Lisdexamfetamine Research Articles

Understanding the neural mechanisms of lisdexamfetamine dimesylate (LDX) pharmacotherapy in Binge Eating Disorder (BED): a study protocol

BackgroundThe efficacy and safety of Lisdexamfetamine dimesylate (LDX) in the treatment of moderate to severe binge eating disorder (BED) has been demonstrated in multiple randomised clinical trials. Despite this, little is known about how LDX acts to improve binge eating symptoms. This study aims to provide a comprehensive understanding of the neural mechanisms by which LDX improves symptoms of BED. We hypothesise that LDX will act by normalising connectivity within neural circuits responsible for reward and impulse control, and that this normalisation will correlate with reduced binge eating episodes.MethodsThis is an open-label Phase 4 clinical trial of LDX in adults with moderate to severe BED. Enrolment will include 40 adults with moderate to severe BED aged 18–40 years and Body Mass Index (BMI) of 20–45 kg/m2, and 22 healthy controls matched for age, gender and BMI. Clinical interview and validated scales are used to confirm diagnosis and screen for exclusion criteria, which include comorbid anorexia nervosa or bulimia nervosa, use of psychostimulants within the past 6 months, and current use of antipsychotics or noradrenaline reuptake inhibitors. Baseline assessments include clinical symptoms, multimodal neuroimaging, cognitive assessment of reward sensitivity and behavioural inhibition, and an (optional) genetic sample. A subset of these assessments are repeated after eight weeks of treatment with LDX titrated to either 50 or 70 mg. The primary outcome measures are resting-state intrinsic connectivity and the number of binge eating episodes. Analyses will be applied to resting-state fMRI data to characterise pharmacological effects across the functional connectome, and assess correlations with symptom measure changes. Comparison of neural measures between controls and those with BED post-treatment will also be performed to determine whether LDX normalises brain function.DiscussionFirst enrolment was in May 2018, and is ongoing. This study is the first comprehensive investigation of the neurobiological changes that occur with LDX treatment in adults with moderate to severe BED.Trial registrationACTRN12618000623291, Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374913&isReview=true. Date of Registration: 20 April 2018.

Examining the heterogeneity of treatment patterns in attention deficit hyperactivity disorder among children and adolescents in the Texas Medicaid population: modeling suboptimal treatment response

Objectives: To examine suboptimal responses (SR) in attention deficit hyperactivity disorder (ADHD) among pediatric patients in the Texas Medicaid program receiving osmotic-release oral system methylphenidate (OROS-MPH) or lisdexamfetamine (LDX) and apply an SR prediction model to identify patients most likely to experience an SR to either OROS-MPH or LDX therapies. Methods: A retrospective cohort study was conducted using Texas Medicaid claims data of ADHD children and adolescents (6–17 years of age) initiating OROS-MPH or LDX. Primary SR endpoints were drug discontinuation, switching, and augmentation 12-months post-ADHD drug initiation. Logistic regression models were developed to predict SR to OROS-MPH and LDX in 1:1 matched groups of children and adolescent cohorts. Results: A total of 3,633 children and 1,611 adolescents were matched for each cohort. SR was observed among more children (76.4% vs 72.3%; p < 0.001) and adolescents (82.7% vs 78.2%; p = 0.002) initiating OROS-MPH compared to LDX. Patient sub-groups with the highest predicted risk of OROS-MPH SR experienced significantly lower observed SR rates (p < 0.05) when initiating LDX (children: 80.6% for OROS-MPH vs 75.8% for LDX; OR = 0.75, 95% CI = 0.60–0.94; adolescents: 87.2% for OROS-MPH vs 80.6% for LDX; OR = 0.61, 95% CI = 0.41–0.89). For patients with highest predicted SR rates to LDX, observed SR rates were not significantly different between patients initiating LDX or OROS-MPH. Conclusions: This study demonstrated how a personalized medicine approach using administrative claims data can be used to identify sub-groups of child and adolescent ADHD patients with different risks for suboptimal response with OROS-MPH or LDX in a Medicaid population.

