Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 163rd Annual Meeting of the American Psychiatric Association

New Orleans, Louisiana / May 22-26, 2010

It is now well recognized that attention-deficit/hyperactivity disorder (ADHD) is not limited to childhood but is a disease that can persist indefinitely. In a new analysis of a large dataset of children, adolescents and adults with ADHD who were treated at the Scarborough Hospital and the Toronto ADHD Clinic over a recent 14-year period, the impact of ADHD on adults was substantial, including a greater likelihood of psychiatric comorbidities, such as depression and anxiety, than children. However, the classic symptoms of short attention span, hyperactivity and impulsivity remained common in older as well as in younger individuals. The data reinforce the importance of effective therapies for ADHD across the age spectrum.

“As the patient ages, anxiety and mood disorders rise in prevalence, regardless of gender, to become the most common comorbidities of adulthood. Substance use is more common in males with the presence of conduct disorder followed by oppositional defiant disorder as the most common predictors,” reported neurologist Dr. Isaac Szpindel, Toronto ADHD Clinic, Ontario. “Awareness of these findings can assist the clinician in diagnosing ADHD and its comorbidities and can further inform or guide the clinician in treatment and medication choice where comorbidity factors are highly influential.”

Blinded Efficacy Study in Adolescents

The persistence of ADHD symptoms into adolescence and adulthood is well established by validated tests that can reproducibly identify persistent, characteristic and debilitating ADHD symptoms throughout life, but the data associating ADHD therapy with meaningful improvements in daily function among adolescents and adults are growing rapidly. The most recent set of evidence was generated by a multicentre double-blind, placebo-controlled study conducted in adolescents. The study agent was lisdexamfetamine dimesylate (LDX), a stimulant that employs a prodrug delivery for extended half-life. In this study, 324 adolescents between the ages of 13 and 17 years were randomized to one of three LDX treatment arms, as follows, or placebo:

30 mg once-daily for the full course of the four-week study;

30 mg for the first week followed by 50 mg for the remaining three weeks;

30 mg for the first week, 50 mg for the second week and 70 mg for the remainder of the study.

The primary outcome was change in ADHD Rating Scale IV (ADHD-RS-IV) from baseline. Secondary efficacy measurements included Clinical Global Impression Improvement (CGI-I) assessments. To be eligible for entry, patients had to have an ADHD-RS-IV score of at least 28. About 70% of patients were male and nearly 80% were Caucasian.

Efficacy and safety assessments were conducted weekly, with highly significant reductions in ADHD scores after the first week relative to baseline and placebo. While the ADHD-RS-IV score fell by approximately six points in the placebo group, it fell by nearly 13 points in all three groups receiving active treatment (P=0.0076). There were further incremental reductions in score in all groups over the subsequent three weeks of the trial, with a numerical but not a significant dose-related effect for greater ADHD-RS-IV reductions at the higher doses. While the reduction in the ADHD-RS-IV score in the placebo group by the end point neared 15 points, the reduction in the active treatment groups all exceeded 20 points (P=0.0056) (Figure 1).

Figure 1.

“These score reductions are pretty incredible as we see highly significant differences by the end of the first week, which is the earliest point that we began to measure,” reported senior author Dr. Ann C. Childress, President, Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada. Although she conceded that LDX, which was approved in the US for children in 2007 and in adults in 2008, is already among the available stimulants that are often employed in adolescents and adults, this study provides an evidence-based set of data on which to confirm efficacy. “These results are important as we look for proven treatments to effectively manage ADHD symptoms in adolescent patients,” Dr. Childress continued. She noted that the results of the CGI-I were consistent with the ADHD-RS-IV results, which also demonstrated weekly and overall improvement in patients receiving active treatment relative to placebo.

Improvement was also seen in relevant ADHD-RS-IV subscale scores, such as inattention and hyperactivity/impulsivity for all study doses relative to placebo. There were no serious side effects or laboratory abnormalities, even though a variety of safety studies, including electrocardiogram (ECG) monitoring, were performed. The most common adverse events were typical of those reported previously with stimulants and included headache, insomnia, loss of appetite and irritability.

The efficacy and safety of LDX in many age groups has been evaluated closely. Although many of the most commonly used stimulants for the treatment of ADHD now come in formulations that extend the duration of action, LDX is the first prodrug of dextroamphetamine; it is ingested in an inert form and then converted to its active moiety. This type of formulation allows for a duration of action of up to 13 hours, which avoids the potential confounders of controlled-release mechanisms employed to extend the activity of many of the other commonly used ADHD agents, such as pH degradation of the capsule coating. Extended-release mechanisms may be defeated by low acid states, such as those induced by proton pump inhibitors taken for gastroesophageal reflux disease.

Adverse Events Differ in Adults vs. Children

In a separate study that was specifically designed to collate safety data from randomized trials, LDX demonstrated a profile that was found to be highly consistent with other stimulants. Importantly, this study gathered data in children, adolescents and adults. There were no safety signals in regard to ECG monitoring in any age group and no changes in vital signs that were consistent or considered clinically meaningful. According to senior author Dr. David Goodman, Johns Hopkins University School of Medicine, Baltimore, Maryland, children were more likely to report upper abdominal discomfort and decreased appetite than adults, while adults were more likely to report dry mouth and headache than children. The sets of complaints tended to be mild and there were no unique or unexpected adverse events in any group.

“The most frequently occurring treatment-emergent adverse events were consistent with the known effects of amphetamine treatment,” Dr. Goodman reported. He acknowledged that weight loss might pose the greatest concern in children because of the potential for adverse effects on development, but the scores for weight in both children and adolescents “remained above mean for age- and sex-matched general populations” following LDX treatment in this database of 290 children, 310 adolescents and 420 adults.

Trial data are necessary to quantify relative risk of adverse events but several investigators, including Dr. Goodman, made the point that the significance of any side effect is always patient-specific in the setting of daily clinical practice. Healthy eating habits are important, independent of appetite, so patients who do not suffer a loss of appetite but develop weight gain from high-calorie diets may be at a relative disadvantage to patients who consume less but pursue a more healthy diet. Similarly, some proportion of patients in most amphetamine trials report some change in sleep quality but the clinical significance is patient-specific, which was emphasized in new sleep data with LDX. Likely to be relevant to other stimulants, these data revealed substantial rates of insomnia at the same time that sleep quality was unchanged or improved on the Pittsburgh Sleep Quality Index (PSQI) in most patients.

Stimulants Do Not Worsen Sleep Quality

In this study, sleep data were gathered from 420 adults who participated in a four-week parallel group study as well as from the 349 patients who then participated in a 12-month open-label extension study. One reason for the disparity between the low number of patients with worsened quality of sleep, even though up to 20% reported some episodes of insomnia, was that the PSQI was evaluated over an extended period while the insomnia incidence was a cumulative total. Only 8.1% of patients reported ongoing sleep problems but less than 4% of patients withdrew from the study for this reason. Importantly, PSQI measures multiple domains of sleep quality, such as sleep efficiency and daytime function, which may provide a more comprehensive overview of the impact of therapy on sleep than spontaneous complaints of insomnia.

“Although sleep complaints at some point in the study were reported by a substantial minority of patients, most subjects had unchanged or improved PSQI scores with LDX treatment. Overall, a smaller proportion of good sleepers at baseline changed to poor sleeper status at the end point than those who were poor sleepers at baseline and changed to good sleeper status at the end point,” reported senior author Dr. Richard Weisler, Duke University Medical Center, Durham, North Carolina. These sleep data in adults are consistent with soon-to-be-published data from a study conducted in children and presented at the 2009 APA meeting. That study, led by Dr. John Giblin, Clinical Study Centers, LLC, Little Rock, Arkansas, showed no differences in sleep latency (time to persistent sleep), wake time after sleep onset, or total sleep time as measured by polysomnography when LDX was compared to placebo in children with ADHD, but it did find a highly significant reduction (P<0.0001) in sleep awakenings, associating LDX with an overall improvement in sleep efficiency.

Studies in Adults

In ADHD, it is unclear whether the different stimulants that have now been licensed for treatment provide the same degree and spectrum of activity, particularly in older individuals. In a post-hoc data analysis from two similarly-designed studies that were combined to compare the efficacy and safety of LDX to mixed amphetamine salts extended-release (MAS XR) in adults, both generated significant global improvements in symptom severity relative to baseline and to a placebo arm. Both also had similar safety profiles, although weight loss and dry mouth were more common in the LDX arm, while insomnia, agitation and anxiety were more common in the MAS XR cohort. The once-daily doses of active drug compared in the study, selected to provide equivalent activity, were LDX 30 mg titrated up to a maximum dose of 70 mg and MAS XR 20 mg titrated up to a maximum dose of 60 mg.

For the end point of change in ADHD-RS-IV, there were some relative differences in efficacy, with the total ADHD-RS-IV score reduced at end point by 8.8 points with MAS XR 40 mg (P=0.001 vs. baseline) and by 10.4 on LDX 70 mg (P<0.001 vs. baseline). Although this translated into a higher effect size for LDX vs. MAS XR, the authors suggested that prospective comparative studies are needed to better understand differences, particularly if the drugs offer benefit on similar domains of quality of life (QoL) and if the relative advantage of LDX, if confirmed, is due primarily to pharmacodynamics or mechanism.

The type of stimulant may be important to optimal results, but employing effective stimulant therapy in individuals with ADHD across the age spectrum may be a more important message from the current studies. In another stimulant study, this one with methylphenidate delivered in an osmotic-release system, the target population was older children (ages 9 to 12). The study randomized 71 patients to a single dose of placebo followed at least seven days later by a single dose of methylphenidate XR or to the opposite sequence. The primary end points included relative change in Dynamic Indicators of Basic Early Literacy Skills (DIBELS), which measures reading accuracy, and Gray Silent Reading Test (GSRT), a test of reading accuracy. The improvement in both DIBELS (P=0.0092) and GSRT (P=0.0038) was highly statistically significant favouring the stimulant.

“Laboratory school studies have contributed to the clinical understanding of the effects of ADHD medications and how they may affect performance on tasks in school-aged children, including, as in this study, older children,” reported Dr. Sharon Wigal, Clinical Professor and Director of Clinical Trials, University of California, Irvine. She indicated that studies of school performance provide readily measured changes, but the effect of these treatments have important implications across a variety of measures of daily functioning, including social skills and QoL.

Summary

The data demonstrating the efficacy of long-acting stimulants on a variety of functions and in a variety of age groups has been valuable for providing more rational decisions about when to consider these therapies. While a multicentre, double-blind, placebo-controlled trial conducted with LDX in adolescents supports the global clinical impression that stimulants are highly effective beyond their classical use in grade school children, the more important message is that these compounds should not be reserved for improving school performance but have the potential for a much broader impact on other important QoL aspects, including improved social interaction with family and peers.

Note: At press time, lisdexamfetamine is not indicated for use in adolescents (13 to 17 years of age) or adults (over 18 years old) in Canada.