Assessment of centanafadine in adults with ADHD: a matching adjusted indirect comparison versus methylphenidate hydrochloride extended release (Concerta).

OBJECTIVE: To compare safety and efficacy of centanafadine versus methylphenidate hydrochloride extended release (ER; Concerta) in adults with ADHD. METHODS: Without head-to-head trials, anchored matching-adjusted indirect comparisons (MAIC) of adverse event rates reported across trials and mean change from baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) score between centanafadine and methylphenidate hydrochloride ER were conducted. Pooled patient-level data from two centanafadine trials (NCT03605680/NCT03605836) and aggregate data from one published methylphenidate hydrochloride ER trial (NCT00937040) were used. Characteristics of individual patients from the centanafadine trials were matched to aggregate baseline characteristics from the methylphenidate hydrochloride ER trial using propensity score weighting. A sensitivity analysis assessed the robustness of the results to the capping of extreme weights (i.e. >99th percentile). RESULTS: Compared with methylphenidate hydrochloride ER, centanafadine was associated with significantly lower risk of dry mouth (risk difference [RD] in percentage points: -11.95), initial insomnia (-11.10), decreased appetite (-8.05), anxiety (-5.39), palpitations (-5.25), and feeling jittery (-4.73) though a significantly smaller reduction in AISRS score (4.16-point). In the sensitivity analysis, the safety results were consistent with the primary analysis but there was no significant difference in efficacy between centanafadine and methylphenidate hydrochloride ER. CONCLUSION: In this MAIC, centanafadine had better safety and possibly lower efficacy than methylphenidate hydrochloride ER. While safety results were robust across analyses, there was no efficacy difference between centanafadine and methylphenidate hydrochloride ER in the sensitivity analysis. Considering its favorable safety profile, centanafadine may be preferred among patients for whom treatment-related adverse events are a concern.

Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release.

BACKGROUND: Head-to-head trials comparing centanafadine, an investigational therapy for adults with attention-deficit/hyperactivity disorder (ADHD), with other treatment options are lacking. OBJECTIVE: To compare safety and efficacy outcomes of centanafadine sustained-release vs lisdexamfetamine dimesylate (lisdexamfetamine), atomoxetine hydrochloride (atomoxetine), and viloxazine extended-release (viloxazine ER), respectively, using matching-adjusted indirect comparison (MAIC). METHODS: This MAIC included patient-level data pooled from 2 centanafadine trials (NCT03605680 and NCT03605836) and published aggregate data from comparable trials of 3 comparators-lisdexamfetamine (NCT00334880), atomoxetine (NCT00190736), and viloxazine ER (NCT04016779)-in adult patients with ADHD. Propensity score weighting was used to match characteristics of individual patients from the centanafadine trials to aggregate baseline characteristics from the respective comparator trials. Safety outcomes were rates of adverse events for which information was available in the centanafadine and respective comparator trials. Efficacy outcome was mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) score (ADHD Rating Scale [ADHD-RS] was used as proxy in the comparison with lisdexamfetamine). Anchored indirect comparisons were conducted across matched populations of the centanafadine and respective comparator trials. RESULTS: After matching, baseline characteristics in the centanafadine trials were the same as those in the respective comparator trials. Compared with lisdexamfetamine, centanafadine was associated with a significantly lower risk of lack of appetite (risk difference [RD] in percentage points: 23.42), dry mouth (19.27), insomnia (15.35), anxiety (5.21), nausea (4.90), feeling jittery (3.70), and diarrhea (3.47) (all P < 0.05) but a smaller reduction in the AISRS/ADHD-RS score (6.58-point difference; P < 0.05). Compared with atomoxetine, centanafadine was associated with a significantly lower risk of nausea (RD in percentage points: 18.64), dry mouth (17.44), fatigue (9.21), erectile dysfunction (6.76), lack of appetite (6.71), and urinary hesitation (5.84) (all P < 0.05) and no statistically significant difference in the change in AISRS score. Compared with viloxazine ER, centanafadine was associated with a significantly lower risk of fatigue (RD in percentage points: 11.07), insomnia (10.67), nausea (7.57), and constipation (4.63) (all P < 0.05) and no statistically significant difference in the change in AISRS score. CONCLUSIONS: In an anchored MAIC, centanafadine showed a significantly better short-term safety profile than lisdexamfetamine, atomoxetine, and viloxazine ER; efficacy was lower than with lisdexamfetamine and comparable (ie, nondifferent) with atomoxetine and viloxazine ER. This MAIC provides important insights on the relative safety and efficacy of common treatment options to help inform treatment decisions in adults with ADHD. Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. STUDY REGISTRATION NUMBERS: NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779.

