New Agents and Assessment Tools for Treating ADHD
New Agents and Assessment Tools for Treating ADHD
While placebo-controlled studies are necessary to demonstrate the efficacy of new products, clinicians often rely on the results of comparison trials to guide decisions related to initiating and titrating ADHD medications. With the expansion in treatments options over the past 20 years, there has been a steady increase in the number of studies comparing two or more products. Several valuable studies have been published over the past year.
In 2013, Coghill and colleagues performed a systematic review of studies comparing long-acting methylphenidate formulations that was published in 2013. The authors reviewed 34 studies, including not only randomized controlled trials, but also pharmacokinetic studies, clinical trials conducted in structured school-like study environments, and an observational study. The authors found no one product superior to the others. When reviewing the studies as a group, efficacy reflected the pharmacokinetics of the drug product. They suggest that the choice of methylphenidate product correspond with the individual patient's needs, as the available products have significant differences not only in length of effect but also in onset and peak effect. They also recommend additional studies of the long-acting methylphenidate products to further evaluate the effects of comorbidities and symptom severity on treatment response.
The efficacy of extended-release guanfacine and atomoxetine was recently evaluated using a new methodology termed matching-adjusted indirect comparison (MAIC). The tool uses patient data from a clinical trial of one treatment to compare to aggregate data from a second treatment. Studies included in the assessment had comparable study designs and patient characteristics. Using MAIC, the authors identified significantly greater reductions in the mean ADHD-RS-IV total scores from baseline to study completion with guanfacine compared to atomoxetine, with a relative improvement of -7.0 (standard error 2.2), p < 0.01. Differences in hyperactivity/impulsivity and inattention subscores were also significant, with relative improvement values of -3.8 (1.2) and -3.2 (1.3) respectively. Using MAIC methodology, guanfacine was found to produce greater improvement in ADHD symptoms than atomoxetine over a wide range of doses. The reductions in ADHD-RS-IV scores remained greater with guanfacine even when comparing low-dose therapy, 0.075–0.09 mg/kg/day, to a standard atomoxetine dose of 1.2 mg/kg/day (relative improvement -6.0 (2.7), p < 0.05), or when comparing standard doses of guanfacine to atomoxetine doses greater than 1.2 mg/kg/day (-7.6 (1.4), p < 0.01).
A comparison of OROS methylphenidate and atomoxetine was published in the June issue of The Journal of Child Psychology and Psychiatry. A total of 102 children with ADHD (mean age 10.5 ± 2.7 years) were enrolled into this randomized, double-blind cross-over study. Each medication was titrated over a 4–6 week period, with a 2-week placebo period between each treatment arm. Sustained attention was assessed by the Conners' Continuous Performance Test II (CPT-II) reaction time (RT), as well as reaction time variability (RTSD), and omission errors. Methylphenidate produced significantly greater improvement than atomoxetine on RT, RTSD, and errors (p < 0.05), indicating a more substantial effect on sustaining attention.
Another comparison study was recently conducted with atomoxetine and lisdexamfetamine. This 9-week randomized, double-blind study enrolled 267 children between 6 and 17 years of age who had an inadequate response to methylphenidate. Patients received either lisdexamfetamine at a dose of 30, 50, or 70 mg once daily or atomoxetine at a dose of 0.5–1.2 mg/kg/day for patients less than 70 kg or 40, 80, or 100 mg/day for those weighing 70 kg or more. A significantly greater number of patients in the lisdexamfetamine group met the criteria for response, a reduction in ADHD-RS-IV total score of 25% or greater (91 versus 77%, p < 0.01). The percentage of patients with a reduction of more than 30% and the percentage with more than a 50% reduction were also significantly higher with lisdexamfetamine. Rates of sustained response in ADHD-RS-IV or CGI Improvement scores over the duration of the study were also higher in the patients given lisdexamfetamine. Adverse effects were similar in the two treatment arms. The authors concluded that lisdexamfetamine produced a more rapid and robust response than atomoxetine in patients who failed to respond to methylphenidate, suggesting that lisdexamfetamine may be a better option in this patient population.
Comparative Studies
While placebo-controlled studies are necessary to demonstrate the efficacy of new products, clinicians often rely on the results of comparison trials to guide decisions related to initiating and titrating ADHD medications. With the expansion in treatments options over the past 20 years, there has been a steady increase in the number of studies comparing two or more products. Several valuable studies have been published over the past year.
Long-acting Methylphenidate
In 2013, Coghill and colleagues performed a systematic review of studies comparing long-acting methylphenidate formulations that was published in 2013. The authors reviewed 34 studies, including not only randomized controlled trials, but also pharmacokinetic studies, clinical trials conducted in structured school-like study environments, and an observational study. The authors found no one product superior to the others. When reviewing the studies as a group, efficacy reflected the pharmacokinetics of the drug product. They suggest that the choice of methylphenidate product correspond with the individual patient's needs, as the available products have significant differences not only in length of effect but also in onset and peak effect. They also recommend additional studies of the long-acting methylphenidate products to further evaluate the effects of comorbidities and symptom severity on treatment response.
Guanfacine-Atomoxetine
The efficacy of extended-release guanfacine and atomoxetine was recently evaluated using a new methodology termed matching-adjusted indirect comparison (MAIC). The tool uses patient data from a clinical trial of one treatment to compare to aggregate data from a second treatment. Studies included in the assessment had comparable study designs and patient characteristics. Using MAIC, the authors identified significantly greater reductions in the mean ADHD-RS-IV total scores from baseline to study completion with guanfacine compared to atomoxetine, with a relative improvement of -7.0 (standard error 2.2), p < 0.01. Differences in hyperactivity/impulsivity and inattention subscores were also significant, with relative improvement values of -3.8 (1.2) and -3.2 (1.3) respectively. Using MAIC methodology, guanfacine was found to produce greater improvement in ADHD symptoms than atomoxetine over a wide range of doses. The reductions in ADHD-RS-IV scores remained greater with guanfacine even when comparing low-dose therapy, 0.075–0.09 mg/kg/day, to a standard atomoxetine dose of 1.2 mg/kg/day (relative improvement -6.0 (2.7), p < 0.05), or when comparing standard doses of guanfacine to atomoxetine doses greater than 1.2 mg/kg/day (-7.6 (1.4), p < 0.01).
Methylphenidate-atomoxetine
A comparison of OROS methylphenidate and atomoxetine was published in the June issue of The Journal of Child Psychology and Psychiatry. A total of 102 children with ADHD (mean age 10.5 ± 2.7 years) were enrolled into this randomized, double-blind cross-over study. Each medication was titrated over a 4–6 week period, with a 2-week placebo period between each treatment arm. Sustained attention was assessed by the Conners' Continuous Performance Test II (CPT-II) reaction time (RT), as well as reaction time variability (RTSD), and omission errors. Methylphenidate produced significantly greater improvement than atomoxetine on RT, RTSD, and errors (p < 0.05), indicating a more substantial effect on sustaining attention.
Atomoxetine-lisdexamfetamine
Another comparison study was recently conducted with atomoxetine and lisdexamfetamine. This 9-week randomized, double-blind study enrolled 267 children between 6 and 17 years of age who had an inadequate response to methylphenidate. Patients received either lisdexamfetamine at a dose of 30, 50, or 70 mg once daily or atomoxetine at a dose of 0.5–1.2 mg/kg/day for patients less than 70 kg or 40, 80, or 100 mg/day for those weighing 70 kg or more. A significantly greater number of patients in the lisdexamfetamine group met the criteria for response, a reduction in ADHD-RS-IV total score of 25% or greater (91 versus 77%, p < 0.01). The percentage of patients with a reduction of more than 30% and the percentage with more than a 50% reduction were also significantly higher with lisdexamfetamine. Rates of sustained response in ADHD-RS-IV or CGI Improvement scores over the duration of the study were also higher in the patients given lisdexamfetamine. Adverse effects were similar in the two treatment arms. The authors concluded that lisdexamfetamine produced a more rapid and robust response than atomoxetine in patients who failed to respond to methylphenidate, suggesting that lisdexamfetamine may be a better option in this patient population.
