: Adults with attention-deficit/hyperactivity disorder treated with atomoxetine were examined for time-to-onset and -resolution of common treatment-emergent adverse events (TEAEs) and male sexual dysfunction, and for changes in blood pressure (BP) and heart rate (HR) upon atomoxetine discontinuation. METHODS: 12-week open-label atomoxetine (40-100 mg/day) was followed by 12-week double-blind maintenance treatment (atomoxetine 80 or 100 mg/day). Responders were then randomized to atomoxetine (n = 266) or placebo (n = 258) for 25-week randomized withdrawal. Examined were (1) median time-to-onset and -resolution of TEAEs during atomoxetine treatment, and (2) within group, visitwise mean changes for sitting HR, systolic BP, and diastolic BP for the postrandomization placebo group. RESULTS: Common adverse events (AEs) appeared early, within week 1 of atomoxetine treatment. Some AEs resolve relatively rapidly, whereas others have a more lingering course of resolution (including male sexual side effects); median resolution times were 3 - 53 days. BP and HR increases during atomoxetine treatment returned to baseline upon atomoxetine discontinuation. CONCLUSION: Atomoxetine is associated with common AEs, with 3- to 53-day median resolution times. TRIAL REGISTRATION: ClincialTrials.gov - NCT00700427.

Differences in maintenance of response upon discontinuation across medication treatments in attention-deficit/hyperactivity disorder.

The attention-deficit/hyperactivity disorder (ADHD) treatment literature has been focused on onset-of-effect and short-term effect size, with little exploration of ADHD symptoms upon medication discontinuation. The objective of this narrative review and analysis was to better understand the relapse of ADHD symptoms upon discontinuation of medication treatment in children, adolescents, and adults with ADHD who have responded to medication treatment and to explore differences among different medications in maintaining treatment response. Randomized withdrawal studies of dexmethylphenidate hydrochloride (d-MPH), methylphenidate modified-release (MPH-LA), lisdexamphetamine dimesylate (LDX), guanfacine extended-release (GXR), and atomoxetine (ATX) in both children/adolescents and adults with ADHD were reviewed. The percentage of relapse was significantly higher and the time-to-relapse significantly shorter with placebo compared to active treatment in patients who were previously stable on 5 weeks to 1 year of active treatment, suggesting clinically significant benefit with continued long-term pharmacotherapy. However, percentage of relapse at each time point studied after discontinuing stimulants and GXR appears substantially higher than observed when discontinuing ATX, suggesting longer maintenance of response after discontinuing ATX than after stimulants and GXR. Additionally, slope of relapse percentages over time appears to be more rapid with stimulants or GXR than with ATX. These differences in maintenance of response among ATX, GXR, and stimulants may reflect differences in mechanisms of action and persistence of the medication effect. Alternatively, they may be due to methodological differences, including study design and response/relapse definitions. Continued investigation is needed regarding factors that affect risk of symptom relapse upon discontinuation of pharmacotherapy.

Validation of the geriatric anxiety inventory in a duloxetine clinical trial for elderly adults with generalized anxiety disorder.

BACKGROUND: The Generalized Anxiety Inventory (GAI) has been developed for use in the assessment of anxiety symptoms in older adults (≥ 65 years), but previous validation work has not examined the psychometric qualities of the instrument in relation to treatment. The objective of this study was to examine the performance of the GAI for its internal reliability, convergent and divergent validity, and its sensitivity to treatment. METHODS: Elderly patients with generalized anxiety disorder (GAD) participated in a 10-week double-blind study of duloxetine treatment for patients with GAD. Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale (HAMA), the Hospital Anxiety and Depression Scale (HADS) anxiety and depression subscales, and the GAI. Internal reliability of the GAI was assessed with Cronbach's α. Correlations among the HAMA, HADS, and GAI scores were analyzed to determine convergent and divergent validity. Patients were also compared on remission status using recommended cut-off scores for the GAI. RESULTS: Patients with GAD, who were at least 65 years of age, were randomly assigned to double-blind treatment with either duloxetine (N = 151) or placebo (N = 140) for 10 weeks acute therapy. The mean change on the GAI was significantly greater with duloxetine compared with placebo treatment (-8.36 vs. -4.96, respectively, p ≤ 0.001). The GAI demonstrated good internal consistency, good convergent and divergent validity, but suggested cut-off values for caseness with the GAI did not correspond to remission status as measured by the HAMA. CONCLUSIONS: Within an elderly patient population with GAD, the GAI demonstrated sound psychometric qualities and sensitivity to change with treatment.

Efficacy comparison of duloxetine and SSRIs at doses approved in Japan.

