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Oliva HNP, Prudente TP, Mayerson TF, Mignosa MM, Oliva IO, Potenza MN, Jegede OO, Angarita GA. Safety of Stimulants Across Patient Populations: A Meta-Analysis. JAMA Netw Open 2025; 8:e259492. [PMID: 40343695 PMCID: PMC12065045 DOI: 10.1001/jamanetworkopen.2025.9492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/08/2025] [Indexed: 05/11/2025] Open
Abstract
Importance The use of stimulant medications has expanded substantially beyond the traditional treatment of attention-deficit/hyperactivity disorder (ADHD) to encompass a variety of other clinical conditions. Understanding the safety of these medications is important as their use increases across diverse patient populations. Objective To assess the safety of stimulant medications as reported in randomized clinical trials (RCTs) investigating methylphenidate, lisdexamfetamine, and other amphetamines. Data Sources A comprehensive literature search was conducted from July 1, 2024, through February 28, 2025, using CINAHL, Embase, PubMed or MEDLINE, ScienceDirect, and Web of Science for studies published since 2000. Keywords included safety, adverse event, side effect, amphetamine, dextroamphetamine, stimulant, lisdexamfetamine, and methylphenidate. Study Selection RCTs published between January 1, 2000, and December 13, 2024, were included. These trials investigated the safety of stimulants in various clinical conditions, including ADHD, depression, binge eating disorder, schizophrenia, Alzheimer disease, and stimulant use disorders as well as in healthy individuals. Trials not focused on safety or adverse events (AEs) of stimulants, nonoriginal research, nonhuman research, trials with concomitant prescriptions other than stimulants, and trials without a placebo group were excluded. Data Extraction and Synthesis Data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Independent reviewers extracted study data, and a random-effects model was used to pool results. Heterogeneity was assessed using the I2 statistic. Main Outcomes and Measures The primary outcome was the risk ratio (RR) of developing any AE in participants taking stimulants vs placebo. Results A total of 93 RCTs were included after exclusions. The methodological quality assessment of the included trials showed overall low or unclear risk of bias. Trials with a duration of up to 52 weeks showed that stimulant medications were associated with an increased risk of overall AEs compared with placebo (RR, 1.34; 90% CI, 1.27-1.41), with high heterogeneity (I2 = 67%). Statistical significance of this finding was maintained when subgroups (ie, methylphenidate, lisdexamfetamine, and other amphetamines) were separately analyzed. Conclusions and Relevance This meta-analysis found an increased risk of overall AEs associated with stimulants compared with placebo. Future research could provide more standardized and consistent assessments of this outcome and may improve understanding about misuse risk.
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Affiliation(s)
- Henrique Nunes Pereira Oliva
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven
- Connecticut Mental Health Center, New Haven
| | | | - Talia F. Mayerson
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven
- Connecticut Mental Health Center, New Haven
| | - Marcella M. Mignosa
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven
- Connecticut Mental Health Center, New Haven
| | | | - Marc N. Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Connecticut Mental Health Center, New Haven
- Child Study Center, Yale University School of Medicine, New Haven, Connecticut
- Department of Neuroscience, Yale University, New Haven, Connecticut
- Connecticut Council on Problem Gambling, Wethersfield
- Wu Tsai Institute, Yale University, New Haven, Connecticut
| | - Oluwole O. Jegede
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Connecticut Mental Health Center, New Haven
| | - Gustavo A. Angarita
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven
- Connecticut Mental Health Center, New Haven
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Chan M, Chan JJ, Wright JM. Effect of amphetamines on blood pressure. Cochrane Database Syst Rev 2025; 3:CD007896. [PMID: 40152309 PMCID: PMC11951410 DOI: 10.1002/14651858.cd007896.pub4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
BACKGROUND Daily ingestion of amphetamines is common, as they are widely prescribed for attention-deficit hyperactivity disorder (ADHD) and other diagnoses. People also use amphetamines recreationally or in an attempt to boost cognitive or athletic performance. Amphetamines have the potential to increase blood pressure, and we do not know if the long-term benefits of daily amphetamine use outweigh the potential harms. OBJECTIVES Primary: to quantify the changes in systolic and diastolic blood pressure in children and adults taking amphetamines, compared to placebo. Secondary: to quantify the changes in heart rate in children and adults taking amphetamines, compared to placebo; to quantify the number of withdrawals due to adverse effects of amphetamine, compared to placebo. SEARCH METHODS We used the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase and two clinical trial registers, together with reference checking and contact with study authors to identify the studies included in the review. We imposed no restrictions on language, publication year or publication status. The latest search date was March 2023. SELECTION CRITERIA Randomized controlled trials (RCTs) that compared the effects of daily oral amphetamines versus placebo on blood pressure. There were no restrictions on participants' age or gender. DATA COLLECTION AND ANALYSIS We used standard methods expected by Cochrane. Primary outcomes were change in systolic and diastolic blood pressure (measured in millimeters of mercury (mmHg) above atmospheric pressure; continuous outcomes). Secondary outcomes were heart rate (measured as beats per minute; continuous outcome) and withdrawals due to adverse effects (dichotomous outcome). We calculated continuous outcomes as mean differences (MD) with 95% confidence intervals (CI). We expressed withdrawals due to adverse effects as a risk ratio with 95% CI. We used a fixed-effect model to pool effect sizes from all studies. MAIN RESULTS We included 56 RCTs with a total of 10,583 participants, both adults and children. Most studies were conducted in North America (mainly the USA), followed by Europe. A few studies took place in Asia (Japan) and Australia. The studies tested racemic amphetamine, dextroamphetamine, mixed amphetamine salts, lisdexamfetamine dimesylate, methylenedioxymethamphetamine (MDMA) and methylphenidate. The amphetamines were prescribed for ADHD, weight loss and other indications. In 48 RCTs, blood pressure was measured within 24 hours of the last dose. Based on data from all included studies, amphetamines increased systolic blood pressure (SBP) by 1.93 mmHg (95% CI 1.54 to 2.31) and diastolic blood pressure (DBP) by 1.84 mmHg (95% CI 1.51 to 2.16) (56 studies, 10,583 participants; high-certainty evidence for both). Amphetamines increased heart rate by 3.71 beats per minute (95% CI 3.27 to 4.14; 47 studies, 10,075 participants; high-certainty evidence). In a subgroup analysis limited to studies that gave participants amphetamines for at least eight weeks, the effects were similar, suggesting that these are sustained effects. These findings suggest that people taking daily oral amphetamines are at increased risk of adverse cardiovascular events. Participants in the amphetamine group were also more likely to withdraw from the study due to adverse effects compared to those given placebo (risk ratio 2.69, 95% CI 2.13 to 3.40; absolute risk increase of 4.3% over an average duration of 1 month; 42 studies, 8952 participants; high-certainty evidence). In general, the studies were well-executed, and the methodology was sound. We judged most studies to have a low risk of bias across most domains. Selection bias (random sequence generation and allocation concealment) was the domain most often rated as at unclear risk of bias, because the methods used were not reported. We judged 13 studies (23%) to have a high risk of bias in at least one of the seven domains, primarily due to high dropout rates, leading to a high risk of attrition bias. AUTHORS' CONCLUSIONS Daily oral amphetamines increase blood pressure, heart rate, and withdrawals due to adverse effects, with these effects observed across all time points, including shorter (≤ four weeks) and longer durations (> four weeks to < eight weeks; ≥ eight weeks) of use. Future trials should measure blood pressure using 24-hour ambulatory monitoring and assess the effect of long-term use.
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Affiliation(s)
- Magnus Chan
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Jocelyn Joy Chan
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - James M Wright
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
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Zheng Y, Liu H, Wang X, Li H, Ruhmann M, Mayer A, Dangel O, Ammer R. Randomized, Double-Blind, Placebo-Controlled Trial on the Efficacy, Safety and Tolerability of Modified-Release Methylphenidate (MPH-MR) in Chinese Children and Adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). CNS Drugs 2025; 39:289-304. [PMID: 39671144 PMCID: PMC11850499 DOI: 10.1007/s40263-024-01136-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/03/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND AND OBJECTIVES The efficacy and safety of modified-release methylphenidate (MPH-MR) in the treatment of attention-deficit/hyperactivity disorder (ADHD) have been shown in both pediatric and adult Caucasian patients. The objective of this study was to assess the efficacy and safety of MPH-MR in Chinese children and adolescents with ADHD. METHODS MICCA was a randomized, double-blind, placebo-controlled trial conducted at 19 sites in China from September 2018 to July 2021. The study enrolled children and adolescents aged 6 to < 18 years with a primary diagnosis of ADHD according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). Patients were randomized 1:1 to once-daily MPH-MR (10-60 mg) or placebo. The study included an up-titration phase of up to 5 weeks and a dose maintenance phase of 4 weeks. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to the end of the maintenance phase (EoM). Secondary endpoints included the change from baseline to EoM in Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) total score, and Clinical Global Impression-Improvement (CGI-I) scores at EoM. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS A total of 221 patients were randomized (MPH-MR: n = 110; placebo: n = 111). The change in the ADHD-RS-IV total score from baseline to EoM was significantly greater for MPH-MR versus placebo, with a least squares (LS) mean (95% confidence interval [CI]) treatment difference of - 4.6 (- 6.92, - 2.30) (p < 0.001). The mean (95% CI) treatment difference for the WFIRS-P total score change from baseline to EoM also significantly favored MPH-MR over placebo (- 6.46 [- 10.57, - 2.34]; p = 0.002). The CGI-I score at EoM was significantly lower in the MPH-MR group compared to the placebo group (2.2 vs 2.5; p = 0.002). Treatment-emergent adverse events were reported for 74 (67.3%) patients in the MPH-MR group and 55 (49.1%) patients in the placebo group. Most TEAEs were mild to moderate in severity. The most common TEAEs for MPH-MR were decreased appetite, nausea and upper respiratory tract infection. Treatment-emergent adverse events leading to study drug discontinuation/study withdrawal were reported in 4 (3.6%) patients in the MPH-MR group and 1 (0.9%) patient in the placebo group. No clinically relevant changes in vital signs were observed during the study. CONCLUSIONS Modified-release methylphenidate was superior to placebo in improving ADHD symptoms and functioning in Chinese pediatric patients with ADHD. Modified-release methylphenidate had a good safety and tolerability profile. Trial Registration http://www.chinadrugtrials.org.cn/ Identifier: CTR20180056 (registered on 21 May 2018).
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Affiliation(s)
- Yi Zheng
- Beijing Anding Hospital of Capital Medical University, Beijing, China
| | - Huaqing Liu
- Beijing Huilongguan Hospital, Beijing, China
| | - Xiuxia Wang
- The second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Haibo Li
- The first Hospital of Jilin University, Changchun, Jilin, China
| | | | - Anke Mayer
- MEDICE Arzneimittel Pütter GmbH & Co. KG, Iserlohn, Germany
| | - Oliver Dangel
- MEDICE Arzneimittel Pütter GmbH & Co. KG, Iserlohn, Germany
| | - Richard Ammer
- MEDICE Arzneimittel Pütter GmbH & Co. KG, Iserlohn, Germany.
- University Hospital Münster, Albert-Schweitzer-Str. 33, 48149, Münster, Germany.
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Shen F, Zhou H. Methylphenidate treatment of a Chinese boy with Becker muscular dystrophy combined with attention deficit hyperactivity disorder: a case report. Front Neurosci 2024; 18:1459582. [PMID: 39659883 PMCID: PMC11628498 DOI: 10.3389/fnins.2024.1459582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 11/13/2024] [Indexed: 12/12/2024] Open
Abstract
Background Becker muscular dystrophy (BMD) is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis, caused by mutations in the DMD gene, which encodes dystrophin protein. Different from Duchenne Muscular Dystrophy (DMD), in which dystrophin is completely absent in muscle tissue, while in BMD, the dystrophin gene can express some protein, but not enough. It has also been shown that a proportion of patients with DMD suffer from attention deficit hyperactivity disorder (ADHD), and the use of the stimulant methylphenidate has been suggested for the treatment of patients with DMD in combination with ADHD. However, there are no case reports on the treatment of co-occurring ADHD in BMD. Case presentation The patient was a 9-year-old boy who presented with elevated serum creatine kinase levels and inattention. The magnetic resonance imaging of the thigh muscles of both lower limbs suggested partial fatty infiltration of the gluteus maximus muscle bilaterally, and a novel heterozygous mutation (c.31 + 6 T > C) was identified in the DMD gene by Next Generation Sequencing (NGS) and the sequencing results were verified by using the Sanger method. The child was also diagnosed with co-morbid ADHD after a thorough evaluation and considering this new diagnosis, we started treatment with methylphenidate at a dose of 18 mg/day, and after 6 months of treatment, he showed a significant improvement in his attention span. Conclusion We identified a novel heterozygous mutation in the DMD gene, which will expand the spectrum of pathogenic variants in BMD. Simultaneously, methylphenidate treatment significantly improved attention in children with BMD co-morbid with ADHD, and this study provides value for future therapeutic protocols for BMD combined with ADHD. However, to the best of our knowledge, this is the only reported case report on the treatment of BMD co-morbid ADHD. So further studies are needed to determine the interrelationship between these disorders and their treatment.
