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JAMA Psychiatry Feb 2024Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear.
OBJECTIVE
To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses.
DATA SOURCES
Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions.
STUDY SELECTION
Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD.
DATA EXTRACTION AND SYNTHESIS
Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses.
MAIN OUTCOME MEASURES
Change in ADHD symptoms and discontinuations due to adverse events.
RESULTS
A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence).
CONCLUSIONS AND RELEVANCE
Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.
Topics: Adult; Male; Humans; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Methylphenidate; Amphetamines; Treatment Outcome
PubMed: 37878348
DOI: 10.1001/jamapsychiatry.2023.3985 -
The Medical Letter on Drugs and... Jan 2020
Review
Topics: Adrenergic alpha-2 Receptor Agonists; Amphetamines; Attention Deficit Disorder with Hyperactivity; Behavior Therapy; Central Nervous System Stimulants; Child; Child, Preschool; Delayed-Action Preparations; Humans; Methylphenidate; Transcutaneous Electric Nerve Stimulation
PubMed: 31999670
DOI: No ID Found -
Expert Opinion on Drug Safety 2023Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent condition that causes persistent problems with attention and/or hyperactivity-impulsivity and often... (Review)
Review
INTRODUCTION
Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent condition that causes persistent problems with attention and/or hyperactivity-impulsivity and often results in significant impairment when left untreated. Medications for this disorder continue to evolve and provide new treatment options. Ongoing review of related medication safety and tolerability remains an important task for prescribers.
AREAS COVERED
This manuscript provides an updated safety review of medications used to treat ADHD in children and adolescents. PubMed and OneSearch online databases were utilized to search for literature relevant to the topic of ADHD medications and safety. Clinical trials of medications used to treat ADHD, systematic reviews and meta-analyses, and articles covering specific safety issues (adverse or unfavorable events) such as cardiovascular effects, seizures, impact on growth, depression, suicidal ideation, substance use disorders, psychosis, and tics are described.
EXPERT OPINION
Available pharmacologic treatments for ADHD have favorable efficacy, safety and tolerability and allow many patients to achieve significant improvement of their symptoms. Despite the availability of multiple stimulant and non-stimulant formulations, some individuals with ADHD may not tolerate available medications or attain satisfactory improvement. To satisfy unmet clinical needs, ADHD pharmaceutical research with stimulant and nonstimulant formulations targeting dopamine, norepinephrine, and novel receptors is ongoing.
Topics: Adolescent; Child; Humans; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Methylphenidate; Atomoxetine Hydrochloride
PubMed: 37843488
DOI: 10.1080/14740338.2023.2271392 -
Psychopharmacology Oct 2023Working memory deficits and associated neurofunctional abnormalities are frequently reported in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate and... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Working memory deficits and associated neurofunctional abnormalities are frequently reported in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate and atomoxetine improve working memory performance and increase activation of regions under-functioning in ADHD. Additionally, methylphenidate has been observed to modulate functional networks involved in working memory. No research, however, has examined the effects of atomoxetine or compared the two drugs.
OBJECTIVES
This study aimed to test methylphenidate and atomoxetine effects on functional connectivity during working memory in boys with ADHD.
METHODS
We tested comparative effects of methylphenidate and atomoxetine on functional connectivity during the n-back task in 19 medication-naïve boys with ADHD (10-15 years old) relative to placebo and assessed potential normalisation effects of brain dysfunctions under placebo relative to 20 age-matched neurotypical boys. Patients were scanned in a randomised, double-blind, cross-over design under single doses of methylphenidate, atomoxetine, and placebo. Controls were scanned once, unmedicated.
RESULTS
Patients under placebo showed abnormally increased connectivity between right superior parietal gyrus (rSPG) and left central operculum/insula. This hyperconnectivity was not observed when patients were under methylphenidate or atomoxetine. Furthermore, under methylphenidate, patients showed increased connectivity relative to controls between right middle frontal gyrus (rMFG) and cingulo-temporo-parietal and striato-thalamic regions, and between rSPG and cingulo-parietal areas. Interrogating these networks within patients revealed increased connectivity between both rMFG and rSPG and right supramarginal gyrus under methylphenidate relative to placebo. Nonetheless, no differences across drug conditions were observed within patients at whole brain level. No drug effects on performance were observed.