Costs associated with adverse events during treatment episodes for adult attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) medication is frequently associated with adverse events (AEs), but limited real-world data exist regarding their costs from a payer's perspective. Therefore, this study evaluated the healthcare costs associated with common AEs among adult patients treated for ADHD in the US. METHODS: Eligible adults treated for ADHD were identified from a large US claims database (1 October 2015-30 September 2021). A retrospective cohort study design was used to assess excess healthcare costs and costs directly related to AE-specific claims per-patient-per-month (PPPM) associated with 10 selected AEs during ADHD treatment. To account for all costs associated with the AE, treatment episodes with a given AE were compared to similar treatment episodes without this AE. Entropy balancing was used to create cohorts with similar characteristics. Studied AEs were selected based on their prevalence in clinical trials for common ADHD medications and were identified from ICD-10-CM diagnosis codes recorded in claims. RESULTS: Among the 461,464 patients included (mean age: 34.2 years; 45.5% males), 49.4% had ≥1 AE during their treatment episode. Treatment episodes with AEs were associated with statistically significant AE-specific medical costs (erectile dysfunction: $57; fatigue: $82; dry mouth: $90; diarrhea: $162; insomnia: $147; anxiety: $281; nausea: $299; constipation: $356; urinary hesitation: $491; feeling jittery: $723) and excess healthcare costs PPPM (erectile dysfunction: $120, fatigue: $248, insomnia: $265, anxiety: $380, diarrhea: $441, dry mouth: $485, nausea: $709, constipation: $802, urinary hesitation: $1,105, feeling jittery: $1,160; p < .05). LIMITATIONS: AEs were identified based on recorded diagnosis on medical claims and likely represent more severe AEs. Therefore, costs may not be representative of milder AEs. CONCLUSIONS: This study found that AEs occurring during ADHD treatment episodes are associated with significant healthcare costs. This highlights the potential of treatments with favorable safety profiles to alleviate the burden experienced by patients and the healthcare system.

Assessment of lisdexamfetamine on executive function in rats: A translational cognitive research.

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

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.

Protocol of a monocentric, double-blind, randomized, superiority, controlled trial evaluating the effect of in-prison OROS-methylphenidate vs. placebo treatment in detained people with attention-deficit hyperactivity disorder (BATIR).

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is characterized by difficulty paying attention, poor impulse control, and hyperactive behavior. It is associated with several adverse health and social outcomes and leads to an increased risk of criminality and recidivism. Worldwide, ADHD is thus highly prevalent in prisons. However, ADHD treatment has been neglected in such environments. Stimulant medications such as osmotic-release oral system methylphenidate (OROS-MPH) are first-line treatments in the general population, but they are under-prescribed in prisons due to concerns about abuse, even though such claims are not empirically supported. This project aims to compare the efficacy of a 3-month in-prison OROS-MPH vs. placebo treatment on the severity of core ADHD symptoms and relevant in- and post-prison outcomes. METHODS: This study is a phase III, double-blinded, randomized, superiority, controlled trial of OROS-MPH vs. placebo. After randomization, the participants will receive 3 months of treatment with OROS-MPH or placebo (1:1 ratio) while incarcerated. Upon release, all participants will be offered the treatment (OROS-MPH) for 1 year but will remain blinded to their initial study group. The study will be conducted at the Division of Prison Health, Geneva, Switzerland, among incarcerated men (n = 150). Measures will include (1) investigator-rated ADHD symptoms, (2) acute events collected by the medical and prison teams, (3) assessment of the risk of recidivism, (4) medication side effects, (5) medication adherence, (6) study retention, (7) health care/prison costs, and (8) 1-year recidivism. Analyses will include bivariable and multivariable modeling (e.g., regression models, mixed-effects models, survival analyses) and an economic evaluation (cost-benefit analysis). DISCUSSION: We expect that early identification and treatment of ADHD in prison will be an important public health opportunity and a cost-effective approach that is likely to reduce the vulnerability of incarcerated individuals and promote pathways out of criminal involvement. The study will also promote standards of care for people with ADHD in prison and provide recommendations for continuity of care after release. TRIAL REGISTRATION: ClinicalTrials.gov NCT05842330 . Registered on June 5, 2023. Kofam.ch SNCTP000005388. Registered on July 17, 2023.