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Affiliation(s)
| | - Hui Zhou
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education (MOE), Chengdu, Sichuan, China
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Rutledge-Jukes H, Jonnalagadda P, McIntosh AP, Krstovski S, Andriani N, Smith IR, Prendergast L, Lynch JM. Lisdexamfetamine's Efficacy in Treating Attention Deficit Hyperactivity Disorder (ADHD): A Meta-Analysis and Review. Cureus 2024; 16:e68324. [PMID: 39350825 PMCID: PMC11441986 DOI: 10.7759/cureus.68324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 10/04/2024] Open
Abstract
Lisdexamfetamine dimesylate, a prodrug stimulant, appears to effectively treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adults. However, an analysis of the treatment effects of the two subscales (inattentiveness and hyperactivity) within the ADHD Rating Scale-IV (ADHD-RS-IV) has not yet been done to determine if clinical significance may be attributed to either one. Nor has there been a meta-analysis of the individual doses of lisdexamfetamine dimesylate. The current meta-analysis utilizes MEDLINE, Embase, Cochrane, PubMed, and clinicaltrials.gov to identify peer-reviewed studies. Selected studies were eligible if they met the following criteria: English language, randomized-controlled trials, and utilized the ADHD-RS-IV scale to assess the efficacy of lisdexamfetamine on treating ADHD in either children or adults. The primary studies utilized were published between January 2007 and April 2024. Many of these studies calculate effect sizes based on several dosages pooled together rather than by individual dosages. We conducted a random-effects meta-analysis to estimate the effect sizes for these pooled dosages on the full ADHD-RS-IV scale and its subscales, as well as to calculate effect sizes on the same scales based on the individual dosages. Our main outcome measures are the ADHD-RS-IV scale and its subscales in individual doses and pooled results in both children and adults. Adverse events during treatment were also analyzed based on stratified dosages. Eleven publications met our inclusion criteria. The analyses indicate that compared to placebo, lisdexamfetamine effectively alleviates the symptoms outlined by the ADHD-RS-IV. Moreover, there are no differences in the individual subscales or in the safety profile. Lisdexamfetamine demonstrates efficacy in treating the symptoms of ADHD, but we report that differing dosages did not yield significant differences in ADHD symptom management.
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Affiliation(s)
- Heath Rutledge-Jukes
- Department of Psychiatry, Washington University School of Medicine, St. Louis, USA
- Medical Education, King of the Curve LLC, St. Louis, USA
| | - Pallavi Jonnalagadda
- Department of Medical Education, Washington University in St. Louis School of Medicine, St. Louis, USA
| | | | - Saso Krstovski
- Department of Biological Sciences, University of Michigan, Ann Arbor, USA
| | - Nicholas Andriani
- Psychiatry, Florida Southern College, Lakeland, USA
- Orthopaedics, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, USA
| | - Ireland R Smith
- Office of Education and Curriculum, Southern Illinois University School of Medicine, Carbondale, USA
| | - Lauren Prendergast
- Department of Neurology, University of Colorado Anschutz Medical Campus, Boulder, USA
| | - James M Lynch
- Office of Education and Curriculum, Southern Illinois University School of Medicine, Carbondale, USA
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Heal DJ, Gosden J, Smith SL. Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2023; 99:251-286. [PMID: 38467483 DOI: 10.1016/bs.apha.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.
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Affiliation(s)
- David J Heal
- DevelRx Limited, BioCity, Pennyfoot Street, Nottingham, United Kingdom; Department of Life Sciences, University of Bath, Bath, United Kingdom.
| | - Jane Gosden
- DevelRx Limited, BioCity, Pennyfoot Street, Nottingham, United Kingdom
| | - Sharon L Smith
- DevelRx Limited, BioCity, Pennyfoot Street, Nottingham, United Kingdom
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Gutiérrez-Casares JR, Segú-Vergés C, Sabate Chueca J, Pozo-Rubio T, Coma M, Montoto C, Quintero J. In silico evaluation of the role of lisdexamfetamine on attention-deficit/hyperactivity disorder common psychiatric comorbidities: mechanistic insights on binge eating disorder and depression. Front Neurosci 2023; 17:1118253. [PMID: 37457000 PMCID: PMC10347683 DOI: 10.3389/fnins.2023.1118253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition well recognized in the pediatric population that can persist into adulthood. The vast majority of patients with ADHD present psychiatric comorbidities that have been suggested to share, to some extent, the pathophysiological mechanism of ADHD. Lisdexamfetamine (LDX) is a stimulant prodrug approved for treating ADHD and, in the US, also for binge eating disorder (BED). Herein, we evaluated, through a systems biology-based in silico method, the efficacy of a virtual model of LDX (vLDX) as ADHD treatment to improve five common ADHD psychiatric comorbidities in adults and children, and we explored the molecular mechanisms behind LDX's predicted efficacy. After the molecular characterization of vLDX and the comorbidities (anxiety, BED, bipolar disorder, depression, and tics disorder), we created a protein-protein interaction human network to which we applied artificial neural networks (ANN) algorithms. We also generated virtual populations of adults and children-adolescents totaling 2,600 individuals and obtained the predicted protein activity from Therapeutic Performance Mapping System models. The latter showed that ADHD molecular description shared 53% of its protein effectors with at least one studied psychiatric comorbidity. According to the ANN analysis, proteins targeted by vLDX are predicted to have a high probability of being related to BED and depression. In BED, vLDX was modeled to act upon neurotransmission and neuroplasticity regulators, and, in depression, vLDX regulated the hypothalamic-pituitary-adrenal axis, neuroinflammation, oxidative stress, and glutamatergic excitotoxicity. In conclusion, our modeling results, despite their limitations and although requiring in vitro or in vivo validation, could supplement the design of preclinical and potentially clinical studies that investigate treatment for patients with ADHD with psychiatric comorbidities, especially from a molecular point of view.
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Affiliation(s)
- José Ramón Gutiérrez-Casares
- Unidad Ambulatoria de Psiquiatría y Salud Mental de la Infancia, Niñez y Adolescencia, Hospital Perpetuo Socorro, Badajoz, Spain
| | - Cristina Segú-Vergés
- Anaxomics Biotech, Barcelona, Spain
- Research Programme on Biomedical Informatics (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | | | | | | | - Carmen Montoto
- Department of Medical, Takeda Farmacéutica España, Madrid, Spain
| | - Javier Quintero
- Servicio de Psiquiatría, Hospital Universitario Infanta Leonor, Departamento de Medicina Legal, Patología y Psiquiatría, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
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Gutiérrez-Casares JR, Quintero J, Segú-Vergés C, Rodríguez Monterde P, Pozo-Rubio T, Coma M, Montoto C. In silico clinical trial evaluating lisdexamfetamine's and methylphenidate's mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients' population. Front Psychiatry 2023; 14:939650. [PMID: 37333910 PMCID: PMC10273406 DOI: 10.3389/fpsyt.2023.939650] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 04/21/2023] [Indexed: 06/20/2023] Open
Abstract
Introduction Attention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment. Methods Herein, we applied a novel in silico method to evaluate virtual LDX (vLDX) and vMPH as treatments for ADHD applying quantitative systems pharmacology (QSP) models. The objectives were to evaluate the model's output, considering the model characteristics and the information used to build them, to compare both virtual drugs' efficacy mechanisms, and to assess how demographic (age, body mass index, and sex) and clinical characteristics may affect vLDX's and vMPH's relative efficacies. Results and Discussion We molecularly characterized the drugs and pathologies based on a bibliographic search, and generated virtual populations of adults and children-adolescents totaling 2,600 individuals. For each virtual patient and virtual drug, we created physiologically based pharmacokinetic and QSP models applying the systems biology-based Therapeutic Performance Mapping System technology. The resulting models' predicted protein activity indicated that both virtual drugs modulated ADHD through similar mechanisms, albeit with some differences. vMPH induced several general synaptic, neurotransmitter, and nerve impulse-related processes, whereas vLDX seemed to modulate neural processes more specific to ADHD, such as GABAergic inhibitory synapses and regulation of the reward system. While both drugs' models were linked to an effect over neuroinflammation and altered neural viability, vLDX had a significant impact on neurotransmitter imbalance and vMPH on circadian system deregulation. Among demographic characteristics, age and body mass index affected the efficacy of both virtual treatments, although the effect was more marked for vLDX. Regarding comorbidities, only depression negatively impacted both virtual drugs' efficacy mechanisms and, while that of vLDX were more affected by the co-treatment of tic disorders, the efficacy mechanisms of vMPH were disturbed by wide-spectrum psychiatric drugs. Our in silico results suggested that both drugs could have similar efficacy mechanisms as ADHD treatment in adult and pediatric populations and allowed raising hypotheses for their differential impact in specific patient groups, although these results require prospective validation for clinical translatability.
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Affiliation(s)
- José Ramón Gutiérrez-Casares
- Unidad Ambulatoria de Psiquiatría y Salud Mental de la Infancia, Niñez y Adolescencia, Hospital Perpetuo Socorro, Badajoz, Spain
| | - Javier Quintero
- Servicio de Psiquiatría, Hospital Universitario Infanta Leonor, Universidad Complutense, Madrid, Spain
| | - Cristina Segú-Vergés
- Anaxomics Biotech, Barcelona, Spain
- Structural Bioinformatics Group, Research Programme on Biomedical Informatics, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | | | | | | | - Carmen Montoto
- Medical Department, Takeda Farmacéutica España, Madrid, Spain
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van Stralen J, Parhar G, Parhar A, Tourjman V, Khattak S, Ahmed T, Donnelly GAE, Ratz J. Real-World Efficacy and Safety of Extended-Release Methylphenidate (PRC-063) in the Treatment of ADHD in Pediatric and Adult Subjects: Results of a Phase IV Multicenter Comparison With Lisdexamfetamine Dimesylate. J Atten Disord 2023; 27:743-756. [PMID: 37144295 PMCID: PMC11020119 DOI: 10.1177/10870547231172767] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
OBJECTIVE To evaluate the real-world efficacy, safety, and functional outcomes of PRC-063 (multilayer-release methylphenidate) versus lisdexamfetamine (LDX) in ADHD subjects in a phase IV, open-label study. METHOD The primary endpoint was the change in the ADHD-DSM-5 Rating Scale (ADHD-5-RS) total score from baseline to Month 4. Secondary endpoints included a non-inferiority comparison between PRC-063 and LDX and measures of functioning and evening behavior. RESULTS One hundred forty-three pediatric and 112 adult subjects were enrolled. Mean ADHD-5-RS scores (standard deviation) were reduced in pediatric (-16.6 [10.4]) and adult (-14.8 [10.6]) subjects treated with PRC-063 (p < .001). PRC-063 was non-inferior to LDX in the pediatric population but not in the adult population. Significant improvements were demonstrated in quality of life and functionality. Both medications were well-tolerated; more adverse events led to study discontinuation in pediatric subjects treated with LDX versus PRC-063. CONCLUSION PRC-063 and LDX significantly improved ADHD symptomatology and functioning and were well-tolerated.
