Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses

Coghill, David; Werner‐Kiechle, Tamara; Farahbakhshian, Sepehr; Bliss, Caleb; Robertson, Brigitte; Huß, Michael

doi:10.1007/s00787-020-01586-5

Cited by 9 publications

(9 citation statements)

References 32 publications

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“…These results are consistent with the literature suggesting that oppositional defiant disorder (ODD), conduct, or internalizing symptoms may exacerbate impairment levels in children with ADHD, especially in the social domains (e.g. Bishop, Mulraney, Rinehart, & Sciberras, 2019;Coghill et al, 2006Coghill et al, , 2020Ros & Graziano, 2018;Wehmeier, Schacht, & Barkley, 2010). For instance, the level of social impairment tends to be heightened when symptoms of or comorbid ODD or conduct disorder co-exist with ADHD (Coghill et al, 2006;Wehmeier et al, 2010), and a meta-analytic review of social functioning found that the relationship between ADHD and social skills deficits (but not peer functioning) was weaker in studies adjusting for the influence of conduct problems than in studies failing to do so (Ros & Graziano, 2018).…”

Section: Discussionsupporting

confidence: 91%

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How much impairment is required for ADHD? No evidence of a discrete threshold

Arildskov

Sonuga‐Barke

Thomsen

et al. 2021

Child Psychology Psychiatry

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Background: A diagnosis of attention-deficit/hyperactivity disorder (ADHD) requires the presence of impairment alongside symptoms above a specific frequency and severity threshold. However, the question of whether that symptom threshold represents anything more than an arbitrary cutoff on a continuum of impairment requires further empirical study. Therefore, we present the first study investigating if the relationship between ADHD symptom severity and functional impairment is nonlinear in a way that suggests a discrete, nonarbitrary symptom level threshold associated with a marked step increase in impairment. Methods: Parent reports on the ADHD-Rating Scale (ADHD-RS-IV), the Weiss Functional Impairment Rating Scale (WFIRS-P), and the Strengths and Difficulties Questionnaire were collected in a general population sample of 1st, 2nd, and 3rd graders (N = 1,914-2,044). Results: Piecewise linear regression analyses and nonlinear regression modeling both demonstrated that the relationship between symptom severity (ADHD-RS-IV total score) and impairment (WFIRS-P mean score) was characterized by a gradual linear increase in impairment with higher symptom severity and no apparent step increase or changing rate of increase in impairment at a certain high ADHD-RS-IV total score level. Controlling for socioeconomic status, sex, and co-occurring conduct and emotional symptoms did not alter these results, though comorbid symptoms had a significant effect on impairment. Conclusions: There was no clear evidence for a discrete, nonarbitrary symptom severity threshold with regard to impairment. The results highlight the continued need to consider both symptoms and impairment in the diagnosis of ADHD.

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Section: Discussionsupporting

confidence: 91%

“…In fact, our high‐end group selected from the continuum included 105 children who had a symptom severity at a level typically considered to be of clinical relevance (percentile ≥ 95) with ADHD‐RS‐IV scores of 28 and above – a threshold similar to that used as an inclusion criteria for clinical trials (e.g. Coghill et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

How much impairment is required for ADHD? No evidence of a discrete threshold

Arildskov

Sonuga‐Barke

Thomsen

et al. 2021

Child Psychology Psychiatry

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“…However, treatment with stimulants and nonstimulants can improve symptoms even in patients with very poor baseline functioning scores and can preclude the need for additional medications to control symptoms. 56,57 These findings are corroborated by articles identified in the present search, in which MTS improved symptoms of ADHD, PD, ODD, and ED in adult patients. 44,46,50 While some studies of MTS have included adults, amphetamine patch data are missing.…”

Section: Discussionsupporting

confidence: 81%

“…Studies in the present analysis reported that while dermal reactions tended to be worse with MTS compared with placebo, 25,44 the majority of erythema cases were mild and transient. In McRae-Clark et al, 45 57.1% of adult patients reported a skin reaction, a greater proportion of study subjects than was observed in any of the pediatric studies (n = 3, 1.3%-3.7%). 38,43,51 This difference may be partially related to small sample size, as McRae-Clark et al 45 included only 14 patients.…”

Section: Safetymentioning

confidence: 84%

Systematic review of transdermal treatment options in attention-deficit/hyperactivity disorder: implications for use in adult patients

Correll

Starling²,

Huß³

2021

CNS Spectr.