Is age of onset and duration of stimulant therapy for ADHD associated with cocaine, methamphetamine, and prescription stimulant misuse?

BACKGROUND: To assess whether age of onset and duration of stimulant therapy for attention-deficit/hyperactivity disorder (ADHD) are associated with cocaine, methamphetamine, and prescription stimulant misuse during adolescence. METHODS: Nationally representative samples of US 10th and 12th grade students (N = 150,395) from the Monitoring the Future study were surveyed via self-administered questionnaires from 16 annual surveys (2005-2020). RESULTS: An estimated 8.2% of youth received stimulant therapy for ADHD during their lifetime (n = 10,937). More than one in 10 of all youth reported past-year prescription stimulant misuse (10.4%)-past-year cocaine (4.4%) and methamphetamine (2.0%) use were less prevalent. Youth who initiated early stimulant therapy for ADHD (≤9 years old) and for long duration (≥6 years) did not have significantly increased adjusted odds of cocaine or methamphetamine use relative to population controls (ie, non-ADHD and unmedicated ADHD youth). Youth who initiated late stimulant therapy for ADHD (≥10 years old) and for short duration (<1 year) had significantly higher odds of past-year cocaine or prescription stimulant misuse in adolescence than those initiating early stimulant therapy for ADHD (≤9 years old) and for long duration (≥6 years). Youth who initiated late stimulant therapy for ADHD (≥10 years) for short duration (<1 year) had significantly higher odds of past-year cocaine, methamphetamine, and prescription stimulant misuse versus population controls during adolescence. No differences in past-year cocaine, methamphetamine, and prescription stimulant misuse were found between individuals who only used non-stimulant therapy for ADHD relative to youth who initiated early stimulant therapy (≤9 years old) and for long duration (≥6 years). CONCLUSIONS: An inverse relationship was found between years of stimulant therapy and illicit and prescription stimulant misuse. Adolescents with later initiation and/or shorter duration of stimulant treatment for ADHD should be monitored for potential illicit and prescription stimulant misuse.

Prescription Stimulant Medical and Nonmedical Use Among US Secondary School Students, 2005 to 2020.

Importance: Recent information on the prevalence of prescription stimulant therapy for attention-deficit/hyperactivity disorder (ADHD) and nonmedical use of prescription stimulants (NUPS) at the school-level among US secondary school students is limited. Objective: To investigate the school-level prevalence of and association between stimulant therapy for ADHD and NUPS among US secondary school students. Design, Setting, and Participants: This cross-sectional study used survey data collected between 2005 and 2020 as part of the Monitoring the Future study (data collected annually via self-administered survey in schools from independent cohorts). Participants were from a nationally representative sample of 3284 US secondary schools. The mean (SD) response rates were 89.5% (1.3%) for 8th-grade students, 87.4% (1.1%) for 10th-grade students, and 81.5% (1.8%) for 12th-grade students. Statistical analysis was performed from July to September 2022. Main Outcome and Measure: Past-year NUPS. Results: The 3284 schools contained 231 141 US 8th-, 10th-, and 12th-grade students (111 864 [50.8%, weighted] female; 27 234 [11.8%, weighted] Black, 37 400 [16.2%, weighted] Hispanic, 122 661 [53.1%, weighted] White, 43 846 [19.0%, weighted] other race and ethnicity). Across US secondary schools, the past-year prevalence of NUPS ranged from 0% to more than 25%. The adjusted odds of an individual engaging in past-year NUPS were higher at secondary schools with higher proportions of students who reported stimulant therapy for ADHD, after controlling for other individual-level and school-level covariates. Students attending schools with the highest rates of prescription stimulant therapy for ADHD had approximately 36% increased odds of past-year NUPS compared with students attending schools with no medical use of prescription stimulants (adjusted odds ratio, 1.36; 95% CI, 1.20-1.55). Other significant school-level risk factors included schools in more recent cohorts (2015-2020), schools with higher proportions of parents with higher levels of education, schools located in non-Northeastern regions, schools located in suburban areas, schools with higher proportion of White students, and schools with medium levels of binge drinking. Conclusions and Relevance: In this cross-sectional study of US secondary schools, the prevalence of past-year NUPS varied widely, highlighting the need for schools to assess their own students rather than relying solely on regional, state, or national results. The study offered new evidence of an association between a greater proportion of the student body that uses stimulant therapy and a greater risk for NUPS in schools. The association between greater school-level stimulant therapy for ADHD and other school-level risk factors suggests valuable targets for monitoring, risk-reduction strategies, and preventive efforts to reduce NUPS.