Effect of lisdexamfetamine on emotional network brain dysfunction in binge eating disorder

We examined the effects of lisdexamfetamine (LDX) treatment on ventral prefrontal cortex (VPFC) and striatal brain activation in binge eating disorder (BED). We hypothesized that participants with BED have an abnormal brain response to palatable food cues, and that VPFC and striatal regions would respond to such cues after LDX treatment. Twenty women with moderate to severe BED consented to a 12-week, open-label trial of LDX with fMRI before and after treatment. Twenty obese women without BED served as healthy controls and received one fMRI. LDX was started at 30 mg/d with a target of 70 mg/d at week 12. At baseline, women with BED showed greater activation in ventrolateral prefrontal cortex (VLPFC), striatum, and globus pallidus to food pictures and brain activation to food pictures predicted clinical outcome at 12 weeks. After 12 weeks of LDX treatment, BED women showed significant reductions in globus pallidus activation. Reductions in ventromedial prefrontal cortex (VMPFC) and thalamus activation specifically correlated with binge eating and obsessive-compulsive symptom reductions, respectively. Results suggest that BED is characterized by an abnormally large VPFC-subcortical brain response to palatable foods that LDX treatment helps modify. Moreover, VPFC-subcortical activation at baseline is a potential biomarker of LDX response.

Clinical Characteristics and Treatment Response to Lisdexamfetamine Dimesylate Versus Placebo in Adults With Binge Eating Disorder: Analysis by Gender and Age.

To describe clinical characteristics and lisdexamfetamine dimesylate (LDX) treatment effects, based on gender and age, in adults diagnosed with moderate to severe binge eating disorder (BED). Adults diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined BED of moderate to severe severity were randomized to 12 weeks of dose-optimized LDX (50 or 70 mg) or placebo in 2 studies (conducted from November 26, 2012, to September 25, 2013 [study 1] and from November 26, 2012, to September 20, 2013 [study 2]). These post hoc analyses pooled data by gender (men vs women) and age (< 40 vs ≥ 40 years) across studies; reported P values are nominal (descriptive and unadjusted). The pooled safety analysis and full analysis sets included 745 and 724 participants, respectively (men, n = 105 and n = 97; women, n = 640 and n = 627; < 40 years, n = 398 and n = 386; ≥ 40 years, n = 347 and n = 338). Across subgroups, most participants had a body mass index ≥ 30 kg/m² (63.0%-75.5%). The mean baseline number of binge eating days/wk was comparable across gender (4.6-4.7) and age (4.6-4.9), as was Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total score (gender, 20.42-21.70; age, 21.40-21.63). Least squares mean (95% CI) treatment differences nominally favored LDX in all subgroups (all P < .001) for changes from baseline in binge eating days/wk at weeks 11-12 and in Y-BOCS-BE total score at week 12; no interactions by gender or age were reported. Consistent with the overall profile of LDX, across all subgroups LDX was associated with higher frequencies of treatment-emergent adverse events than placebo and with increases in blood pressure and pulse. Across gender and age, participants exhibited comparable clinical characteristics and responses to dose-optimized LDX compared with placebo. ClinicalTrials.gov identifiers: NCT01718483 and NCT01718509.

Lisdexamfetamine dimesylate in adult ADHD with anxiety disorder and depression comorbidity: A 17-week cross-over study

Children diagnosed with cancer are living longer and the survivor population is growing. However, most survivors develop late effects of radiation and chemotherapy shortly to years after completion of therapy, and the receipt of follow-up visits that are recommended by the Children's Oncology Group (COG) is suboptimal nationally.The aims of this study are to: 1) evaluate the impact of a patient-controlled electronic personal health record (ePHR) and system (SurvivorLink) on care visit attendance, risk-based surveillance, and other secondary outcomes (i.e., patient activation, quality of life (QOL)); 2) measure the use, acceptability, and perceived usefulness of, and satisfaction with SurvivorLink; and 3) assess facilitators and barriers to implementation.This hybrid effectiveness–implementation, clustered randomized control trial (RCT) evaluates the effect of SurvivorLink among pediatric cancer survivors and their parents on receipt of follow-up cancer care. We will recruit 20 pediatric survivor clinics with half receiving the intervention and half acting as a waitlist control. Parents of survivors and survivors will complete baseline, 3 and 12 month surveys that assess SurvivorLink use, patient self-efficacy, and intentions to return for follow-up. We will use mixed methods and multi-informant assessment to assess implementation outcomes (i.e., acceptability, feasibility, appropriateness).New approaches are needed to facilitate the receipt of long-term follow-up care among pediatric cancer survivors. This study will assess whether SurvivorLink is effective in increasing receipt of follow-up cancer care. Moreover, it will explore the influences of context and other moderators of clinical practice change in pediatric cancer survivorship.

