Placebo response and its determinants in children with ADHD across multiple observers and settings: A randomized clinical trial

Fageera, Weam; Traicu, Alexandru; Sengupta, Sarojini M.; Fortier, Marie-Ève; Choudhry, Zia; Labbe, Aurélie; Grizenko, Natalie; Joober, Ridha

doi:10.1002/mpr.1572

Cited by 16 publications

(9 citation statements)

References 44 publications

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“…We observed a relatively high rate of response in the placebo group for both ADHD symptoms and EFD, which was not surprising considering that high placebo response rates were often reported in clinical trials of ADHD [27][28][29].…”

Section: Discussionsupporting

confidence: 73%

Executive Function Outcome of Treatment with Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Post-Hoc Analysis of Four Randomized Clinical Trials

Faraone

Goméni²,

Hull

et al. 2021

Pediatr Drugs

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Aim The aim of this study was to evaluate the effect of viloxazine extended-release capsules (viloxazine ER; Qelbree™) on executive function deficits (EFDs) in pediatric subjects (6-17 years of age) with attention-deficit/hyperactivity disorder (ADHD). Methods Data from four phase III placebo-controlled trials of 100-600 mg/day viloxazine ER (6-8 weeks of treatment) were used to evaluate the change from baseline (CFB) in the Conners 3rd Edition Parent Short Form-Executive Function (C3PS-EF) content scale T-score. Subjects were defined as EFD responders if they had C3PS-EF T-score > 70 at baseline and < 65 at end of study. ADHD symptoms were assessed with ADHD Rating Scale 5th Edition (ADHD-RS-5). Subjects were defined as ADHD symptom responders if they had a ≥ 50% reduction in CFB ADHD-RS-5 Total score at Week 6. The number needed to treat (NNT) and Cohen's d effect sizes were estimated for EFD and ADHD symptoms. Results A total of 1154 subjects were included in the analysis. Statistically significant improvements in EFDs were observed with viloxazine ER versus placebo (p = 0.0002). There were 52.5% of EFD or ADHD symptom responders in the viloxazine ER treatment group and 35.4% in the placebo group (p < 0.0001). The NNT was 5.8. The Cohen's d effect size for EFD and ADHD symptoms was 0.31. Conclusion Consistent with the efficacy of viloxazine ER demonstrated in pivotal trials, viloxazine ER significantly reduced EFDs in subjects with ADHD. Moreover, a substantial proportion of subjects treated with viloxazine ER had large improvements in EFDs, ADHD symptoms, or both.

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Section: Discussionsupporting

confidence: 73%

Executive Function Outcome of Treatment with Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Post-Hoc Analysis of Four Randomized Clinical Trials

Faraone

Goméni²,

Hull

et al. 2021

Pediatr Drugs

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“…Still in contrast to this study, we did not find a significant effect of continued methylphenidate treatment on parent-rated aggression. A possible explanation for less evident findings regarding parent-ratings could be that teachers report a lower placebo response than parents do, as found in a recently published placebo-controlled crossover trial with methylphenidate (Fageera et al, 2018). No effects of discontinuation were observed on child-rated symptoms, child-and parent-rated QoL, or parenting stress, suggesting that patients may be withdrawn from methylphenidate without deterioration of QoL, aggression, nor an increase in parenting stress.…”

Section: Discussionmentioning

confidence: 92%

Effects of Discontinuing Methylphenidate on Strengths and Difficulties, Quality of Life and Parenting Stress

