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BMJ Open Jan 2017Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD.... (Comparative Study)
Comparative Study
Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis.
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles.
METHODS AND ANALYSIS
We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings.
ETHICS AND DISSEMINATION
No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences.
TRIAL REGISTRATION NUMBER
CRD42014008976.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Adult; Attention Deficit Disorder with Hyperactivity; Bupropion; Central Nervous System Stimulants; Child; Clinical Protocols; Clonidine; Dose-Response Relationship, Drug; Humans; Methylphenidate; Network Meta-Analysis; Treatment Outcome
PubMed: 28073796
DOI: 10.1136/bmjopen-2016-013967 -
Pharmacoepidemiology and Drug Safety Dec 2016The purposes of the study were to develop a refill pattern method to identify polypharmacy in pharmacy billing records and to compare the method with traditional days'... (Comparative Study)
Comparative Study
PURPOSE
The purposes of the study were to develop a refill pattern method to identify polypharmacy in pharmacy billing records and to compare the method with traditional days' supply overlap algorithms.
METHODS
This method is characterized by the assessment of prescription refill pattern. Concomitant therapy is assumed when two drugs are dispensed repeatedly during the active days' supply of each other. We tested the refill pattern method in a simplified scenario in which two drugs (methylphenidate/dexmethylphenidate and atomoxetine) for attention deficit/hyperactivity disorder (ADHD) were considered. Children who had at least one prescription of methylphenidate/dexmethylphenidate or atomoxetine in 2008 were included for the calculation of 2-year prevalence of ADHD treatment polypharmacy. Results were compared with traditional method that requires a minimum overlap of 30, 60 or 90 days of filled prescriptions. We compared polypharmacy prevalence estimated by the two methods and explored reasons for disagreement.
RESULTS
Among 131 385 children who had at least one prescription of methylphenidate/dexmethylphenidate or atomoxetine, the refill pattern method identified 4021 patients who had ADHD treatment polypharmacy (2-year prevalence = 3.1%). This prevalence estimate fell between those from a 30- to 60-day overlap method. The Cohen's kappa regarding determination of polypharmacy was 0.83, 0.92 and 0.80 considering 90-, 60- and 30-day overlap method, respectively.
CONCLUSIONS
The refill pattern method can be used as another way to measure polypharmacy in administrative claims databases and can be adapted to a wide variety of research questions, diseases and study populations. Copyright © 2016 John Wiley & Sons, Ltd.
Topics: Adolescent; Algorithms; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Child; Databases, Factual; Dexmethylphenidate Hydrochloride; Female; Humans; Male; Methylphenidate; Pharmacoepidemiology; Polypharmacy; Time Factors
PubMed: 27528378
DOI: 10.1002/pds.4082 -
Journal of Child and Adolescent... Dec 2016This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB)... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVES
This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB) during acute and long-term treatment of youth with attention-deficit/hyperactivity disorder.
METHODS
Two hundred seven participants aged 7-14 years enrolled in an 8-week double-blind randomized trial of GUAN-IR (1-3 milligrams (mg)/day), DMPH (5-20 mg/day), or COMB with fixed-flexible dosing and titrated to optimal behavioral response. Heart rate, systolic blood pressure (BP), diastolic BP, and electrocardiograms were assessed at baseline, end of blinded optimization, and over a 1-year open-label maintenance phase.
RESULTS
During acute titration, GUAN-IR decreased heart rate, systolic BP, and diastolic BP; DMPH increased heart rate, systolic BP, diastolic BP, and corrected QT (QTc) interval; COMB increased diastolic BP, but had no effects on heart rate, systolic BP, or QTc. During maintenance, GUAN-IR-associated decreases in heart rate and DMPH-associated increases in systolic BP returned to baseline values. Other variables across the three groups remained unchanged from the end of blinded titration. There were no discontinuations due to CV adverse events.