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Affiliation(s)
| | | | | | - Valérie Tourjman
- Centre de recherche de l’Institut universitaire en santé mentale de Montréal, Montréal, QC, Canada
| | | | | | | | - Jodan Ratz
- Elvium Life Sciences, Toronto, ON, Canada
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Storebø OJ, Storm MRO, Pereira Ribeiro J, Skoog M, Groth C, Callesen HE, Schaug JP, Darling Rasmussen P, Huus CML, Zwi M, Kirubakaran R, Simonsen E, Gluud C. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3:CD009885. [PMID: 36971690 PMCID: PMC10042435 DOI: 10.1002/14651858.cd009885.pub3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
BACKGROUND Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015. OBJECTIVES To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate. SELECTION CRITERIA We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life. DATA COLLECTION AND ANALYSIS Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach. MAIN RESULTS We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants. Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias. PRIMARY OUTCOMES methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -0.88 to -0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of -10.58 (95% CI -12.58 to -8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68). SECONDARY OUTCOMES methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD -0.62, 95% CI -0.91 to -0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI -0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear. Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials. Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
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Affiliation(s)
- Ole Jakob Storebø
- Psychiatric Research Unit, Region Zealand Psychiatry, Slagelse, Denmark
- Child and Adolescent Psychiatric Department, Region Zealand, Roskilde, Denmark
- Department of Psychology, University of Southern Denmark, Odense, Denmark
| | | | | | - Maria Skoog
- Clinical Study Support, Clinical Studies Sweden - Forum South, Lund, Sweden
| | - Camilla Groth
- Pediatric Department, Herlev University Hospital, Herlev, Denmark
| | | | | | | | | | - Morris Zwi
- Islington Child and Adolescent Mental Health Service, Whittington Health, London, UK
| | - Richard Kirubakaran
- Cochrane India-CMC Vellore Affiliate, Prof. BV Moses Centre for Evidence Informed Healthcare and Health Policy, Christian Medical College, Vellore, India
| | - Erik Simonsen
- Research Unit, Mental Health services, Region Zealand Psychiatry, Roskilde, Denmark
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital ─ Rigshospitalet, Copenhagen, Denmark
- Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Fan HC, Chiang KL, Chang KH, Chen CM, Tsai JD. Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges. Int J Mol Sci 2023; 24:ijms24065270. [PMID: 36982345 PMCID: PMC10049646 DOI: 10.3390/ijms24065270] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/20/2023] [Accepted: 03/01/2023] [Indexed: 03/12/2023] Open
Abstract
Comorbidities are common in children with epilepsy, with nearly half of the patients having at least one comorbidity. Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder characterized by hyperactivity and inattentiveness level disproportional to the child’s developmental stage. The burden of ADHD in children with epilepsy is high and can adversely affect the patients’ clinical outcomes, psychosocial aspects, and quality of life. Several hypotheses were proposed to explain the high burden of ADHD in childhood epilepsy; the well-established bidirectional connection and shared genetic/non-genetic factors between epilepsy and comorbid ADHD largely rule out the possibility of a chance in this association. Stimulants are effective in children with comorbid ADHD, and the current body of evidence supports their safety within the approved dose. Nonetheless, safety data should be further studied in randomized, double-blinded, placebo-controlled trials. Comorbid ADHD is still under-recognized in clinical practice. Early identification and management of comorbid ADHD are crucial to optimize the prognosis and reduce the risk of adverse long-term neurodevelopmental outcomes. The identification of the shared genetic background of epilepsy and ADHD can open the gate for tailoring treatment options for these patients through precision medicine.
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Affiliation(s)
- Hueng-Chuen Fan
- Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, Wuchi, Taichung 435, Taiwan
- Department of Rehabilitation, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan
- Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan
| | - Kuo-Liang Chiang
- Department of Pediatric Neurology, Kuang-Tien General Hospital, Taichung 433, Taiwan
- Department of Nutrition, Hungkuang University, Taichung 433, Taiwan
| | - Kuang-Hsi Chang
- Department of Medical Research, Tungs’ Taichung Metroharbor Hospital, Wuchi, Taichung 435, Taiwan
| | - Chuan-Mu Chen
- Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan
- The iEGG and Animal Biotechnology Center, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: (C.-M.C.); (J.-D.T.); Tel.: +886-4-22840319-701 (C.-M.C.); +886-4-24730022-21731 (J.-D.T.)
| | - Jeng-Dau Tsai
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Correspondence: (C.-M.C.); (J.-D.T.); Tel.: +886-4-22840319-701 (C.-M.C.); +886-4-24730022-21731 (J.-D.T.)
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Idrees I, Bellato A, Cortese S, Groom MJ. The effects of stimulant and non-stimulant medications on the autonomic nervous system (ANS) functioning in people with ADHD: A systematic review and meta-analysis. Neurosci Biobehav Rev 2023; 144:104968. [PMID: 36427764 DOI: 10.1016/j.neubiorev.2022.104968] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 11/12/2022] [Accepted: 11/19/2022] [Indexed: 11/25/2022]
Abstract
We carried out a systematic review and meta-analysis to investigate the effects of stimulant and non-stimulant medications on autonomic functioning in people with ADHD (PROSPERO: CRD42020212439). We searched (9th August 2021) PsycInfo, MEDLINE, EMBASE, Web of Science and The Cochrane Library, for randomised and non-randomised studies reporting indices of autonomic activity, (electrodermal, pupillometry and cardiac), pre- and post-medication exposure in people meeting DSM/ICD criteria for ADHD. In the narrative syntheses, we included 5 electrodermal studies, 1 pupillometry study and 57 studies investigating heart rate and blood pressure. In the meta-analyses, 29 studies were included on blood pressure and 32 on heart rate. Administration of stimulants, and to a lesser degree, non-stimulants increased heart rate and blood pressure in people with ADHD. Similarly, an upregulation of arousal, reflected in increased electrodermal activity and pupil diameter was observed following stimulant use. Yet, the methodological diversity of studies presented in this review reinforces the need for more standardised and rigorous research to fully understand the relationship between arousal, medication, and behaviour in ADHD.
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Affiliation(s)
- Iman Idrees
- Academic Unit of Mental Health & Clinical Neurosciences, School of Medicine, Institute of Mental Health, University of Nottingham, Nottingham, UK.
| | - Alessio Bellato
- School of Psychology, University of Nottingham Malaysia, Malaysia
| | - Samuele Cortese
- Academic Unit of Mental Health & Clinical Neurosciences, School of Medicine, Institute of Mental Health, University of Nottingham, Nottingham, UK; Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA
| | - Madeleine J Groom
- Academic Unit of Mental Health & Clinical Neurosciences, School of Medicine, Institute of Mental Health, University of Nottingham, Nottingham, UK
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Childress AC, Lloyd E, Jacobsen L, Gunawardhana L, Johnson SA, Findling RL. Efficacy and Safety of Lisdexamfetamine in Preschool Children With Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry 2022; 61:1423-1434. [PMID: 35577034 DOI: 10.1016/j.jaac.2022.03.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/03/2022] [Accepted: 05/06/2022] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To evaluate the acute efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) vs placebo (PBO) in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). METHOD This phase 3, double-blind, fixed-dose study randomly assigned children (aged 4-5 years) with ADHD to 6 weeks of LDX (5, 10, 20, 30 mg) or PBO. The prespecified primary (change from baseline at week 6 in ADHD Rating Scale IV, Preschool version, total score [ADHD-RS-IV-PS-TS]) and key secondary (Clinical Global Impression-Improvement [CGI-I] score at week 6) efficacy endpoints were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and changes in pulse and blood pressure (BP). RESULTS The study comprised 199 participants randomly asigned 5:5:5:5:6 to receive 5, 10, 20, 30 mg LDX or PBO, respectively. Least squares (LS) mean (95% CI) treatment difference at week 6 between pooled LDX (10, 20, 30 mg) and PBO was statistically significant for ADHD-RS-IV-PS-TS change (-5.9 [-11.01, -0.78], p = .0242; effect size [ES], -0.43). CGI-I scores improved (ie, 1-2 on CGI-I) in 41.7% for pooled LDX and 24.3% for PBO (p = .0857). The LS mean (95% CI) treatment difference between pooled LDX and PBO for CGI-I score at week 6 was -0.6 (-1.03, -0.16; p = .0074; ES, -0.52). Frequency of TEAEs was 46.6% across all 4 LDX doses vs 42.2% with PBO; the most frequent TEAEs were decreased appetite (13.7% vs 8.9%, respectively) and irritability (9.6% vs 0%). Discontinuations because of TEAEs were 5.5% for all LDX doses and 4.4% for PBO. Mean ± SD pulse/BP changes from baseline at week 6/early termination were numerically greater with LDX vs PBO (pulse beats/min: 2.7 ± 10.79 vs 1.2 ± 9.90; systolic BP, mm Hg: 1.0 ± 7.51 vs 0.3 ± 6.06; diastolic BP, mm Hg: 1.7 ± 5.90 vs 0.0 ± 6.88). CONCLUSION In children aged 4 to 5 years with ADHD, LDX was more efficacious than PBO in reducing symptoms. The observed ES for change in ADHD-RS-IV-PS-TS appears to be smaller in magnitude than has been reported for studies of LDX conducted in older children and adolescents. LDX was generally well tolerated, and no new safety signals were identified. CLINICAL TRIAL REGISTRATION INFORMATION Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-Deficit/Hyperactivity Disorder; http://www. CLINICALTRIALS gov; NCT03260205.
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Affiliation(s)
- Ann C Childress
- Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada.
| | - Eric Lloyd
- Takeda Development Center Americas, Inc., Lexington, Massachusetts
| | - Leslie Jacobsen
- Neurogene Inc., New York; Shire, a member of the Takeda group of companies, Lexington, Massachusetts
| | | | - Steven A Johnson
- Takeda Development Center Americas, Inc., Lexington, Massachusetts
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14
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A novel school-based approach to screening for attention deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 2022; 31:909-917. [PMID: 33515089 DOI: 10.1007/s00787-021-01721-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/11/2021] [Indexed: 10/22/2022]
Abstract
Current approaches to screening for ADHD result in high rates of false positives. A proof of concept study to investigate the added benefits in the school-based detection of ADHD of adding a standardised teacher to teacher interview to traditional parent and teacher report questionnaires. A school-based study of diagnostic accuracy of ADHD using a novel 2-stage screening process. Participants were all 1026 pupils enrolled in grades 1 to 6 (ages 6-12 years) of a school in Hunan Province, China. The primary outcome was a diagnosis of ADHD on the Kiddie Schedule for Affective Disorders and Schizophrenia Present Lifetime version. 230 (22.4%) of the 1026 students screened positive at Stage 1 (parent and teacher questionnaires) (Sensitivity 0.86 [95% CI, 0.75 to 0.96], specificity 0.80 [95% CI, 0.78-0.83], false positive rate 0.20 (95% CI, 0.18 to 0.23), false negative rate was 0.14 (95% CI, 0.12 to 0.16). 65 remained screen-positive at the Stage 2 screen (teacher to teacher SNAP-IV interview). 36/65 (55.4%) of these Stage 2 screen positive participants and 1/144 (0.7%) of the screen negative subjects met DSM-IV criteria for ADHD (sensitivity 0.83 [95% CI, 0.71-0.95]; specificity of 0.97 [95% CI, 0.96-0.98]; false positive rate 0.03 [95% CI, 0.01 to 0.04], false negative rate 0.16 [95% CI, 0.15 to 0.19]. Adding teacher to teacher interviews to traditional questionnaire-based screening has the potential to improve the clinical utility of school-based screening for ADHD reducing the proportion of false positives, without a negative impact on sensitivity.
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15
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Childress AC, Lloyd E, Johnson SA, Gunawardhana L, Arnold V. A Long-Term, Open-Label Safety and Tolerability Study of Lisdexamfetamine Dimesylate in Children Aged 4-5 Years with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol 2022; 32:98-106. [PMID: 35230142 PMCID: PMC8971990 DOI: 10.1089/cap.2021.0138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Objective: To evaluate the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in preschool-aged children (4-5 years of age inclusive) diagnosed with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 3 open-label study (ClinicalTrials.gov registry: NCT02466386) enrolled children aged 4-5 years meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for a primary ADHD diagnosis and having baseline ADHD Rating Scale-IV Preschool version total scores (ADHD-RS-IV-PS-TS) ≥24 for girls or ≥28 for boys and baseline Clinical Global Impressions-Severity scores ≥4. Participants were directly enrolled or enrolled after completing one of two antecedent short-term LDX studies. Over 52 weeks of treatment, participants received once-daily dose-optimized LDX (5-30 mg). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital sign changes. Clinical outcomes included ADHD-RS-IV-PS-TS changes from baseline. Results: Among 113 participants in the safety set, optimized LDX dose was 5, 10, 15, 20, and 30 mg in 1 (0.9%), 12 (10.6%), 21 (18.6%), 26 (23.0%), and 53 (46.9%) participants, respectively. Of the safety set, 69 participants (61.1%) completed the study. TEAEs were reported in 76.1% of participants; no serious TEAEs were reported. Only one type of TEAE was reported in >10% of participants (decreased appetite, 15.9%). Mean ± standard deviation (SD) changes in vital signs and body weight from baseline to week 52/or early termination (ET; n = 101) were 1.9 ± 7.73 mmHg for systolic blood pressure, 3.1 ± 7.58 mmHg for diastolic blood pressure, 4.7 ± 11.00 bpm for pulse, and 0.6 ± 1.38 kg for body weight. Over the course of the study, mean ± SD change in ADHD-RS-IV-PS-TS from baseline to week 52/ET was -24.2 ± 13.34 (n = 87). Conclusions: In this long-term 52-week study of children aged 4-5 years with ADHD, dose-optimized LDX (5-30 mg) was well tolerated and associated with reductions from baseline in ADHD symptoms.
