Robert Lasser

Lisdexamfetamine Dimesylate Augmentation in Adults With Persistent Executive Dysfunction After Partial or Full Remission of Major Depressive Disorder

Evaluate lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy for executive dysfunction in partially or fully remitted major depressive disorder (MDD). This randomized, placebo-controlled study (NCT00985725) enrolled 143 adults (18–55 years) with mild MDD (Montgomery-Åsberg Depression Rating Scale (MADRS) score ⩽18) and executive dysfunction (Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report Global Executive Composite (GEC) T score ⩾60) on stable antidepressant monotherapy for ⩾8 weeks. After 2 weeks of screening, participants were randomized to 9 weeks of double-blind LDX (20–70 mg/day) or placebo augmentation, followed by 2 weeks of single-blind placebo. The primary end point was change from baseline to week 9/end of study (EOS) in BRIEF-A Self-Report GEC T score; secondary assessments included the BRIEF-A Informant Report, MADRS, and treatment-emergent adverse events (TEAEs). Of 143 randomized participants, 119 completed double-blind treatment (placebo, n=59; LDX, n=60). Mean±standard deviation (SD) BRIEF-A GEC T scores decreased from baseline (placebo, 74.2±8.88; LDX, 76.8±9.66) to week 9/EOS (placebo, 61.4±14.61; LDX, 55.2±16.15); the LS mean (95% CI) treatment difference significantly favored LDX (−8.0 (−12.7, −3.3); P=0.0009). The LS mean (95% CI) treatment difference for MADRS total score also significantly favored LDX (−1.9 (−3.7, 0.0); P=0.0465). TEAE rates were 73.6% with placebo and 78.9% with LDX; serious TEAE rates were 4.2 and 2.8%. In this trial, LDX augmentation significantly improved executive dysfunction and depressive symptoms in participants with mild MDD. The safety profile of LDX was consistent with prior studies in adults with attention-deficit/hyperactivity disorder.

Comparison of the burden of illness for adults with ADHD across seven countries: a qualitative study

BackgroundThe purpose of this study was to expand the understanding of the burden of illness experienced by adults with Attention Deficit-Hyperactivity Disorder (ADHD) living in different countries and treated through different health care systems.MethodsFourteen focus groups and five telephone interviews were conducted in seven countries in North America and Europe, comprised of adults who had received a diagnosis of ADHD. The countries included Canada, France, Germany, Italy, The Netherlands, United Kingdom, and United States (two focus groups in each country). There were 108 participants. The focus groups were designed to elicit narratives of the experience of ADHD in key domains of symptoms, daily life, and social relationships. Consonant with grounded theory, the transcripts were analyzed using descriptive coding and then themed into larger domains.ResultsParticipants’ statements regarding the presentation of symptoms, childhood experience, impact of ADHD across the life course, addictive and risk-taking behavior, work and productivity, finances, relationships and psychological health impacts were similarly themed across all seven countries. These similarities were expressed through the domains of symptom presentation, childhood experience, medication treatment issues, impacts in adult life and across the life cycle, addictive and risk-taking behavior, work and productivity, finances, psychological and social impacts.ConclusionsThese data suggest that symptoms associated with adult ADHD affect individuals similarly in different countries and that the relevance of the diagnostic category for adults is not necessarily limited to certain countries and sociocultural milieus.

A Randomized Controlled Trial of the Efficacy and Safety of Lisdexamfetamine Dimesylate as Augmentation Therapy in Adults With Residual Symptoms of Major Depressive Disorder After Treatment With Escitalopram