Efficacy and safety of methylphenidate and behavioural parent training for children aged 3-5 years with attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled, and sham behavioural parent training-controlled trial.

BACKGROUND: There is insufficient evidence to support treatment recommendations for preschool children aged 3-5 years with attention-deficit hyperactivity disorder (ADHD). We aimed to investigate the efficacy and safety of methylphenidate and behavioural parent training in reducing the frequency and severity of symptoms and improving global functioning in preschool children with ADHD. METHODS: We did an 8-week, randomised, double-blind, placebo-controlled and sham behavioural parent training-controlled clinical trial (the MAPPA Study) in children aged 3-5 years with moderate-to-severe ADHD. The trial was conducted at the Institute of Psychiatry, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil. Participants were randomly assigned (1:1:1) to receive immediate-release methylphenidate plus educational intervention (sham behavioural parent training), placebo medication plus behavioural parent training, or placebo medication plus educational intervention. Randomisation was done by an independent research manager by use of a permuted block randomisation procedure. Parents, teachers, study staff, and evaluators remained masked to group allocation. Methylphenidate and placebo were titrated to a maximum dose of 1·25 mg/kg per day administered orally twice daily, and behavioural parent training and the educational intervention were delivered weekly through 90 min sessions with both the child and parent, conducted by two psychologists or learning therapists. The primary outcomes were parents' and teachers' composite scores of the Swanson, Nolan, and Pelham-IV scale (SNAP-IV-P/T), the Clinical Global Impressions Severity (CGI-S) scale, and the Children's Global Assessment Scale (CGAS). This trial is registered with ClinicalTrials.gov, NCT02807870, and is now complete. All participants were invited to participate in an open observational follow-up, which is ongoing. FINDINGS: Between Aug 21, 2016, and Oct 21, 2019, 153 children were randomly assigned to receive methylphenidate plus the educational intervention (n=51), placebo plus behavioural parent training (n=51), or placebo plus the educational intervention (n=51). Nine (6%) children discontinued treatment. All participants were included in the intention-to-treat analysis. Children in the methylphenidate plus educational intervention group showed greater reductions in the SNAP-IV-P/T (endpoint mean difference -3·93 [95% CI -7·14 to -0·73], p=0·049; effect size -0·55 [95% CI -0·99 to -0·10]) and CGI-S scores (endpoint mean difference -0·49 [-0·82 to -0·17], p=0·0088; effect size -0·70 [-1·16 to -0·24]) and a greater increase in CGAS scores (endpoint mean difference 5·25 [95% CI 2·09 to 8·40], p=0·0036; effect size 0·80 [95% CI 0·32 to 1·28]) than children in the placebo plus educational intervention group. Children in the placebo plus behavioural parent training group did not have significantly different SNAP-IV-P/T scores (endpoint mean difference -3·18 [95% CI -6·38 to 0·02], p=0·077; effect size -0·44 [95% CI -0·89 to 0·003]) or CGI-S scores (endpoint mean difference -0·35 [-0·68 to -0·03], p=0·052; effect size -0·50 [-0·96 to -0·04]) compared to children in the placebo plus educational intervention group, but they had a greater increase in CGAS scores compared to the placebo plus educational intervention group (endpoint mean difference 3·69 [0·53 to 6·85], p=0·033; effect size 0·56 [0·08 to 1·04]). Children in the methylphenidate plus educational intervention versus placebo plus behavioural parent training group did not have statistically or clinically significant differences in primary outcomes. Children in the methylphenidate plus educational intervention group had more mild adverse events than the other two groups, and there were no between-group differences for moderate or severe adverse events. INTERPRETATION: Methylphenidate was effective in reducing ADHD symptoms and improving functionality, and behavioural parent training was effective in improving functionality for preschool children with ADHD after 8 weeks of treatment. FUNDING: São Paulo Research Foundation and Brazilian National Council for Scientific and Technological Development.