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Affiliation(s)
- Ann C. Childress
- Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada, USA.,Address correspondence to: Ann C. Childress, MD, Center for Psychiatry and Behavioral Medicine, 7351 Prairie Falcon Rd, Suite 160, Las Vegas, NV 89128, USA
| | - Eric Lloyd
- Takeda Pharmaceuticals USA, Inc., Bannockburn, Illinois, USA
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16
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Hasan SS, Bal N, Baker I, Kow CS, Khan MU. Adverse Drug Reaction Reporting and Prescribing Trends of Drugs for Attention Deficit Hyperactivity Disorder in Primary Care England, 2010-2019. J Atten Disord 2022; 26:467-475. [PMID: 33666114 PMCID: PMC8785293 DOI: 10.1177/1087054721997556] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE We investigated the prescription trends and adverse drug reactions (ADRs) of ADHD drugs in primary care, England between 2010 and 2019. METHODS The Prescription Cost Analysis database presenting the primary care prescriptions data and the Interactive Drug Analysis Profiles presenting all suspected ADRs reported for each drug were screened. The data were analyzed using linear regression analysis to examine the annual average change per year. RESULTS The prescription items dispensed for ADHD showed an average 11.07% (95% CI 10.54-11.60, p = .001) increase per year and there was a mean 11.54% (95% CI 11.03-12.06, p = .001) increase per year in the costs. The overall reporting of serious and fatal ADR was reduced by 1.79% per year for ADHD drugs. Guanfacine showed a 40% mean increase per year. CONCLUSION The increasing use of ADHD drugs within primary care in England could be a result of multiple factors such as growing ADHD prevalence.
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Affiliation(s)
- Syed Shahzad Hasan
- University of Huddersfield, UK
- Syed Shahzad Hasan, Department of Pharmacy, University of Huddersfield, Queensgate, Huddersfield, Kirklees HD1 3DH, UK.
| | | | | | - Chia Siang Kow
- International Medical University, Kuala Lumpur, Malaysia
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Hai T, Duffy HA, Lemay JA, Lemay JF. Impact of stimulant medication on behaviour and executive functions in children with attention-deficit/hyperactivity disorder. World J Clin Pediatr 2022; 11:48-60. [PMID: 35096546 PMCID: PMC8771318 DOI: 10.5409/wjcp.v11.i1.48] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/08/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Children with attention-deficit/hyperactivity disorder (ADHD) often exhibit behaviour challenges and deficits in executive functions (EF). Psychostimulant medications [e.g., methylphenidate (MPH)] are commonly prescribed for children with ADHD and are considered effective in 70% of the cases. Furthermore, only a handful of studies have investigated the long-term impact of MPH medication on EF and behaviour.
AIM To evaluate behaviour and EF challenges in children with ADHD who were involved in an MPH treatment trial across three-time points.
METHODS Thirty-seven children with ADHD completed a stimulant medication trial to study the short- and long-term impact of medication. Children with ADHD completed three neuropsychological assessments [Continuous Performance Test (CPT)-II, Digit Span Backwards and Spatial Span Backwards]. Parents of children with ADHD completed behaviour rating scales [Behaviour Rating Inventory of Executive Functioning (BRIEF) and Behaviour Assessment System for Children-Second Edition (BASC-2)]. Participants were evaluated at: (1) Baseline (no medication); and (2) Best-dose (BD; following four-week MPH treatment). Additionally, 18 participants returned for a long-term naturalistic follow up (FU; up to two years following BD).
RESULTS Repeated measure analyses of variance found significant effects of time on two subscales of BRIEF and four subscales of BASC-2. Neuropsychological assessments showed some improvement, but not on all tasks following the medication trial. These improvements did not sustain at FU, with increases in EF and behaviour challenges, and a decline in performance on the CPT-II task being observed.
CONCLUSION Parents of children with ADHD reported improvements in EF and behaviours during the MPH trial but were not sustained at FU. Combining screening tools and neuropsychological assessments may be useful for monitoring medication responses.
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Affiliation(s)
- Tasmia Hai
- Werklund School of Education, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Hanna A Duffy
- Werklund School of Education, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Julie Anne Lemay
- Department of Paediatrics, Alberta Children's Hospital/Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada
| | - Jean François Lemay
- Department of Paediatrics, Alberta Children's Hospital/Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada
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Heal DJ, Gosden J, Smith SL. New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development. Curr Top Behav Neurosci 2022; 57:79-126. [PMID: 35507283 DOI: 10.1007/7854_2022_332] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trials together with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.
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Affiliation(s)
- David J Heal
- DevelRx Ltd, Nottingham, UK.
- Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
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Gutiérrez-Casares JR, Quintero J, Jorba G, Junet V, Martínez V, Pozo-Rubio T, Oliva B, Daura X, Mas JM, Montoto C. Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate. Front Psychiatry 2021; 12:741170. [PMID: 34803764 PMCID: PMC8595241 DOI: 10.3389/fpsyt.2021.741170] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/05/2021] [Indexed: 11/13/2022] Open
Abstract
Regulatory agencies encourage computer modeling and simulation to reduce the time and cost of clinical trials. Although still not classified in formal guidelines, system biology-based models represent a powerful tool for generating hypotheses with great molecular detail. Herein, we have applied a mechanistic head-to-head in silico clinical trial (ISCT) between two treatments for attention-deficit/hyperactivity disorder, to wit lisdexamfetamine (LDX) and methylphenidate (MPH). The ISCT was generated through three phases comprising (i) the molecular characterization of drugs and pathologies, (ii) the generation of adult and children virtual populations (vPOPs) totaling 2,600 individuals and the creation of physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models, and (iii) data analysis with artificial intelligence methods. The characteristics of our vPOPs were in close agreement with real reference populations extracted from clinical trials, as did our PBPK models with in vivo parameters. The mechanisms of action of LDX and MPH were obtained from QSP models combining PBPK modeling of dosing schemes and systems biology-based modeling technology, i.e., therapeutic performance mapping system. The step-by-step process described here to undertake a head-to-head ISCT would allow obtaining mechanistic conclusions that could be extrapolated or used for predictions to a certain extent at the clinical level. Altogether, these computational techniques are proven an excellent tool for hypothesis-generation and would help reach a personalized medicine.
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Affiliation(s)
- José Ramón Gutiérrez-Casares
- Unidad Ambulatoria de Psiquiatría y Salud Mental de la Infancia, Niñez y Adolescencia, Hospital Perpetuo Socorro, Badajoz, Spain
| | - Javier Quintero
- Servicio de Psiquiatría, Hospital Universitario Infanta Leonor, Universidad Complutense, Madrid, Spain
| | - Guillem Jorba
- Anaxomics Biotech, Barcelona, Spain
- Research Programme on Biomedical Informatics (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Valentin Junet
- Anaxomics Biotech, Barcelona, Spain
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
| | | | | | - Baldomero Oliva
- Research Programme on Biomedical Informatics (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Xavier Daura
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | | | - Carmen Montoto
- Medical Department, Takeda Farmacéutica España, Madrid, Spain
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20
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Weiss MD, Cutler AJ, Kollins SH, Donnelly GAE. Efficacy and Safety of a Long-Acting Multilayer-Release Methylphenidate Formulation (PRC-063) in the Treatment of Adolescent Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Clinical Trial with a 6-Month Open-Label Extension. J Child Adolesc Psychopharmacol 2021; 31:610-622. [PMID: 34637343 DOI: 10.1089/cap.2021.0034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Objectives: To study the safety and efficacy of the long-acting methylphenidate formulation PRC-063 in adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Adolescents 12 to ≤17 years who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for ADHD and had a baseline ADHD Rating Scale DSM-5 (ADHD-5-RS) score ≥24 participated in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study. Participants were randomized 1:1:1:1:1 to receive placebo or one of four doses of PRC-063 once daily for 4 weeks. The primary endpoint was change from baseline in least-squares mean clinician-rated ADHD-5-RS total score for PRC-063 (all doses combined) versus placebo. Other efficacy assessments included Conners third Edition: Self-Report (C3SR) and Clinical Global Impression-Improvement (CGI-I). A subset of double-blind study participants entered a subsequent open-label, dose-optimized study. Safety outcomes in both studies included treatment-emergent adverse events (TEAEs). Results: Three hundred fifty-four participants were included in the primary analysis. The least-squares mean change from baseline in ADHD-5-RS total score was -15.17 for PRC-063 versus -10.98 for placebo (least-squares mean difference -4.2, p = 0.0067). For individual PRC-063 doses, improvements in ADHD-5-RS total score versus placebo were significant for 45 mg (p = 0.0155) and 70 mg (p = 0.0401), but not for 25 or 85 mg. A significant improvement for PRC-063 versus placebo was recorded for C3SR Inattention (p = 0.0168), but not for the other C3SR subscales. About 52.7% of participants randomized to PRC-063 were responders based on CGI-I versus 32.4% of those randomized to placebo (p = 0.0004). Further improvements in ADHD symptoms based on ADHD-5-RS were observed from 1 month through 6 months of open-label treatment (p < 0.0001). There were two serious adverse events (both during the open-label study), one of which (aggressive behavior) was assessed as related to study drug. The only TEAEs that occurred in >10% of participants during double-blind treatment were decreased appetite (20.1%) and headache (15.0%). Most TEAEs were of mild or moderate severity. Conclusion: PRC-063 significantly improved ADHD symptomatology in adolescents. It was generally well tolerated, with an AE profile consistent with other long-acting stimulants. NCT02139111 and NCT02168127.
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Affiliation(s)
- Margaret D Weiss
- Child and Adolescent Psychiatry, Cambridge Health Alliance, Cambridge, Massachusetts, USA
| | - Andrew J Cutler
- Department of Psychiatry, Neuroscience Education Institute and SUNY Upstate Medical University, Lakewood Ranch, Florida, USA
| | - Scott H Kollins
- Holmusk, Durham, North Carolina, USA.,Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina, USA
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21
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Coghill DR, Werner-Kiechle T, Farahbakhshian S, Bliss C, Robertson B, Huss M. Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses. Eur Child Adolesc Psychiatry 2021; 30:809-821. [PMID: 32691164 PMCID: PMC8060241 DOI: 10.1007/s00787-020-01586-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 02/24/2020] [Indexed: 11/16/2022]
Abstract
Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement.
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Affiliation(s)
- David R. Coghill
- grid.1008.90000 0001 2179 088XDepartments of Paediatrics and Psychiatry, Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, VIC 3010 Australia ,grid.1058.c0000 0000 9442 535XMurdoch Children’s Research Institute, Parkville, VIC Australia
| | | | | | - Caleb Bliss
- grid.419849.90000 0004 0447 7762Shire, a Takeda company, Lexington, MA USA
| | - Brigitte Robertson
- grid.419849.90000 0004 0447 7762Shire, a Takeda company, Lexington, MA USA
| | - Michael Huss
- grid.5802.f0000 0001 1941 7111Child and Adolescent Psychiatry, Johannes Gutenberg-University Mainz, Mainz, Germany
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22
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Najib J, Didenko E, Meleshkina D, Yusupov K, Maw K, Ramnarain J, Tabassum M. Review of lisdexamfetamine dimesylate in children and adolescents with attention deficit/hyperactivity disorder. Curr Med Res Opin 2020; 36:1717-1735. [PMID: 32845786 DOI: 10.1080/03007995.2020.1815002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Lisdexamfetamine dimesylate is a stimulant prodrug with low abuse and diversion potential that is used in treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults. This current literature review article aims to examine safety and efficacy of LDX in children and adolescents for the treatment of ADHD based on currently available data. METHODS Relevant English language articles were identified through computerized searches of the MEDLINE database (PubMed and EMBASE) and clinical trials registry up to January 2020 using the following search terms: lisdexamfetamine dimesylate, pro-drug stimulant, attention-deficit and hyperactivity disorders, ADHD, safety, efficacy, children, adolescents, Vyvanse. Forty-two articles were reviewed, 34 of which were included into this review, selected by the limit "clinical trials". This article represents the pharmacological profile, efficacy and safety data of LDX for the treatment of ADHD in children and adolescents. RESULTS The collection of studies reviewed identified that LDX was both safe and efficacious in the treatment of ADHD. The most commonly exhibited side effects were appetite suppression, weight loss, headache and insomnia. In comparison to placebo, LDX significantly improved ADHD symptoms and overall quality of life in children and adolescents. In comparison to atomoxetine, LDX showed statistically significant improvements in inattention, impulsivity, and activities of daily living. In comparison to OROS-MPH and placebo, LDX and OROS-MPH showed improvements with the CGI-I score, and ADHD-RS-IV, however, LDX was superior. CONCLUSION Patients have seen statistically significant improvements in their ADHD symptomatology in the classroom environment, health related quality of life, and their overall behavior in comparison to placebo, atomoxetine, and OROS-MPH. However, clinical judgment should be utilized when prescribing LDX due to patient specific needs and the side effect profile.