Evaluation of the response of lisdexamfetamine in children and adolescents with ADHD: quasi-experimental study

Introduction. Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders. Although lisdexamfetamine dimesylate (LDX) offers a treatment alternative, clinical evidence of LDX for ADHD has not been explored in Latin American pediatric population. Objective. To evaluate the LDX response in Mexican pediatric patients with ADHD. Method. We designed a quasi-experimental, uncontrolled before and after study to evaluate the LDX response in patients with severe ADHD. We established a diagnosis of ADHD according to DSM-5 criteria. We formed three groups: without previous treatment (group A), in treatment with stimulant drugs (group B) or in treatment with non-stimulant drugs (group C). Prior to the start of the study, letters of consent and informed consent were signed. We evaluated the effect of LDX based on the difference between ADHD-RS scores at the beginning and after six months. Results. We recruited a total of 144 patients (group A: 48 patients, group B: 57 patients, group C: 39 patients). All the groups showed a significant decrease in the mean score of ADHD-RS (Attention Deficit Hyperactivity Disorder Rating Scale) at six months (group A 37.57 vs. 22.34, p

Progress in Developing Pharmacologic Agents to Treat Bulimia Nervosa.

This paper reviews past and current progress in developing pharmacologic agents for the treatment of individuals with bulimia nervosa (BN). We searched the literature and clinical trial registries for compounds studied in BN, the related condition, binge eating disorder (BED), and preclinical models of binge-eating behavior. Drug classes evaluated included antidepressants, antiepileptic drugs, stimulants and other medications for attention-deficit/hyperactivity disorder, opioid antagonists, and weight loss agents, among others. The only available drugs with established efficacy in BN at this time include antidepressants (especially selective serotonin reuptake inhibitors [SSRIs]) and the antiepileptic topiramate, though the efficacy of these compounds is modest at best. The only medications we found currently receiving empirical study in people with BN were fluoxetine, other serotonergic antidepressants, intranasal naloxone, lisdexamfetamine dimesylate, phentermine-topiramate combination, the antiandrogenic oral contraceptive ethinyl estradiol plus drospirenone, and prazosin. Preclinical models suggest that nociceptin receptor antagonists, the selective serotonin 5-HT2C receptor agonist lorcaserin, monoamine stabilizers, and selective orexin-1 receptor antagonists might be helpful. We found no evidence of a drug developed specifically for the treatment of individuals with BN. Future areas for research in the pharmacotherapy of BN are suggested. Importantly, until drugs are developed specifically for eating disorders, drugs developed for other conditions that are centrally acting and associated with beneficial psychotropic effects and/or reduced appetite or weight loss might be considered for repurposing in BN.

Identification, Characterization and Quantification of Process-Related and Degradation Impurities in Lisdexamfetamine Dimesylate: Identifiction of Two New Compounds.

Twelve impurities (process-related and degradation) in lisdexamfetamine dimesylate (LDX), a central nervous system (CNS) stimulant drug, were first separated and quantified by high-performance liquid chromatography (HPLC) and then identified by liquid chromatography mass spectrometry (LC-MS). The structures of the twelve impurities were further confirmed and characterized by IR, HRMS and NMR analyses. Based on the characterization data, two previously unknown impurities formed during the process development and forced degradation were proposed to be (2S)-2,6-di-(lysyl)-amino-N-[(1S)-1-methyl-2-phenyl ethyl]hexanamide (Imp-H) and (2S)-2,6-diamino-N-[(1S)-1-methyl-2-(2-hydroxyphenyl)ethyl] hexanamide (Imp-M). Furthermore, these two compounds are new. Probable mechanisms for the formation of the twelve impurities were discussed based on the synthesis route of LDX. Superior separation was achieved on a YMC-Pack ODS-AQ S5 120A silica column (250 × 4.6 mm × 5 μm) using a gradient of a mixture of acetonitrile and 0.1% aqueous methanesulfonic acid solution. The HPLC method was optimized in order to separate, selectively detect, and quantify all the impurities. The full identification and characterization of these impurities should prove useful for quality control in the manufacture of lisdexamfetamine dimesylate.

