Effetti del Metilfenidato sulla crescita in bambini e adolescenti ADHD. Revisione sistematica e monitoraggio prospettico a lungo termine dei parametri auxologici: analisi preliminari dei risultati dello studio europeo di farmacovigilanza ADDUCE

Stimulant medications represent the main effective treatment in improving the core symptoms of ADHD. However, in the last 30 years, there has been increasing concern about the risks associated with these medications in particular with respect to possible growth deficits, due to their impact on weight, height and BMI. The aim of this work was to provide an extensive update of the literature on methylphenidate (MPH) long-term adverse effects on growth and pubertal maturation in ADHD and to evaluate, within the prospective pharmaco-vigilance EU funded ADDUCE (ADHD DRUGS USE CHRONIC EFFECTS) study, whether MPH for ADHD is associated with a statistically and clinically significant increase in long-term (> 1 year) risk of negative effects on the rate of growth velocity and on bone and pubertal maturation and to explore the application of the monitoring of bone age as a helpful tool able to add value to the routine measures of growth within the clinical care. The systematic review included a Pubmed and a centralized search carried out up to July 2015, using Ovid Medline, Embase and PsychInfo. The review was centred on human studies focusing on the impact of MPH exposure on growth in ADHD children and adolescents diagnosed according to DSM criteria. In total 38 eligible studies were identified covering a total of 6385 subjects. Analysis of the impact of MPH was performed in 3790 subjects. Nineteen studies did not support the hypothesis of a correlation between a growth deficit and treatment. Nineteen studies (n =2018 subjects) found instead significant changes on height, weight and BMI z scores. Height deficit appeared more evident during the first 6-12 months with a subsequent normalization. Dose, drug holidays, the length of treatment and the basal growth parameter appeared as possible important mediating factors. Within the multicentre ADDUCE longitudinal study, a total of 1397 subjects have been enrolled in the four countries involved into the projects (Italy, Germany, Hungary and UK). For the purpose of the present work, growth parameters were analysed for 267 Italian children and adolescents (129 drug naïve ADHD starting MPH for the first time; 113 unmedicated ADHD and 25 non ADHD), aged 6 to 17 years old. Weight, height and BMI, their Z-scores and pubertal maturation were assessed at baseline and every six months within 24 months of follow up. Height velocity and the SDS for height velocity were calculated at 12 and 24 months. Bone age by the X-ray of left wrist was further assessed for 44 drug naïve ADHD children, aged 6-12, at three time points of the ADDUCE longitudinal protocol, baseline visit and after 12 and 24 months. Baseline data analysis revealed normal growth parameters for the ADHD population with height, weight and BMI Z-score within the expected growth national norms. At the 12 and 24 month observation, absolute values of height and weight continued to increase in all subjects. Medication did not cause any significant impact on height neither on pubertal maturation. BMI Z-score decreased significantly only during the first 12 month of treatment (p=.04). Growth velocity SDS at T12 was not significantly different when compared to T24. The calculation of the predicted adult height by using the bone age confirmed no suppressive effect of stimulants on height remaining substantially similar at the different time-points of follow up (T0= 178.37 ±7.2; T12=177.18±7.8; T24=178.63±8.0). In conclusion, results from the present work revealed that the condition of ADHD per se does not appear to include an altered pattern of growth and that MPH has a modest impact mainly on weight and only a marginal effect on height with a minimal clinical influence generally remittent in adulthood. On the bases of the present evidences is however considered appropriate to refer to the current clinical guidelines for an adequate drug monitoring of growth and pubertal parameters in children on stimulant medication.