BACKGROUND: Approved doses of antidepressants in Japan are usually lower than those in the USA and European Union, but to date meta-analyses comparing antidepressants have all used the higher doses approved in the USA and European Union and often have used indirect comparisons. The purpose of this study was to conduct an integrated database analysis of patient level data to compare the effects of duloxetine with those of selective serotonin reuptake inhibitors (SSRIs) at the doses approved in Japan. METHODS: Pooled data were analyzed from four randomized, double-blind, placebo-controlled studies that compared duloxetine at the dose range approved in Japan (40-60 mg/day) with other SSRIs (paroxetine 20 mg/day or escitalopram 10 mg/day) and placebo in patients with major depressive disorder. In total, 1,694 patients were included in the analysis (duloxetine, n=688; selective serotonin reuptake inhibitors, n=690; placebo, n=316). The primary outcome measure was the mean change from baseline at week 8 in 17-item Hamilton Rating Scale for Depression (HAMD17) total and subscale scores. RESULTS: Duloxetine and both selective serotonin reuptake inhibitors were superior to placebo in HAMD17 total score at week 8 in both the all-randomized group and the more severe subgroup (HAMD17 total scores ≥19). Duloxetine was superior to SSRIs in improving the HAMD17 Retardation subscale score (least squares mean difference [95% confidence interval]): all-randomized group, -0.33 [-0.60, -0.07], P=0.015; severe subgroup, -0.45 [-0.83, -0.07], P=0.020). CONCLUSION: Within the dose range approved in Japan for patients with major depressive disorder, duloxetine and selective serotonin reuptake inhibitors demonstrated comparable overall efficacy, with a possible advantage for duloxetine in improving loss of energy and interest. To the best of our knowledge, this analysis is unique not only in evaluating dosages specific to Japan, but also in using individual patient data and the same endpoint across studies to allow for strictly direct head-to-head data comparisons as opposed to pooling direct and indirect comparisons.

Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study.

We assessed the executive function in adults with attention-deficit/hyperactivity disorder (ADHD) during atomoxetine treatment in a randomized withdrawal trial. Responders (Conners' ADHD Rating Scale-Investigator Rated: Screening Version [adult prompts] ≥30% reduction from baseline and Clinical Global Impression Scale-ADHD Severity score ≤3) to open-label atomoxetine (40-100 mg/d, 12 weeks) entered a 37-week double-blind maintenance period. Patients who maintained response (double-blind atomoxetine for 12 weeks) were randomized 1:1 to atomoxetine (80-100 mg/d, n = 266) or placebo (n = 258) for 25 weeks (total duration, 1 year). Patients and investigators were blinded to response criteria and randomization timing. Change in executive function was assessed with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report and Informant T scores from the randomization to the last-observation-carried-forward postrandomization week 25 (after week 17). Of the enrolled patients (n = 2017; mean age, 33.2 years; male, 58.7%), 524 responders were randomized. During open-label atomoxetine, subscales and individual items on both BRIEF-A questionnaires showed significant improvement (P < 0.001). After randomization, the following T scores improved significantly (P ≤ 0.05) with patients in the atomoxetine group versus those in the placebo group: global executive composite, behavioral regulation, and metacognition indices; plan/organize, working memory, inhibit, task monitor and shift (both BRIEF-A questionnaires), emotional control and organization of materials (BRIEF-A Informant), and initiate (BRIEF-A Self-Report). Atomoxetine significantly improved the executive function compared with placebo, which was maintained for 25 weeks or more; the executive function of patients in the placebo group worsened but did not return to baseline levels after randomization.

Patency of skeletonized versus pedicled internal thoracic artery in coronary bypass graft surgery: a systematic review, meta-analysis and meta-regression.

