-
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Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions.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 -
Frontiers in Pharmacology 2024Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that... (Review)
Review
Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that the neural circuits underlying the regulation and expression of social behaviors are highly overlapped with those targeted by psychostimulants, which in most cases have strong rewarding and, consequently, addictive properties. In the present work, we provide an overview regarding the effects of illicit and prescription psychostimulants, such as cocaine, amphetamine-type stimulants, methylphenidate or modafinil, upon social behaviors such as social play, maternal behavior, aggression, pair bonding and social cognition and how psychostimulants in both animals and humans alter them. Finally, we discuss why these effects can vary depending on numerous variables such as the type of drug considered, acute long-term use, clinical recreational consumption, or the presence or absence of concomitant risk factors.
PubMed: 38725665
DOI: 10.3389/fphar.2024.1364630 -
Geriatrics (Basel, Switzerland) Jul 2023Apathy is a complex multi-dimensional syndrome that affects up to 70% of individuals with Alzheimer's disease (AD). Whilst many frameworks to define apathy in AD exist,... (Review)
Review
Apathy is a complex multi-dimensional syndrome that affects up to 70% of individuals with Alzheimer's disease (AD). Whilst many frameworks to define apathy in AD exist, most include loss of motivation or goal-directed behaviour as the central feature. Apathy is associated with significant impact on persons living with AD and their caregivers and is also associated with accelerated cognitive decline across the AD spectrum. Neuroimaging studies have highlighted a key role of fronto-striatial circuitry including the anterior cingulate cortex (ACC), orbito-frontal cortex (OFC) and associated subcortical structures. Importantly, the presence and severity of apathy strongly correlates with AD stage and neuropathological biomarkers of amyloid and tau pathology. Following from neurochemistry studies demonstrating a central role of biogenic amine neurotransmission in apathy syndrome in AD, recent clinical trial data suggest that apathy symptoms may improve following treatment with agents such as methylphenidate-which may have an important role alongside emerging non-pharmacological treatment strategies. Here, we review the diagnostic criteria, rating scales, prevalence, and risk factors for apathy in AD. The underlying neurobiology, neuropsychology and associated neuroimaging findings are reviewed in detail. Finally, we discuss current treatment approaches and strategies aimed at targeting apathy syndrome in AD, highlighting areas for future research and clinical trials in patient cohorts.
PubMed: 37489323
DOI: 10.3390/geriatrics8040075 -
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 -
JAMA Psychiatry May 2024Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts...
IMPORTANCE
Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain.
OBJECTIVE
To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan).
EXPOSURES
Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy.
MAIN OUTCOMES AND MEASURES
Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure.
RESULTS
The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD.
CONCLUSIONS AND RELEVANCE
The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.
Topics: Humans; Female; Pregnancy; Central Nervous System Stimulants; Prenatal Exposure Delayed Effects; Child; Attention Deficit Disorder with Hyperactivity; Adolescent; Adult; Young Adult; United States; Neurodevelopmental Disorders; Methylphenidate; Autism Spectrum Disorder; Male; Middle Aged; Pregnancy Complications; Cohort Studies; Amphetamine; Dextroamphetamine; Medicaid
PubMed: 38265792
DOI: 10.1001/jamapsychiatry.2023.5073 -
Proceedings of the National Academy of... Sep 2023Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than... (Randomized Controlled Trial)
Randomized Controlled Trial
Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist , a noradrenaline reuptake inhibitor , or a preferential dopamine reuptake inhibitor , and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.
Topics: Humans; Acetylcholine; Methylphenidate; Nicotine; Norepinephrine; Reboxetine; Double-Blind Method
PubMed: 37639601
DOI: 10.1073/pnas.2305596120 -
Expert Opinion on Emerging Drugs Mar 2024Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million.... (Review)
Review
INTRODUCTION
Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient.
AREAS COVERED
After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action.
EXPERT OPINION
Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.