[Increasing methylphenidate abuse: Tracking and profiles during 13-years]. / Augmentation de l'abus de méthylphénidate : repérage et profils sur 13 années.

BACKGROUND: Methylphenidate is indicated for attention deficit hyperactivity disorder (ADHD). Several studies have evaluated its abuse in specific populations (students, drug users) and few in the general population. This work describes the extent of its abuse in a region of more than 5 million inhabitants. METHOD: Based on regional health insurance data from 2005 to 2017, the clustering method identifies different methylphenidate use profiles according to several characteristics (number of different prescribers and pharmacies, number of dispensations, number of defined daily dose dispensed). The groups characterised by high values of these variables will be qualified as "deviant". RESULTS: In 13 years, the number of patients with at least one dispensation in the first quarter has been multiplied by 5.8 times. The proportion of adults has increased (20% in 2017) and their number has been multiplied by 10. Five groups are identified, three of them are characterised by "deviant" behaviour. Group 5 (n=11, 0.04%) has higher values than 4 (n=112, 0.4%) and 3 (n=407, 1.6%). These patients are older and more frequently use benzodiazepines and opiate substitution drugs. Groups 1 (n=13,132, 51%) and 2 (n=11,941, 46.7%) are more likely to be taken up by young subjects. The number of subjects with "deviant" behaviour increased until 2011 and after a decrease, the highest number of subjects concerned has been observed since 2015. CONCLUSION: In view of the increase of subjects with "deviant" behaviour, it is necessary to make the medical community and patients aware on the risk of abuse of methylphenidate. The recent extension of the indication for ADHD in adults and the broadening of the conditions of prescription require increased vigilance.

Understanding the Impact of Stimulants on Sleep in ADHD: Evidence from Systematic Assessment of Sleep in Adults.

Stimulants are widely prescribed to manage attention-deficit/hyperactivity disorder (ADHD) in adults. Stimulants promote wakefulness and can produce insomnia side effects. We hypothesized that systematic studies of sleep effects would reveal patterns of sleep impairment that may be important for clinicians to monitor and manage. We conducted a review and analysis of studies that measured sleep systematically during stimulant treatment in adults. We identified nine studies that met our search criteria, including four double-blind placebo-controlled studies. All studies recorded self-report subjective sleep quality data, three studies collected actigraphy data, and three studies collected polysomnography data. One study found better subjective sleep quality under open-label treatment conditions. Both polysomnography studies found improvement in aspects of sleep patterns. Two of the actigraphy studies suggested that adults receiving stimulant treatment may have less movement during sleep, and one showed reduction in amount of sleep. Further research could inform best practices for maintaining sleep quality during stimulant treatment.

Stimulant Prescribing Error Assessment Rubric Development.

OBJECTIVE: Stimulant medications are used to treat attention-deficit/hyperactivity disorder (ADHD) in adults. However, stimulants are among the most frequently prescribed medications that have a potential to be used nonmedically. We sought to define types of errors associated with treatment of ADHD in adults and to describe a classification rubric for stimulant-related prescribing faults. METHODS: An expert panel conducted a scoping review of the literature and rubric development. The literature search including relevant English language publications indexed in Medline (1990-present, human) and Embase (1990-present, human). In addition, we reviewed relevant documentation such as medication labels and guides containing information related to medications used for the treatment of adult ADHD. The initial version draft rubric was developed by adapting an existing framework for prescribing errors. The expert panel further defined a classification rubric and developed error subcategories, classifications, and descriptions. RESULTS: Two error categories were identified. Category 1 errors are errors resulting from prescribing faults, which further included errors in decision making/judgment; errors related to monitoring for potential harm of stimulants; possible errors: events that should generally be avoided or be used with caution; and suboptimal prescribing. Category 2 errors result from prescription writing, further defined as failure to communicate essential information and transcription errors. CONCLUSIONS: This study provides a comprehensive description of medication errors associated with stimulant and related medications. Our findings have the potential to assist decision making and to tailor delivery programs, recommendations, guidelines, and clinical decision support health information technology on stimulant prescribing and monitoring.

Assessment of Stimulant Use and Cardiovascular Event Risks Among Older Adults.