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Affiliation(s)
- Jadwiga Najib
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
- Departments of Pharmacy and Psychiatry, Mount Sinai West Hospital Center, New York, NY, USA
| | - Ekaterina Didenko
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
| | - Daria Meleshkina
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
| | - Kamila Yusupov
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
| | - Kateryna Maw
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
| | - Justin Ramnarain
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
| | - Maliha Tabassum
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
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23
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Siffel C, Page M, Maxwell T, Thun B, Kolb N, Rosenlund M, von Bredow D, Keja J. Patterns of Lisdexamfetamine Dimesylate Use in Children, Adolescents, and Adults with Attention-Deficit/Hyperactivity Disorder in Europe. J Child Adolesc Psychopharmacol 2020; 30:439-447. [PMID: 32315539 PMCID: PMC7475084 DOI: 10.1089/cap.2019.0173] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Objectives: Lisdexamfetamine dimesylate (LDX) is approved in some European countries for the second-line treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents when response to previous methylphenidate (MPH) treatment is considered clinically inadequate, and as a first-line treatment in adults. Limited evidence exists on the real-world use of LDX across Europe. This retrospective study evaluated LDX drug utilization patterns from eight European countries for up to 5 years. Methods: Data were collected from national registries (Denmark, Finland, Norway, Sweden), electronic medical records (Germany, Spain, United Kingdom), and prescription databases (Switzerland) in eight European countries. Patients were included if they were prescribed LDX at least once since the LDX launch date in each country. Demographic and clinical characteristics, and LDX prescription data included patient age and gender, a recorded diagnosis of ADHD, the number of prescriptions per participant, previous MPH prescription recorded, average daily dose, treatment persistence, discontinuation, and switching of medications. Results: Overall, information for 59,292 patients (437,272 LDX prescriptions) was analyzed. Most patients were male (58.1%-84.3%) and fewer than 1% were under 6 years of age. Extensive use of LDX in adults was observed in four countries (Denmark, Finland, Norway, and Sweden), including countries where LDX was not approved for this age group. Most patients had a recorded diagnosis of ADHD (61.9%-95.4%). The mean number of prescriptions per patient ranged from 5.4 to 10.0. At least 79.6% of patients with ADHD had a recorded previous MPH prescription. Mean duration of LDX exposure ranged from 233.1 to 410.8 days. The average daily dose of LDX was ≤70 mg/day for most patients (79.4%-99.7%). The 5-year discontinuation rate ranged from 22.8% to 70.6% and was below 40% for most countries. The proportion of patients switching from LDX to other medications was ≤33.8. Conclusions: This study provides the first long-term, real-world information related to LDX use by children, adolescents, and adults in Europe in the 5 years since its first launch in the region. Most LDX prescriptions fulfilled label requirements regarding a recorded diagnosis of ADHD before treatment initiation, previous MPH use, and an average daily dose of ≤70 mg/day. LDX was largely prescribed within the indicated age range, although adult use of LDX was high in some countries where LDX is not approved for this population.
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Affiliation(s)
- Csaba Siffel
- Global Evidence and Outcomes, Data Sciences Institute, Shire, a Takeda Company, Lexington, Massachusetts, USA.,College of Allied Health Sciences, Augusta University, Augusta, Georgia, USA.,Address correspondence to: Csaba Siffel, MD, PhD, Shire, a Takeda Company, 300 Shire Way, Lexington, MA 02421, USA
| | - Matthew Page
- Marketed Products Group, Chief Medical Office, Shire, a Takeda Company, Cambridge, Massachusetts, USA
| | - Tricia Maxwell
- Marketed Products Group, Chief Medical Office, Shire, a Takeda Company, Cambridge, Massachusetts, USA
| | | | | | - Mats Rosenlund
- Real World Solutions, IQVIA, Solna, Sweden.,Department of Learning, Informatics, Management and Ethics (LIME), Karolinska Institutet, Stockholm, Sweden
| | | | - Jacco Keja
- Real World Solutions, IQVIA, Paris, France
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24
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Coghill DR, Newcorn JH, Chen J, Werner-Kiechle T, Banaschewski T. Post hoc analyses of response rates to pharmacological treatments in children and adolescents with attention-deficit/hyperactivity disorder. J Psychopharmacol 2020; 34:874-882. [PMID: 32043417 PMCID: PMC7376623 DOI: 10.1177/0269881120904949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
INTRODUCTION AND OBJECTIVES Lack of consensus regarding how best to define treatment response hinders translation from trials to the clinic. These post hoc analyses examine three commonly used response criteria in six trials of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS Data from four short-term randomised controlled trials (RCTs) and two long-term open-label studies were analysed. Children and adolescents with ADHD received either dose-optimised (30-70 mg/day) or fixed-dose (70 mg/day) LDX. The RCTs included osmotic-release oral system methylphenidate (OROS-MPH) or atomoxetine (ATX) as a head-to-head comparator or as a reference treatment. Three definitions of response were used in these analyses: reductions of ⩾30% or ⩾50% in ADHD Rating Scale IV (ADHD-RS-IV) total score plus a Clinical Global Impressions - Improvement (CGI-I) score of 1 or 2, or an ADHD-RS-IV total score of ⩽18. RESULTS At the end point, LDX response rates for the least stringent criterion of ⩾30% reduction in ADHD-RS-IV total score plus a CGI-I score of 1 or 2 ranged from 69.6% to 82.6%. The proportion achieving the more stringent criterion of a reduction in ADHD-RS-IV total score of ⩾50% plus a CGI-I score of 1 or 2 at the end point ranged from 59.8% to 74.8%. An ADHD-RS-IV total score of ⩽18 at the end point was achieved by 56.7-79.9% of participants. Response rates remained stable throughout the long-term open-label studies. CONCLUSIONS Response rates were similar for the two more stringent response criteria. The less stringent criterion resulted in higher response rates and may include partial responders.
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Affiliation(s)
- David R Coghill
- Departments of Paediatrics and Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia,Murdoch Children’s Research Institute, Melbourne, Australia,David R Coghill, Departments of Paediatrics and Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Level 2 West, Royal Children’s Hospital, Melbourne, VIC 3052, Australia.
| | - Jeffrey H Newcorn
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jie Chen
- Shire, a member of the Takeda group of companies, Lexington, MA, USA
| | | | - Tobias Banaschewski
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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25
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Childress AC, Findling RL, Wu J, Kollins SH, Wang Y, Martin P, Robertson B. Lisdexamfetamine Dimesylate for Preschool Children with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol 2020; 30:128-136. [PMID: 32233956 PMCID: PMC7153646 DOI: 10.1089/cap.2019.0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Objectives: Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4-5 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores ≥28 (boys) or ≥24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Results: Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were -1.1 (7.31) and 1.5 (6.93) mmHg and -0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was -26.1 (-32.2 to -20.0). Pharmacokinetic parameters of d-amphetamine, a major active metabolite of LDX, were characterized: d-amphetamine exposure increased with LDX dose; mean tmax and t1/2, respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. Conclusions: In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6-17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.
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Affiliation(s)
- Ann C. Childress
- Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada.,Address correspondence to: Ann C. Childress, MD, Center for Psychiatry and Behavioral Medicine, 7351 Prairie Falcon Road, Suite 160, Las Vegas, NV 89128
| | - Robert L. Findling
- Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - James Wu
- Biostatistics, Shire, a member of the Takeda group of companies, Lexington, Massachusetts
| | - Scott H. Kollins
- Department of Psychiatry and Behavioral Science, Duke University, Durham, North Carolina
| | - Yi Wang
- Clinical Pharmacology and Pharmacokinetics, Shire, a member of the Takeda group of companies, Lexington, Massachusetts
| | - Patrick Martin
- Clinical Pharmacology and Pharmacokinetics, Shire, a member of the Takeda group of companies, Lexington, Massachusetts
| | - Brigitte Robertson
- Global Clinical Development, Shire, a member of the Takeda group of companies, Lexington, Massachusetts
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26
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Vallejo-Valdivielso M, de Castro-Manglano P, Díez-Suárez A, Marín-Méndez JJ, Soutullo CA. Clinical and Neuropsychological Predictors of Methylphenidate Response in Children and Adolescents with ADHD: A Naturalistic Follow-up Study in a Spanish Sample. Clin Pract Epidemiol Ment Health 2019; 15:160-171. [PMID: 32174998 PMCID: PMC7040471 DOI: 10.2174/1745017901915010160] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/12/2019] [Accepted: 11/15/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Methylphenidate (MPH) is the most commonly used medication for Attention-Deficit/Hyperactivity Disorder (ADHD), but to date, there are neither consistent nor sufficient findings on conditions differentiating responsiveness to MPH response in ADHD. OBJECTIVE To develop a predictive model of MPH response, using a longitudinal and naturalistic follow-up study, in a Spanish sample of children and adolescents with ADHD. METHODS We included all children and adolescents with ADHD treated with MPH in our outpatient Clinic (2005 to 2015), evaluated with the K-SADS interview. We collected ADHD-RS-IV.es and CGI-S scores at baseline and at follow up, and neuropsychological testing (WISC-IV, Continuous Performance Test (CPT-II) & Stroop). Clinical response was defined as >30% reduction from baseline of total ADHD-RS-IV.es score and CGI-S final score of 1 or 2 maintained for the previous 3 months. RESULTS We included 518 children and adolescents with ADHD, mean (SD) age of patients was 11.4 (3.3) years old; 79% male; 51.7% had no comorbidities; and 75.31% had clinical response to a mean MPH dose of 1.2 mg/kg/day. Lower ADHD-RS-IV.es scores, absence of comorbidities (oppositional-defiant symptoms, depressive symptoms and alcohol/cannabis use), fewer altered neuropsychological tests, higher total IQ and low commission errors in CPT-II, were significantly associated with a complete clinical response to methylphenidate treatment. CONCLUSION Oppositional-defiant symptoms, depressive symptoms, and a higher number of impaired neuropsychological tests are associated with worse clinical response to methylphenidate. Other stimulants or non-stimulants treatment may be considered when these clinical and neuropsychological variables converged in the first clinical interview.
