Amphetamines for attention deficit hyperactivity disorder in children and adolescents

For the current issue of the Journal, we asked Dr. Mark Feldman to comment on and put into context the recent Cochrane Review on Amphetamines for attention deficit hyperactivity disorder in children and adolescents. Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric conditions affecting children and adolescents. Amphetamines are among the most commonly prescribed medications to manage ADHD. There are three main classes of amphetamines: dexamphetamine, lisdexamphetamine and mixed amphetamine salts, which can be further broken down into short- and long-acting formulations. A systematic review assessing their efficacy and safety in this population has never been conducted. To assess the efficacy and safety of amphetamines for ADHD in children and adolescents. Parallel-group and cross-over randomized controlled trials (RCTs) comparing amphetamine derivatives against placebo in a paediatric population (<18 years) with ADHD. Two authors independently extracted data on participants, settings, interventions, methodology and outcomes for each included study. For continuous outcomes, we calculated the standardized mean difference (SMD) and for dichotomous outcomes, we calculated the risk ratio (RR). Where possible, we conducted meta-analyses using a random-effects model. We also performed a meta-analysis of the most commonly reported adverse events in the primary studies. We included 23 trials (8 parallel-group and 15 cross-over trials), with 2675 children aged 3 to 17 years. All studies compared amphetamines to placebo. Study durations ranged from 14 to 365 days, with the majority lasting less than 6 months. Most studies were conducted in the United States; three studies were conducted across Europe. We judged 11 included studies to be at a high risk of bias due to insufficient blinding methods, failing to account for dropouts and exclusions from the analysis, and failing to report on all outcomes defined a priori. We judged the remaining 12 studies to be at unclear risk of bias due to inadequate reporting. Amphetamines improved total ADHD core symptom severity according to parent ratings (SMD −0.57; 95% confidence interval [CI] −0.86 to −0.27; 7 studies; 1247 children/adolescents; very low quality evidence), teacher ratings (SMD −0.55; 95% CI −0.83 to −0.27; 5 studies; 745 children/adolescents; low quality evidence) and clinician ratings (SMD −0.84; 95% CI −1.32 to −0.36; 3 studies; 813 children/adolescents; very low quality evidence). In addition, the proportion of responders as rated by the Clinical Global Impression—Improvement (CGI-I) scale was higher when children were taking amphetamines (RR 3.36; 95% CI 2.48 to 4.55; 9 studies; 2207 children/adolescents; very low quality evidence). The most commonly reported adverse events included decreased appetite, insomnia/trouble sleeping, abdominal pain, nausea/vomiting, headaches and anxiety. Amphetamines were associated with a higher proportion of participants experiencing decreased appetite (RR 6.31; 95% CI 2.58 to 15.46; 11 studies; 2467 children/adolescents), insomnia (RR 3.80; 95% CI 2.12 to 6.83; 10 studies; 2429 children/adolescents) and abdominal pain (RR 1.44; 95% CI 1.03 to 2.00; 10 studies; 2155 children/adolescents). In addition, the proportion of children who experienced at least one adverse event was higher in the amphetamine group (RR 1.30; 95% CI 1.18 to 1.44; 6 studies; 1742 children/adolescents; low quality evidence). We performed subgroup analyses for amphetamine preparation (dexamphetamine, lisdexamphetamine, mixed amphetamine salts), amphetamine release formulation (long acting versus short acting) and funding source (industry versus nonindustry). Between-group differences were observed for proportion of participants experiencing decreased appetite in both the amphetamine preparation (P<0.00001) and amphetamine release formulation (P value = 0.008) subgroups, as well as for retention in the amphetamine release formulation subgroup (P value = 0.03). Most of the included studies were at high risk of bias and the overall quality of the evidence ranged from low to very low on most outcomes. Although amphetamines seem efficacious at reducing the core symptoms of ADHD in the short-term, they were associated with a number of adverse events. This review found no evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting amphetamine preparations. Future trials should be longer in duration (i.e., more than 12 months), include more psychosocial outcomes (e.g., quality of life and parent stress) and be transparently reported. The full text of the Cochrane Review is available in The Cochrane Library: Salima Punja S, Shamseer L, Hartling L, Urichuk U, Vandermeer B, Nikles J, Vohra S. Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD009996. DOI: 10.1002/14651858.CD009996.pub2. This Cochrane review of Amphetamines, and an earlier Cochrane review of Methylphenidate (1), both conclude that there is only low quality evidence supporting the use of stimulants in the treatment of ADHD. Though the methodology and conclusions of the Cochrane reviewers have been criticized (2), whether or not to treat ADHD with stimulants becomes a high-stakes decision. On the one hand, when the relative risk of adverse effects is considered, amphetamines may lead to appetite suppression, insomnia and to a lesser extent, abdominal pain. On the other hand, when one considers the prognosis for children who are not treated with stimulant medication, the ‘high-stakes’ come in to focus. Randomized controlled trials (RCTs) are the gold standard for determining efficacy. However, the best available evidence on long-term prognosis does not come from short-term RCTs examined by Cochrane reviews. The best available evidence, from albeit observational research, informs us that those affected with ADHD who chose not to take stimulants (or perhaps who were not prescribed stimulants) are less likely to do well in a number of profoundly important areas. Population-based observational studies indicate that stimulant treatment is associated with better math and reading scores (3) particularly if started earlier in childhood (4,5) and more importantly with better employment outcomes (6). Well-controlled observational studies, from uniquely well-integrated administrative databases, indicate that stimulant medications (particularly extended-release preparations (7)) are associated with reduced morbidity and mortality related to motor vehicle injury (8) and a reduced likelihood of incarceration (9). Given the potential benefits, but also the potential for adverse effects, the decision to trial stimulant medication should be predicated on a simple tenet; first be sure that the problem is worse than the treatment: The DSM criteria explicitly requires ‘functional impairment’ to make a diagnosis of ADHD. Daydreamers who are doing fine should not be treated with stimulant medication. However, if a child’s learning or self esteem is suffering because of inattention leading to poor academic performance or suffering because of difficulties with impulse control leading to poor social interactions, it’s time to intervene. Many kids with ADHD will have comorbid behavioural, developmental or mental health problems requiring behavioural, developmental or mental health interventions. To treat the core features of ADHD, however, stimulant medications will continue to be important. Stimulant medication (in combination with nonpharmacologic support) continues to be first line therapy for children over the age of 6 years struggling with ADHD. Within the class of stimulants, there is little evidence to favour amphetamines over methylphenidates. The choice of preparation should be based on duration of action (and how that fits with the age and activities of the child), the palatability and response to treatment. Some mid-day appetite suppression is acceptable if appetite returns by dinnertime. Dosing requirements and appearance of adverse effects are highly variable and careful titration is a key to success. This Cochrane review did not find differences in efficacy between shorter and longer acting stimulants. However, extended-release preparations are indeed more effective because they are more likely to be used as prescribed (10). Cochrane reviews examining RCTs will not be able to examine long-term outcomes. RCTs simply cannot feasibly or ethically require subjects to take placebo pills prospectively for 20 years. Although this Cochrane review of amphetamines for ADHD found evidence of a large treatment effect from low-quality short-term, randomized controlled trials, these, coupled with long-term observational research, constitute the best available evidence; for children struggling with ADHD despite educational and behavioural support, the best available evidence supports judicious treatment with extended-release stimulant medication.

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