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Background Adults with attention-deficit/hyperactivity disorder (ADHD) often face delays in diagnosis and remain untreated, despite significant negative impacts. To evaluate the safety and efficacy of transdermal treatment options in children, adolescents, and adults, a systematic literature review was conducted, with a focus on the implications of transdermal therapies for ADHD in adults. Methods A MEDLINE/Embase/BIOSIS/SCOPUS database search was conducted December 4, 2019, for English-language articles of interventional clinical trials using transdermal formulations for the treatment of ADHD without publication date limit. Assessed outcomes included efficacy, safety, adherence, abuse potential, cost efficacy, and health-related quality of life. Results Of 23 eligible publications, 18 were in children or adolescents (n = 1699; range 23-305), and 5 in adults (n = 274; range 14-90); all included methylphenidate transdermal system (MTS). All seven pediatric publications reporting change in ADHD symptomology from baseline reported a significant improvement with MTS treatment. Similarly, in three adult publications, ADHD symptoms improved significantly with MTS treatment. Safety findings in pediatric and adult studies were comparable; the most frequently reported treatment-emergent adverse events (TEAEs), namely, headache, decreased appetite, and insomnia, were reported in 13/16 (81%) of publications reporting specific TEAEs. MTS-related dermal reactions were mostly mild and transient. Discontinuation due to dermal reactions was reported in 10 studies (range 0%-7.1% [1 of 14 patients]). MTS compliance was high when assessed (97%-99%). Conclusions Transdermal therapies provide a useful treatment formulation for ADHD. Studies of MTS and other transdermal formulations, such as amphetamine, in adult patients are needed in this underserved population.

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“…In contrast to these results, a 13-week, double-blind, placebo-controlled RCT found that once-daily GXR (1–7 mg per day) did not improve the WFIRS-P LSP score in adolescents (13–17 years of age) with ADHD at Week 13 [ 12 ]. Coghill et al [ 13 ] reviewed two Phase 3 clinical trials of LDX and one of GXR and concluded that LDX was more effective than GXR in improving the WFIRS-P LSP score. LDX, however, was not more effective than OROS-MPH in improving the same score [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

A post hoc analysis of the effect of viloxazine extended-release capsules on learning and school problems in children and adolescents with attention-deficit/hyperactivity disorder

Faraone

Goméni²,

Hull

et al. 2021

Eur Child Adolesc Psychiatry

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Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms vs. placebo was reported in a series of pediatric clinical trials of viloxazine extended-release capsules (viloxazine ER; Qelbree™). This post hoc analysis of those studies evaluated the effect of viloxazine ER on learning and school problems (LSPs). We used data from four Phase 3 placebo-controlled trials of 100–600 mg/day viloxazine ER (N = 1354; 6–17 years of age). LSPs were evaluated using the School domain of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P-S) and the Learning Problems content scale of the Conners 3rd Edition-Parent Short Form (C3PS-LP) at baseline and end of study (≥ Week 6). ADHD symptoms were assessed weekly using the ADHD Rating Scale 5th Edition. The analyses were performed using the general linear mixed model with participant as a random effect. The responder analyses were performed using the Chi-square test. Viloxazine ER demonstrated significantly greater improvements in WFIRS-P-S (p < 0.0001) and C3PS-LP (p = 0.0113) scores vs. placebo. The response rate for the WFIRS-P-S was significantly greater for viloxazine ER vs. placebo (p = 0.001), and the number needed to treat (NNT) was 10.3 (effect size 0.7). Conversely, response rates for C3PS-LP did not differ between groups (p = 0.9069). In addition to ADHD symptoms improvement demonstrated in previous studies, viloxazine ER significantly reduced LSPs in pediatric subjects with ADHD. The responder analyses and NNT estimates indicate that a substantial number of children and adolescents with ADHD treated with viloxazine ER improved in clinically assessed LSPs.

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Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses

Cited by 9 publications

References 32 publications

How much impairment is required for ADHD? No evidence of a discrete threshold

How much impairment is required for ADHD? No evidence of a discrete threshold

Systematic review of transdermal treatment options in attention-deficit/hyperactivity disorder: implications for use in adult patients

A post hoc analysis of the effect of viloxazine extended-release capsules on learning and school problems in children and adolescents with attention-deficit/hyperactivity disorder

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