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Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

SUBMITTER: Huss M

PROVIDER: S-EPMC5505611 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

Huss Michael M Duhan Praveen P Gandhi Preetam P Chen Chien-Wei CW Spannhuth Carsten C Kumar Vinod V

Neuropsychiatric disease and treatment 20170704

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimizati ...[more]

PMID: 28740389

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Project description:OBJECTIVE:To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. METHODS:Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20?mg/day; participants were titrated in 10-20?mg/day increments weekly based on efficacy and tolerability (maximum dose, 60?mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60?mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. RESULTS:Mean MPH ERCT daily dose increased weekly from 29.4?mg/day after the first dose adjustment at week 1 (n?=?90) to 42.8?mg/day after the final adjustment at week 5 (n?=?86). Final optimized MPH ERCT dose ranged from 20 to 60?mg/day. Mean final optimized MPH ERCT dose ranged from 40.0?mg/day in 6-8 year-old participants to 44.8?mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60?mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20?mg/day (42.4 [1.34] vs. 35.1 [2.55]; p?=?0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. CONCLUSIONS:Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

Project description:ObjectiveTo synthesise existing knowledge of the efficacy and safety of long-acting versus short-acting methylphenidate for paediatric attention deficit hyperactivity disorder (ADHD).DesignSystematic review and meta-analysis.Data sourcesElectronic literature search of CENTRAL, MEDLINE, PreMEDLINE, CINAHL, EMBASE, PsychINFO, Scopus and Web of Science for articles published in the English language between 1950 and 2012. Reference lists of included studies were checked for additional studies.Study selectionRandomised controlled trials of paediatric ADHD patients (<18 years), comparing a long-acting methylphenidate form to a short-acting methylphenidate form.Data extractionTwo authors independently selected trials, extracted data and assessed risk of bias. Continuous outcomes were compared using standardised mean differences (SMDs) between treatment groups. Adverse events were compared using risk differences between treatment groups. Heterogeneity was explored by subgroup analysis based on the type of long-acting formulation used.ResultsThirteen RCTs were included; data from 882 participants contributed to the analysis. Meta-analysis of three studies which used parent ratings to report on hyperactivity/impulsivity had an SMD of -0.30 (95% CI -0.51 to -0.08) favouring the long-acting forms. In contrast, three studies used teacher ratings to report on hyperactivity and had an SMD of 0.29 (95% CI 0.05 to 0.52) favouring the short-acting methylphenidate. In addition, subgroup analysis of three studies which used parent ratings to report on inattention/overactivity indicate that the osmotic release oral system generation long-acting formulation was favoured with an SMD of -0.35 (95% CI -0.52 to -0.17), while the second generation showed less efficacy than the short-acting formulation with an SMD of 0.42 (95% CI 0.17 to 0.68). The long-acting formulations presented with slightly more total reported adverse events (n=578) as compared with the short-acting formulation (n=566).ConclusionsThe findings from this systematic review indicate that the long-acting forms have a modest effect on the severity of inattention/overactivity and hyperactivity/impulsivity according to parent reports, whereas the short-acting methylphenidate was preferred according to teacher reports for hyperactivity.

Project description:ObjectiveSleep problems is the most common side effect of methylphenidate (MPH) treatment in ADHD youth and carry potential to negatively impact long-term self-regulatory functioning. This study aimed to examine whether applying machine learning approaches to pre-treatment demographic, clinical questionnaire, environmental, neuropsychological, genetic, and neuroimaging features can predict sleep side effects following MPH administration.MethodThe present study included 83 ADHD subjects as a training dataset. The participants were enrolled in an 8-week, open-label trial of MPH. The Barkley Stimulant Side Effects Rating Scale was used to determine the presence/absence of sleep problems at the 2nd week of treatment. Prediction of sleep side effects were performed with step-wise addition of variables measured at baseline: demographics (age, gender, IQ, height/weight) and clinical variables (ADHD Rating Scale-IV (ADHD-RS) and Disruptive Behavior Disorder rating scale) at stage 1, neuropsychological test (continuous performance test (CPT), Stroop color word test) and genetic/environmental variables (dopamine and norepinephrine receptor gene (DAT1, DRD4, ADRA2A, and SLC6A2) polymorphisms, blood lead, and urine cotinine level) at stage 2, and structural connectivities of frontostriatal circuits at stage 3. Three different machine learning algorithms ((Logistic Ridge Regression (LR), support vector machine (SVM), J48) were used for data analysis. Robustness of classifier model was validated in the independent dataset of 36 ADHD subjects.ResultsClassification accuracy of LR was 95.5% (area under receiver operating characteristic curve (AUC) 0.99), followed by SVM (91.0%, AUC 0.85) and J48 (90.0%, AUC 0.87) at stage 3 for predicting sleep problems. The inattention symptoms of ADHD-RS, CPT response time variability, the DAT1, ADRA2A DraI, and SLC6A2 A-3081T polymorphisms, and the structural connectivities between frontal and striatal brain regions were identified as the most differentiating subset of features. Validation analysis achieved accuracy of 86.1% (AUC 0.92) at stage 3 with J48.ConclusionsOur results provide preliminary support to the combination of multimodal classifier, in particular, neuroimaging features, as an informative method that can assist in predicting MPH side effects in ADHD.

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Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

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Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

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