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Affiliation(s)
- María Vallejo-Valdivielso
- Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Pamplona, Navarra, Spain
- IDISNA (Health Research Institute of Navarra - Instituto de Investigación Sanitaria de Navarra), Navarra, Spain
| | - Pilar de Castro-Manglano
- Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Madrid, Spain
- IDISNA (Health Research Institute of Navarra - Instituto de Investigación Sanitaria de Navarra), Navarra, Spain
| | - Azucena Díez-Suárez
- Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Pamplona, Navarra, Spain
- IDISNA (Health Research Institute of Navarra - Instituto de Investigación Sanitaria de Navarra), Navarra, Spain
| | | | - Cesar A. Soutullo
- Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Pamplona, Navarra, Spain
- Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Madrid, Spain
- IDISNA (Health Research Institute of Navarra - Instituto de Investigación Sanitaria de Navarra), Navarra, Spain
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27
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Poulton AS, Eslick GD. Effective Stimulant Dosing in Attention-Deficit/Hyperactivity Disorder-Reply. JAMA Pediatr 2019; 173:1211-1212. [PMID: 31633775 DOI: 10.1001/jamapediatrics.2019.3820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Alison S Poulton
- Charles Perkins Centre Nepean, The University of Sydney, Penrith, New South Wales, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, Department of Surgery, The University of Sydney, Penrith, New South Wales, Australia
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28
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Ermer J, Martin P, Corcoran M, Matsuo Y. A phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adult subjects. Neuropsychopharmacol Rep 2019; 40:16-29. [PMID: 31765110 PMCID: PMC7292221 DOI: 10.1002/npr2.12082] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 08/28/2019] [Accepted: 08/29/2019] [Indexed: 11/09/2022] Open
Abstract
Aim To assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adults. Methods A phase 1, double‐blind, randomized, placebo‐controlled, single‐ and multiple‐dose study in Japanese and Caucasian subjects. Subjects received lisdexamfetamine 20 mg or placebo on Day 1, then lisdexamfetamine 20 mg/d (Days 4‐8), 50 mg/d (Days 9‐13), 70 mg/d (Days 14‐18), or matching placebo. Pharmacokinetic parameters for lisdexamfetamine and d‐amphetamine were estimated by noncompartmental analysis. Results Fifteen Japanese and 19 Caucasian subjects were enrolled and randomized. The lisdexamfetamine and d‐amphetamine plasma concentration‐time curves were similar for both ethnic groups following single and multiple doses. Mean area under the concentration‐time curves for d‐amphetamine were higher (by 11%‐15%) in Japanese than Caucasian subjects following multiple dosing of lisdexamfetamine. Mean bodyweight was 17% lower in Japanese than Caucasian subjects. Weight‐corrected means for oral clearance were similar in both ethnic groups, with no unexpected accumulation of d‐amphetamine. Lisdexamfetamine was generally well tolerated by both ethnic groups, with no serious adverse events reported. The 10/12 Japanese and 11/16 Caucasian subjects who received lisdexamfetamine completed the study; two Japanese and three Caucasian subjects discontinued due to adverse events. Most adverse events were of mild severity. Conclusion Pharmacokinetics were generally similar for Japanese and Caucasian subjects; the minor differences observed were likely due to bodyweight differences in the two ethnic groups. Lisdexamfetamine was generally well tolerated. Adverse events were consistent with the established safety profile of lisdexamfetamine and were similar in both ethnic groups. This phase 1, double‐blind, randomized, placebo‐controlled study was conducted to assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian subjects. Fifteen Japanese and 19 Caucasian subjects were enrolled and randomized to receive lisdexamfetamine 20 mg (Day 1), 20 mg/d (Days 4‐8), 50 mg/d (Days 9‐13), and 70 mg/d (Days 14‐18), or matching placebo. Pharmacokinetics were generally similar for Japanese and Caucasian subjects; minor differences observed were likely due to bodyweight differences in the two ethnic groups, and lisdexamfetamine was generally well tolerated.![]()
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Coghill DR, Joseph A, Sikirica V, Kosinski M, Bliss C, Huss M. Correlations Between Clinical Trial Outcomes Based on Symptoms, Functional Impairments, and Quality of Life in Children and Adolescents With ADHD. J Atten Disord 2019; 23:1578-1591. [PMID: 28836895 PMCID: PMC6732817 DOI: 10.1177/1087054717723984] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To assess relationships between treatment-associated changes in measures of ADHD symptoms, functional impairments, and health-related quality of life in children and adolescents with ADHD. METHOD Pearson correlation coefficients were calculated post hoc for changes from baseline to endpoint in outcomes of one randomized, placebo- and active-controlled trial of lisdexamfetamine (osmotic-release methylphenidate reference) and one of guanfacine extended-release (atomoxetine reference). RESULTS Changes in ADHD Rating Scale IV (ADHD-RS-IV) total score generally correlated moderately with changes in Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE:PRF) Achievement and Risk Avoidance ( r ≈ .4), but weakly with Resilience, Satisfaction, and Comfort ( r ≈ .2); and moderately with Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) total score ( r ≈ .5). CHIP-CE PRF Achievement and Risk Avoidance correlated moderately to strongly with WFIRS-P total score ( r ≈ .6). CONCLUSION The ADHD-RS-IV, CHIP-CE:PRF, and WFIRS-P capture distinct but interconnected aspects of treatment response in individuals with ADHD.
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Affiliation(s)
- David R. Coghill
- University of Melbourne, Victoria,
Australia,University of Dundee, UK,David R. Coghill, Departments of Paediatrics and
Psychiatry, Faculty of Medicine, Dentistry, and Health Science, University of Melbourne,
Melbourne, Victoria 3010, Australia.
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Abstract
Pediatric-onset multiple sclerosis (MS) comprises 2-5% of MS cases, and is known to be associated with high disease activity and the accumulation of disability at an earlier age than their adult-onset counterparts. Appropriate therapy leading to disease control has the potential to alter the known trajectory of adverse long-term physical, cognitive, and psychosocial outcomes in this population. Thus, optimizing treatment for children and adolescents with MS is of paramount importance. The last decade has seen a growing number of disease-modifying therapies approved for relapsing MS in adults, and available agents now include oral, injectable, and infusion therapies. Recently, the development of randomized controlled MS trials in youth has led to the first agent approved by the US FDA for the treatment of pediatric MS-fingolimod. With this, we have entered a new era of knowledge and treatment in this population and ongoing pediatric trials are expected to further inform clinical management. With the emergence of highly effective therapies targeting the inflammatory component of the disease, there has been increased interest in identifying treatment strategies that instead target mechanisms such as remyelination/repair, neuroprotection, or rehabilitation. The potential role for such emerging therapies in the treatment of pediatric MS remains an important area of study. In this review, we discuss current evidence for MS therapies in children including the treatment of acute relapses, disease-modifying therapies, and symptomatic management. We will also discuss evidence for emerging therapies, including remyelinating and neuroprotective agents.
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Affiliation(s)
- Colin Wilbur
- Department of Pediatrics, Faculty of Medicine and Dentistry, Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - E Ann Yeh
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada.
- Division of Neurosciences and Mental Health, SickKids Research Institute, Toronto, ON, Canada.
- Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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Steingard R, Taskiran S, Connor DF, Markowitz JS, Stein MA. New Formulations of Stimulants: An Update for Clinicians. J Child Adolesc Psychopharmacol 2019; 29:324-339. [PMID: 31038360 PMCID: PMC7207053 DOI: 10.1089/cap.2019.0043] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In the last 15 years, there has been a marked increase in the number of available stimulant formulations with the emphasis on long-acting formulations, and the introduction of several novel delivery systems such as orally dissolving tablets, chewable tablets, extended-release liquid formulations, transdermal patches, and novel "beaded" technology. All of these formulations involve changes to the pharmaceutical delivery systems of the two existing compounds most commonly employed to treat attention-deficit/hyperactivity disorder (ADHD), amphetamine (AMP) and methylphenidate (MPH). In addition to these new formulations, our knowledge about the individual differences in response has advanced and contributes to a more nuanced approach to treatment. The clinician can now make increasingly informed choices about these formulations and more effectively individualize treatment in a way that had not been possible before. In the absence of reliable biomarkers that can predict individualized response to ADHD treatment, clinical knowledge about differences in MPH and AMP pharmacodynamics, pharmacokinetics, and metabolism can be utilized to personalize treatment and optimize response. Different properties of these new formulations (delivery modality, onset of action, duration of response, safety, and tolerability) will most likely weigh heavily into the clinician's choice of formulation. To manage the broad range of options that are now available, clinicians should familiarize themselves in each of these categories for both stimulant compounds. This review is meant to serve as an update and a guide to newer stimulant formulations and includes a brief review of ADHD and stimulant properties.
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Affiliation(s)
- Ronald Steingard
- Child Mind Institute, New York, New York.,Address correspondence to: Ronald Steingard, MD, Child Mind Institute, 101 East 56th Street, New York, NY 10022
| | - Sarper Taskiran
- Child Mind Institute, New York, New York.,Department of Psychiatry, Koc University School of Medicine, Istanbul, Turkey
| | - Daniel F. Connor
- Division of Child and Adolescent Psychiatry, Department of Psychiatry University of Connecticut School of Medicine, Farmington, Connecticut
| | - John S. Markowitz
- Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida
| | - Mark A. Stein
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
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Abstract
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 ≥ 6 years (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.
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Affiliation(s)
- James E Frampton
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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Weiss M, Childress A, Mattingly G, Nordbrock E, Kupper RJ, Adjei AL. Relationship Between Symptomatic and Functional Improvement and Remission in a Treatment Response to Stimulant Trial. J Child Adolesc Psychopharmacol 2018; 28:521-529. [PMID: 30036076 PMCID: PMC6201781 DOI: 10.1089/cap.2017.0166] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To evaluate the relationship between symptom and functional improvement and remission in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) enrolled in an 11-week open-label dose-optimization phase of an methylphenidate extended release (MPH-MLR) pivotal study. METHODS Assessments included the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) and ADHD Rating Scale, Fourth Edition (ADHD-RS-IV). Definitions included the following: symptom improvement (≥30% decrease in ADHD-RS-IV total score); symptom remission (ADHD-RS-IV total score ≤18); functional improvement (decrease in WFIRS-P total score ≥0.25 [minimally important difference]); and functional remission (WFIRS-P total score ≤0.65). RESULTS Two hundred children completed the open-label phase. At initial assessment, functional impairment was evident across all WFIRS-P domains and similar between children and adolescents. Those who were treatment naive had more functional impairment (WFIRS-P total: 0.82 vs. 0.70, p = 0.02). Significant improvements in all WFIRS-P domains were noted at open-label end (p < 0.001), with the largest improvement in Learning. At open-label end, 94% of children and adolescents demonstrated symptom improvement, of which 57% also showed functional improvement, and 75% of children and adolescents showed symptom remission, of which 81% also showed functional remission. CONCLUSIONS Children and adolescents treated with MPH-MLR showed moderate-to-large improvement in functioning during 3 months of treatment, both overall and in specific domains. However, a significant number of those who would be considered symptomatic responders failed to show improvement in functioning or continue to have significant functional impairment. Treatment with MPH-MLR showed that both symptomatic and functional remission are achievable goals. Identification of children and adolescents who have been successfully treated for their symptoms, but continue to suffer functional impairment, will allow us to offer additional targeted treatment interventions over and above medication to address residual difficulties.
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Affiliation(s)
- Margaret Weiss
- University of Arkansas for Medical Sciences, Child and Adolescent Psychiatry, Child Study Center, Little Rock, Arkansas.,Address correspondence to: Margaret Weiss, MD, PhD, FRCP(C), Child and Adolescent Psychiatry, Child Study Center, 11 Children's Way, Little Rock, AR 72202
| | - Ann Childress
- Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, Nevada
| | - Greg Mattingly
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.,Midwest Research Group, St. Louis, Missouri
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Cerrillo-Urbina AJ, García-Hermoso A, Pardo-Guijarro MJ, Sánchez-López M, Santos-Gómez JL, Martínez-Vizcaíno V. The Effects of Long-Acting Stimulant and Nonstimulant Medications in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Meta-Analysis of Randomized Controlled Trials. J Child Adolesc Psychopharmacol 2018; 28:494-507. [PMID: 29897263 DOI: 10.1089/cap.2017.0151] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE The aim of this study was to assess the efficacy and safety of stimulant and nonstimulant medications in children and adolescents using as an outcome measure the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV), and to examine the effect of medications in different ADHD subtypes (i.e., inattention and hyperactivity/impulsivity). METHODS MEDLINE, Scopus, EMBASE, EBSCO (E-journal, CINAHL and SportDiscus), PUBMED, and The Cochrane Central Register of Controlled Trials databases were searched. Randomized controlled trials (RCTs) with parallel group or placebo-controlled studies comparing the effect of medications (stimulants or nonstimulants) in children and adolescents with ADHD were included. The main outcomes were the ADHD-RS-IV total score and subtypes (inattention and hyperactivity/impulsivity). Treatment-emergent adverse events (TEAEs) and secondary outcomes such as systolic and diastolic blood pressure, and pulse rate were considered. RESULTS The search strategy identified 15 RCTs, including a total of 4648 children and/or adolescents diagnosed with ADHD aged 6 to 17 years old. Overall, both stimulant and nonstimulant medications reduce the ADHD-RS-IV score with a standardized mean difference (SMD) of -0.70 (confidence interval [95% CI], -0.85 to -0.55); in subgroup analyses, the SMD was -0.83 (95% CI, -1.11 to -0.54) for stimulant medications and -0.58 (95% CI, -0.69 to -0.46) for nonstimulant medications. Similar results were observed in inattention and hyperactivity/impulsivity subtypes. The placebo group also showed a medium effect SMD of -0.68 (95% CI, -0.82 to -0.54). The most frequent TEAEs for stimulant and nonstimulant medications, respectively, were decreased appetite (28.6% and 14.2%) and somnolence (4.4% and 34.1%). CONCLUSIONS These results suggest that both stimulant and nonstimulant medications mitigate ADHD symptoms in children and adolescents, although subgroup analyses suggest a greater effectiveness of stimulant medications.
