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The Lancet. Psychiatry Sep 2018The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are... (Comparative Study)
Comparative Study Meta-Analysis
Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.
BACKGROUND
The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.
METHODS
We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976.
FINDINGS
133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints.
INTERPRETATION
Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs.
FUNDING
Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Adult; Attention Deficit Disorder with Hyperactivity; Bupropion; Central Nervous System Stimulants; Child; Clonidine; Dose-Response Relationship, Drug; Humans; Methylphenidate; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 30097390
DOI: 10.1016/S2215-0366(18)30269-4 -
Pharmacology & Therapeutics Feb 2022Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, causing functional... (Review)
Review
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, causing functional impairment. Its prevalence lies at approximately 5% in children and adolescents and at approximately 2.5% in adults. The disorder follows a multifactorial etiology and shows a high heritability. Patients show a high interindividual and intraindividual variability of symptoms, with executive deficits in several cognitive domains. Overall, ADHD is associated with high rates of psychiatric comorbidities, and insufficient treatment is linked to adverse long-term outcomes. Current clinical guidelines recommend an individualized multimodal treatment approach including psychoeducation, pharmacological interventions, and non-pharmacological interventions. Available medications include stimulants (methylphenidate, amphetamines) and non-stimulants (atomoxetine, guanfacine, clonidine). While available pharmacological treatment options for ADHD show relatively large effect sizes (in short-term trials) and overall good tolerability, there is still a need for improvement of current pharmacotherapeutic strategies and for the development of novel medications. This review summarizes available pharmacological treatment options for ADHD in children and adolescents, identifies current issues in research and evidence gaps, and provides an overview of ongoing efforts to develop new medications for the treatment of ADHD in children and adolescents by means of a systematic cross-sectional analysis of the clinical trials registry www.clinicaltrials.gov.
Topics: Adolescent; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Cross-Sectional Studies; Humans; Methylphenidate
PubMed: 34174276
DOI: 10.1016/j.pharmthera.2021.107940 -
American Family Physician Oct 2014Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in children, and the prevalence is increasing. Physicians should evaluate for ADHD...
Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in children, and the prevalence is increasing. Physicians should evaluate for ADHD in children with behavioral concerns (e.g., inattention, hyperactivity, impulsivity, oppositionality) or poor academic progress using validated assessment tools with observers from several settings (home, school, community) and self-observation, if possible. Physicians who inherit a patient with a previous ADHD diagnosis should review the diagnostic process, and current symptoms and treatment needs. Coexisting conditions (e.g., anxiety, learning, mood, or sleep disorders) should be identified and treated. Behavioral treatments are recommended for preschool-aged children and may be helpful at older ages. Effective behavioral therapies include parent training, classroom management, and peer interventions. Medications are recommended as first-line therapy for older children. Psychostimulants, such as methylphenidate and dextroamphetamine, are most effective for the treatment of core ADHD symptoms and have generally acceptable adverse effect profiles. There are fewer supporting studies for atomoxetine, guanfacine, and clonidine, and they are less effective than the psychostimulants. Height, weight, heart rate, blood pressure, symptoms, mood, and treatment adherence should be recorded at follow-up visits.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Child, Preschool; Cognitive Behavioral Therapy; Humans
PubMed: 25369623
DOI: No ID Found -
European Child & Adolescent Psychiatry Mar 2022In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of... (Review)
Review
In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.
Topics: Adult; Attention Deficit Disorder with Hyperactivity; Child; Female; Guanfacine; Humans; Male; Risperidone; Tic Disorders; Tourette Syndrome
PubMed: 34757514
DOI: 10.1007/s00787-021-01899-z -
Medicina Sep 2023Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. Frequently... (Review)
Review
Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. Frequently associated with sensory dysfunction, other neurodevelopmental disorders, neuropsychiatric disorders, epilepsy and/or sleep disorders. This condition will accompany people throughout their lives, which will generate various support and treatment needs. Although there are no drugs that modify the core symptoms of autism, various drugs have shown their usefulness in associated conditions. Atypical antipsychotics for hyperactivity, impulsivity, agitation, auto or heteroaggression crises. Serotonin reuptake inhibitors, to decrease anxiety, obsessive-compulsive symptoms, and irritability/agitation. Stimulants and atomoxetine used for hyperactivity, inattention, and impulsivity. Clonidine and guanfacine show some efficacy on hyperactivity and stereotyped behaviors. Buspirone has been used for restrictive behaviors and anxiety. There are drugs in the research phase such as oxytocin, vasopressin and even some developed for specific entities related to autism such as arbaclofen in Fragile X and Trofinetide that has just been approved for use in Rett syndrome. As specific entities and their pathophysiology are identified, it is likely that tailored treatments will be developed for each entity associated with autism..
