Lisdexamfetamine Most Efficacious, Methylphenidate Best Tolerated in ADHD

March 22, 2017

Researchers compared the safety and efficacy of leading ADHD treatments.

A meta-analysis of 34 randomized controlled trials compared the safety and efficacy of leading medications used to treat symptoms of attention-deficit/hyperactivity disorder (ADHD).

Results showed that ADHD symptoms improved more with lisdexamfetamine (Vyvanse/Shire) than with several other ADHD medications; however, methylphenidate immediate release (Ritalin/Novartis, others) was judged the best tolerated.

The analysis also determined a greater probability of therapeutic effect with guanfacine extended release (GXR) (Intuniv/Shire, others) than with another non-stimulant ADHD medication, atomoxetine (Strattera/Lilly), although possibly not as well tolerated.

The conclusions from this mixed treatment comparison (MTC) were qualified with the acknowledgement that the authors are employees of, or consultants to Shire, the manufacturer of both Vyvanse and Intuniv; and that there were too little data to compare methylphenidate immediate release on one measure of efficacy, and to distinguish between all agents on discontinuation due to adverse effect. In addition, the comparative analysis did not include some treatments, such as mixed amphetamine salts (Adderall/Shire, others).

Despite such limitations, the results presented by lead author Alain Joseph, PhD (photo) and colleagues were consistent between the ADHD Rating Scale Version IV (ADHD-RS-IV) measure of symptoms and the Clinical Global Impression-Improvement (CGI-I) response, taken in controlled trials involving between 16 and 222 subjects per study arm, conducted between 1994 and 2016.

"To our knowledge, this is the first systematic comparison of the safety and efficacy of GXR with other pharmacotherapies available, indicated, or frequently used to treat children and adolescents with ADHD within a network meta-analysis and MTC," Joseph said.

The randomized controlled trials included in the analysis were conducted with children and adolescents ranging from 8.5 to 14.6 years who were diagnosed with ADHD without comorbid psychiatric conditions. All trials utilized a placebo or active comparator; involved at least one of the targeted medications; and reported efficacy or safety outcomes after study durations of between three to 16 weeks.

The ADHD-RS-IV and CGI-I were among the efficacy measures applied in all trials. All but two trials specified that these were investigator scored based on interviews with parents, while the other two did not show that an alternative to this common practice was used. Safety and tolerability were ascertained from both all-cause discontinuations and discontinuation due to adverse effects.

The average daily dose of lisdexamfetamine ranged from 44.4 to 51.52mg, for methylphenidate extended release 18 to 39.03mg, for methylphenidate immediate release 17.35 to 30.76mg, for atomoxetine 17.46 to 47.09 mg, and for guanfacine extended release 2.87 to 4.3mg.

Lisdexamfetamine was associated with the largest reduction in the ADHD-RS-IV measure of symptoms from baseline, calculated with Bayesian credible interval (CrI) at 95%, at -14.98 (-17.4 to -12.80), compared to -9.33 (-11.63 to-7.04) for methylphenidate extended release, -8.68 (-10.63 to 06.72) for guanfacine extended release, and -6.88 (-8.22 to -5.49) for atomoxetine.

There were insufficient data to analyze methylphenidate immediate release. The analysis of probability that lisdexamfetamine was most efficacious by this symptom measure was 99.96%.

Lisdexamfetamine also demonstrated the highest likelihood (expressed as relative risk [RR]) to be associated with a CGI-I measure of overall improvement, with a score of 1 (very much improved) or 2 (much improved), although overlapping the probability range with methylphenidate extended release.

The point estimates of RR were 2.56 (95% CrI 2.21-2.91) for lisdexamfetamine, 2.13(1.7-2.54) for methylphenidate extended release, 1.94 (1.59-2.29) for guanfacine extended release, 1.77 (1.31-2.26) for atomoxetine, and 1.62 (1.05-2.17) for methylphenidate immediate release. The analysis that lisdexamfetamine was most efficacious by this measure of overall improvement was 96.21%.

Results showed methylphenidate immediate release was the treatment least likely to be discontinued due to any cause, and the probability of it being the least likely to be discontinued due to adverse effect was only at 63.9%.

Although all treatments were generally comparable, guanfacine extended release had a slightly greater probability of being discontinued due to adverse event than other treatments.

The comparison of ADHD medications on efficacy and safety measures, “Comparative Efficacy and Safety of Attention-deficit/Hyperactivity Disorder Pharmacotherapies, Including Guanfacine Extended Release: A Mixed Treatment Comparison,” was published online March 3 in European Child and Adolescent Psychiatry.

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