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Affiliation(s)
| | - Antonio García-Hermoso
- 2 Laboratorio de Ciencias de la Actividad Física, el Deporte y la Salud, Facultad de Ciencias Médicas, Universidad de Santiago de Chile , USACH, Santiago, Chile
| | - María Jesús Pardo-Guijarro
- 1 Social and Health Care Research Center , Universidad de Castilla-La Mancha, Cuenca, Spain .,3 Faculty of Education, Universidad de Castilla-La Mancha , Cuenca, Spain
| | - Mairena Sánchez-López
- 1 Social and Health Care Research Center , Universidad de Castilla-La Mancha, Cuenca, Spain .,4 Faculty of Education, Universidad de Castilla-La Mancha , Ciudad Real, Spain
| | | | - Vicente Martínez-Vizcaíno
- 1 Social and Health Care Research Center , Universidad de Castilla-La Mancha, Cuenca, Spain .,6 Facultad de Ciencias de la Salud, Universidad Autónoma de Chile , Talca, Chile
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Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis. Eur Child Adolesc Psychiatry 2018; 27:1335-1345. [PMID: 29460165 DOI: 10.1007/s00787-018-1125-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 02/09/2018] [Indexed: 12/12/2022]
Abstract
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.
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Liang EF, Lim SZ, Tam WW, Ho CS, Zhang MW, McIntyre RS, Ho RC. The Effect of Methylphenidate and Atomoxetine on Heart Rate and Systolic Blood Pressure in Young People and Adults with Attention-Deficit Hyperactivity Disorder (ADHD): Systematic Review, Meta-Analysis, and Meta-Regression. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:ijerph15081789. [PMID: 30127314 PMCID: PMC6121294 DOI: 10.3390/ijerph15081789] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 08/16/2018] [Accepted: 08/18/2018] [Indexed: 12/04/2022]
Abstract
Objectives: This meta-analysis aims to study the effects of atomoxetine and methylphenidate on heart rate (HR), systolic blood pressure (SBP), and a number of adverse cardiac events on patients receiving treatment for attention-deficit hyperactive disorder (ADHD) in comparison to placebo and between atomoxetine and methylphenidate. Methods: We searched the following databases: PubMed, EMBASE, and ScienceDirect. Meta-analysis was performed on studies that examined the relationships between methylphenidate or atomoxetine and HR, SBP, as well as a number of adverse cardiac events. These studies were either placebo-controlled or comparison studies between methylphenidate and atomoxetine. Meta-regression identified patient- and treatment-related factors that may contribute to heterogeneity. Results: Twenty-two studies were included and the total number of participants was 46,107. Children/adolescents and adults treated with methylphenidate had more significant increases in post- vs. pre-treatment HR (p < 0.001) and SBP (p < 0.001) than those treated by placebo. Children and adolescents treated with atomoxetine had more significant increases post- vs. pre-treatment HR (p = 0.025) and SBP (p < 0.001) than those treated with methylphenidate. Meta-regression revealed mean age of participants, mean dose, and duration of atomoxetine and methylphenidate as significant moderators that explained heterogeneity. There were no differences in the number of adverse cardiac events between participants with methylphenidate treatment and placebo or atomoxetine. Conclusions: Children/adolescents and adults treated with methylphenidate resulted in significant increases in post- vs. pre-treatment HR and SBP as compared to placebo. Similarly, children and adolescents treated with atomoxetine had significant increases in post- vs. pre-treatment HR and SBP than those treated with methylphenidate. These findings have potential implications for continuous monitoring of HR and SBP throughout the course of treatment although the risk for adverse cardiac events were insignificant.
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Affiliation(s)
- Edwin F Liang
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
| | - Samuel Z Lim
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
| | - Wilson W Tam
- Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
| | - Cyrus S Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
| | - Melvyn W Zhang
- National Addiction Management Service, Institute of Mental Health, Singapore 539747, Singapore.
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, M5T 1R8, ON, Canada.
- Institute of Medical Science, University of Toronto, Toronto M5T 1R8, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto M5T 1R8, ON, Canada.
- Department of Pharmacology, University of Toronto, Toronto M5T 1R8, ON, Canada.
| | - Roger C Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
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Brams M, Childress AC, Greenbaum M, Yu M, Yan B, Jaffee M, Robertson B. SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results of a Randomized, Double-Blind Placebo-Controlled Study. J Child Adolesc Psychopharmacol 2018; 28:19-28. [PMID: 28816509 PMCID: PMC5771539 DOI: 10.1089/cap.2017.0053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE The aim of this study was to evaluate the efficacy, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS This randomized, double-blind dose-optimization study enrolled children and adolescents (6-17 years) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ADHD criteria and having baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥28. Participants were randomized 1:1 to placebo or dose-optimized SHP465 MAS (12.5-25 mg) for 4 weeks. Total score change (baseline to week 4) on the ADHD-RS-IV (primary endpoint) and the Clinical Global Impressions-Improvement (CGI-I) scale score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments (secondary endpoints) included treatment-emergent adverse events (TEAEs) and vital sign changes. RESULTS Of 264 randomized participants (placebo, n = 132; SHP465 MAS, n = 132), 234 (placebo, n = 118; SHP465 MAS, n = 116) completed the study. The least squares mean (95% confidence interval) treatment difference significantly favored SHP465 MAS over placebo for ADHD-RS-IV total score change from baseline to week 4 (-9.9 [-13.0, -6.8]; p < 0.001; effect size = 0.80) and CGI-I score at week 4 (-0.8 [-1.1, -0.5]; p < 0.001; effect size = 0.65). TEAE frequency was 46.6% (61/131) with placebo and 67.4% (89/132) with SHP465 MAS; no serious TEAEs were reported. TEAEs reported at a frequency of ≥5% and ≥2 times the placebo rate were decreased appetite, insomnia, irritability, nausea, and decreased weight. Mean ± standard deviation increases (baseline to final on-treatment assessment) were higher with SHP465 MAS than placebo for pulse (5.7 ± 11.78 vs. 0.7 ± 10.79), systolic blood pressure (3.8 ± 9.15 vs. 2.1 ± 8.72), and diastolic blood pressure (4.0 ± 8.23 vs. 0.5 ± 7.45). CONCLUSIONS SHP465 MAS demonstrated superiority over placebo in improving ADHD symptoms and global functioning in children and adolescents with ADHD. The safety and tolerability profile of SHP465 MAS was consistent with that of SHP465 MAS in adults and other long-acting psychostimulants in children and adolescents.
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Affiliation(s)
- Matthew Brams
- Baylor College of Medicine, Houston, Texas.,Address correspondence to: Matthew Brams, MD, Baylor College of Medicine, 550 Westcott, Suite 310, Houston, TX 77007
| | - Ann C. Childress
- Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada
| | | | - Ming Yu
- Shire, Lexington, Massachusetts
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Santosh PJ, Singh J. Drug treatment of autism spectrum disorder and its comorbidities in children and adolescents. BJPSYCH ADVANCES 2018. [DOI: 10.1192/apt.bp.115.014597] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SummaryAutism spectrum disorder (ASD) is a complex, multifactorial disorder, the prevalence of which is rising. Specific biomarkers are yet to be identified for the classic ASD phenotypes, so despite treatment advances, most interventions focus on the comorbid disorders of ASD and have little impact on the underlying pathogenesis of the disorder. This article describes drug treatments that target the core symptoms of ASD and its comorbid conditions in children and adolescents. Difficulties and challenges encountered when treating the most frequent comorbidities are discussed, with emphasis on the safety, tolerability and efficacy of medications. In view of its widespread use, complementary and alternative medicine is also described.
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Growth and Puberty in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. CNS Drugs 2018; 32:455-467. [PMID: 29790103 PMCID: PMC5976689 DOI: 10.1007/s40263-018-0514-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents. OBJECTIVE The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder. METHODS Children and adolescents aged 6-17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and self-reported pubertal status using Tanner staging. RESULTS The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatment-emergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease. Growth retardation of moderate intensity was reported as a treatment-emergent adverse event for two participants. From baseline to the last on-treatment assessment, there were increases in mean weight of 2.1 kg (standard deviation 5.83) and height of 6.1 cm (standard deviation 4.90), and a body mass index decrease of 0.5 kg/m2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36 weeks of the study and then stabilised. Changes from baseline to the last on-treatment assessment in mean z-scores for weight, height and body mass index were significantly less than zero (- 0.51, - 0.24 and - 0.59, respectively; nominal p < 0.0001). The proportion of participants with a z-score of < - 1 ranged from 5.1% (baseline) to 22.1% (week 84) for weight, 8.2% (baseline) to 12.6% (week 96) for height, and 8.3% (baseline) to 28.8% (week 96) for body mass index. Thirteen participants (4.1%) shifted to a weight below the fifth percentile at the last on-treatment assessment from a higher weight category at baseline. At the last on-treatment assessment, most participants remained at their baseline Tanner stage or had shifted higher. CONCLUSIONS Findings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2 years were consistent with previous studies of stimulant medications. Whilst mean weight and height increased over the course of the study, there was a small but transient reduction in mean weight, height and body mass index z-scores. A small increase in the proportion of participants in the lowest weight and body mass index categories highlights the importance of the regular monitoring of weight and height. There was no evidence of delayed onset of puberty. CLINICALTRIALS. GOV IDENTIFIER NCT01328756.
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Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate. CNS Drugs 2018; 32:85-95. [PMID: 29383572 PMCID: PMC5843702 DOI: 10.1007/s40263-017-0487-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS. GOV IDENTIFIER NCT01328756.
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Robb AS, Findling RL, Childress AC, Berry SA, Belden HW, Wigal SB. Efficacy, Safety, and Tolerability of a Novel Methylphenidate Extended-Release Oral Suspension (MEROS) in ADHD. J Atten Disord 2017; 21:1180-1191. [PMID: 24874348 DOI: 10.1177/1087054714533191] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To test whether an optimal dose of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]) would significantly reduce symptoms of ADHD in children. METHOD A randomized, double-blind, placebo-controlled, cross-over, efficacy, safety, and tolerability study of MEROS in 45 children aged 6 to 12 years (open-label dose-optimization phase, followed by double-blind cross-over period). RESULTS MEROS was significantly more efficacious than placebo during double-blind cross-over laboratory classroom days (Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale and Permanent Product Measure of Performance). During the open-label phase, improvements were observed in scores of ADHD Rating Scale-IV, and Clinical Global Impression-Severity and -Improvement Scales. No occurrences of suicidal ideation or behavior were recorded; the most common open-label treatment-emergent adverse events were typical of stimulant use: decreased appetite, insomnia, and abdominal pain. CONCLUSION MEROS was efficacious in the treatment of children aged 6 to 12 years with ADHD, with a safety profile similar to that of other extended-release methylphenidate pharmacotherapies.
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Affiliation(s)
| | | | - Ann C Childress
- 3 Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USA
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Relative Bioavailabilities of Lisdexamfetamine Dimesylate and D-Amphetamine in Healthy Adults in an Open-Label, Randomized, Crossover Study After Mixing Lisdexamfetamine Dimesylate With Food or Drink. Ther Drug Monit 2017; 38:769-776. [PMID: 27661399 PMCID: PMC5158093 DOI: 10.1097/ftd.0000000000000343] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Supplemental Digital Content is Available in the Text. Background: This open-label, crossover study examined lisdexamfetamine dimesylate (LDX) and d-amphetamine pharmacokinetics in healthy adults after administration of an intact LDX capsule or after the capsule was emptied into orange juice or yogurt and the contents consumed. Methods: Healthy adult volunteers (N = 30) were administered a 70-mg LDX capsule or the contents of a 70-mg capsule mixed with yogurt or orange juice using a 3-way crossover design. Blood samples were collected serially for up to 96 hours after dose. Pharmacokinetic endpoints included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from zero to infinity (AUC0–∞) or to last assessment (AUClast). Relative LDX and d-amphetamine bioavailabilities from the contents of a 70-mg LDX capsule mixed with orange juice or yogurt were compared with those from the intact LDX capsule using bioequivalence-testing procedures. Results: Geometric least squares mean ratios (90% confidence intervals [CIs]) for d-amphetamine (active moiety) were within the prespecified bioequivalence range (0.80–1.25) when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.971 (0.945, 0.998); AUC0–∞: 0.986 (0.955, 1.019); AUClast: 0.970 (0.937, 1.004)] or yogurt [Cmax: 0.970 (0.944, 0.997); AUC0–∞: 0.945 (0.915, 0.976); AUClast: 0.944 (0.912, 0.977)]. Geometric least squares mean ratios (90% CIs) for LDX (inactive prodrug) were below the accepted range when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.641 (0.582, 0.707); AUC0–∞: 0.716 (0.647, 0.792); AUClast: 0.708 (0.655, 0.766)]; the lower 90% CI for Cmax [0.828 (0.752, 0.912)] was below the accepted range when the contents of a 70-mg LDX capsule were mixed with yogurt. Conclusions: Relative bioavailability of d-amphetamine (the active moiety) did not differ across administrations, which suggests that emptying an LDX capsule into orange juice or yogurt and consuming it is an alternative to intact capsules.
