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16 Aug 2019

Greenhill LL et al. J Am Acad Child Adolesc Psychiatry 2019; Epub ahead of print

Over the past 4 decades, there have been conflicting reports on whether short-term suppression of growth in children with ADHD treated with stimulant medication is associated with loss of adult height. More recently, follow-up studies of individuals receiving long-term treatment for ADHD have demonstrated that cumulative exposure to stimulant medication (referred to in terms of methylphenidate equivalents [ME]) has increased over the decades, although these studies did not report any link between dose or duration of stimulant treatment and adult height. However, post hoc analyses of growth rates in participants receiving a range of cumulative ME doses in the Multimodal Treatment of ADHD (MTA) study at 16-year follow-up suggested that extended use of stimulant medication may be linked to shorter height in adulthood (Swanson et al. 2017). This study aimed to expand on these analyses by determining whether different levels of cumulative stimulant exposure were associated with different growth trajectories in MTA study participants, and whether the observed growth suppression was linear throughout the study period, or occurred at specific developmental periods.

The MTA study was originally designed as a 1.2-year randomised controlled trial comparing pharmacological and psychosocial treatments in children with ADHD. The study recruited 579 children (aged 7.0–9.9 years) with combined-type ADHD according to the Diagnostic and Statistical Manual of Mental Disorders–4th Edition. Subsequently, 289 age- and sex-matched classmates were recruited 2 years after baseline as a local normative comparison group (LNCG) for follow-up. The MTA and LNCG participants were prospectively followed-up from 2 to 16 years after baseline. At each assessment, trained researchers measured participants’ height (cm) and weight (kg), and these raw data were transformed into standardised scores (z height, z weight and z body mass index [BMI], accounting for natural differences in growth patterns between genders) using growth norms published by the US Centers for Disease Control and Prevention.

The MTA participants with ADHD were categorised, based on self-selected patterns of stimulant medication use according to the Services for Children and Adolescents Parent Interview (SCAPI),* with reported doses of all approved stimulants transformed into ME doses, into one of the following subgroups: Consistent use (use of stimulant medication [defined as ≥10 mg/day ME] ≥50% of days during every between-assessment interval); Inconsistent use (use of stimulant medication ≥50% of days during some but not all intervals); and Negligible use (use of stimulant medication <50% of days for all intervals).

To assess potential interactions between growth suppression and duration and consistency of stimulant medication, a mixed-model multiple regression analysis (SAS Proc Mixed) was conducted with three independent variables: pattern of prolonged medication use (4-level variable comprising the Consistent, Inconsistent, Negligible and LNCG subgroups), prior stimulant treatment before entering the MTA (2-level variable: yes or no) and assessment point (10-level variable: 0, 1.2, 2, 3, 6, 8, 10, 12, 14 and 16 years after baseline). The dependent variables were the height, weight and BMI z scores. A significance level of p < 0.05, without adjustment, was used to identify main effects and interactions. To further evaluate developmental trends, paired comparisons of least square mean (LSM) estimates of z scores were performed for each subgroup at each assessment point. The paired comparisons at each assessment point were then used to differentiate between medication- and ADHD-related effects, and to estimate the potential dose-response effect of cumulative stimulant doses.

The mixed-model multiple regression analysis included 98.1% (568/579) of the original MTA study participants and 89.2% (258/289) of the LNCG; at the 16-year assessment, the mean age in each group was 24.7 (standard deviation [SD] 1.31) years and 24.4 (SD 1.36) years, respectively. Among the MTA participants, 9.3% (n = 52) had a Consistent pattern of stimulant medication use, 65.9% (n = 374) had an Inconsistent pattern and 24.8% (n = 141) had Negligible medication use by the 16-year assessment. In total, 211 of the 568 participants with ADHD had received stimulant treatment prior to MTA entry; of these, 29 were in the Consistent subgroup (constituting 54.7% of that group), 146 were in the Inconsistent subgroup (42.1%) and 36 were in the Negligible subgroup (25.5%). The study findings were as follows:

Height trajectories

  • The mixed-model regression analyses identified subgroup (F = 2.22, p < 0.0001) and prior medication (F = 2.22, p < 0.001) as the main effects upon standardised height scores, with the subgroup-by-assessment-point interaction also demonstrating significance (F = 2.81, p < 0.0001).
  • Paired comparisons demonstrated that medication-related effects on height z scores (i.e. Consistent vs Negligible and Inconsistent vs Negligible comparisons) peaked at the 3-year (mean age 11.4 years) and 6-year (mean age 14.4 years) assessments, with differences in z height LSMs then declining over time, suggesting that these periods in development may be particularly affected by medication-related growth suppression.
  • z height trajectories for the LNCG and Inconsistent group were flat, indicating average growth speed. However, the growth trajectories of the Consistent and Negligible groups diverged significantly by the 3-year assessment (z height difference = –0.6242, p > 0.0003) due to an upward trajectory in the Negligible group, suggesting faster-than-average growth tempo. By the 6-year assessment, the Consistent subgroup’s z height had decreased to a minimum of –0.2306 (difference vs Negligible subgroup = –0.4963; p < 0.0058), suggesting medication-related growth deceleration with consistent stimulant use. The height of both the Consistent and Negligible subgroups decreased in adolescence, later stabilising in adulthood.
  • z height scores in the Inconsistent group were significantly higher than those for the Consistent subgroup at each assessment point, except for the 3-year assessment (not significant).
  • The paired comparison of Negligible vs LNCG, assessing ADHD-related effects on height, demonstrated that the Negligible group were significantly taller than their non-ADHD peers in the LNCG group at the 2- and 3-year assessment points (i.e. at 10.4 and 11.7 years of age, respectively), although there was no significant height difference between these two groups at later assessment points.

Weight and BMI trajectories

  • The mixed-model regression analyses of z weight and z BMI scores showed that the main effect of assessment and the subgroup-by-assessment interaction were significant.
  • For children with ADHD in both the Consistent and Inconsistent subgroups, z scores for both weight and BMI decreased abruptly soon after stimulant medication initiation (i.e. by the 1.2-year assessment), but then rapidly increased in adolescence. This resulted in convergence of the weight and BMI trajectories of the Consistent, Inconsistent and Negligible subgroups in adolescence, with both weight and BMI continuing to increase into adulthood for all three groups, in contrast to height scores, which stabilised in adulthood.
  • Furthermore, pairwise comparisons demonstrated that, whereas mean z weight and BMI scores were lower in both the Consistent and Inconsistent ADHD groups compared with the LNCG in childhood, the opposite was true in adolescence and adulthood (p < 0.0001). The authors acknowledged that this may have been due to weight increases in adolescence regardless of medication use, but also noted that these results are consistent with reports of a link between childhood ADHD and adulthood obesity (Cortese et al. 2013), and suggested that BMI should be closely monitored in adolescents with ADHD.

There were several limitations to this study, including the fact that the prospective growth assessments in this study were uncontrolled and observational, so it was not possible to establish causal relationship patterns of medication use and growth trajectories. The non-ADHD LNCG group was also recruited 2 years after MTA baseline, by which time changes in the growth trajectories of the MTA participants had already been observed. Additionally, a lack of randomised treatment assignment after the 1.2-year MTA study period resulted in changes in participants’ medication status, with self-selected starting and stopping of medication. This could have allowed bias to be introduced into the follow-up study, with differences in participants’ baseline and post-baseline characteristics potentially influencing medication patterns. Furthermore, source bias may have been introduced by the fact that the self-selected subgroups of medication pattern were populated based on parent-reported SCAPI assessments when participants were <18 years old, but based on participant-report from age 18 years.

The authors concluded that these results expand upon previously published analyses of adult height outcomes in the MTA study, by identifying key periods in development (mean age 11.7 and 14.9 years) at which children and adolescents with ADHD may be most susceptible to stimulant-associated growth suppression. They also opined that the relatively flat growth trajectory of the Inconsistent subgroup, in addition to smaller decreases in final adult height compared with those with consistent use of stimulant medication, may link to the fact that stimulant use was shown to be the most common medication use pattern in the MTA follow-up study. They suggested future research should focus on whether planned medication interruptions may ameliorate stimulant-related growth deceleration, and that the timing and consistency of stimulant treatment should be carefully considered in order to minimise the risk of medication-associated growth trajectory changes in children with ADHD.

Read more about effects of long-term stimulant medication on growth trajectories in the MTA study here

 

*The SCAPI was administered to parents during assessments of participants aged up to 18 years, at 1.2, 2, 3, 6, 8 and in some cases 10 years after baseline. After MTA participants reached the age of 18 years, participant self-report was used to assess medication use. The SCAPI was also used to determine the proportion of participants who were already receiving medication when they entered the MTA study
To assess medication- and disorder-related effects, the four subgroups were split into stimulant-treated (Consistent and Inconsistent) and non–stimulant-treated (Negligible and LNCG) participants, allowing estimation of possible medication-related effects via two comparisons (Consistent vs Negligible and Inconsistent vs Negligible), and estimation of ADHD-related effects via a Negligible vs LNCG comparison. A Consistent vs Inconsistent comparison enabled the potential dose-response effect of cumulative stimulant doses to be estimated

Cortese S, Ramos Olazagasti MA, Klein RG, et al. Obesity in men with childhood ADHD: a 33-year controlled, prospective, follow-up study. Pediatrics 2013; 131: e1731-e1738.

Greenhill LL, Swanson JM, Hechtman L, et al. Trajectories of growth associated with long-term stimulant medication in the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry 2019; Epub ahead of print.

Swanson JM, Arnold LE, Molina BSG, et al. Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry 2017; 58: 663-678.

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