Topics: Child; Humans; Risperidone; Antipsychotic Agents; Autism Spectrum Disorder; Aripiprazole; Riluzole
PubMed: 38296815
DOI: 10.1080/14728214.2024.2313650 -
Expert Opinion on Pharmacotherapy 2023The data suggests that in children and adolescents, bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) may be strongly correlated. Even though... (Review)
Review
INTRODUCTION
The data suggests that in children and adolescents, bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) may be strongly correlated. Even though drugs for ADHD and BD are largely accepted, there is relatively little research on the management of comorbidity in children and adolescents, particularly in terms of safety. We provide a synthesis of these findings because one hasn't been made yet.
AREAS COVERED
As a primary outcome, we wanted to determine whether stimulant or non-stimulant treatment of children and adolescents with ADHD and comorbid BD was effective. As a secondary outcome, we wanted to determine tolerability, especially the risk of mood switch.
EXPERT OPINION
The findings of this systematic review suggest that methylphenidate, when used with a mood stabilizer, may be safe and not significantly increase the risk of a manic switch or psychotic symptoms when used to treat ADHD that co-occurs with a BD. In situations where stimulants are ineffective or have low tolerance, atomoxetine also seems to be a good alternative, and also in cases of co-morbid anxiety, oppositional defiant disorder, conduct disorders, ICT disorders, and substance use disorders. Additional research with a higher level of evidence is necessary to corroborate these preliminary findings.
Topics: Child; Humans; Adolescent; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Atomoxetine Hydrochloride; Methylphenidate; Central Nervous System Stimulants
PubMed: 37300473
DOI: 10.1080/14656566.2023.2224920 -
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 Medical Internet Research Aug 2023Methylphenidate is an effective first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, many adverse effects of methylphenidate have been...
BACKGROUND
Methylphenidate is an effective first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, many adverse effects of methylphenidate have been recorded from randomized clinical trials and patient-reported outcomes, but it is difficult to determine abuse from them. In the context of COVID-19, it is important to determine how drug use evaluation, as well as misuse of drugs, have been affected by the pandemic. As people share their reasons for using medication, patient sentiments, and the effects of medicine on social networking services (SNSs), the application of machine learning and SNS data can be a method to overcome the limitations. Proper machine learning models could be evaluated to validate the effects of the COVID-19 pandemic on drug use.
OBJECTIVE
To analyze the effect of the COVID-19 pandemic on the use of methylphenidate, this study analyzed the adverse effects and nonmedical use of methylphenidate and evaluated the change in frequency of nonmedical use based on SNS data before and after the outbreak of COVID-19. Moreover, the performance of 4 machine learning models for classifying methylphenidate use based on SNS data was compared.
METHODS
In this cross-sectional study, SNS data on methylphenidate from Twitter, Facebook, and Instagram from January 2019 to December 2020 were collected. The frequency of adverse effects, nonmedical use, and drug use before and after the COVID-19 pandemic were compared and analyzed. Interrupted time series analysis about the frequency and trends of nonmedical use of methylphenidate was conducted for 24 months from January 2019 to December 2020. Using the labeled training data set and features, the following 4 machine learning models were built using the data, and their performance was evaluated using F- scores: naïve Bayes classifier, random forest, support vector machine, and long short-term memory.
RESULTS
This study collected 146,352 data points and detected that 4.3% (6340/146,352) were firsthand experience data. Psychiatric problems (521/1683, 31%) had the highest frequency among the adverse effects. The highest frequency of nonmedical use was for studies or work (741/2016, 36.8%). While the frequency of nonmedical use before and after the outbreak of COVID-19 has been similar (odds ratio [OR] 1.02 95% CI 0.91-1.15), its trend has changed significantly due to the pandemic (95% CI 2.36-22.20). Among the machine learning models, RF had the highest performance of 0.75.
CONCLUSIONS
The trend of nonmedical use of methylphenidate has changed significantly due to the COVID-19 pandemic. Among the machine learning models using SNS data to analyze the adverse effects and nonmedical use of methylphenidate, the random forest model had the highest performance.
Topics: Humans; Methylphenidate; Central Nervous System Stimulants; Bayes Theorem; Cross-Sectional Studies; Pandemics; COVID-19; Attention Deficit Disorder with Hyperactivity; Drug-Related Side Effects and Adverse Reactions; Disease Outbreaks; Machine Learning; Substance-Related Disorders
PubMed: 37585250
DOI: 10.2196/45146