Importance: Use of stimulants continues to increase among older adults for a variety of indications. An association between stimulant use and increased risk of cardiovascular (CV) events has been established among children and young adults, but few studies have explored the risk of CV events among older patients, a group with increased baseline risk. Objective: To evaluate the association between stimulant use and risk of CV events among older adults. Design, Setting, and Participants: This propensity score-matched cohort study, with 4 nonusers per 1 user, was conducted from July 1, 2017, to June 27, 2019, using data from population-based health care databases from Ontario, Canada, from January 1, 2002, to December 31, 2016. Included individuals were outpatients aged 66 years or older. Exposures: Initiation of a prescription stimulant. Main Outcomes and Measures: The primary outcome was a CV event, defined as a composite of emergency department visit or hospitalization for myocardial infarction, stroke or transient ischemic attack (TIA), or ventricular arrhythmia. Risk of CV event was assessed at 30 days, 180 days, and 365 days after initiation of stimulants from Cox proportional hazard models. A secondary analysis assessed each component of the primary outcome separately. Results: Among 6457 older adults who initiated a prescription stimulant (ie, the exposed group) and 24 853 older adults who did not initiate such treatment (ie, the unexposed group), the distribution of baseline patient characteristics was well balanced after matching (sex: 3173 [49.1%] men vs 12 112 [48.7%] men; standardized difference, 0.01; median [IQR] age: 74 [69-80] years vs 74 [69-80] years; standardized difference, 0.01). Within this cohort, there were 932 CV events during the 365-day follow-up (5.11 events per 100 person-years among individuals who initiated stimulants). In the primary analysis, stimulant initiation was associated with increased risk of CV events at 30 days (hazard ratio [HR], 1.4; 95% CI, 1.1-1.8) but not at 180 days (HR, 1.2; 95% CI, 0.9-1.6) or 365 days (HR, 1.0; 95% CI, 0.6 to 1.8). In the secondary analysis, stimulant initiation was associated with increased risk of ventricular arrhythmias (HR, 3.0; 95% CI, 1.1-8.7) and stroke or TIA (HR, 1.6; 95% CI, 1.1-2.1) at 30 days. Conclusions and Relevance: This cohort study found that stimulant use was associated with an early increase in CV events among older adults with no association for long-term use.

Methamphetamine-Associated Heart Failure Hospitalizations Across the United States: Geographic and Social Disparities.

Background Although methamphetamine abuse is associated with the development of heart failure (HF), nationwide data on methamphetamine-associated HF (MethHF) hospitalizations are limited. This study evaluates nationwide HF hospitalizations associated with substance abuse to better understand MethHF prevalence trends and the clinical characteristics of those patients. Methods and Results This cross-sectional period-prevalence study used hospital discharge data from the National Inpatient Sample to identify adult primary HF hospitalizations with a secondary diagnosis of abuse of methamphetamines, cocaine, or alcohol in the United States from 2002 to 2014. All 2014 MethHF admissions were separated by regional census division to evaluate geographical distribution. Demographics, payer information, and clinical characteristics of MethHF hospitalizations were compared with all other HF hospitalizations. Total nationwide MethHF hospitalizations increased from 547 in 2002 to 6625 in 2014 with a predominance on the West Coast. Methamphetamine abuse was slightly more common among primary HF hospitalizations compared with all-cause hospitalizations (7.4 versus 6.4 per 1000; Cohen h=0.012; P<0.001). Among HF hospitalizations, patients with MethHF were younger (mean age, 48.9 versus 72.4 years; Cohen d=1.93; P<0.001), more likely to be on Medicaid (59.4% versus 8.8%; Cohen h=1.16; P<0.001) or uninsured (12.0% versus 2.6%; Cohen h=0.36; P<0.001), and more likely to present to urban hospitals (43.8% versus 28.3%; Cohen h=0.32; P<0.001) than patients with non-methamphetamine associated HF. Patients with MethHF had higher rates of psychiatric comorbidities and were more likely to leave the hospital against medical advice. Conclusions MethHF hospitalizations have significantly increased in the United States, particularly on the West Coast. Coordinated public health policies and systems of care are needed to address this rising epidemic.

Impact of CNS Stimulants for Attention-Deficit/Hyperactivity Disorder on Growth: Epidemiology and Approaches to Management in Children and Adolescents.

