Stimulants or α2-Adrenergic Agonists as First Line in ADHD?

Abstract

Source: Harstad E, Shults J, Barbaresi W, et al. α2-adrenergic agonists or stimulants for preschool-age children with attention-deficit/hyperactivity disorder [published online ahead of print May 4, 2021]. JAMA. doi:10.1001/jama.2021.6118Investigators from multiple institutions conducted a retrospective chart review to compare reported improvement in preschool children diagnosed with attention-deficit/hyperactivity disorder (ADHD) with use of α2-adrenergic agonists (A2A) or stimulants. Children seen at 1 of 7 developmental-behavioral programs in the US with a diagnosis of ADHD and who received an A2A or stimulant at <72 months of age between 2013–2017 were included. Data were abstracted from participants’ medical records and included demographics, coexisting conditions, type and dose of ADHD medication used, start and stop dates for medication treatment, reported improvement in ADHD symptoms, and medication adverse effects.The primary predictor was medication used as first treatment, categorized as an A2A (guanfacine, clonidine) or stimulant (methylphenidate, amphetamine). The primary outcome was medication treatment response, determined by coding the clinic notes of participants’ medical chart using a clinical global improvement scale and categorized as associated with improvement or no improvement. A secondary outcome was medication adverse effects, which also were determined by coding clinic notes. Investigators determined the association between medication used and outcomes after controlling for potential confounders such as age, coexisting conditions, and clinic site.There were 497 children included in analysis. The median age was 62 months, and 82% were male. Stimulants were used as the first medication to manage ADHD in 65% of participants; A2As were used in 35%.There were significantly fewer participants who were rated as associated with improvement after first treatment with an A2A compared to those treated with stimulants (66% vs 78%; difference, 12%; 95% CI, 2.3%, 22.0%). After controlling for confounders, this effect remained: The risk of treatment being associated with improvement was lower for A2As vs stimulants (relative risk, 0.87; 95% CI, 0.72, 1.00). Several adverse effects were reported more often in participants receiving stimulants (appetite suppression, increased moodiness, and difficulty falling asleep), with only daytime sleepiness being more frequent in children receiving A2A.The investigators concluded that although the majority of preschool-aged children treated with A2As as first treatment for ADHD reported improvement, this proportion was significantly less than those treated with stimulants. Adverse effects of A2As were less frequent than those of stimulants.Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Rates of ADHD among preschool-aged children are on the rise, from 1% in 2007–2008 to 2.4% in 2016.1 ADHD in this age child is associated with important negative outcomes, such as expulsion from preschool, impaired peer interactions, and increased family stress.2 While the American Academy of Pediatrics recommends behavioral interventions for initial treatment, less than 20% achieve an adequate response with behavioral intervention alone.3,4 The AAP then suggests stimulant medication when behavioral interventions fail.3 However, in the setting of severe irritability and oppositionality, the American Academy of Child and Adolescent Psychiatry’s Preschool Psychopharmacology Working Group recommends alpha-agonist medication.4 The current investigators sought to determine which treatment regimen is best for preschool-aged children with ADHD. Prior to the current study, there was only a small case series that addressed symptom improvement among preschool-aged children in response to alpha agonists.6 The current investigators demonstrated that while children prescribed both A2As and stimulants showed improvement, stimulants may have been more efficacious. However, stimulants were associated with more adverse effects.The current investigators acknowledge that it was difficult to assess why a specific medication was prescribed or why it was stopped or changed. Also, due to the methodology, assessment of improvement could be qualified only as “improved” or “much improved.” More granular detail using rating scales was not possible. Another important caveat is that this study included participants treated at 7 academic subspecialty practices. Since most children are diagnosed by primary care physicians (PCPs) and 64% to 75% of prescriptions for ADHD are written by PCPs, these findings may not be generalizable for the many children treated by PCPs.7While a randomized controlled trial is ideal, it can be particularly challenging in preschool-aged children. Thus, the current multicenter study helps close the data gap for this vulnerable population.Among preschool-aged children with ADHD, both stimulants and A2As result in improvement, although with a different side effect profile.Can the apparent increase in ADHD be attributed to increased prevalence or to over-diagnosis? As heretical as it may sound, this hypothesis has been previously proposed.8