OBJECTIVE Evaluate the efficacy and safety of lisdexamfetamine dimesylate augmentation for major depressive disorder (MDD) in escitalopram nonremitters. METHOD In this proof-of-concept study (conducted from July 2009-August 2010) with a prespecified critical α = .10, adults with nonpsychotic MDD (DSM-IV-TR criteria) and residual depressive symptoms (17-item Hamilton Depression Rating Scale score ≥ 4) after 8 weeks of open-label escitalopram were randomized to 6 weeks of lisdexamfetamine dimesylate (20-50 mg/d) or placebo augmentation. The primary endpoint, Montgomery-Asberg Depression Rating Scale (MADRS) total score change in escitalopram nonremitters (MADRS total score > 10) from week 8 (augmentation baseline) to week 14/end of study, was assessed using analysis of covariance, with last observation carried forward. RESULTS For nonremitters (placebo, n = 64; lisdexamfetamine dimesylate, n = 65), the least squares (LS) mean (90% CI) treatment difference for MADRS total score reduction at week 14/end of study (-2.3 [-4.5 to -0.1]; P = .0902) met the prespecified criterion for lisdexamfetamine dimesylate superiority (adjusted effect size, -0.3); the number needed to treat for MADRS remission (MADRS total score ≤ 10) was 6.7. The LS mean treatment difference in remitters was not statistically significant (1.2 [-1.6 to 4.0]; P = .4726). Among randomized participants, 49.4% (42/85) receiving placebo and 60.2% (53/88) receiving lisdexamfetamine dimesylate had ≥ 1 treatment-emergent adverse event, the most frequent with lisdexamfetamine dimesylate being dry mouth and headache (both 11.4%). Mean (SD) vital sign and electrocardiogram changes (placebo vs lisdexamfetamine dimesylate) were 0.5 (8.98) versus 2.3 (9.04) mm Hg (systolic blood pressure), -1.0 (7.19) versus 0.9 (6.61) mm Hg (diastolic blood pressure), -0.4 (7.39) versus 4.8 (8.64) beats per minute (heart rate), and -1.6 (11.23) versus -4.9 (11.84) milliseconds (Fridericia-adjusted QTc). CONCLUSIONS Lisdexamfetamine dimesylate augmentation reduced depressive symptoms in participants with inadequate escitalopram response. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00905424.

The Effects of Lisdexamfetamine Dimesylate on Emotional Lability in Children 6 to 12 Years of Age With ADHD in a Double-Blind Placebo-Controlled Trial:

Objective: To evaluate the effect of lisdexamfetamine dimesylate (LDX) on emotional lability (EL) in children with ADHD. Method: Post hoc analyses of a placebo-controlled trial of LDX-stratified children (aged 6-12 years) with ADHD to prominent and not prominent EL at baseline (score >3 or ≤3, respectively, on Conners’ Parent Rating Scale [CPRS] items of anger, loss of temper, and irritability). Efficacy was assessed by change in CPRS EL scores and ADHD Rating Scale-IV (ADHD-RS-IV) total and subscale scores. Safety measures included treatment-emergent adverse events (TEAEs). Results: LDX showed improvement versus placebo (p < .0005) for EL item least squares (LS) mean change scores at endpoint and throughout the day. At baseline, 138 and 73 participants randomized to LDX treatment and having baseline and endpoint CPRS scores were categorized with CPRS-derived prominent and not prominent baseline EL, respectively; 41 and 31 participants randomized to placebo were categorized with CPRS-derived prominent and not prominent baseline EL, respectively. ADHD-RS-IV total and subscale scores decreased with LDX regardless of baseline EL severity. TEAEs included decreased appetite, insomnia, upper abdominal pain, headache, and irritability. Conclusion: EL and ADHD symptoms improved with LDX regardless of baseline EL symptom severity. LDX demonstrated a safety profile consistent with long-acting psychostimulant use.

Long-term treatment outcomes with lisdexamfetamine dimesylate for adults with attention-deficit/hyperactivity disorder stratified by baseline severity