Assessment of lisdexamfetamine dimesylate stability and identification of its degradation product by NMR spectroscopy

Lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant indicated for the treatment of the attention-deficit/hyperactivity disorder (ADHD), was subjected to forced degradation studies by acid and alkaline hydrolysis and the degradation profile was studied. To obtain between 10–30% of degraded product, acid and alkaline conditions were assessed with solutions of 0.01 M, 0.1 M, 0.5 M, and 1 M of DCl and NaOD. These solutions were analyzed through 1 H NMR spectra. Acid hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and 4.38%, 9.69%, and 17.75% of degradation LDX, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) DCl. And alkaline hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and a degradation LDX extension of 8.5%, 14.30%, and 22.91%, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) NaOD. LDX solutions subjected to 1 M (4 + 12 h) acid and alkaline hydrolysis were evaluated by NMR spectra (1 H NMR, 13 C NMR, HSQC and HMBC). LDX degradation product (DP) was identified and its structure elucidated as a diastereoisomer of LDX: (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl] hexanamide without their physical separation.

PMH27 - RETROSPECTIVE HEALTHCARE CLAIMS DATA ANALYSIS FOR CHILDREN/ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER RECEIVING SECOND-LINE PHARMACOTHERAPY IN GERMANY, EVALUATING PATIENT CHARACTERISTICS AND HEALTHCARE COSTS

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder associated with persistent and cross-situational occurring symptoms, including inattention, hyperactivity and/or impulsivity. The study aimed to evaluate healthcare claims data (demographics, co-occurring disorders and healthcare costs) for children/adolescents with ADHD treated with second-line lisdexamfetamine (LDX) or atomoxetine (ATX) in Germany. This was a retrospective claims data analysis conducted using the InGef research database containing anonymized healthcare claims of approximately 4 million individuals covered by statutory health insurance in Germany. Children/adolescents (6–17 years) with an ADHD diagnosis and first prescription of second-line LDX or ATX after methylphenidate treatment were included in the study. Demographic characteristics, co-occurring mental and behavioural disorders (by ICD-10-GM code groups) and direct healthcare costs were analysed in an individual 1-year post-index period after identification in 2014. A total of 451 children/adolescents with ADHD treated with LDX and 176 treated with ATX were identified (81% and 79% male patients, respectively). The LDX cohort was statistically significantly older (mean age 11.4 vs 10.9 years; p=0.0065). Behavioural/emotional disorders (F91-98) with specific childhood/adolescence onset were reported for 55% and 58% patients in the LDX and ATX cohorts, respectively. Disorders of psychological development (F80-89) were reported for 47% and 52%, respectively. Lower mean inpatient costs were reported in the LDX cohort compared with the ATX cohort (€1979 vs €3189; p=0.0028). The difference in inpatient costs led to significantly lower mean overall 1-year direct healthcare costs per patient in the LDX than ATX cohorts (€4485 vs €6018; p=0.0004). There may be a need for an individualized approach to the treatment of children/adolescents with ADHD, particularly considering common co-occurring mental and behavioural disorders reported. In Germany, children/adolescents treated with second-line ATX compared with LDX incurred significantly higher overall direct healthcare costs. Further multivariate analyses are needed to validate the study outcomes.

2.22 Lisdexamfetamine Dimesylate for Preschool Children With ADHD

2.22 Lisdexamfetamine Dimesylate for Preschool Children With ADHD

Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis.