Topics: Humans; Autistic Disorder; Stereotyped Behavior; Anxiety; Anxiety Disorders; Autism Spectrum Disorder
PubMed: 37714122
DOI: No ID Found -
Current Neuropharmacology 2021Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral condition found in 5-10% of school-age children and in 2-5% of adults. Stimulants affecting the... (Review)
Review
Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral condition found in 5-10% of school-age children and in 2-5% of adults. Stimulants affecting the dopaminergic, noradrenergic and/or serotonergic systems are commonly used for treatment in children and adults, including women of childbearing age. The data on the effects of stimulants (methylphenidate and amphetamines) in pregnancy are generally reassuring, but methylphenidate might slightly increase the rate of cardiac malformations and of spontaneous abortions, while amphetamines might slightly increase the risk for premature birth, low birth weight and other pregnancy complications. Bupropion, a dopamine and norepinephrine reuptake inhibitor, when used as an antidepressant, appears to be safe in pregnancy. The data on the use of atomoxetine, guanfacine and clonidine in pregnancy are scarce. Importantly, there are practically no data on the long-term neurodevelopmental effects of most of these drugs. The published data on the development of children born to methamphetamineabusing women may be misleading since these women generally use other drugs, including alcohol, and the home environment where the child is raised may not be optimal. The treating physician should judge the need for treatment during pregnancy in relation to the severity of the clinical symptoms. If needed, methylphenidate is preferred over amphetamines because breast feeding is possible. If one uses non-stimulant medications, bupropion seems to be the preferred drug.
Topics: Adult; Attention Deficit Disorder with Hyperactivity; Breast Feeding; Central Nervous System Stimulants; Child; Female; Humans; Methylphenidate; Pharmaceutical Preparations; Pregnancy; Pregnancy Outcome
PubMed: 33245274
DOI: 10.2174/1570159X18666201127164000 -
PloS One 2017Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for... (Meta-Analysis)
Meta-Analysis
The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials.
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents.
METHODS AND FINDINGS
We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution.
CONCLUSIONS
Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Behavior Therapy; Central Nervous System Depressants; Central Nervous System Stimulants; Child; Complementary Therapies; Female; Humans; Male; Randomized Controlled Trials as Topic
PubMed: 28700715
DOI: 10.1371/journal.pone.0180355 -
Journal of Psychopharmacology (Oxford,... Jan 2018An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was... (Review)
Review
An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.
Topics: Animals; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Brain; Consensus; Guanfacine; Humans; Melatonin; Methylphenidate; Psychopharmacology; Sleep Wake Disorders
PubMed: 29237331
DOI: 10.1177/0269881117741766 -
Frontiers in Pharmacology 2022Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of... (Review)
Review
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999-2021. A total of 695 interventional trials were manually assessed from clinicaltrial.gov with the search term « ADHD», and trial data has been used for analysis. A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants (e.g., methylphenidate hydrochloride, lisdexamfetamine dimesylate, amphetamine sulfate, mixed amphetamine salts, a combination of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride), selective noradrenaline reuptake inhibitors (atomoxetine, viloxazine), and alpha2 adrenergic receptor agonists (guanfacine hydrochloride, clonidine hydrochloride). Several studies investigated antidepressants (e.g., bupropion hydrochloride, vortioxetine), and atypical antipsychotics (e.g., quetiapine, aripiprazole) but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.
PubMed: 36467081
DOI: 10.3389/fphar.2022.1066988