BACKGROUND: It is suggested that the skeletonization harvesting technique influences the patency rates of internal thoracic artery (ITA) after coronary artery bypass graft (CABG) surgery in comparison to conventional (pedicled) harvesting. We conducted a meta-analysis to determine whether there is any difference between skeletonized versus pedicled ITA in terms of patency after CABG. METHODS: We performed a systematic-review using MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles to search for studies that performed angiographic evaluation within the first two years after CABG between these two groups until December 2013. The principal summary measures were odds ratio (OR) with 95% Confidence Interval (CI) and P values (statistically significant when <0.05). The OR's were combined across studies using weighted DerSimonian-Laird random effects model and weighted Mantel-Haenszel fixed effects. Meta-analysis, sensitivity analysis and meta-regression were completed using the software Comprehensive Meta-Analysis version 2 (Biostat Inc., Englewood, New Jersey). RESULTS: Five studies involving 1764 evaluated conduits (1145 skeletonized; 619 pedicled) met the eligibility criteria. There was no evidence for important heterogeneity of effects among the studies. The overall OR (95% CI) for graft occlusion showed no statistical significant difference between groups (fixed effect model: OR 1.351, 95% CI 0.408 to 4.471, P = 0.801; random effect model: OR 1.351, 95% CI 0.408 to 4.471, P = 0.801). In sensitivity analysis, no difference regarding to left or right ITA was also observed. In meta-regression, we observed no statistically significant coefficients for graft occlusion and proportion of female, diabetics, renal failure, age, off-pump surgery or urgency, which means that the effect is not modulated by these factors. CONCLUSION: In terms of patency, skeletonized ITA appears to be non-inferior in comparison to pedicled ITA after CABG.

Prognostic factors of improvement in health-related quality of life in atomoxetine-treated children and adolescents with attention-deficit/hyperactivity disorder, based on a pooled analysis.

The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR-QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or ≥5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74-1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (≥25 % reduction in ADHD Rating Scale scores in the first 4-6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99-6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD.

Pulmonary valve replacement after operative repair of tetralogy of Fallot: meta-analysis and meta-regression of 3,118 patients from 48 studies.

Because the real benefit of pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot who develop pulmonary insufficiency remains unclear, it is necessary to analyze the evidence published around the world. We performed a systematic review of studies that reported data about the effect of PVR in patients with repaired tetralogy of Fallot that developed pulmonary insufficiency, until December 2012. The variables chosen to represent the benefit were both right ventricular (RV) and left ventricular measures, QRS duration, and functional class. The principal summary measures were difference in means with 95% confidence interval and p values (considered statistically significant when p < 0.05). The differences in means were combined across studies with the weighted DerSimonian-Laird random effects model. Meta-analysis, sensitivity analysis, and meta-regression were completed with the software Comprehensive Meta-Analysis (version 2, Biostat, Inc., Englewood, New Jersey). Forty-eight studies involving 3,118 patients met the eligibility criteria. The pooled 30-day mortality was 0.87% (47 studies; 27 of 3,100 patients); the pooled 5-year mortality was 2.2% (24 studies; 49 of 2,231 patients); the pooled 5-year re-PVR was 4.9% (15 studies; 88 of 1,798 patients). The results of this meta-analysis demonstrate that after PVR: 1) the RV experiences improvement of its volumes and function; 2) the left ventricle experiences improvement of its function; 3) QRS duration decreases; 4) symptoms improve; 5) pre-operative RV geometry modulates the effect of PVR; and 6) there is important heterogeneity of the effects among the studies, and few publication biases. In conclusion, PVR seems to be a positive approach in the analyzed scenario.

Long-term quality-of-life and functioning comparison of atomoxetine versus other standard treatment in pediatric attention-deficit/hyperactivity disorder.

Psychopharmacological agents were shown to be important for improving the quality of life (QoL) of patients with attention-deficit/hyperactivity disorder (ADHD). A short-term, 10-week study found atomoxetine (ATX) to be effective in improving QoL of ADHD patients. We compared, for the first time, long-term treatment outcomes of ATX and other early standard therapy (OEST, any pharmacological ADHD treatment except ATX) in QoL and functional impairment in pharmacologically naive children/ adolescents in a randomized, controlled, open-label study at 6 and 12 months. Patients received ATX (0.5-1.8 mg/kg per day) or OEST (mainly methylphenidate). Quality of life and functioning were assessed by the Child Health and Illness Profile-Child Edition, Parent Rating Form and the Weiss Functional Impairment Rating Scale-Parent Report. Three hundred ninety-eight patients (79.4% male; mean age, 9.3 years) received study treatment. The Child Health and Illness Profile-Child Edition, Parent Rating Form achievement domain t scores significantly improved from baseline to 6 months from means of 28.0 to 37.1 for ATX and from 28.3 to 40.7 for OEST. Mean t scores at 12 months were 40.0 for ATX and 41.0 for OEST. The Weiss Functional Impairment Rating Scale-Parent Report total score improved from baseline to 6 months in both groups (ATX: mean 1.02 to 0.63; OEST: 0.96 to 0.59). Both treatments were safe with no statistically significant difference in the overall rate of adverse events. Overall, the improvements in QoL and functional impairment observed over time for ATX and OEST were meaningful and stable over the study period of 12 months. Between-group differences were small but sometimes statistically significant, providing the first-time long-term comparative symptomatic and QoL analysis between ATX and OEST.