Psychostimulants are the first-line treatment in adults with attention-deficit hyperactivity disorder (ADHD). This meta-analysis aimed to evaluate the efficacy, acceptability, and tolerability of lisdexamfetamine (LDX), mixed amphetamine salts (MASs), modafinil (MDF), and methylphenidate (MPH) in comparison with placebo. We systematically searched PubMed/MEDLINE and Clinicaltrials.gov in May 2016, along with CENTRAL and EU Clinical Trials Register in February 2016, for the randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted on adults diagnosed with ADHD. Substantial comorbidity, substance abuse or dependence, and nonpharmacological interventions represented grounds for exclusion. Published reports were the sole source for data extraction. Improvement in ADHD symptoms was the primary outcome. Random-effects model meta-analysis was applied to calculate the standardized mean difference (SMD) with 95% CIs. The search retrieved 701 records, of which 20 studies were eligible for analysis. High effect size (expressed as SMD) in reducing ADHD symptoms was observed for LDX (-0.89; 95% CI = -1.09, -0.70), whereas MASs (-0.64; 95% CI = -0.83, -0.45) and MPH (-0.50; 95% CI = -0.58, -0.41) reduced symptoms moderately compared with placebo. No efficacy was shown for MDF (0.08; 95% CI; -0.18, 0.34). Relevance to Patient Care and Clinical Practice: In this meta-analysis, the efficacy, tolerability, and acceptability of psychostimulants were compared with that for placebo. Five of the included trials have not been evaluated in any of the previously published meta-analyses. The results suggest that LDX has the largest effect size and has a promising potential for treating adults with ADHD.

LiMA: a study protocol for a randomised, double-blind, placebo controlled trial of lisdexamfetamine for the treatment of methamphetamine dependence

IntroductionMethamphetamine dependence is a growing public health concern. There is currently no pharmacotherapy approved for methamphetamine dependence. Lisdexamfetamine (LDX) dimesylate, used in the treatment of attention-deficit hyperactivity disorder and binge...

Alprazolam-induced dose-dependent anorgasmia: case analysis.

Sexual dysfunctions are associated with multiple medical and psychiatric disorders, as well as pharmacotherapies used to treat these disorders. Although sexual dysfunctions negatively affect both quality of life and treatment adherence, patients infrequently volunteer these symptoms and clinicians do not pose directed questions to determine their presence or severity. This issue is especially important in psychiatric patients, for whom most common psychotropics may cause sexual dysfunctions (antidepressants, antipsychotics, anxiolytics and mood-stabilising agents). There is limited literature addressing benzodiazepines, and alprazolam in particular. To report dose-dependent alprazolam anorgasmia. Case analysis with PubMed literature review. A 30-year-old male psychiatric patient presented with new-onset anorgasmia in the context of asymptomatic generalised anxiety disorder, social anxiety, panic disorder with agoraphobia, obsessive-compulsive disorder, major depression in remission, and attention-deficit hyperactivity disorder treated with escitalopram 10 mg q.a.m., gabapentin 1000 mg total daily dose, lisdexamfetamine dimesylate 70 mg q.a.m., nortriptyline 60 mg q.h.s. and alprazolam extended-release 2.5 mg total daily dose. All psychotropic doses had been constant for >6 months excluding alprazolam, which was titrated from 1 mg to 2.5 mg total daily dose. The patient denied any sexual dysfunction with alprazolam at 1 mg q.d. and 1 mg b.i.d. Within 1 week of increasing alprazolam to 2.5 mg total daily dose, the patient reported anorgasmia. Anorgasmia was alprazolam dose-dependent, as anorgasmia resolved with reduced weekend dosing (1 mg b.i.d. Saturday/1.5 mg total daily dose Sunday). Sexual dysfunction is an important adverse effect negatively influencing therapeutic outcome. This case reports alprazolam-induced dose-dependent anorgasmia. Clinicians/patients should be aware of this adverse effect. Routine sexual histories are indicated. None.

Lisdexamfetamine Dimesylate: A Review in Paediatric ADHD.

Lisdexamfetamine dimesylate (lisdexamfetamine; Elvanse®; Tyvense®), an orally-active dexamfetamine prodrug, is indicated in the EU for the treatment of attention-deficit hyperactivity disorder (ADHD) in children aged ≥ 6years (including adolescents) when the response to previous methylphenidate (MPH) treatment is clinically inadequate. The original approval of the drug was based on the results of phase III trials in children and adolescents with ADHD who had an inadequate response to previous pharmacotherapy (e.g. MPH) or were treatment naïve. In these studies, short-term treatment with flexibly-dosed lisdexamfetamine demonstrated greater efficacy than atomoxetine, based on a prospective comparison, and osmotic-release oral system (OROS)-MPH, based on a post hoc comparison. Improvements in ADHD symptoms were accompanied by improvements in health-related quality of life and functioning that were maintained as long as treatment with lisdexamfetamine was continued in a long-term extension of one of these trials. In subsequent phase IV head-to-head studies in adolescents with ADHD and an inadequate response to previous pharmacotherapy, lisdexamfetamine demonstrated greater efficacy than OROS-MPH when both medications were force-titrated, but not when they were flexibly-titrated. Lisdexamfetamine was generally well tolerated, with an adverse event profile (e.g. decreased appetite, headache, weight reduction, insomnia and irritability) typical of that reported for other stimulants. Thus, lisdexamfetamine provides an alternative option for the treatment of children and/or adolescents with ADHD who have not responded adequately to previous ADHD pharmacotherapies.

