A treatment can improve the primary symptom measure and still produce more adverse events. The two findings are not contradictory, and neither should disappear from an account of a stimulant trial.
The study population and regimen
Brams and colleagues randomized 264 children and adolescents aged 6–17 with ADHD: 132 to oral SHP465 mixed amphetamine salts and 132 to placebo. Active treatment was optimized within 12.5–25 mg/day over a four-week study.
Two hundred thirty-four completed the study, 116 active and 118 placebo participants. The safety comparison used 132 active recipients and 131 placebo recipients, because a randomized participant did not contribute exposure to that analysis.
What improved?
The primary ADHD rating-scale change favored mixed salts by −9.9 points versus placebo, with a 95% confidence interval of −13.0 to −6.8. The standardized effect size was 0.80. The clinician global-improvement comparison also favored active treatment.
These outcomes establish a short-term group benefit on the tested ratings. They are not an objective test of every aspect of functioning, and a standardized effect size is not the percentage of participants who improved.
What happened to adverse events?
Treatment-emergent adverse events were reported by 89 of 132 active recipients, 67.4%, and 61 of 131 placebo recipients, 46.6%. Appetite reduction, insomnia, irritability, nausea and decreased weight were prominent events meeting the paper’s reporting criteria.
No serious treatment-emergent adverse events were reported. That observation is important but cannot establish that rare serious events never occur. A four-week trial of this size has limited ability to characterize uncommon or delayed outcomes.
Vital signs were separate measurements
Mean increases were higher with active treatment for pulse and blood pressure. The reported pulse changes were 5.7 versus 0.7 beats per minute; systolic changes were 3.8 versus 2.1 mmHg, and diastolic changes 4.0 versus 0.5 mmHg.
Those are average changes, with substantial individual variability. They do not define a safe physiological threshold for a particular child, nor do they establish that every observed event was caused by treatment.
What does dose optimization imply?
Investigators adjusted dosing to response and tolerability. The result therefore concerns an optimization strategy within the tested range, rather than proving that a single fixed dose benefits all ages equally.
Participants with several potentially confounding or high-risk conditions were excluded. The short, industry-sponsored trial did not assess driving, long-term development or illicit methamphetamine exposure. Its balanced interpretation retains both the symptom benefit and the increased adverse-event frequency, without turning either into a universal treatment recommendation.
Scientific source
Brams M, Childress AC, Greenbaum M, et al. SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results of a Randomized, Double-Blind Placebo-Controlled Study. Journal of Child and Adolescent Psychopharmacology. 2018;28:19–28. doi:10.1089/cap.2017.0053. Original commentary on the supplied paper.
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