CONCLUSION
GUAN-IR, DMPH, and COMB were well tolerated and safe. Expected changes in CV parameters during acute titration were seen in GUAN-IR and DMPH groups, with COMB values falling intermediately between the two other treatment groups. No serious CV events occurred in any participant. GUAN-IR- and DMPH-associated CV changes generally returned to baseline with sustained therapy. These data suggest that COMB treatment might attenuate long-term CV effects of GUAN-IR and stimulant monotherapy, possibly reducing risk of the small but statistically significant changes associated with either single treatment. Clinicaltrials.gov Identifier: NCT00429273.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Attention Deficit Disorder with Hyperactivity; Blood Pressure; Central Nervous System Stimulants; Child; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Female; Guanfacine; Heart Rate; Humans; Male; Time Factors
PubMed: 27483130
DOI: 10.1089/cap.2015.0264 -
Drug Metabolism and Disposition: the... Mar 2016The postulate that twice the milligram/kilogram dose of dl-methylphenidate (dl-MPH) would result in equal exposure to d-MPH compared with half that milligram/kilogram... (Randomized Controlled Trial)
Randomized Controlled Trial
The postulate that twice the milligram/kilogram dose of dl-methylphenidate (dl-MPH) would result in equal exposure to d-MPH compared with half that milligram/kilogram dose of the chiral switch product dexmethylphenidate (d-MPH) was tested. Using a randomized, crossover study design, 12 men and 12 women received either immediate-release (IR) dl-MPH (0.3 mg/kg) or IR d-MPH (0.15 mg/kg). Relative bioavailability comparisons included partial area under the plasma concentration-time curves (pAUC0-3 h) for d-MPH. The pAUC0-3 h is a new regulatory metric presently only required for bioequivalence testing of a specific dl-MPH modified-release product. The geometric mean ratios for both the Cmax and area under the plasma concentration-time curve (AUC0-∞) were within the 90% confidence interval (CI) regulatory range of 0.8-1.25, indicating that these two drugs were bioequivalent in terms of d-MPH. However, the pAUC0-3 h geometric mean ratio for d-MPH after IR dl-MPH versus IR d-MPH was 0.76 (P < 0.001; 90% CI, 0.67-0.87), showing significantly less early exposure to the d-isomer than IR d-MPH. The 1-hour d-MPH concentration after dl-MPH was 56% of that after the enantiopure drug. The maximum d-MPH plasma concentration (Cmax) for dl-MPH was also significantly lower for dl-MPH (P < 0.05; CI, 1.02-1.19), whereas the AUC0-∞ ratio of 0.89 was not significantly different (P = 0.21; CI, 0.98-1.13). The AUC0-3 h difference reported here points to the potential limitations of using bioequivalence for sound predictions of dose-response relationships. Knowledge of the greater early exposure to d-MPH after the pure d-isomer drug compared with the racemate may contribute to drug individualization/optimization in the treatment of attention deficit hyperactivity disorder.
Topics: Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Female; Humans; Male; Methylphenidate; Young Adult
PubMed: 26729760
DOI: 10.1124/dmd.115.067975 -
Neuropsychiatric Disease and Treatment 2015The efficacy of dexmethylphenidate (d-MPH) has been proven in the treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD).
BACKGROUND
The efficacy of dexmethylphenidate (d-MPH) has been proven in the treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD).
OBJECTIVE
The aim of this systematic review is to determine the efficacy, acceptability, and tolerability of d-MPH in child and adolescent ADHD.
METHODS
The searches of SCOPUS, MEDLINE, CINAHL, and Cochrane Controlled Trials Register were performed in February 2015. All randomized controlled trials of d-MPH versus placebo that were performed in children and adolescents with ADHD up to 18 years of age were included in the study. The efficacy was measured by using the pooled mean-endpoint or mean-changed scores of ADHD rating scales and the response rate. Acceptability and tolerability were measured by using the pooled rates of overall discontinuation and discontinuation due to adverse events, respectively.
RESULTS
A total of 1,124 children and adolescents diagnosed as having ADHD were included in this review. In a laboratory school setting, the pooled mean-change and mean-endpoint scores in the d-MPH-treated group were significantly greater than those of the placebo-treated group with standardized mean difference (95% confidence interval [CI]) of -1.20 (-1.73, -0.67), I (2)=95%. Additionally, the pooled mean-changed scores of the ADHD rating scales for teachers and parents in the d-MPH-treated group were significantly greater than that of the placebo-treated group with weighted mean difference (95% CI) of -13.01 (-15.97, -10.05), I (2)=0% and (95% CI) of -12.99 (-15.57, -10.42), I (2)=0%, respectively. The pooled response rate in the d-MPH-treated groups had a significance higher than that of the placebo-treated group. The rates of pooled overall discontinuation and discontinuation due to adverse events between the two groups were not significantly different.
CONCLUSION
Based on the findings in this review, it can be concluded that d-MPH medication is efficacious and tolerable in child and adolescent ADHD. However, the acceptability of d-MPH is no greater than that of the placebo. Further systematic studies may confirm these findings.
PubMed: 26648726
DOI: 10.2147/NDT.S91765 -
Expert Opinion on Pharmacotherapy 2015Attention deficit/hyperactivity disorder (ADHD) persists into adulthood in about 50% of the affected children, with high rates of comorbidity with bipolar disorder (BD).... (Review)
Review
INTRODUCTION
Attention deficit/hyperactivity disorder (ADHD) persists into adulthood in about 50% of the affected children, with high rates of comorbidity with bipolar disorder (BD). Stimulants and atomoxetine (ATX) are effective treatments for ADHD, but their use in adults with comorbid BD (ADHD-BD) has not been extensively studied and may be problematic.
AREAS COVERED
The aim of the paper is to summarize the available literature regarding the use of these medications in ADHD-BD adult patients. Results of randomized-controlled and open-label trials, case reports, and case series are reviewed. We also reviewed data relative to some specific issues of this comorbidity in adults, especially substance use disorder, malingering, and stimulants misuse.
EXPERT OPINION
ADHD-BD may be associated with more severe symptoms, course, and worst outcome of both conditions. The frequent coexistence with alcohol and substance abuse may further complicate treatment management. Stimulants are the most effective medications for ADHD, but their use may be contraindicated in the presence of a comorbid drug abuse or in patients that simulate or exaggerate ADHD symptoms in order to obtain stimulants for diversion or abuse. ATX may be effective in the treatment of ADHD symptoms in BD patients, with a modestly increased risk of (hypo)manic switches and destabilization of the mood disorder when utilized in association with mood stabilizers. In the majority of the cases, a hierarchical approach is desirable, with mood stabilization preceding the treatment of ADHD symptoms. Although systematic trials on the use of stimulants and ATX in ADHD-BD comorbidity in adulthood are necessary, both treatments should be considered possible options to be carefully evaluated once the patient has been stabilized.
Topics: Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Central Nervous System Stimulants; Comorbidity; Humans; Substance-Related Disorders; Treatment Outcome
PubMed: 26364896
DOI: 10.1517/14656566.2015.1079620 -
European Neuropsychopharmacology : the... Oct 2015The attention-deficit/hyperactivity disorder (ADHD) treatment literature has been focused on onset-of-effect and short-term effect size, with little exploration of ADHD... (Review)
Review
The attention-deficit/hyperactivity disorder (ADHD) treatment literature has been focused on onset-of-effect and short-term effect size, with little exploration of ADHD symptoms upon medication discontinuation. The objective of this narrative review and analysis was to better understand the relapse of ADHD symptoms upon discontinuation of medication treatment in children, adolescents, and adults with ADHD who have responded to medication treatment and to explore differences among different medications in maintaining treatment response. Randomized withdrawal studies of dexmethylphenidate hydrochloride (d-MPH), methylphenidate modified-release (MPH-LA), lisdexamphetamine dimesylate (LDX), guanfacine extended-release (GXR), and atomoxetine (ATX) in both children/adolescents and adults with ADHD were reviewed. The percentage of relapse was significantly higher and the time-to-relapse significantly shorter with placebo compared to active treatment in patients who were previously stable on 5 weeks to 1 year of active treatment, suggesting clinically significant benefit with continued long-term pharmacotherapy. However, percentage of relapse at each time point studied after discontinuing stimulants and GXR appears substantially higher than observed when discontinuing ATX, suggesting longer maintenance of response after discontinuing ATX than after stimulants and GXR. Additionally, slope of relapse percentages over time appears to be more rapid with stimulants or GXR than with ATX. These differences in maintenance of response among ATX, GXR, and stimulants may reflect differences in mechanisms of action and persistence of the medication effect. Alternatively, they may be due to methodological differences, including study design and response/relapse definitions. Continued investigation is needed regarding factors that affect risk of symptom relapse upon discontinuation of pharmacotherapy.
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Humans; Recurrence; Withholding Treatment
PubMed: 26169574
DOI: 10.1016/j.euroneuro.2015.06.003 -
Journal of Clinical Psychopharmacology Aug 2015The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the... (Comparative Study)
Comparative Study Randomized Controlled Trial
The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the time course of maximal drug exposure after a single dose. In a 4-way, randomized, crossover study design, 12 men and 12 women normal volunteers received d-MPH (0.15 mg/kg) or dl-MPH (0.3 mg/kg) with or without ethanol (0.6 g/kg). Serial visual analog scales were used as surrogates for drug abuse liability ("high," "good," "like," "stimulated," and "any drug effect"). Combining pure d-MPH with ethanol significantly (P < 0.005) increased the area under the effect curves (AUC(0-5.25h)) of all 5 subscales. The dl-MPH-ethanol combination significantly (P < 0.05) increased these AUCs with the exception of like (P = 0.08). Effects of the pure d-MPH-ethanol combination exhibited delayed potentiation relative to dl-MPH-ethanol. A pharmacokinetic interaction between the l-isomer of dl-MPH and ethanol has previously been shown to increase early exposure to d-MPH. Administration of the pure isomer d-MPH precludes this absorption phase pharmacokinetic interaction with ethanol. This notwithstanding, the pure d-MPH-ethanol combination resulted in comparable, if not greater, cumulative stimulant potentiation than the dl-MPH-ethanol combination. These findings provide evidence of a pharmacodynamic component to d-MPH-ethanol synergistic interactions and carry implications for the rational drug individualization in the treatment of attention-deficit/hyperactivity disorder.
Topics: Affect; Central Nervous System Stimulants; Cross-Over Studies; Dexmethylphenidate Hydrochloride; Drug Synergism; Ethanol; Female; Humans; Male; Methylphenidate
PubMed: 26075488
DOI: 10.1097/JCP.0000000000000348 -
Journal of Pharmaceutical Sciences Dec 2014We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol... (Review)
Review
We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder.
Topics: Animals; Biomarkers; Dopamine; Dopamine Agonists; Esterification; Ethanol; Humans; Methylphenidate
PubMed: 25303048
DOI: 10.1002/jps.24202 -
CNS Drugs Sep 2014We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep. (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of extended-release dexmethylphenidate and mixed amphetamine salts on sleep: a double-blind, randomized, crossover study in youth with attention-deficit hyperactivity disorder.
OBJECTIVE
We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep.
METHODS
This was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status.
RESULTS
Sixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time (F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo (p < 0.05). A significant dose effect was found on actual sleep duration (F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo (p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up.
CONCLUSIONS
Higher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT00393042.
Topics: Actigraphy; Adolescent; Amphetamines; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Cross-Over Studies; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Salts; Sleep; Surveys and Questionnaires; Time Factors; Treatment Outcome
PubMed: 25056567
DOI: 10.1007/s40263-014-0181-3