Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naïve children with ADHD

Abstract

Randomized placebo-controlled trials have reported efficacy of methylphenidate (MPH) for Attention-deficit/hyperactivity disorder (ADHD); however, selection biases due to strict entry criteria may limit the generalizability of the findings. Few ecologically valid studies have investigated effectiveness of MPH in representative clinical populations of children. This independently funded study aims to describe treatment responses and their predictors during the first 12 weeks of MPH treatment using repeated measurements of symptoms and adverse reactions (ARs) to treatment in 207 children recently diagnosed with ADHD. The children were consecutively included from the Child and Adolescent Mental Health Centre, Mental Health Services, The Capital Region of Denmark. The children (mean age, 9.6 years [range 7-12], 75.4% males) were titrated with MPH, based on weekly assessments of symptoms (18-item ADHD-rating scale scores, ADHD-RS-C) and ARs. At study-end 187 (90.8%) children reached a mean end-dose of 1.0 mg/kg/day. A normalisation/borderline normalisation on ADHD-RS-C was achieved for 168 (81.2%) children on the Inattention and/or the Hyperactivity-Impulsivity subscale in week 12, and 31 (15.0%) children were nonresponders, which was defined as absence of normalisation/borderline normalisation (n = 19) or discontinuation due to ARs (n = 12), and eight (3.8%) children dropped out from follow-up. Nonresponders were characterised by more severe symptoms of Hyperactivity-Impulsivity and global impairment before the treatment. ARs were few; the most prominent were appetite reduction and weight loss. A decrease in AR-like symptoms during the treatment period questions the validity of currently available standard instruments designed to measure ARs of MPH. This ecologically valid observational study supports prior randomized placebo-controlled trials; 81.2% of the children responded favourably in multiple domains with few harmful effects to carefully titrated MPH. Clinical trial registration: ClinicalTrials.gov with registration number NCT04366609.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. TREND, flow diagram of inclusion.

ICD-10 = International Classification of Diseases and Related Health Problems, ADHD = Attention-deficit/hyperactivity disorder, MPH = Methylphenidate, INDICES = INDIvidualised drug therapy based on pharmacogenetics: focus on carboxylesterase 1, AR = Adverse reaction, SAR = Serious adverse reaction. 1 = Treatment initiated after the study inclusion period was terminated. 2 = Clinician decision of patient’s discontinuation of treatment with MPH due to adverse events, ARs, and SARs.

Fig 2. Examples of graphs for estimations sum scores of inattention, hyperactivity-impulsivity, and adverse reactions throughout the 12 weeks as estimated by the linear mixed models, n = 207.

Clinician rated ADHD-Rating-Scale (ADHD-RS-C); Inattention subscale, 9 items [range 0–27] and Hyperactivity-Impulsivity subscale, 9 items [range 0–27]. Clinician rated Barkley’s Stimulant Side Effect Rating Scale (BSSERS-C), 17 items, [range 0–153]. Explanatory variables: Sex, age (7 to 9 years and 10 to 12 years), functional impairments in week 0, and Clinical Global Impression Severity (CGI-S). CGI-S devided into: 1–3 = Not ill, borderline ill, mildly ill. CGI-S 4 = Moderately ill, CGI-S 5 = Markedly ill. CGI-S 6–7 = Severly ill, among the most extreme ill patients.