Matthijssen

Dietrich

Bierens

et al. 2020

Journal of Child and Adolescent Psychopharmacology

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Objectives: To study the effects of discontinuation of long-term methylphenidate use on secondary outcome measures of strengths and difficulties, quality of life (QoL), and parenting stress. Methods: Ninety-four children and adolescents aged 8 to 18 years who had used methylphenidate for over 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg extended release methylphenidate) or to gradual withdrawal over 3 to 4 weeks placebo. We used mixed models for repeated measures to investigate effects on parent, teacher, and child ratings of hyperactivity/inattention and comorbid symptoms with the Strengths and Difficulties Questionnaire (SDQ), investigator-and teacher-rated oppositional symptoms (Conners Teacher Rating Scale-Revised: short form [CTRS-R:S]), and parent-rated aggression with the Retrospective Modified Overt Aggression Scale. QoL was assessed with the Revised Questionnaire for Children and Adolescents to record health-related quality of life and parenting stress with the Nijmegen Parental Stress Index. Results: Hyperactivity/inattention scores from the parent-and teacher-rated SDQ (difference in mean change over time of respectively:-1.1 [95% confidence interval, CI,-2.0 to-0.3]; p = 0.01;-2.9 [95% CI-2.9 to-0.7; p = 0.01]) and oppositional scores of the teacher-rated CTRS-R:S (difference in mean change-1.9 95% CI [-3.1 to-0.6; p < 0.01]) deteriorated to a significantly larger extent in the discontinuation group than in the continuation group. We did not find effects on other symptom domains, aggression, QoL, and parenting stress after discontinuation of methylphenidate. Conclusion: Our study suggests beneficial effects of long-term methylphenidate use beyond 2 years for oppositional behaviors in the school environment. Similarly, beneficial effects were found on hyperactivity-inattention symptoms as rated by parent and teacher scales, confirming our primary study on investigator ratings of attention-deficit/hyperactivity disorder. However, discontinuation of methylphenidate did not appear to have impact on other comorbid problems or aspects of the child's or parental functioning.

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“…The effect size of teacher ratings (d=20.52) was substantially larger than that of the investigator ratings; it was more in line with the effect sizes observed in trials for teacher ratings when medication is initiated and was mostly driven by effects on hyperactivity. Teachers were recently found to report a lower placebo response than parents did in a placebocontrolled crossover trial with methylphenidate (31). This may be an explanation for the higher teacher-based effect size compared with that of investigators, as the latter was based on information from parents.…”

Section: Discussionmentioning

confidence: 99%

Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study

Matthijssen¹,

Dietrich²,

Bierens

et al. 2019

AJP

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The benefits of long-term use of methylphenidate treatment in children and adolescents with attention deficit hyperactivity disorder (ADHD), as frequently prescribed in clinical practice, are unclear. The authors investigated whether methylphenidate remains beneficial after 2 years of use.Methods: Ninety-four children and adolescents (ages 8-18 years) who had been treated in regular care with methylphenidate for more than 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg/day of extended-release methylphenidate) or gradual withdrawal over 3 weeks, to 4 weeks of placebo. The primary outcome measure was the investigator-rated ADHD Rating Scale (ADHD-RS); secondary outcome measures were the investigator-rated Clinical Global Impressions improvement scale (CGI-I) and the Conners' Teacher Rating Scale-Revised: Short Form (CTRS-R:S). Continuous ratings were analyzed with mixed model for repeated measures analyses, and the CGI-I with a chi-square test. Results:The mean ADHD-RS scores at baseline for the continuation and discontinuation groups, respectively, were 21.4 (SD=9.7) and 19.6 (SD=8.9); after 7 weeks, the mean scores were 21.9 (SD=10.8) and 24.7 (SD=11.4), with a significant between-group difference in change over time of 24.6 (95% CI=28.7, 20.56) in favor of the group that continued methylphenidate treatment. The ADHD-RS inattention subscale and the CTRS-R:S ADHD index and hyperactivity subscale also deteriorated significantly more in the discontinuation group. The CGI-I indicated worsening in 40.4% of the discontinuation group, compared with 15.9% of the continuation group.Conclusions: Continued treatment with methylphenidate remains effective after long-term use. Some individual patients may, however, be withdrawn from methylphenidate without deterioration. This finding supports guideline recommendations that patients be assessed periodically to determine whether there is a continued need for methylphenidate treatment.

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Placebo response and its determinants in children with ADHD across multiple observers and settings: A randomized clinical trial

Cited by 16 publications

References 44 publications

Executive Function Outcome of Treatment with Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Post-Hoc Analysis of Four Randomized Clinical Trials

Executive Function Outcome of Treatment with Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Post-Hoc Analysis of Four Randomized Clinical Trials

Effects of Discontinuing Methylphenidate on Strengths and Difficulties, Quality of Life and Parenting Stress

Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study

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