CONCLUSIONS
This study shows shared modulating effects of methylphenidate and atomoxetine on parieto-insular connectivity but exclusive effects of methylphenidate on connectivity increases in fronto-temporo-parietal and fronto-striato-thalamic networks in ADHD.
Topics: Male; Humans; Child; Adolescent; Methylphenidate; Attention Deficit Disorder with Hyperactivity; Atomoxetine Hydrochloride; Brain; Frontal Lobe; Central Nervous System Stimulants; Magnetic Resonance Imaging
PubMed: 37500785
DOI: 10.1007/s00213-023-06422-7 -
The Lancet. Psychiatry Feb 2024
Topics: Child; Adolescent; Humans; Methylphenidate; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; World Health Organization
PubMed: 38245024
DOI: 10.1016/S2215-0366(23)00437-6 -
Journal of the American Academy of... Jan 2021To examine the efficacy of pharmacological treatments for restricted and repetitive behaviors (RRB) in autism spectrum disorders (ASD). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To examine the efficacy of pharmacological treatments for restricted and repetitive behaviors (RRB) in autism spectrum disorders (ASD).
METHOD
We searched PubMed, Embase, and CENTRAL to identify all double-blind, randomized, placebo-controlled trials that examined the efficacy of pharmacological agents in the treatment of ASD and measured RRB as an outcome. Our primary outcome was the standardized mean difference in rating scales of RRB.
RESULTS
We identified 64 randomized, placebo-controlled trials involving 3,499 participants with ASD. Antipsychotics significantly improved RRB outcomes compared to placebo (standardized mean difference [SMD] = 0.28, 95% CIs = 0.08-0.49), z = 2.77, p = .01) demonstrating a small effect size. Larger significant positive effects on RRB in ASD were seen in individual studies with fluvoxamine, buspirone, bumetanide, divalproex, guanfacine, and folinic acid that have not been replicated. Other frequently studied pharmacological treatments in ASD including oxytocin, omega-3 fatty acids, selective serotonin reuptake inhibitors (SSRI), and methylphenidate did not demonstrate significant benefit in reducing RRB compared to placebo (oxytocin: SMD = 0.23, 95% CI = -0.01 to 0.47, z = 1.85, p = .06; omega-3 fatty acids: SMD = 0.19, 95% CI = -0.05 to 0.43, z = 1.54, p = .12; SSRI: SMD = 0.09, 95% CI = -0.21 to 0.39, z = 0.60, p = .56; methylphenidate: SMD = 0.18, 95% CI = -0.11 to 0.46, z = 1.23, p = .22).
CONCLUSION
The results of the present meta-analysis suggest that currently available pharmacological agents have at best only a modest benefit for the treatment of RRB in ASD, with the most evidence supporting antipsychotic medications. Additional randomized controlled trials with standardized study designs and consistent and specific assessment tools for RRB are needed to further understand how we can best help ameliorate these behaviors in individuals with ASD.