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults

Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.

Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in Attention-Deficit/Hyperactivity Disorder

BackgroundPrefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition. MethodsTwenty-five adults with ADHD were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task after 3 to 4 weeks of lisdexamfetamine treatment and 3 weeks off medication in a randomized, counterbalanced, hybrid crossover design. Drug, trial type, and face emotion (happy, sad, or neutral) were included as within-subjects factors in repeated measures analyses of activation and connectivity. ResultsLisdexamfetamine was associated with increased right amygdala activation and reduced psychophysiological interactions with the orbital aspect of the left inferior frontal gyrus specifically for responses to sad faces compared with placebo, but there was no effect on the accuracy of response execution or inhibition. The relative gain in right amygdala activation in response to sad faces for lisdexamfetamine was correlated with a reduction in symptoms of ADHD. ConclusionsTreatment with lisdexamfetamine potentiates affective encoding in amygdala, purportedly via catecholaminergic mechanisms, but functionally disconnects the amygdala from inferior frontal regions that encode behavioral significance—resulting in reduced emotional bias of cognitive control. Pinpointing the neurophysiologic underpinnings of therapeutic improvement with lisdexamfetamine represents a first step in developing targeted approaches to treatment of ADHD.

Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis.

The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n=4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.

Relationships between clinical scales and binge eating days in adults with moderate to severe binge eating disorder in two Phase III studies.

ObjectivesIn two Phase III studies, lisdexamfetamine dimesylate (LDX) reduced binge eating (BE) days/week in adults with moderate to severe binge eating disorder (BED) and was associated with improvement based on the Clinical Global Impressions–Improvement (CGI-I) scale. In this study, post hoc analyses examined the relationships between clinical observations and clinical rating scales in individuals with BED.Clinical trial registrationNCT01718483 (ClinicalTrials.gov/ct2/show/NCT01718483); NCT01718509 (ClinicalTrials.gov/ct2/show/NCT01718509).MethodsTwo 12-week, double-blind, placebo-controlled studies randomized (1:1) adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, BED criteria and with protocol-defined moderate to severe BED (study 1, N=383; study 2, N=390) to placebo or dose-optimized LDX (50 or 70 mg). Assessments included the number of BE days/week, CGI–Severity (CGI-S) and CGI-I scores, and Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total scores. For these post hoc analyses, data were pooled across studies and treatment arms. Statistical assessments included Spearman correlations and equipercentile linking analyses (ELA). Reported P-values are nominal (descriptive and not adjusted for multiplicity).ResultsAt baseline, nominally significant correlations with CGI-S scores were reported for BE days/week (r=0.374; P<0.0001) and Y-BOCS-BE total scores (r=0.319; P<0.0001). Baseline ELA for CGI-S further characterized this relationship: a CGI-S score of 4 (moderately ill) corresponding to 3.504 BE days/week and a Y-BOCS-BE total score of 18.6. Nominally significant correlations with CGI-I scores were reported for changes from baseline at study endpoint for BE days/week (r=0.647; P<0.0001) and Y-BOCS-BE total scores (r=0.741; P<0.0001). ELA for CGI-I scores at study endpoint showed that a CGI-I score of 1 (very much improved) corresponds to a reduction from baseline of 4.504 BE days/week and 19.4 points for Y-BOCS-BE total score.ConclusionThese post hoc analyses suggest that indices of global disease severity and improvement positively correlate with BE behavior and with obsessive and compulsive features of BED, measured by the Y-BOCS-BE, supporting the clinical relevance of BED treatment outcomes.

Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder

ABSTRACTIntroduction: The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED).Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED.Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of abuse needs to be assessed prior to prescribing.