Central nervous system stimulants are established treatments for pediatric attention-deficit/hyperactivity disorder with robust efficacy data. Reductions in appetite, weight, and growth velocity are some of the most common concerns regarding the long-term use of central nervous system stimulants in developing children. They are associated with suppression of weight and body mass index in childhood. However, both weight and body mass index often progressively increase over adolescence at rates faster than those seen in non-attention-deficit/hyperactivity disorder youth to the degree that attention-deficit/hyperactivity disorder is associated with elevated body mass index by the end of adolescence regardless of medication use. The capacity of central nervous system stimulants to slow growth was identified 50 years ago. Recent work has established that the growth deficits accumulate during the first 2 years of use and may persist provided medication is used. Early initiation coupled with persistent use through adolescence is most likely to be associated with clinical impactful growth suppression. There has been limited formal investigation of treatments for stimulant-associated reductions in weight and height. The most robust evidence exists for drug holidays improving weight gain. Observational studies suggest that limiting lifetime exposure or discontinuing medication is associated with greater adult height. Additional research is needed to identify the causal mechanisms driving the observed slowing in growth as well as the identification of predictors of clinically impactful growth suppression.

Treatment with Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) and the Risk of All-Cause Poisoning in Children and Adolescents: A Self-Controlled Case Series Study.

BACKGROUND: Children and adolescents with attention deficit hyperactivity disorder (ADHD) are at higher risk of all-cause poisoning by drugs and chemicals (intentional or accidental). Currently, there is limited data on whether medication treatment for ADHD can reduce the risk of all-cause poisoning. METHODS: Patients aged 5-18 years with a methylphenidate (MPH) prescription and an incident poisoning diagnosis between January 2001 and June 2020 were identified from the Hong Kong Clinical Data Analysis and Reporting System. A self-controlled case series study design was used to compare the incidence rate ratios (IRRs) of all-cause poisoning during different risk windows (30 days before the first MPH prescription, exposure periods within 30 days of the first prescription, and periods of subsequent exposure) compared with the reference window (other non-exposure periods). RESULTS: 42,203 patients were prescribed ADHD medication in Hong Kong during the study period. Of these, 417 patients who had both an MPH prescription and poisoning incident recorded were included in the main analysis. Compared with other non-exposed periods, a higher risk of poisoning was found in the 30 days before the first prescription (IRR 2.64, 95% confidence interval [CI] 1.33-5.22) and exposure periods within 30 days of the first prescription (IRR 2.18, 95% CI 1.06-4.48), but not during prolonged exposure. However, compared with 30 days before the first prescription as well as exposure periods within 30 days of the first prescription, there was a lower risk during the subsequent exposure (IRRs 0.49 and 0.60, respectively). Similar results to the main analysis were also found in the subgroup analysis of intentional poisoning and females, but not in that of accidental poisoning and males. CONCLUSIONS: The risk of all-cause poisoning was higher shortly before and after the first MPH prescription and became lower during the subsequent prescription period. Our results do not support an association between the use of MPH and an increased risk of all-cause poisoning in children and adolescents and, in fact, suggest that longer-term use of MPH may be associated with a lower risk of all-cause poisoning, although this latter finding requires further study.

Caffeinated energy drinks in the Canadian context: health risk assessment with a focus on cardiovascular effects.

In Canada, caffeinated energy drinks (CEDs) currently sold under Temporary Marketing Authorizations must meet strict eligibility criteria. These criteria, which include compositional and labelling requirements, were developed based on the outcome of a health risk assessment conducted by Health Canada (HC) in 2013. HC updated its assessment by reviewing new information with the focus on potential cardiovascular effects associated with the consumption of CEDs available for sale in Canada. Due to limited data on CED consumption among Canadians to derive accurate exposure information, the composition of a typical CED was characterized to assess the potential effects of single ingredients and synergistic interactions between ingredients on the cardiovascular system. Surveillance data on potential adverse effects related to CED consumption was also analyzed. After extensive review, HC's updated assessment confirms the current risk management approach for CEDs is health protective for Canadian consumers, including the potential for cardiovascular effects. The available evidence supports that moderate consumption (up to 500 mL per day) of a typical CED authorized for sale in Canada is safe for the general population of healthy adults and adolescents. It also re-confirms that vulnerable sub-populations (i.e., children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals) should not consume CEDs. Novelty: Consumption up to 500 mL per day of a typical CED is not associated with an increased risk of cardiovascular effects. Children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals should not consume CEDs.