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Journal of Clinical PsychopharmacologyStimulants can cause psychotic symptoms at high doses and with parenteral use, but it remains uncertain whether the clinical use of prescription stimulants (PS) at...
PURPOSE/BACKGROUND
Stimulants can cause psychotic symptoms at high doses and with parenteral use, but it remains uncertain whether the clinical use of prescription stimulants (PS) at therapeutic doses precipitates psychosis or influences long-term psychosis risk. Although serious, psychosis is a relatively uncommon event that is difficult to detect in brief randomized controlled trials. There have been several large-scale observational studies of PS and psychosis risk, which have not been reviewed; therefore, we conducted a systematic review of observational studies of PS and psychosis risk in adults and children.
METHODS/PROCEDURE
We conducted a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered with International Prospective Register of Systematic Reviews (CRD42021243484). Eligible studies were longitudinal observational studies, either cohort or case-control, published in English that reported on PS exposure and risk of psychotic events or disorders. Risk of bias assessments were performed with the ROBINS-I instrument.
FINDINGS/RESULTS
There were 10,736 reports screened, and 8 were ultimately included (n = 232,567 patients): 4 retrospective cohort studies, 1 nested case-control study, 2 self-controlled case series, and 1 prospective cohort study. Exposure to methylphenidate (MPH) was more commonly studied than amphetamine (AMPH). In the 3 studies with lowest risk of bias, there was no effect of MPH exposure on psychosis risk, but there was evidence for increased risk with AMPH in 1 study.
IMPLICATIONS/CONCLUSIONS
We conclude that observational studies do not support a clear-cut effect of prescribed MPH on psychosis risk but that AMPH has been less well studied and may increase psychosis risk.
Topics: Adult; Amphetamine; Case-Control Studies; Central Nervous System Stimulants; Child; Humans; Methylphenidate; Prescriptions; Prospective Studies; Psychotic Disorders; Retrospective Studies
PubMed: 35489031
DOI: 10.1097/JCP.0000000000001552 -
Neuroscience and Biobehavioral Reviews Jun 2021Studies have demonstrated an increased risk of accidents and injuries in children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). However,... (Review)
Review
Studies have demonstrated an increased risk of accidents and injuries in children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about how accident risk may alter over the lifespan. Additionally, it would be important to know if the most common types of accidents and injuries differ in ADHD patients over different age groups. Furthermore, there is increasing evidence of an ameliorating effect of ADHD medication on accident risk. Lastly, the underlying risk factors and causal mechanisms behind increased accident risk remain unclear. We therefore conducted a systematic review focusing on the above described research questions. Our results suggested that accident/injury type and overall risk changes in ADHD patients over the lifespan. ADHD medication appeared to be similarly effective at reducing accident risk in all age groups. However, studies with direct comparisons of accident/injuries and effects of medication at different age groups or in old age are still missing. Finally, comorbidities associated with ADHD such as substance abuse appear to further increase the accident/injury risk.
Topics: Accidents; Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Comorbidity; Humans; Longevity; Methylphenidate
PubMed: 33582234
DOI: 10.1016/j.neubiorev.2021.02.002 -
The Cochrane Database of Systematic... Nov 2017Children with autistic spectrum disorder (ASD) frequently present with inattention, impulsivity and hyperactivity, which are the cardinal symptoms of attention deficit... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Children with autistic spectrum disorder (ASD) frequently present with inattention, impulsivity and hyperactivity, which are the cardinal symptoms of attention deficit hyperactivity disorder (ADHD). The effectiveness of methylphenidate, a commonly used ADHD treatment, is therefore of interest in these children.
OBJECTIVES
To assess the effects of methylphenidate for symptoms of ADHD (inattention, impulsivity and hyperactivity) and ASD (impairments in social interaction and communication, and repetitive, restricted or stereotypical behaviours) in children and adolescents aged 6 to 18 years with ASD.
SEARCH METHODS
In November 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 11 other databases and two trials registers. We also checked reference lists and contacted study authors and pharmaceutical companies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that investigated the effect of methylphenidate versus placebo on the core symptoms of ASD or ADHD-like symptoms, or both, in children aged 6 to 18 years who were diagnosed with ASD or pervasive developmental disorder. The primary outcome was clinical efficacy, defined as an improvement in ADHD-like symptoms (inattention, impulsivity and hyperactivity) and in the core symptoms of ASD (impaired social interaction, impaired communication, and stereotypical behaviours), and overall ASD. Secondary outcomes examined were: rate of adverse events; caregiver well-being; need for institutionalisation, special schooling or therapy to achieve learning outcomes; and overall quality of life.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodological procedures. We combined outcome measures that used different psychometric scales, where clinically appropriate. We used a coefficient of 0.6 to calculate standard deviations and adjust for the studies' cross-over design. We considered a standardised mean difference (SMD) of 0.52 as the minimum clinically relevant inter-treatment difference. We applied the GRADE rating for strength of evidence for each outcome.
MAIN RESULTS
The studies: we included four cross-over studies, with a total of 113 children aged 5 to 13 years, most of whom (83%) were boys. We included two studies with five-year-old children since we were unable to obtain the disaggregated data for those aged six years and above, and all other participants were in our target age range. All participants resided in the USA. The duration of treatment in the cross-over phase was one week for each dose of methylphenidate. Studies used a range of outcome scales, rated by parents, teachers or both; clinicians; or programme staff. We report parent-rated outcomes separately. Risk of bias: we considered three trials to be at high risk of bias due to selective reporting and all trials to be at unclear risk of bias for blinding of participants and assessors, due to the potential for recognising the side effects of methylphenidate. We judged all trials to be at low or unclear risk of bias for other items. Primary outcomes: the meta-analysis suggested that high-dose methylphenidate (0.43 mg/kg/dose to 0.60 mg/kg/dose) had a significant and clinically relevant benefit on hyperactivity, as rated by teachers (SMD -0.78, 95% confidence interval (CI) -1.13 to -0.43; 4 studies, 73 participants; P < 0.001; low-quality evidence) and parents (mean difference (MD) -6.61 points, 95% CI -12.19 to -1.03, rated on the hyperactivity subscale of the Aberrant Behviour Checklist, range 0 to 48; 2 studies, 71 participants; P = 0.02; low-quality evidence). Meta-analysis also showed a significant but not clinically relevant benefit on teacher-rated inattention (MD -2.72 points, 95% CI -5.37 to -0.06, rated on the inattention subscale of the Swanson, Nolan and Pelham, Fourth Version questionnaire, range 0 to 27; 2 studies, 51 participants; P = 0.04; low-quality evidence). There were inadequate data to conduct a meta-analysis on the symptom of impulsivity. There was no evidence that methylphenidate worsens the core symptoms of ASD or benefits social interaction (SMD -0.51, 95% CI -1.07 to 0.05; 3 studies, 63 participants; P = 0.07; very low-quality evidence), stereotypical behaviours (SMD -0.34, 95% CI -0.84 to 0.17; 3 studies, 69 participants; P = 0.19; low-quality evidence), or overall ASD (SMD -0.53, 95% CI -1.26 to 0.19; 2 studies, 36 participants; P = 0.15; low-quality evidence), as rated by teachers. There were inadequate data to conduct a meta-analysis on the symptom of impaired communication.
SECONDARY OUTCOMES
no data were available for the secondary outcomes of caregiver well-being; need for institutionalisation, special schooling options or therapy to achieve learning outcomes; or overall quality of life. No trials reported serious adverse events. The only adverse effect that was significantly more likely with treatment was reduced appetite as rated by parents (risk ratio 8.28, 95% CI 2.57 to 26.73; 2 studies, 74 participants; P < 0.001; very low-quality evidence). Subgroup analysis by dose did not identify any significant differences in effect on our primary outcomes between low-, medium- or high-dose ranges.
AUTHORS' CONCLUSIONS
We found that short-term use of methylphenidate might improve symptoms of hyperactivity and possibly inattention in children with ASD who are tolerant of the medication, although the low quality of evidence means that we cannot be certain of the true magnitude of any effect. There was no evidence that methylphenidate has a negative impact on the core symptoms of ASD, or that it improves social interaction, stereotypical behaviours, or overall ASD. The evidence for adverse events is of very low quality because trials were short and excluded children intolerant of methylphenidate in the test-dose phase. Future RCTs should consider extending the duration of treatment and follow-up. The minimum clinically important difference also needs to be confirmed in children with ASD using outcome scales validated for this population.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Central Nervous System Stimulants; Child; Child, Preschool; Cross-Over Studies; Female; Humans; Male; Methylphenidate; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29159857
DOI: 10.1002/14651858.CD011144.pub2 -
Journal of the American Academy of... Jan 2008Recent studies have provided variable information on the frequency and context of diversion and the use of nonprescribed and prescribed stimulant medications in... (Review)
Review
OBJECTIVE
Recent studies have provided variable information on the frequency and context of diversion and the use of nonprescribed and prescribed stimulant medications in adolescent and young adult populations. The purpose of this systematic review of the literature is to evaluate the extent and characteristics of stimulant misuse and diversion in attention-deficit/hyperactivity disorder (ADHD) and non-ADHD individuals.
METHOD
We conducted a systematic review of the literature of available studies looking at misuse and diversion of prescription ADHD medications using misuse, diversion, stimulants, illicit use, and ADHD medications as key words for the search.
RESULTS
We identified 21 studies representing 113,104 subjects. The studies reported rates of past year nonprescribed stimulant use to range from 5% to 9% in grade school- and high school-age children and 5% to 35% in college-age individuals. Lifetime rates of diversion ranged from 16% to 29% of students with stimulant prescriptions asked to give, sell, or trade their medications. Recent work suggests that whites, members of fraternities and sororities, individuals with lower grade point averages, use of immediate-release compared to extended-release preparations, and individuals who report ADHD symptoms are at highest risk for misusing and diverting stimulants. Reported reasons for use, misuse, and diversion of stimulants include to concentrate, improve alertness, "get high," or to experiment.
CONCLUSIONS
The literature suggests that individuals both with and without ADHD misuse stimulant medications. Recent work has begun to document the context, motivation, and demographic profile of those most at risk for using, misusing, and diverting stimulants. The literature highlights the need to carefully monitor high-risk individuals for the use of nonprescribed stimulants and educate individuals with ADHD as to the pitfalls of the misuse and diversion of the stimulants.
Topics: Adolescent; Adult; Amphetamines; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Cross-Sectional Studies; Drug Prescriptions; Female; Health Surveys; Humans; Illicit Drugs; Male; Methylphenidate; Self Administration; Substance-Related Disorders; United States
PubMed: 18174822
DOI: 10.1097/chi.0b013e31815a56f1 -
Journal of Geriatric Psychiatry and... Jan 2017Apathy is one of the most frequent neuropsychiatric symptoms encountered in Alzheimer disease (AD). Early diagnosis and timely treatment of apathy in AD seem to be of... (Review)
Review
OBJECTIVE
Apathy is one of the most frequent neuropsychiatric symptoms encountered in Alzheimer disease (AD). Early diagnosis and timely treatment of apathy in AD seem to be of great importance, since apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress.
DESIGN
Within this context, we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies that have investigated the effect of pharmacological and nonpharmacological treatments of apathy in AD.
RESULTS
Acetylcholinesterase inhibitors, gingko biloba, methylphenidate, and a variety of nonpharmacological interventions were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity of the studies and the small amount of studies where apathy was a primary outcome measure are limiting factors to evaluate for group effects.
CONCLUSION
Treatment of apathy in AD is a complicated and an underexplored field. Standardized and systematic efforts primarily focused on the study of apathy in AD may establish a benefit from individualized treatment for specific disease groups that would stem from a combination of both pharmacological and nonpharmacological interventions.
Topics: Aged; Alzheimer Disease; Apathy; Caregivers; Cholinesterase Inhibitors; Disease Management; Female; Humans; Male; Phytotherapy; Psychotherapy
PubMed: 28248559
DOI: 10.1177/0891988716678684 -
Sports Medicine - Open Jan 2022Stimulant medications used for the treatment of Attention Deficit-Hyperactivity Disorder (ADHD) are believed to provide a physical advantage in athletics, but several of...
BACKGROUND
Stimulant medications used for the treatment of Attention Deficit-Hyperactivity Disorder (ADHD) are believed to provide a physical advantage in athletics, but several of these medications are not regulated by the World Anti-Doping Association. Given the prevalence of ADHD among the athlete population and concern for abuse of ADHD medications, this review and meta-analysis aimed to evaluate effects of ADHD medications on athletic performance, thereby appraising the validity of claims of performance enhancement.
METHODS
A search of MEDLINE, Embase, CINAHL, and Cochrane Review databases was performed for all randomized controlled trials evaluating athletic performance after ingestion of placebo or ADHD treatment medications from August 2020 through November 2020. All RCTs identified from these search criteria were included for screening, with exclusion of any animal studies. Two reviewers (JB, CK) assessed methodological quality and risk of bias using CONSORT 2010 and Cochrane Collaboration tools. Study results were compiled with corresponding p values for each finding. Effect sizes (Cohen's D) for athletic performance and physiological changes were aggregated for each study. Studies were further screened for homogeneity that would allow for meta-analysis. Heterogeneity was calculated using I2.
RESULTS
A total of 13,033 abstracts evaluating amphetamine, methamphetamine, methylphenidate, and bupropion were screened. The final analysis included nine studies, six of which found significant improvement in athletic performance with use of stimulant medications (p < 0.05). Methylphenidate and amphetamine were consistently identified to have a performance effect. Secondary effects identified included significant increase in heart rate, core temperature, and elevation of various serum hormone levels (p < 0.05). Effect size evaluation found seven studies demonstrating small to large effects on physical performance, as well as in categories of cardiometabolic, temperature, hormone, and ratings of perceived exertion, to varying degrees. A meta-analysis was performed on two studies, demonstrating conflicting results.
CONCLUSIONS
Dopaminergic/noradrenergic agonist medications appear to have a positive effect on athletic performance, as well as effects on physiological parameters. Further consideration of medications currently not regulated, i.e. bupropion, is warranted given evidence of athletic performance enhancement. PROSPERO trial registration number: CRD42020211062; 10/29/2020 retrospectively registered.
PubMed: 35022919
DOI: 10.1186/s40798-021-00374-y -
Journal of Pain and Symptom Management Apr 2011Cancer-related fatigue (CRF) is a common and distressing symptom affecting patients with cancer. There is an increasing number of drug trials examining potential... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Cancer-related fatigue (CRF) is a common and distressing symptom affecting patients with cancer. There is an increasing number of drug trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs in this area, and an up-to-date assessment of the evidence for its use is needed.
OBJECTIVES
To assess and summarize the increasing evidence for the use of psychostimulants, particularly methylphenidate, in the treatment of CRF.
METHODS
A systematic review of electronic databases was conducted from inception to the start of October 2009, together with cross-referencing of cited abstracts and hand searching of relevant cancer journals.
RESULTS
A meta-analysis was conducted on five psychostimulant trials (n=426 participants). The overall standardized mean difference was -0.28 (95% confidence interval [CI] -0.48, -0.09; P=0.005), although several trials failed to find any benefit over placebo. There were no differences in the frequency of adverse events between methylphenidate and placebo: combined odds ratio 1.24 (95% CI 0.42, 3.62).
CONCLUSION
There is preliminary evidence for the use of psychostimulants to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF.
Topics: Central Nervous System Stimulants; Clinical Trials as Topic; Fatigue; Humans; Methylphenidate; Neoplasms
PubMed: 21251796
DOI: 10.1016/j.jpainsymman.2010.06.020 -
Revista Da Associacao Medica Brasileira... 2013To review the effects of methylphenidate on cognitive enhancement, memory, and performance in medical students. (Review)
Review
OBJECTIVE
To review the effects of methylphenidate on cognitive enhancement, memory, and performance in medical students.
METHODS
A review of four databases (LILACS, PubMed, ScienceDirect, and SciELO), analyzing the title and abstract of all articles published between 1990 and 2012 in English, Portuguese, and Spanish. Selected articles were read in entirety, including in the review those that met the established criteria.
RESULTS
The prevalence of use among medical students reached 16%, with no gender difference. Most students began using the drug after entering the university, and the reasons cited to justify it are related to enhancing academic performance.
CONCLUSION
There is no evidence in the literature that the use of methylphenidate is beneficial in terms of memory or learning. The drug simply increases wakefulness and alertness, reducing the time of sleep.
Topics: Central Nervous System Stimulants; Cognition; Humans; Methylphenidate; Motivation; Students, Medical
PubMed: 23680277
DOI: 10.1016/j.ramb.2012.10.007 -
Journal of the American Academy of... May 2024We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to...
OBJECTIVE
We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and non-stimulants.
METHOD
From the dataset of a published network meta-analysis (Cortese et al., 2018), updated on 27 February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1.
RESULTS
We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedges g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults.
CONCLUSION
In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD.
STUDY PREREGISTRATION INFORMATION
Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/;qvgps.
PubMed: 38823477
DOI: 10.1016/j.jaac.2024.05.023 -
Health Technology Assessment... Jul 2006To assess the clinical and cost-effectiveness of oral methylphenidate hydrochloride (MPH), dexamfetaminesulphate (DEX) and atomoxetine (ATX) in children and adolescents... (Review)
Review
A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.
OBJECTIVES
To assess the clinical and cost-effectiveness of oral methylphenidate hydrochloride (MPH), dexamfetaminesulphate (DEX) and atomoxetine (ATX) in children and adolescents (<18 years of age) diagnosed with attention deficit hyperactivity disorder (ADHD) (including hyperkinetic disorder).
DATA SOURCES
Electronic databases covering 1999--July 2004 for MPH, 1997--July 2004 for DEX and 1981--July 2004 for ATX.
REVIEW METHODS
Selected studies were assessed using modified criteria based on CRD Report No. 4. Clinical effectiveness data were reported separately for each drug and by the type of comparison. Data for MPH were also analysed separately based on whether it was administered as an immediate release (IR) or extended release (ER) formulation. For all drugs, the data were examined by dose. Data for the core outcomes of hyperactivity (using any scale), Clinical Global Impression [as a proxy of quality of life (QoL)] and adverse events were reported. For crossover studies, the mean and standard deviation (SD) for each outcome were data extracted for end of trial data (i.e. baseline data were not considered). For parallel studies, change scores were reported where given, otherwise means and SDs were presented for end of trial data. In addition, mean differences with 95% confidence intervals were calculated for each study. For adverse events, self-ratings were reported when used, otherwise, parent reports were utilised. Percentages of participants reporting adverse events were used to calculate numbers of events in each treatment arm. All the clinical effectiveness data and economic evaluations (including accompanying models) included in the company submissions were assessed. A new model was developed to assess the cost-effectiveness of the alternative treatments in terms of cost per quality-adjusted life-year. To achieve this, a mixed treatment comparison model was used to estimate the differential mean response rates. Monte Carlo simulation was used to reflect uncertainty in the cost-effectiveness results.
RESULTS
In total, 65 papers met the inclusion criteria. The results suggest that MPH and DEX are effective at reducing hyperactivity and improving QoL (as determined by Clinical Global Impression) in children, although the reliability of the MPH study results is not known and there were only a small number of DEX studies. There was consistent evidence that ATX was superior to placebo for hyperactivity and Clinical Global Impression. Studies on ATX more often reported the study methodology well, and the results were likely to be reliable. Very few studies made direct head-to-head comparisons between the drugs or examined a non-drug intervention in combination with MPH, DEX or ATX. Adequate and informative data regarding the potential adverse effects of the drugs were also lacking. The results of the economic evaluation clearly identified an optimal treatment strategy of DEX first-line, followed by IR-MPH for treatment failures, followed by ATX for repeat treatment failures. Where DEX is unsuitable as a first-line therapy, the optimal strategy is IR-MPH first-line, followed by DEX and then ATX. For patients contraindicated to stimulants, ATX is preferred to no treatment. For patients in whom a midday dose of medication is unworkable, ER-MPH is preferred to ATX, and ER-MPH12 appears more cost-effective than ER-MPH8. As identified in the clinical effectiveness review, the reporting of studies was poor, therefore this should be borne in mind when interpreting the model results.
CONCLUSIONS
Drug therapy seems to be superior to no drug therapy, no significant differences between the various drugs in terms of efficacy or side effects were found, mainly owing to lack of evidence, and the additional benefits from behavioural therapy (in combination with drug therapy) are uncertain. Given the lack of evidence for any differences in effectiveness between the drugs, the economic model tended to be driven by drug costs, which differed considerably. Future trials examining MPH, DEX and ATX should include the assessment of tolerability and safety as a priority. Longer term follow-up of individuals participating in trials could further inform policy makers and health professionals. Such data could potentially distinguish between these drugs in a clinically useful way. In addition, research examining whether somatic complaints are actually related to drug treatment or to the disorder itself would be informative.
Topics: Adolescent; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Child; Child, Preschool; Cost-Benefit Analysis; Dextroamphetamine; Humans; Methylphenidate; Models, Economic; Propylamines; Treatment Outcome
PubMed: 16796929
DOI: 10.3310/hta10230