Abstract Objective: To examine the impact of baseline severity on lisdexamfetamine dimesylate (LDX) efficacy in a long-term study of adults with attention-deficit/hyperactivity disorder (ADHD). Research design and methods: Adults from a 4-week, placebo-controlled, forced dose-escalation study with LDX (30–70 mg/day) or placebo were enrolled in a long-term, open-label dose-optimization study for an additional 12 months. In post hoc analyses, participants were stratified by baseline severity (from the prior short-term study) with Clinical Global Impressions-Severity (CGI-S) scores of 4 (moderately), 5 (markedly), or ≥6 (severely/extremely ill). ADHD-Rating Scale IV (ADHD-RS-IV) with adult prompts (primary) and CGI-Improvement (CGI-I) were used to assess effectiveness. Clinical response was defined as a ≥30% decrease in ADHD-RS-IV from baseline and a CGI-I of 1 or 2; symptomatic remission was defined as ADHD-RS-IV ≤18. Treatment-emergent adverse events (TEAEs) were monitored. Results: Participants had baseline CGI-S scores of 4 (n = 114), 5 (n = 188), or ≥6 (n = 43). At endpoint, mean (SD) change from baseline in ADHD-RS-IV was greater (p < 0.0001) for participants with CGI-S = 5 (−26.4 [11.77]) and ≥6 (−32.3 [9.81]) than for participants with CGI-S = 4 (−19.5 [9.97]). At endpoint, 81.6%, 84.6%, and 88.4% of participants were very much/much improved (CGI-I of 1 or 2) in CGI-S categories of 4, 5, and ≥6, respectively. Clinical response criteria were met by 78.9%, 83.5%, and 88.4% and symptomatic remission criteria by 64.0%, 65.4%, and 72.1% of participants with CGI-S = 4, 5, and ≥6, respectively. The most frequently reported TEAEs with participant incidence ≥10% for any LDX dose were upper respiratory tract infection (21.8%), insomnia (19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite (14.3%), and irritability (11.2%). Conclusions: Some aspects of these analyses (e.g., open-label design without placebo control, inclusion and exclusion criteria of the demographic profile of participants, and the post hoc nature of the statistical analysis) limit interpretation. However, long-term LDX treatment demonstrated increased degree of symptom improvement with greater baseline symptom severity. Rates of clinical response and symptomatic remission tended to be greater for those with greater baseline severity. LDX demonstrated a safety profile consistent with long-acting stimulant use.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder

BackgroundDespite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD.MethodsIn a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an “optimal” LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission.ResultsFour hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits.ConclusionIn the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months.Trial registrationClinical Trial Numbers: NCT00334880 and NCT01070394Clinical Trial Registry: clinicaltrials.govURLshttp://www.clinicaltrials.gov/show/NCT00334880http://www.clinicaltrials.gov/ct2/show/NCT01070394?term=NCT01070394&rank=1

Executive Function Deficits in Children with Attention-Deficit/Hyperactivity Disorder and Improvement with Lisdexamfetamine Dimesylate in an Open-Label Study

OBJECTIVE To assess the effects of lisdexamfetamine dimesylate (LDX) on executive function (EF) behaviors in children with attention-deficit/hyperactivity disorder (ADHD). METHODS This observational, open-label, 7-week, dose-optimization study of LDX (20-70  mg/day) in children with ADHD evaluated efficacy with the ADHD Rating Scale IV; safety measures included adverse events (AEs). EF was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). Post hoc analyses examined BRIEF scores by sex, ADHD subtype, comorbid psychiatric symptoms, and common treatment-emergent AEs (TEAEs). ADHD Rating Scale IV scores were assessed in subjects categorized by baseline BRIEF global executive composite T scores with clinically significant (≥65) or not clinically significant (<65) impairment in EF. RESULTS Mean (standard deviation) change from baseline to endpoint for BRIEF of -17.9 (12.5) for Global Executive Composite, -15.4 (12.6) for Behavioral Regulation Index, and -17.6 (12.3) for Metacognition Index demonstrated improvement with LDX (pooled doses; p < 0.0001 for all). Improvements in BRIEF scores were seen regardless of sex, ADHD subtype, comorbid psychiatric symptoms, common TEAEs, or baseline EF impairment category. TEAEs included decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia. CONCLUSIONS Improvements were demonstrated in EF behaviors and ADHD symptoms with LDX. LDX safety profile was consistent with long-acting stimulant use.

Clinically Relevant Changes in Emotional Expression in Children with ADHD Treated with Lisdexamfetamine Dimesylate.

Objective: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. Method: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to determine proportion of participants with different categories of clinical response based on (a) clinically significant (movement >2 SD from baseline mean)/reliable change (not due to measurement error) and (b) standard error of measurement (SEM) as a measure of clinically meaningful change. Results: With LDX, no participants showed clinically significant/reliable improvement; 0.7% showed clinically significant/reliable deterioration of EE by reliable change index and movement from baseline mean. One third of participants had improved EE by SEM criteria; 9.2% had categorical worsening. Conclusion: Using clinically meaningful change and clinically significant/reliable change categories derived from the EESC, most participants had no worsening of EE with LDX.

Efficacy and safety of gantenerumab in prodromal Alzheimer’s disease: Results from scarlet road—a global, multicenter trial

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr

Biomarker data from scarlet road: A global phase 3 study of gantenerumab in patients with prodromal Alzheimer's disease

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr