TITLE: High-dose Stimulants for Attention-Deficit/Hyperactivity … · High-dose stimulants for...

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TITLE: High-dose Stimulants for Attention-Deficit/Hyperactivity Disorder: A Review of the Clinical Effectiveness, Safety and Guidelines

DATE: 3 March 2016

CONTEXT AND POLICY ISSUES

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioural condition in children and adolescents, that often persists into adulthood.1 Based on epidemiological studies from Australia, Brazil, New Zealand, the United States and Germany, the number of children with ADHD may range from 3% to upwards of 11%,1 and up to 60% of individuals may have symptoms persisting to adulthood.1,2 In Canada, the prevalence of ADHD in adults is estimated to be 4.4%.2The prevalence of the complete syndrome ADHD in adults is rare, but individual symptoms, such as inattentiveness or impulsivity, may still persist.1 A diagnosis is often made after recognition of excessive inattention, impulsivity, and hyperactivity, that impairs an individual’s functioning or development.3 Presentation of ADHD symptoms may differ by an individual’s age. Both children and adolescents may experience inattention and impulsivity, but adolescents may experience less hyperactivity.4 Adults with ADHD most often experience inattention, which may involve difficulty in focusing, shifting attention, or sustaining attention.1 Individuals with ADHD may be easily distracted and have trouble controlling their actions. Difficulty in controlling these symptoms may affect an individual’s personal, work, or school life and often interventions are warranted. Interventions for individuals with ADHD include education for individuals and their families, educational adjustments, psychological interventions, behavioural or occupational interventions, and medical management.2 As ADHD is a chronic condition, long-term treatment may be necessary.5 Individuals with more severe ADHD may require medical interventions.2,6 Regarding medical management, psychostimulants are considered to be first-line treatment for individuals with ADHD.4 This review considers the use of short, intermediate, and/or long acting stimulants, such as, methylphenidate, amphetamine, dextro-amphetamine, and lisdexamfetamine, in children and adults. Many persons with ADHD require individualized, optimal dose-titration to address symptoms, and it is recommended that patients start on the lowest possible dose and titrate

High-dose stimulants for ADHD 2

upwards to appropriately manage symptoms.2 This review aims to address concerns regarding the effectiveness and safety of the use of stimulants at higher than recommended doses. RESEARCH QUESTIONS

1. What is the effectiveness and safety of high dose stimulants in children and adolescents (six to 18 years) with attention-deficit/hyperactivity disorder (ADHD)?

2. What is the comparative effectiveness and safety of high dose stimulants in adults (> 18 years) with ADHD?

3. What are the evidence-based guidelines regarding the use of high dose stimulants in patients with ADHD?

KEY FINDINGS

Five relevant studies were included in this review; no evidence-based guidelines were identified. One systematic review regarding methylphenidate use in adults with ADHD was identified; it is uncertain whether high doses of methylphenidate are more effective than low doses of methylphenidate for treating symptoms of ADHD. One randomized controlled trial regarding lisdexamfetamine dimesylate use in adolescents with ADHD was identified; high doses of study medication were more effective than placebo at addressing symptoms, but had uncertain effects on quality of life measures. Three non-randomized studies regarding adverse events for adolescents and adults using high doses of methylphenidate were identified; these doses were generally well tolerated by patients. METHODS

Literature Search Methods This report makes use of a literature search conducted for a previous CADTH report.7 The original literature search was conducted in January 2015 on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit retrieval by study type. Where possible, retrieval was limited to the human population. The initial search was also limited to English-language documents published between January 1, 2010 and January 26, 2015. For the current report, database searches were rerun on February 3, 2016 to capture any articles published since the initial search date. In addition, searches were run on Ovid Medline and Ovid Embase for documents published between January 1, 2015 and February 3, 2016. The search of major health technology agencies was also updated to include documents published since January 2015. Rapid Response reports are organized so that the evidence for each research question is presented separately.


Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria Population Children and adolescents (six to 18 years) and adults (>18 years) with

ADHD, with or without co-morbidities in out-patient and in-patient (e.g., mental health facilities) settings

Intervention High-dose stimulants (i.e., above the recommended dose);

Short, intermediate, and/or long acting stimulants (e.g., methylphenidate, amphetamine, dextro-amphetamine, lisdexamfetamine)

Comparator Standard practice (e.g., stimulants prescribed within the recommended maximum dose and/or in combination with non-stimulants);

Placebo

Outcomes Efficacy outcomes (including but not limited to: changes in severity of ADHD symptoms, cognitive and adaptive skills, functional outcomes, quality of life

and psychiatric morbidity, caregiver satisfaction, time to onset of effectiveness, duration of effectiveness);

Safety outcomes (including but not limited to: overall adverse events, withdrawals due to adverse events, missed dose, non-compliance, abuse potential, development of substance abuse disorder, long-term safety (e.g.,

cardiac safety, hepatotoxicity, growth effects, psychiatric effects, etc.)) Study Designs Health technology assessments, systematic reviews, meta-analyses,

randomized controlled trials, non-randomized studies, evidence-based guidelines

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2010. Additionally, upon full-text review of the studies included in the previous CADTH report7 on this topic, three8-10 of the previously identified articles were not included in this review. One did not report on high doses,10 one was within maximum approved doses,8 and one did not report enough information to determine whether patients were receiving high doses.9The remaining five articles are summarized in this report. Critical Appraisal of Individual Studies

The included systematic reviews were critically appraised using the AMSTAR checklist,11 and clinical studies were critically appraised using Downs and Black checklist.12 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described.


SUMMARY OF EVIDENCE Quantity of Research Available

A total of 176 citations were identified in the updated literature search. Following screening of titles and abstracts, 165 citations were excluded and 11 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles identified from the updated search, all 11 publications were excluded. Three reported on combined analyses for moderate and high doses and did not report outcomes specific to high doses,3,6,13 one reported on preclinical outcomes,14 two did not provide enough information to determine the intervention dose,15,16 and the remaining were not high dose.17-20 therefore, no newly identified publications met the inclusion criteria and were included in this report. Five studies from the previous CADTH report7 are included in this report. Appendix 1 describes the PRISMA flowchart of the study selection of the updated search. Additional references of potential interest are provided in Appendix 5. Summary of Study Characteristics

A summary of the study characteristics is presented in Appendix 2. Study Design One systematic review (SR),1 one randomized controlled trial (RCT),4 and three open-label non-randomized studies5,21,22 were included. The RCT was a four week, double-blind, placebo controlled study, that recruited patients from 45 sites across the United States.4 Participants started on the lowest dose of study medication, and proceeded to a three week stepwise forced-dose titration phase, with one week of dose maintenance.4 The remaining three clinical studies were open-label and non-randomized.5,21,22 Follow-up varied by study, from eight weeks22 to six and 12 months.5 The follow-up period was uncertain for one study.21 Participants in two of the studies underwent a dose-titration phase to determine a clinically effective dose.5,22 Country of Origin The SR by Epstein1 was performed by authors from Israel. The remaining studies were from the United States of America.

4,5,21,22

Patient Population The SR by Epstein1 assessed adults with ADHD. The age of participants in the SR ranged from 17 to 56 years. The number of participants in the relevant analyses ranged from 136 to 282. Race or gender of the participants in the included studies was not reported.


One study, by Adler,5 also assessed adults with ADHD. The age of participants in this study ranged from 18 to 65 years. There were 550 patients included in this study, 52% of whom were male. The race of participants was not reported. The remaining three studies included adolescents with ADHD. The study by Newcorn22 included 182 adolescents in their analysis. The age of participants ranged from 13 to 18 years, with a mean age of 14.6 years. The majority of participants were white (75.3%) and male (80.2%). The study by Stevens21 included 17 adolescents. The age of participants ranged from 11 to 20 years, with a mean age of 16.2 years. The majority of participants were white (88%) and male (76%). The study by Findling4 included 314 participants. The mean age of participants was 14.6 years; the age range was not reported, but participants aged 13 to 17 comprised 99.8% of the total number of participants. The majority of participants were white (79.0%) and male (70.3%). Interventions and Comparators The following interventions and comparators were reported by the included studies:

High dose osmotic release oral system (OROS) methylphenidate (MPH) versus low dose OROS MPH5,21,22

High dose immediate-release MPH versus placebo, versus low dose immediate-release MPH1

Lisdexamfetamine dimesylate (LDX) versus placebo4

For the SR by Epstein,1 a subgroup analysis was performed for high doses of MPH (doses greater than 0.9 milligrams per kilograms per day (mg/kg/d)). The authors stated that doses of 60 mg to 70 mg were considered clinically high, and would correspond to a dose of 0.9 mg/kd/d for a 75 kg adult. Thus, the authors considered studies with greater than 0.9 mg/kg/d doses to be high. The comparator for this analysis was placebo. Confidence intervals of outcomes for high dose versus low dose (≤ 0.9 mg/kd/d) were also compared. The clinical study by Adler, of OROS MPH in adults, reported on the doses of 36 mg/d, 54 mg/d, 72 mg/d, 90 mg/d, and 108 mg/d.5 Descriptive comparisons were made between doses.5 For the study by Stevens,21 the mean total daily dose of OROS MPH was 169 mg/day (± 31 mg/day; range, 126 to 270 mg/day). There was no comparator for this study. For the study by Newcorn,22 OROS MPH in 18 mg/d, 36 mg/d, 54 mg/d, and 72 mg/d doses were administered to adolescents. Doses were compared to each other. For the study by Findling,4 LDX in 30 mg/d, 50 mg/d, and 70 mg/d doses were administered to adolescents. This was compared to placebo. Outcomes Three non-randomized studies of OROS MPH.5,21,22 measured safety and adverse events. The primary outcome of these studies was not drug effectiveness by dose, but rather, plasma concentrations of MPH,21 predictors of dose-response,22 or overall efficacy (not explored by dose).5 Efficacy and safety of LDX were the primary outcomes for the study by Findling.4 Efficacy was determined by improvements in the ADHD Rating Scale IV (ADHD-RS-IV), Clinical


Global Impressions-Improvement (CGI-I), and Youth Quality of Life-Research Version (YQOL-RS).4 The following outcomes were reported for high dose MPH in the SR by Epstein:1

hyperactivity (by the hyperactivity subscale of ADHD Rating Scale, and subscale of DSM-IV ADHD Rating Scale);

impulsivity (by the impulsivity subscale of ADHD Rating Scale, and inattention subscale of DSM-IV ADHD Rating Scale);

and inattentiveness (by the inattentiveness subscale of ADHD Rating Scale, inattention subscale of DSM-IV ADHD Rating Scale, and inattentive ADHD symptom scores).

Summary of Critical Appraisal

A summary of the critical appraisal can be found in Appendix 3. The SR by Epstein,1 clearly reported the study aims and results. The literature search was thorough, including multiple databases, and a search for unpublished literature; the search process was clearly documented a list of included and excluded was provided. Screening and data extraction occurred in duplicate. A quality assessment of the included studies was provided and appropriately used in formulating author conclusions. Clinical heterogeneity was reported as I2 values, and used to explore reasons for differences within pooled studies. Overall this SR was of high quality, however, information about participant demographics (e.g., race and gender) were poorly reported. It was uncertain whether this information was available for the included studies. Generalizability of these results is uncertain, due to the lack of demographic information. There was uncertainty in regards to the generalizability of results to other populations of individuals with ADHD in the other studies as well, particularly the generalizability to the Canadian context as no relevant Canadian studies were identified. Two studies did not report race1,5 and the SR1 did not report gender for the included participants. Of the studies that reported race or gender, the majority (range of 75.3% to 88%) of participants were white4,21,22 and male (52% to 88%).4,5,21,22 This was a particular concern for the studies that did not clearly report their sampling strategy, or how patients were recruited.5,21,22 Few studies included participants recruited from more than one centre,4,5 which is more likely to represent clinical practice, compared to the studies that did not specify where patients were recruited from.21,22 It is possible selection bias occurred and that participants in these studies are not representative of the populations from which they were sampled. Three of the studies were non-randomized, and participants were not blinded to the study intervention.5,21,22 Questions related to the integrity of randomization and blinding were not applicable for these studies. For the RCT, randomization appeared to be computer automated which was likely to minimize potential biases, but overall not well described. There was no discussion of allocation concealment, which may subject this study to selection bias.4 A sample size calculation was provided (at least 300 participants, and 75 participants in each study group) and the study was adequately powered (90% power at a significance level of 0.05 (2-sided)).4 The study was double-blinded (participants and investigators) and medications were identical to aid in the blinding process.4 Additionally, the quality of life instrument used by the RCT was non-specific to ADHD, and may not have been appropriately comprehensive to capture changes in


an ADHD population.4 Changes in quality of life due to the study intervention were not significant, and the impact of medication on quality of life remains uncertain.4 Summary of Findings

A summary of the main study findings and author conclusions can be found in Appendix 4.

What is the effectiveness and safety of high dose stimulants in children and adolescents (six to 18 years) with ADHD?

Two studies reported on safety outcomes for OROS MPH.21,22 Both studies found that high doses were well tolerated by adolescents. Commonly reported adverse events for adolescents receiving a 72 mg/d dose of OROS MPH were abdominal pain, anorexia, headache, insomnia, nervousness, and somnolence; though less than 10% of patients experienced any one of the symptoms (1% for abdominal pain to 9% for headache).22 The majority of patients (57.3%) in this study reported at least one adverse event, though this was most common in the 18 mg/d group.22 When examining plasma concentrations of OROS MPH, concentration was not associated with systolic blood pressure, diastolic blood pressure, or heart rate.21 Study authors concluded that high concentrations of OROS MPH did not result in vital sign abnormalities.21

Regarding efficacy, one of the studies on OROS MPH reported that the majority (approximately 65%) of patients needed 54 mg/d or 72 mg/d to achieve an adequate response.22 The main objective of this study was to determine predictors of dose-response, of which, only baseline ADHD severity was a significant predictor of dose.

One study reported on the efficacy and safety of LDX in adolescents.5 This study found all doses of LDX, including 70 mg/d, to be more effective than placebo for symptoms measured by the ADHD-RS-IV and CGI-I. There was no significant difference in quality of life, measured by YQOL-RS, for any dose of LDX compared to placebo. 71.8% of participants receiving 70 mg/d of LDX experienced a treatment-emergent adverse event. The five most common adverse events at this dose were decreased appetite, headache, weight decreased, insomnia, and irritability.

What is the comparative effectiveness and safety of high dose stimulants in adults (> 18 years) with ADHD?

One SR1 reported on the effectiveness for high dose stimulants in adults with ADHD. When compared to placebo, high dose immediate-release MPH was more effective for the outcomes of inattentiveness, and this finding was statistically significant. For the outcomes of hyperactivity and impulsivity, high dose immediate-release MPH was not statistically significantly more effective than placebo. The study authors compared the findings of the high dose analysis to the low dose analysis (compared 95% confidence intervals), and found no difference between the doses; no direct comparative analyses of high dose versus low dose MPH was performed. The authors concluded that higher dose MPH is not associated with greater efficacy, when compared to low dose MPH. However, there remains uncertainty as these findings are based on few (three) studies.


One non-randomized study5 reported on the safety of high dose OROS MPH in adults. No statistical analyses were performed comparing doses, but the authors report descriptive statistics on vital signs and adverse events. More patients experienced an adverse event at 108 mg/d of OROS MPH (76%) that those receiving 36 mg/d (54%). Most of these adverse events were mild in nature; there were no deaths and eight patients experienced serious adverse events at any dose. The most common adverse events (≥ 5% of patients) for those receiving the highest dose were: dry mouth, anxiety, irritability, upper respiratory infection, bronchitis, increased heart rate, tachycardia, decreased weight, and vomiting. The most common adverse events (≥ 5% of patients) for those receiving the lowest dose were: decreased appetite, headache, and insomnia. More patients discontinued the study due to an adverse event at the lowest dose (8.5%) compared to the highest dose (8.3%). This was primarily owing to patients poorly tolerating the 36 mg/d dose, and not being able to receive a smaller dose in this study.

What are the evidence-based guidelines regarding the use of high dose stimulants in patients with ADHD? No relevant evidence-based guidelines were identified regarding the use of high dose stimulants in patients with ADHD. However, a clinical practice guideline2 with uncertain methodology that did not meet inclusion criteria for this report is provided in Appendix 5. Limitations

Few studies reported on the use of high dose stimulants above the recommended range for any aged population. The SR was limited by a small number of studies (three studies) reporting on high dose MPH use1 and one of the clinical studies had small number of patients (17 adolescents).

21 The majority of participants in the included studies were white males, thus the

effectiveness and safety of high dose stimulants remains uncertain for other patient populations. Effectiveness and safety of high dose stimulants in children is uncertain, as the included studies reported on adults1,5 or adolescents.4,21,22 As well, the effectiveness of high dose stimulants in these populations is still uncertain, as only two studies addressed questions of drug efficacy1,4 and the remaining studies reported on safety and adverse events.5,21,22 The primary aim of one study was to determine predictors of dose-response,22 and of another the primary aim was to determine the plasma concentration of the study drug.21 Therefore, drug effectiveness is uncertain for these studies. The studies were also limited in terms of the drugs investigated. Four studies assessed MPH1,5,21,22 and one study assessed LDX.4 No relevant studies on the safety and efficacy of high doses of other stimulants for ADHD were identified. The studies also occurred over a short time period, with only one study5 reporting outcomes at six months or one year. The other studies were conducted over a much shorter time period: four weeks,

4 eight weeks,

22 and uncertain time

period.21 The studies included in the SR were conducted over three to six weeks.1 These shorter studies may not have captured treatment related adverse events that occurred at a later date. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

In this review, five relevant studies on high dose stimulants for adolescents and adults with ADHD were identified. With regards to adults taking OROS MPH it is uncertain whether high doses are more effective than low doses for treating symptoms of ADHD; high doses may be


more effective than placebo for improving inattentiveness, based on the findings of one systematic review.1 Additionally, high doses of OROS MPH seem to be well tolerated in adult patients, in a study reporting outcomes up to one year.5 For adolescents, two studies regarding high dose OROS MPH found that patients tolerated these doses with few serious adverse events.5,22 Though the majority of participants receiving OROS MPH, regardless of dose, experienced an adverse event in one study.22 LDX use in adolescents was reported by one study.4 This study found that LDX at all doses, including a high dose of 70 mg/d, was more effective than placebo at treating symptoms of ADHD, and was well tolerated by patients.4 This review is limited in terms of the patient population. Relevant studies regarding the use of high dose stimulants in children (those younger than 11 years) were not identified, and the effectiveness and safety of these interventions is uncertain for this patient population. Additionally, there is uncertainty regarding the generalizability of findings as the majority of the patients in the included studies were white males. It is also limited in terms of the stimulants used, with four studies regarding MPH use, and one study regarding LDX use. Relevant evidence-based guidelines were not identified, and the use of high dose stimulants for ADHD in clinical practice is uncertain. Overall, the use of high dose stimulants for ADHD has uncertain effectiveness when compared to low doses, in both adults and adolescents. Individuals taking high dose stimulants may experience adverse events, though these were typically mild, and study authors generally found study medications to be well tolerated. PREPARED BY:

Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


REFERENCES

1. Epstein T, Patsopoulos NA, Weiser M. Immediate-release methylphenidate for attention

deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2014 Sep 18;9:CD005041.

2. Canadian ADHD practice guidelines (CAP guidelines) [Internet]. 3rd ed. Markham (ON): Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA); 2011. [cited 2016 Feb 12]. Available from: http://www.caddra.ca/cms4/pdfs/caddraGuidelines2011.pdf

3. Storebo OJ, Krogh HB, Ramstad E, Moreira-Maia CR, Holmskov M, Skoog M, et al. Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ (Online) [Internet]. 2015 Nov 25 [cited 2016 Feb 9];351(Article Number: h5203). Available from: http://www.bmj.com/content/bmj/351/bmj.h5203.full.pdf

4. Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M, Ferreira-Cornwell MC, et al. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011 Apr;50(4):395-405.

5. Adler LA, Orman C, Starr HL, Silber S, Palumbo J, Cooper K, et al. Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: an open-label, dose-titration, 1-year study. J Clin Psychopharmacol. 2011 Feb;31(1):108-14.

6. Storebo OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015 Nov 25;11:CD009885.

7. High dose stimulants for attention deficit hyperactivity disorder: clinical effectiveness, safety, and guidelines [Internet]. Ottawa: CADTH; 2015 Jan 29. [cited 2016 Feb 22]. (Rapid response report: reference list). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/feb-2015/RA0728%20High-dose%20stimulants%20ADHD%20Final.pdf

8. Faraone SV, Spencer TJ, Kollins SH, Glatt SJ, Goodman D. Dose response effects of lisdexamfetamine dimesylate treatment in adults with ADHD: an exploratory study. J Atten Disord [Internet]. 2012 Feb [cited 2016 Feb 12];16(2):118-27. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355536/pdf/nihms374903.pdf

9. Biederman J, Mick E, Fried R, Wilner N, Spencer TJ, Faraone SV. Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD. Eur Neuropsychopharmacol. 2011 Jul;21(7):508-15.

http://www.caddra.ca/cms4/pdfs/caddraGuidelines2011.pdfhttp://www.bmj.com/content/bmj/351/bmj.h5203.full.pdfhttps://www.cadth.ca/sites/default/files/pdf/htis/feb-2015/RA0728%20High-dose%20stimulants%20ADHD%20Final.pdfhttps://www.cadth.ca/sites/default/files/pdf/htis/feb-2015/RA0728%20High-dose%20stimulants%20ADHD%20Final.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355536/pdf/nihms374903.pdf


10. Song DH, Choi S, Joung YS, Ha EH, Kim BN, Shin YJ, et al. Titrating optimal dose of osmotic-controlled release oral delivery (OROS)-methylphenidate and its efficacy and safety in Korean children with ADHD: A multisite open labeled study. Psychiatry Investig [Internet]. 2012 Sep [cited 2016 Feb 12];9(3):257-62. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440475/pdf/pi-9-257.pdf

11. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2016 Mar 2];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

12. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2016 Mar 2];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf

13. Coughlin CG, Cohen SC, Mulqueen JM, Ferracioli-Oda E, Stuckelman ZD, Bloch MH. Meta-analysis: reduced risk of anxiety with psychostimulant treatment in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2015 Oct;25(8):611-7.

14. Yorbik O, Mutlu C, Ozilhan S, Eryilmaz G, Isiten N, Alparslan S, et al. Plasma methylphenidate levels in youths with attention deficit hyperactivity disorder treated with OROS formulation. Ther Drug Monit. 2015 Jun;37(3):347-52.

15. Rosch KS, Fosco WD, Pelham WE Jr, Waxmonsky JG, Bubnik MG, Hawk LW Jr. Reinforcement and stimulant medication ameliorate deficient response inhibition in children with attention-deficit/hyperactivity disorder. J Abnorm Child Psychol. 2016 Feb;44(2):309-21.

16. Helseth SA, Waschbusch DA, Gnagy EM, Onyango AN, Burrows-MacLean L, Fabiano GA, et al. Effects of behavioral and pharmacological therapies on peer reinforcement of deviancy in children with ADHD-only, ADHD and conduct problems, and controls. J Consult Clin Psychol. 2015 Apr;83(2):280-92.

17. Zelnik N, Terkel-Dawer R. The clinical profile of children with ADHD that require OROS-methylphenidate combined with shorter-acting formulations. Atten Defic Hyperact Disord. 2015 Dec;7(4):313-8.

18. Luman M, Papanikolau A, Oosterlaan J. The unique and combined effects of reinforcement and methylphenidate on temporal information processing in attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2015 Aug;35(4):414-21.

19. Wigal SB, Nordbrock E, Adjei AL, Childress A, Kupper RJ, Greenhill L. Efficacy of methylphenidate hydrochloride extended-release capsules (Aptensio XRTM) in children and adolescents with attention-deficit/hyperactivity disorder: A phase III, randomized, double-blind study. CNS Drugs [Internet]. 2015 Apr [cited 2016 Feb 9];29(4):331-40. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425805/pdf/40263_2015_Article_241.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440475/pdf/pi-9-257.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425805/pdf/40263_2015_Article_241.pdf


20. Luman M, Goos V, Oosterlaan J. Instrumental learning in ADHD in a context of reward: intact learning curves and performance improvement with methylphenidate. J Abnorm Child Psychol. 2015 May;43(4):681-91.

21. Stevens JR, George RA, Fusillo S, Stern TA, Wilens TE. Plasma methylphenidate concentrations in youths treated with high-dose osmotic release oral system formulation. J Child Adolesc Psychopharmacol. 2010 Feb;20(1):49-54.

22. Newcorn JH, Stein MA, Cooper KM. Dose-response characteristics in adolescents with attention-deficit/hyperactivity disorder treated with OROS methylphenidate in a 4-week, open-label, dose-titration study. J Child Adolesc Psychopharmacol. 2010 Jun;20(3):187-96.


Appendix 1: Selection of Included Studies from Updated Literature Search

165 citations excluded

11 potentially relevant articles retrieved for scrutiny (full text, if

available)

0 potentially relevant reports retrieved from other sources (grey

literature, hand search)

11 potentially relevant reports

11 reports excluded: -irrelevant intervention (8) -irrelevant preclinical outcomes (1) -not enough information provided regarding intervention (2)

5 reports included in the review from previous CADTH

report (0 newly identified reports included in review)

176 citations identified from electronic literature search and

screened


APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses

First Author, Publication

Year,

Country

Search Databases and Dates Types and numbers of

primary

studies included

Population Characteristics

Intervention Comparator(s) Clinical Outcomes, Length of

Follow-Up

Epstein,1

2014, Israel CENTRAL, MEDLINE, EMBASE, PsycINFO, Web of

Science, DARE, ClinicalTrials.gov, International Clinical Trials Registry

Platform, reference lists of relevant papers to 2013

3 RCTs regarding

high dose stimulant (11 RCTs total)

Adults with ADHD (age range, 17 to

56)

Immediate-release methylphenidate (>

0.9 mg/kg/d)

Placebo Inattentiveness, hyperactivity,

impulsivity; Included studies

ranged from 3 weeks to 6 weeks

ADHD = attention deficit hyperactivity disorder; d = day; kg = kilograms; mg = milligrams; RCT = randomized controlled trial

Table A2: Characteristics of Included Clinical Studies

First Author, Publication

Year, Country, Study Name

Study Design Patient Characteristics Intervention(s) Comparator(s) Clinical Outcomes

Adults

Adler,5 2010, USA

Long-Term Safety of OROS

Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder

Non-randomized, open-label,

dose-titration phase study

550 adults with ADHD (52% male)

Mean age = 39.1 years Age range: 18 to 65 years

OROS MPH 36 mg/d, 54 mg/d, 72 mg/d, 90 mg/d,

108 mg/d

Descriptive comparison between doses

SBP, DBP, heart rate, weight loss (> 10% decrease), weight

gain (> 10% increase), adverse events at 6 months or

12 months

Adolescents

Findling,4 2011, USA

Efficacy and Safety of

Lisdexamfetamine Dimesylate in Adolescents With Attention-Deficit/Hyperactivity Disorder

RCT, double-blind, placebo-controlled,

forced dose-titriation

314 adolescents with ADHD (309 in efficacy analysis; 310 in safety population) (70.3%

male) Mean age = 14.6 years (SD

1.31 years)

LDX 30 mg/d, 50 mg/d, 70 mg/d

Placebo Efficacy, adverse events, vital signs; 4 week follow-up


Table A2: Characteristics of Included Clinical Studies First Author, Publication

Year, Country, Study Name Study Design Patient Characteristics Intervention(s) Comparator(s) Clinical Outcomes

Age range: participants aged

13 to 17 years comprised 99.8% of the total

Race: 79.0% White, 14.8% African American, 14.8% Hispanic/Latino

Moderately or markedly ill (by ADHD-RS-IV) = 95.2% of

participants Combined ADHD subtype:

63.9% of LDX participants, 70.1% of placebo participants

Newcorn,22

2010, USA

Dose-Response Characteristics in Adolescents

with Attention-Deficit/Hyperactivity Disorder Treated with OROS

®

Methylphenidate in a 4-Week, Open-Label, Dose-Titration Study

Non-

randomized, open-label, dose-titration

phase study

220 adolescents with ADHD

(182 patients in the analysis) (80.2% male)

Mean age = 14.6 years (± 1.5)

Age range: 13 to 18 years Race: 75.3% White, 13.7%

black, 11.0% other

OROS MPH 18

mg, 36 mg, 54 mg, 72 mg

N/A Predictors of effective

dose for OROS MPH Adverse events

8 week open-label follow-up

Stevens,21

2010, USA Plasma Methylphenidate

Concentrations in Youths Treated with High-Dose Osmotic Release Oral System

Formulation

Non-randomized, non-

comparative study

17 youths with ADHD (76% male) Mean age = 16 years Age range: 11 to 20 years Race: 88% White, 12% Native American

OROS-MPH at higher than FDA approved doses (>

72 mg/day)

N/A SAE, adverse cardiovascular outcomes, SBP, DBP,

heart rate Uncertain follow-up

period


Table A2: Characteristics of Included Clinical Studies First Author, Publication

Year, Country, Study Name Study Design Patient Characteristics Intervention(s) Comparator(s) Clinical Outcomes

Comorbid diagnoses:

depressive spectrum disorders (47%), pervasive developmental disorders

(41%), oppositional defiant disorder (41%), bipolar spectrum disorder (29%),

fetal alcohol syndrome (12%)

ADHD = attention-deficit/hyperactivity disorder; DBP = diastolic blood pressure; FDA = Food and Drug Administration; mg = milligrams; LDX = lisdexamfetamine dimesylate; MPH = methylphenidate; N/A = not applicable; OROS = osmotic release oral system; RCT = randomized controlled trial; SAE = serious adverse effects; SBP = systolic blood pressure; SD =

standard deviation; USA = United States of America


APPENDIX 3: Critical Appraisal of Included Publications

Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using

AMSTAR11 link to AMSTAR checklist Strengths Limitations

Epstein1 The SR had a comprehensive literature search,

including multiple databases and a search for

unpublished data.

Literature screening and data extraction was done in duplicate, by two reviewers. The

literature search process was clearly documented, and lists of included and excluded studies were provided.

The quality of the included studies was assessed (risk of bias) and clearly reported. These assessments were appropriately used in

formulating the authors’ conclusions.

It was appropriately determined that publication bias could not be assessed as there were too few studies.

Clinical heterogeneity was explored and reported as an I

2.

Information about participant demographics for the included studies was not well reported, if

available (e.g., information about gender, race, etc. was not reported for the individual studies, and the SR does not state whether this

information was available).

Generalizability of these results is uncertain, due to lacking information about participant

characteristics and limited number of studies.

High heterogeneity of the relevant analyses suggests it may not have been appropriate to

pool these results, and further exploration into the heterogeneity was needed.

SR = systematic review

Table A4: Strengths and Limitations of Clinical Studies using Downs and Black12 link to Downs

and Black Strengths Limitations

Adler, 20115

Authors clearly reported their objectives, and safety results of the study.

Assessments used were clearly reported and unlikely to be subjected to bias.

This was a multicentre study, which is more likely to reflect clinical practice.

The sampling strategy used to obtain patients was not clearly defined, especially for those patients not recruited from the previous RCT. It

is uncertain whether these patients are representative of the population from which they were sampled.

Though the study was multicentre, little information was provided on the centres and how representative they were of the population of interest.

There was no statistical analysis of differences in safety between doses; safety was presented as descriptive statistics (percentages of

patients experiencing the events).

The primary aim of this study was to assess safety, and efficacy of different doses is

uncertain. Relevance to this review is limited in terms of dose efficacy.

Findling, 20114 Authors clearly reported their objectives.

Inclusion and exclusion criteria for participants were clearly reported.

Sample size calculation was provided and adequate numbers for an appropriately

Instruments used to measure outcomes may

not have been appropriate for this study population (i.e., quality of life measures may not be sensitive to changes in an ADHD

population).

http://amstar.ca/Amstar_Checklist.phphttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf


Table A4: Strengths and Limitations of Clinical Studies using Downs and Black12 link to Downs

and Black Strengths Limitations

powered study were discussed. Adequate recruitment for each study group was achieved.

Study recruitment took place at many sites (45) and is likely to be more inclusive of clinical practice.

Randomization was computer automated and

likely to minimize bias.

Doses were identical to aid blinding.

Some selection bias may have occurred, and patients may not be generalizable to a wider patient population. This study included mainly

male, white, moderately ill patients.

Exact p values for non-significant results were not reported.

Newcorn, 201022 Authors clearly reported their objectives.

Reasons for withdrawal and progression of patients through the dose-titration phase are well reported.

Baseline characteristics of the included patients are well reported.

Recruitment and sampling of patients was not

well reported in this publication, and selection bias is uncertain. The majority of participants were white males.

An inclusive list of all adverse events is not reported, or if their reported adverse events are inclusive of all events.

Confidence intervals and p values are not reported for all analyses.

Analyses were conducted post hoc, and derivative of a previously published RCT.

Some bias due to data dredging and selective reporting may have occurred.

The primary aim of this study was to assess

safety, and efficacy of different doses is uncertain. Relevance to this review is limited in this regard.

Stevens, 201021

Authors clearly report their objectives, aims, and hypotheses of the study.

Patient demographic information was clearly

reported.

Adverse events are reported.

Patients with comorbid diagnoses were included, which is more likely to be reflective of

clinical practice.

The sampling strategy used to obtain patients was not clearly defined, and it is uncertain if they are representative of the population from

which they were sampled. The extent to which the results can be generalized to other populations is also uncertain.

The sample size was small and no sample size calculation was provided.

Patients may differ from each other in clinically relevant ways, for example, the length of

exposure to high dose stimulants may vary amongst the patients. This was either not captured or not reported.

The findings of the study are not well reported. The exact p value for measures of association was not reported; instead, it was only reported

that the results were not significant.

The study’s primary objective was to measure plasma levels of methylphenidate and has

limited relevance to this review in terms of dose efficacy.

RCT = randomized controlled trial

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf


APPENDIX 4: Main Study Findings and Author’s Conclusions

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

Epstein, 20141

No direct comparative analyses between high-

dose versus low-dose were performed Inattentiveness:

4 studies pooled for low dose MPH o Std mean difference = -0.84 (95% CI, -1.44

to -0.25; I2 = 73%)

3 studies pooled for high dose

o Immediate-release methylphenidate vs. placebo: std. mean difference = -0.44 (95% CI, -0.79 to -0.10; I

2 = 58%) (lower negative

numbers indicate more improvement with methylphenidate)

o Statistically significant result favours

immediate-release methylphenidate Hyperactivity:

4 studies pooled for low dose MPH o Std mean difference = -0.61 (95% CI, -1.41

to 0.19; I2 = 90%)

2 studies pooled for high dose o Immediate-release methylphenidate vs.

placebo: std. mean difference = -0.63 (95% CI, -1.49 to 0.23; I

2 = 90%)

o Non-statistically significant result favours immediate-release methylphenidate

Impulsivity:

3 studies reported for low dose MPH o Std mean difference = -0.62 (95% CI, -1.32

to 0.08; I2 = 75%)

2 studies pooled for high dose o Immediate-release methylphenidate vs.

placebo: std. mean difference = -0.76 (95% CI, -1.92 to 0.40; I

2 = 87%)

o Non-statically significant result favours

immediate-release methylphenidate

“The direction of the effect in this subgroup

analysis, which included only two studies for two outcomes and all three for the outcome of inattentiveness, favored treatment with

immediate-release methylphenidate.” Page 20

“As the 95% CIs of high dose and low dose overlap, the data show no differences between doses. Evidence from the subgroup analysis

does not indicate that a higher dose of immediate-release methylphenidate is associated with higher efficacy-an observation

that is limited by the few and generally small studies included.” Page 20

“A subgroup analysis of high versus low doses

of immediate-release methylphenidate was conducted. Results do not indicate that a higher dose of immediate-release

methylphenidate was associated with higher efficacy, and they do not lend support to the current recommendation of immediate-release

methylphenidate doses of up to 1.3 mg/kg/d (Biederman 2006a)-an observation that is limited by the few and generally small studies

included.” Page 22

Adler, 20115

Vital Signs

SBP < 70 mm Hg: 0% for all doses

SBP > 140 mm Hg: 36 mg = 14 (2.6%); 54 mg = 18 (3.8%); 72 mg = 19 (5.3%); 90 mg = 15

(6.7%); 108 mg = 6 (5.7%)

DBP < 50 mm Hg: 36 mg = 0; 54 mg = 1 (0.2%); 72 mg = 1 (0.3%); 90 mg = 0; 108 mg = 1 (0.9%)

DBP > 90 mm Hg: 36 mg = 18 (3.3%); 54 mg =

“The study demonstrated that OROS

methylphenidate, in a dose range of 36 to 108 mg/d, was generally safe and well tolerated in adults treated for ADHD for up to 1 year.” Page

112

“As with all stimulants, heart rate and BP should be monitored during the dose-titration

phase and throughout treatment, particularly in those subjects whose underlying medical


Table A5: Summary of Findings of Included Studies

Main Study Findings Author’s Conclusions 26 (5.5%); 72 mg = 24 (6.7%); 90 mg = 11 (4.9%); 108 mg = 3 (2.8%)

Heart rate, < 50 bpm: 36 mg = 8 (1.5%); 54 mg = 2 (0.4%); 72 mg = 3 (0.8%); 90 mg = 2 (0.9%); 108 mg = 1 (0.9%)

Heart rate, > 100 bpm: 36 mg = 10 (1.9%); 54 mg = 22 (4.6%); 72 mg = 18 (5.0%); 90 mg = 16 (7.2%); 108 mg = 11 (10.4%)

Weight

> 10% decrease: 36 mg = 7 (1.3%); 54 mg = 14 (3.0%); 72 mg = 20 (5.6%); 90 mg = 16 (7.2%);

108 mg = 19 (18.1%)

> 10% increase: 36 mg = 1 (0.2%); 54 mg = 1 (0.2%); 72 mg = 1 (0.3%); 90 mg = 1 (0.4%);

108 mg = 1 (1.0%) Adverse Event

Any AE: 36 mg = 298 (54.2%); 54 mg = 259 (53.8%); 72 mg = 221 (61.0%); 90 mg = 151 (66.5%); 108 mg = 82 (75.9%)

Serious AE: 36 mg = 1 (0.2%); 54 mg = 1 (0.2%); 72 mg = 3 (0.8%); 90 mg = 0; 108 mg = 3 (2.8%)

Discontinuation due to AE: 36 mg = 47 (8.5%);

54 mg = 28 (5.8%); 72 mg = 17 (4.7%); 90 mg = 9 (4.0%); 108 mg = 9 (8.3%)

AE in ≥ 10% in any dose

Decreased appetite: 36 mg = 12.5%; 54 mg = 9.1%; 72 mg = 6.6%; 90 mg = 5.3%; 108 mg =

7.4%

Headache: 36 mg = 11.1%; 54 mg = 8.7%; 72 mg = 7.5%; 90 mg = 9.7%; 108 mg = 8.3%

Insomnia: 36 mg = 9.2%; 54 mg = 4.2%; 72 mg

= 6.4%; 90 mg = 8.8%; 108 mg = 9.3%

Dry mouth: 36 mg = 6.2%; 54 mg = 3.1%; 72 mg = 5.2%; 90 mg = 4.0%; 108 mg = 6.5%

Anxiety: 36 mg = 3.3%; 54 mg = 6.2%; 72 mg = 6.6%; 90 mg = 4.0%; 108 mg = 5.6%

URTI: 36 mg = 2.2%; 54 mg = 3.5%; 72 mg = 5.8%; 90 mg = 4.8%; 108 mg = 14.8%

Nausea: 36 mg = 4.5%; 54 mg = 4.4%; 72 mg = 1.9%; 90 mg = 4.0%; 108 mg = 4.6%

Heart rate increased: 36 mg = 3.1%; 54 mg = 2.5%; 72 mg = 2.8%; 90 mg = 6.6%; 108 mg =

8.3%

Irritability: 36 mg = 2.2%; 54 mg = 3.1%; 72 mg = 4.4%; 90 mg = 4.0%; 108 mg = 5.6%

conditions might be compromised by increases in these parameters.” Page 113



Main Study Findings Author’s Conclusions

Findling, 20114 ADHD-RS-IV

Inattention and hyperactivity/impulsivity subscales showed improvement

Placebo-adjusted least squares mean

differences at endpoint (negative indicates improvement): o 30 mg/d: -5.5 (95% CI, -9.7 to -1.3; p ≤

0.0056) o 50 mg/d: -8.3 (95% CI, -12.5 to -4.1; p ≤

0.0056)

o 70 mg/d: -7.9 (95% CI, -12.1 to -3.8; p ≤ 0.0056)

CGI-I

69.1% of participants improved on LDX (all doses) versus 39.5% of participants on placebo

(p ≤ 0.0001)

57.9%, 73.6%, and 76.0% improved on 30 mg/d, 50 mg/d, an 70 mg/d respectively

YQOL-R

Positive number indicates improvement; NS compared to placebo

30 mg/d: baseline mean = 79.3 (SD 10.03); endpoint mean = 81.1 (11.09)

50 mg/d: baseline mean = 80.5 (10.63);

endpoint mean = 81.3 (11.86)

70 mg/d: baseline mean = 78.8 (15.38); endpoint mean = 81.3 (14.66)

Placebo: baseline mean = 79.2 (11.08);

endpoint mean = 81.3 (12.16) Adverse Events

56 (71.8%) treatment-emergent adverse events for 70 mg/d (65.4% on 30 mg/d; 68.8% on 50 mg/d; 58.4% on placebo)

Most common TEAEs on 70 mg/d: decreased appetite (37.2%), dizziness (6.4%), dry mouth (5.1%), fatigue (5.1%), headache (15.4%), insomnia (14.15), irritability (10.3%), nasal

congestion (6.4%), URTI (5.1%), vomiting (2.6%), weight decreased (15.4%)

Safety

70 mg/d change from baseline at endpoint -mean (standard error)

o SBP, mm Hg: 1.7 (1.21) o DBP, mm Hg: 3.4 (0.80) o Pulse rate, bpm: 5.4 (1.27)

70 mg/d overall at endpoint – n (%)

“Symptoms were significantly improved in each LDX dose group versus placebo, beginning at week 1 and throughout the study.” Page 402

“… efficacy of LDX versus placebo was

demonstrated with all doses at the time points studied, using ADHD-RS-IV and CGI-I measures. YQOL-R scores did not improve

versus those observed with placebo, but no worsening of QOL occurred.” Page 403



Main Study Findings Author’s Conclusions o SBP, ≥ 120 mm Hg: 20 (26.7%) o SBP, ≥ 120 mm Hg and ≥ 10 mm Hg: 5

(6.7%) o SBP, ≥ 130 mm Hg at 2 consecutive weeks:

3 (4.0%)

o SBP, ≥ 130 mm Hg and increase from baseline ≥ mm Hg: 0

o DBP, ≥ 80 mm Hg: 5 (6.7%)

o DBP, ≥ 80 mm Hg and increase from baseline of ≥ 10 mm Hg: 4 (5.3%)

o Pulse, ≥ 100 bpm: 3 (4.0%)

o Pulse, ≥ 100 bpm and increase from baseline of ≥ 15 bpm: 3 (4.0%)

Newcorn, 201022 Predictors of Effective Dose

Parent-rated ADHD-RS at baseline (i.e., baseline ADHD severity) was the only significant predictor of weight-based or absolute

dose (p ≤ 0.0029) (no point estimates were provided)

Adverse Events

Reported as AE by absolute dose group o 18 mg: n = 220

o 36 mg: n = 193 o 54 mg: n = 140 o 72 mg: n = 85

Abdominal pain: 18 mg = 9 (4%); 36 mg = 4 (2%); 54 mg = 6 (4%); 72 mg = 1 (1%)

Anorexia: 18 mg = 22 (10%); 36 mg = 13 (7%); 54 mg = 8 (6%); 72 mg = 5 (6%)

Headache: 18 mg = 25 (11%); 36 mg = 22 (11%); 54 mg = 11 (8%); 72 mg = 8 (9%)

Insomnia: 18 mg = 16 (7%); 36 mg = 6 (3%); 54

mg = 7 (5%); 72 mg = 4 (5%)

Nervousness: 18 mg = 6 (3%); 36 mg = 7 (4%); 54 mg = 0 (0%); 72 mg = 2 (2%)

Somnolence: 18 mg = 3 (1%); 36 mg = 3 (2%); 54 mg = 3 (2%); 72 mg = 3 (4%)

“The only significant predictor of effective dose was baseline ADHD symptom severity, although the relationship was modest. Age, height, and weight did not predict final dose.”

Page 190

“Adolescents may be effectively and safely treated with once-daily doses up to 72 mg of

OROS®, with the majority requiring doses of 54

or 72 mg to achieve an adequate response. Adolescents are likely to require higher

absolute doses than younger children, but their weight-adjusted dose is not higher than it is in children.” Page 195

Stevens, 201021

No SAE reported during inpatient hospitalization

No adverse cardiovascular outcomes during inpatient hospitalization

No association between OROS MPH and SBP: r2 = 0.05 (exact p value not reported but was not

significant)

No association between OROS MPH and DBP: r2 = 0.04 (exact p value not reported but was not

significant)

“In this small patient sample receiving higher than FDA-approved doses of extended-release MPH, the OPOS formulation was well

tolerated; no clinically meaningful vital sign abnormalities were observed in this medically healthy group.” Page 51



Main Study Findings Author’s Conclusions

No association between OROS MPH and heart rate: r

2 = 0.00 (exact p value not reported but

was not significant) ADHD = attention-deficit/hyperactivity disorder; AE = adverse event; bpm = beats per minute; CGI-I = Clinical Global Impressions-Improvement; DBP = diastolic blood pressure; FDA = Food and Drug Administration; mm Hg = millimeters of mercury; MPH = methylphenidate; NS = not signif icant; OROS = osmotic release oral system; RS = rating scale; SAE = serious adverse effects; SBP = systolic blood pressure; SD = standard deviation; Std. = standard; URTI = upper respiratory tract infection


APPENDIX 5: Additional References of Potential Interest Previous CADTH Report

High dose stimulants for attention deficit hyperactivity disorder: clinical effectiveness, safety, and guidelines [Internet]. Ottawa: CADTH; 2015 Jan 29. [cited 2016 Feb 22]. (Rapid response report: reference list). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/feb-2015/RA0728%20High-dose%20stimulants%20ADHD%20Final.pdf Articles from the previous CADTH report that upon full-text review were excluded Biederman J, Mick E, Fried R, Wilner N, Spencer TJ, Faraone SV. Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD. Eur Neuropsychopharmacol. 2011 Jul;21(7):508-15. Faraone SV, Spencer TJ, Kollins SH, Glatt SJ, Goodman D. Dose response effects of lisdexamfetamine dimesylate treatment in adults with ADHD: an exploratory study. J Atten Disord [Internet]. 2012 Feb [cited 2016 Feb 12];16(2):118-27. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355536/pdf/nihms374903.pdf

Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M, Ferreira-Cornwell MC, et al. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011 Apr;50(4):395-405.

Canadian Clinical Practice Guidelines – Uncertain Methodology Canadian ADHD practice guidelines (CAP guidelines) [Internet]. 3rd ed. Markham (ON): Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA); 2011. [cited 2016 Feb 12]. Available from: http://www.caddra.ca/cms4/pdfs/caddraGuidelines2011.pdf See: pages 7.11 to 7.16, 7.17 to 7.20 Systematic Review – Combined Moderate and High Dose

Storebo OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015 Nov 25;11:CD009885

See also: Storebo OJ, Krogh HB, Ramstad E, Moreira-Maia CR, Holmskov M, Skoog M, et al. Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ (Online) [Internet]. 2015 Nov 25 [cited 2016 Feb 9];351(Article Number: h5203). Available from: http://www.bmj.com/content/bmj/351/bmj.h5203.full.pdf

https://www.cadth.ca/sites/default/files/pdf/htis/feb-2015/RA0728%20High-dose%20stimulants%20ADHD%20Final.pdfhttps://www.cadth.ca/sites/default/files/pdf/htis/feb-2015/RA0728%20High-dose%20stimulants%20ADHD%20Final.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355536/pdf/nihms374903.pdfhttp://www.caddra.ca/cms4/pdfs/caddraGuidelines2011.pdfhttp://www.bmj.com/content/bmj/351/bmj.h5203.full.pdf

Context and policy issuesResearch questionSkey FindingsMethodsLiterature Search MethodsSelection Criteria and MethodsExclusion CriteriaCritical Appraisal of Individual Studies

Summary of EVIDENCEQuantity of Research AvailableSummary of Study CharacteristicsSummary of Critical AppraisalSummary of FindingsLimitations

Conclusions and implications for decision or policy makingReferencesAppendix 2: Characteristics of Included PublicationsAppendix 3: Critical Appraisal of Included PublicationsAppendix 4: Main Study Findings and Author’s ConclusionsAppendix 5: Additional References of Potential Interest

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