Topics: Antipsychotic Agents; Autism Spectrum Disorder; Double-Blind Method; Humans; Methylphenidate; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors
PubMed: 32387445
DOI: 10.1016/j.jaac.2020.03.007 -
Psychiatria Danubina 2021
Topics: Ecchymosis; Humans; Methylphenidate; Postoperative Complications
PubMed: 33857043
DOI: 10.24869/psyd.2021.65 -
Current Topics in Behavioral... 2022This chapter focusses on the benefits and limitations of stimulant medications in the treatment of ADHD. We highlight the key similarities and differences between the... (Review)
Review
This chapter focusses on the benefits and limitations of stimulant medications in the treatment of ADHD. We highlight the key similarities and differences between the different stimulants used to treat ADHD and briefly discuss mechanisms of action, pharmacokinetics, and pharmacodynamics. We will discuss some of the political, ethical, and moral discussions about the use of stimulants including a consideration of the treatment of subsyndromal ADHD and the use of stimulants as cognitive enhancers. We review the comparative efficacy and effectiveness between stimulants and non-pharmacological treatments for ADHD, between stimulant classes and formulations and between stimulant and non-stimulant medications. We discuss the effects on core symptoms, common associated symptoms, cognition, and more distal outcomes including quality of life and functioning and issues related to tolerance, tolerability and adverse effects. Looking at the clinical implications of these findings, we discuss the importance of measurement-based care in the treatment of ADHD. Finally, we will look at the benefits and limitations of stimulants across several different populations and clinical subgroups.
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Humans; Methylphenidate; Quality of Life
PubMed: 35503597
DOI: 10.1007/7854_2022_331 -
European Child & Adolescent Psychiatry Jul 2021For patients with attention deficit hyperactivity disorder and comorbid conduct-dissocial disorder, a combination therapy of the psychostimulant methylphenidate and the... (Review)
Review
For patients with attention deficit hyperactivity disorder and comorbid conduct-dissocial disorder, a combination therapy of the psychostimulant methylphenidate and the antipsychotic risperidone may be prescribed. Case reports describe the occurrence of movement disorders under this combination therapy, but clinical trials had limited power to detect these events. This study aimed (1) to summarise published case reports and (2) to analyse pharmacovigilance data consisting of adverse drug event reports to elucidate these reactions. PubMed, Embase, and APA PsycInfo were used to retrieve case reports. For the pharmacovigilance data, aggregated information on individual case safety reports (ICSRs) within the database of suspected adverse drug events by the WHO were analysed. ICSRs were assessed for disproportionality in reporting. Thirteen published case reports (62% male) on movement disorders were identified, with ages between 5 and 15 years. Seven reports (54%) described incidents when risperidone was tapered down or switched to methylphenidate. From the WHO, we identified 25,556 ICSRs (16,118 for methylphenidate, 8,614 for risperidone, and 824 for both). Of these, 953 (5.9%), 1356 (15.7%), and 159 (19.3%) ICSRs reported movement disorders in association with methylphenidate, risperidone or both, respectively. The analyses on disproportionality showed an increased number of ICSRs with movement disorders when the two drugs were coded in combination. The potential of movement disorders as adverse effects might be amplified when methylphenidate and risperidone are used in combination. The results from the literature underline the necessity of caution and patient monitoring when risperidone dosing is modified during methylphenidate therapy.
Topics: Attention Deficit Disorder with Hyperactivity; Combined Modality Therapy; Comorbidity; Conduct Disorder; Databases, Factual; Humans; Methylphenidate; Movement Disorders; Pharmacovigilance; Risperidone; World Health Organization
PubMed: 32621088
DOI: 10.1007/s00787-020-01589-2 -
Primary Care Mar 2023Attention-deficit hyperactivity disorder is a neurodevelopmental disorder involving dysregulation of multiple neural circuits, manifesting in symptoms such as... (Review)
Review
Attention-deficit hyperactivity disorder is a neurodevelopmental disorder involving dysregulation of multiple neural circuits, manifesting in symptoms such as inattention, impulsivity, and hyperactivity. Diagnosis requires onset of symptoms before age 12 years. However, symptoms often persist throughout lifetime, although they may change over time. The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition formally lists the clinical criteria. Management involves pharmacologic agents, such as stimulant and/or nonstimulant medications, and providers should monitor closely for any adverse effects. Nonpharmacologic interventions may be implemented and can be used in conjunction with pharmacotherapy, although medications should be at the forefront of treatment.
Topics: Child; Humans; Adolescent; Young Adult; Attention Deficit Disorder with Hyperactivity; Methylphenidate; Central Nervous System Stimulants
PubMed: 36822725
DOI: 10.1016/j.pop.2022.10.004