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Abstract
The diagnostic criteria for attention-deficit hyperactivity disorder (ADHD) require both symptoms and impairment to be present. Impairment in functioning is commonly the primary reason for referral, and is also a better predictor of long-term outcomes than ADHD symptoms. And yet, only recently has research begun to examine the impact of ADHD treatments on functional impairment using efficient and psychometrically sound outcome measures. In this article, we identify several noteworthy multidimensional measures of functional impairment (ADHD FX, Barkley Functional Impairment Scale [BFIS], Impairment Rating Scale [IRS], Weiss Functional Impairment Rating Scale [WFIRS]) utilized in recent clinical trials for ADHD, and describe their psychometric properties and clinical utility. We also review existing evidence on the impact of pharmacological and behavioral treatments on different domains of functional impairment in ADHD youth as measured by these specific measures. Further research is needed to evaluate longitudinal effects of ADHD treatments on functional impairment, and the use of these measures in adaptive treatment designs.
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Sieluk J, Palasik B, dosReis S, Doshi P. ADHD medications and cardiovascular adverse events in children and adolescents: cross-national comparison of risk communication in drug labeling. Pharmacoepidemiol Drug Saf 2017; 26:274-284. [PMID: 28083936 DOI: 10.1002/pds.4164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 12/02/2016] [Accepted: 12/13/2016] [Indexed: 11/06/2022]
Abstract
PURPOSE Regulators approve written medical information for healthcare professionals and consumers, but the consistency of these sources has not been studied. We investigated the consistency of information regarding four cardiovascular risks of attention-deficit/hyperactivity disorder (ADHD) medications approved in four countries. METHODS Professional and consumer product labeling for five ADHD medications approved in Australia, Canada, the UK, and the USA were obtained in March/April 2016. Language describing the relationship between medication and elevated blood pressure and/or heart rate, myocardial infarction, stroke, and sudden death was extracted verbatim and classified into one of four categories based on the described relationship between medication and adverse event: "confirmed," "unconfirmed," "mixed," and "not mentioned." We judged the consistency of messages delivered to healthcare professionals and consumers as either "consistent" or "inconsistent." RESULTS We obtained 20 healthcare professional labels and 20 corresponding consumer labels for the five ADHD medications registered in all four countries. Not all professional and consumer labeling contained language regarding all four adverse events. Of the 80 theoretically evaluable drug-risk pairs, 38 (48%) were not evaluable because of absence of mention of the adverse event in the consumer label. For the remaining 42, the potential causal relationship was expressed consistently in professional and consumer labeling in 25 (60%) cases. The cardiovascular risk profile was not described consistently across all four countries for any of the five drugs. CONCLUSIONS Product labeling provides healthcare professionals and consumers with inconsistent messages regarding the potential causal relationship between stimulant use and specific cardiovascular risks in children and adolescents. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Jan Sieluk
- Pharmaceutical Health Services Research Department, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Brittany Palasik
- University of Utah Hospitals and Clinics, Salt Lake City, UT, USA
| | - Susan dosReis
- Pharmaceutical Health Services Research Department, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Peter Doshi
- Pharmaceutical Health Services Research Department, University of Maryland School of Pharmacy, Baltimore, MD, USA
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Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison. Eur Child Adolesc Psychiatry 2017; 26:875-897. [PMID: 28258319 PMCID: PMC5532417 DOI: 10.1007/s00787-017-0962-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 02/13/2017] [Indexed: 10/29/2022]
Abstract
This study compared the clinical efficacy and safety of attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in children and adolescents 6-17 years of age. A systematic literature review was conducted to identify randomized controlled trials (RCTs) of pharmacologic monotherapies among children and adolescents with ADHD. A Bayesian network meta-analysis was conducted to compare change in symptoms using the ADHD Rating Scale Version IV (ADHD-RS-IV), Clinical Global Impression-Improvement (CGI-I) response, all-cause discontinuation, and adverse event-related discontinuation. Thirty-six RCTs were included in the analysis. The mean (95% credible interval [CrI]) ADHD-RS-IV total score change from baseline (active minus placebo) was -14.98 (-17.14, -12.80) for lisdexamfetamine dimesylate (LDX), -9.33 (-11.63, -7.04) for methylphenidate (MPH) extended release, -8.68 (-10.63, -6.72) for guanfacine extended release (GXR), and -6.88 (-8.22, -5.49) for atomoxetine (ATX); data were unavailable for MPH immediate release. The relative risk (95% CrI) for CGI-I response (active versus placebo) was 2.56 (2.21, 2.91) for LDX, 2.13 (1.70, 2.54) for MPH extended release, 1.94 (1.59, 2.29) for GXR, 1.77 (1.31, 2.26) for ATX, and 1.62 (1.05, 2.17) for MPH immediate release. Among non-stimulant pharmacotherapies, GXR was more effective than ATX when comparing ADHD-RS-IV total score change (with a posterior probability of 93.91%) and CGI-I response (posterior probability 76.13%). This study found that LDX had greater efficacy than GXR, ATX, and MPH in the treatment of children and adolescents with ADHD. GXR had a high posterior probability of being more efficacious than ATX, although their CrIs overlapped.
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Coghill DR, Banaschewski T, Nagy P, Otero IH, Soutullo C, Yan B, Caballero B, Zuddas A. Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe. CNS Drugs 2017; 31:625-638. [PMID: 28667569 PMCID: PMC5511319 DOI: 10.1007/s40263-017-0443-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management. OBJECTIVES Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD. METHODS Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale. RESULTS Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by ≥5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m2 (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30% or ≥50% reduction from baseline in ADHD-RS-IV total score, respectively. CONCLUSIONS The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period. CLINICALTRIALS. GOV IDENTIFIER NCT01328756.
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Affiliation(s)
- David R Coghill
- Departments of Paediatrics and Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
- University of Dundee, Dundee, UK.
| | - Tobias Banaschewski
- Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Peter Nagy
- Vadaskert Child and Adolescent Psychiatry Hospital and Outpatient Clinic, Budapest, Hungary
| | | | | | | | | | - Alessandro Zuddas
- Child and Adolescent Neuropsychiatry Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
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Luan R, Mu Z, Yue F, He S. Efficacy and Tolerability of Different Interventions in Children and Adolescents with Attention Deficit Hyperactivity Disorder. Front Psychiatry 2017; 8:229. [PMID: 29180967 PMCID: PMC5694170 DOI: 10.3389/fpsyt.2017.00229] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 10/25/2017] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Our study is an analysis of multiple publications involving assessing the comparable efficacy and tolerability of six interventions, which are lisdexamfetamine dimesylate (LDX), atomoxetine (ATX), methylphenidate (MPH), clonidine hydrochloride (CLON), guanfacine extended release (GXR), and bupropion, for young patients (6-18 years old) suffering from attention deficit hyperactivity disorder (ADHD). METHODS A conventional meta-analysis (MA) was performed to give direct comparisons and a network meta-analysis (NMA) was used to show the combination of direct and indirect evidence. Ranking preference for all the interventions under a certain outcome was given by the surface of cumulative ranking curve area (SUCRA). RESULTS Overall, 15,025 participants from 73 studies were involved in our analysis. In the pairwise MA, LDX was associated with less withdrawal than ATX for lack of efficacy. MPH showed less effectiveness than LDX according to ADHD Rating Scale score. Based on the analysis of our NMA, significant results of efficacy that LDX is a competitive drug were observed when evaluating LDX in comparison with other drugs except for CLON. ATX and GXR presented higher rates of abdominal pain morbidity versus inactive treatment. CONCLUSION The stimulants LDX and MPH are still highly recommended because they are highly effective and are tolerated well by patients. Among the non-stimulants, CLON can be taken into consideration for its appreciable effectiveness and tolerability. ATX and GXR can be seen as moderate choices.
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Affiliation(s)
- Ruiling Luan
- Department of Pharmacy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Zhiling Mu
- Department of Pediatrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Fang Yue
- Department of Pediatrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Shaoying He
- Department of Pediatrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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Ermer JC, Pennick M, Frick G. Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy. Clin Drug Investig 2016; 36:341-56. [PMID: 27021968 PMCID: PMC4823324 DOI: 10.1007/s40261-015-0354-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults. LDX is hydrolysed in the blood to yield d-amphetamine, and the pharmacokinetic profile of d-amphetamine following oral administration of LDX has a lower maximum plasma concentration (Cmax), extended time to Cmax (Tmax) and lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release (IR) d-amphetamine. The therapeutic action of LDX extends to at least 13 h post-dose in children and 14 h post-dose in adults, longer than that reported for any other long-acting formulation. Drug-liking scores for LDX are lower than for an equivalent dose of IR d-amphetamine, which may result from the reduced euphorigenic potential associated with its pharmacokinetic profile. These pharmacokinetic and pharmacodynamic characteristics of LDX may be beneficial in the management of symptoms in children, adolescents and adults with ADHD.
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Lunsford-Avery JR, Krystal AD, Kollins SH. Sleep disturbances in adolescents with ADHD: A systematic review and framework for future research. Clin Psychol Rev 2016; 50:159-174. [PMID: 27969004 DOI: 10.1016/j.cpr.2016.10.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 09/15/2016] [Accepted: 10/21/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Biological mechanisms underlying symptom and prognostic heterogeneity in Attention-Deficit/Hyperactivity Disorder (ADHD) are unclear. Sleep impacts neurocognition and daytime functioning and is disrupted in ADHD, yet little is known about sleep in ADHD during adolescence, a period characterized by alterations in sleep, brain structure, and environmental demands as well as diverging ADHD trajectories. METHODS A systematic review identified studies published prior to August 2016 assessing sleep in adolescents (aged 10-19years) with ADHD or participating in population-based studies measuring ADHD symptoms. RESULTS Twenty-five studies were identified (19 subjective report, 6 using actigraphy/polysomnography). Findings are mixed but overall suggest associations between sleep disturbances and 1) ADHD symptoms in the population and 2) poorer clinical, neurocognitive, and functional outcomes among adolescents with ADHD. Common limitations of studies included small or non-representative samples, non-standardized sleep measures, and cross-sectional methodology. CONCLUSIONS Current data on sleep in adolescent ADHD are sparse and limited by methodological concerns. Future studies are critical for clarifying a potential role of sleep in contributing to heterogeneity of ADHD presentation and prognosis. Potential mechanisms by which sleep disturbances during adolescence may contribute to worsened symptom severity and persistence of ADHD into adulthood and an agenda to guide future research are discussed.
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Affiliation(s)
- Jessica R Lunsford-Avery
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 2608 Erwin Road Suite 300, Durham, NC 27705, United States.
| | - Andrew D Krystal
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 2608 Erwin Road Suite 300, Durham, NC 27705, United States; Departments of Psychiatry and Neurology, University of California San Francisco School of Medicine, 401 Parnassus Avenue, San Francisco, CA 94143, United States
| | - Scott H Kollins
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 2608 Erwin Road Suite 300, Durham, NC 27705, United States
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Li Y, Gao J, He S, Zhang Y, Wang Q. An Evaluation on the Efficacy and Safety of Treatments for Attention Deficit Hyperactivity Disorder in Children and Adolescents: a Comparison of Multiple Treatments. Mol Neurobiol 2016; 54:6655-6669. [DOI: 10.1007/s12035-016-0179-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 09/28/2016] [Indexed: 11/25/2022]
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