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.

159th Annual Meeting of the American Psychiatric Association

Toronto, Ontario / May 20-25, 2006

A wide range of options in the attention-deficit hyperactivity disorder (ADHD) armamentarium, including mixed amphetamine salts (MAS) compounds, methylphenidate (MPH) and atomoxetine, are transforming the quality of life for children, adolescents and, increasingly, adults with ADHD. These medications are enhancing performance at school, at play and at work.

According to lead investigator Dr. Stephen Faraone, SUNY-Upstate Medical University, Syracuse, New York, stimulants appear more effective in the treatment of ADHD symptoms when compared to other agents such as atomoxetine. These findings were demonstrated in a meta-analysis that included 29 controlled clinical trials involving a total of 4464 children between the ages of eight and 15. The studies evaluated 15 agents using 17 different measures of ADHD symptoms to assess their efficacy. Results showed that the effect size for MAS was considerably higher than for any other types of ADHD agents or non-stimulant.

Even when differences in study design were adjusted for, “we detected significantly larger effect sizes for short- and long-acting stimulants vs. non-stimulants or other medications,” investigators stated. Specifically, the effect size on ADHD total scores for MAS was 0.92 vs. 0.80 for MPH and 0.73 for atomoxetine. (Short- and long-acting stimulants did not differ from one another in terms of effect size, according to total ADHD scores.)

MAS also had a greater effect size on hyperactive-impulsivity scores in the same meta-analysis. “Psychostimulant therapy tends to be significantly more effective than non-stimulant therapy for the management of ADHD in youths,” the authors concluded.

Safety Issues

Safety issues remain important, even though the reinstatement of the MAS extended-release (XR) formulation last year by Canadian federal regulatory officials indicates that there is no reason to withhold MAS XR therapy for ADHD patients, provided a thorough medical history and physical examination to rule out any underlying structural cardiac defects as is indicated for all ADHD agents, this includes stimulants and non-stimulants.

Indeed, a study carried out by Dr. Timothy Wilens, Director, Substance Abuse Program, Pediatric Psychopharmacology Unit, Massachusetts General Hospital and Associate Professor of Psychiatry, Harvard Medical School, Boston, and colleagues, in which ADHD adults with hypertension were treated with ADHD medications, found no effect of ADHD treatment on either systolic or diastolic blood pressure. The issue of sudden cardiac death reported to be a risk with stimulant use has also been resolved, as data show that the rate of sudden cardiac death is actually lower at approximately 0.26 to 0.5 episodes/100,000 patients/year compared to a general population rate of 0.6 to six episodes/100,000 patients/year.

Even competitive student athletes whose risk of sudden cardiac death on stimulant use is higher than for non-athletes were not deemed to be at high enough risk to warrant special consideration by regulatory officials. That said, Dr. Wilens reminded delegates that physicians need to evaluate patients being considered for ADHD therapy for a history of personal or acquired cardiac disease and rule out any symptoms that might be suggestive of underlying structural heart disease, including palpitations, chest pain, syncope or family history of premature cardiac death.

Efficacy in Adults

It has been estimated that no more than 10 to 20% of adults with ADHD have been diagnosed with the disorder and only one or two out of 20 adults with ADHD receive treatment. Thus, the diagnosis and treatment of ADHD in adults is clearly wanting.

The Qu.E.S.T. (Quality of Life, Effectiveness, Safety, and Tolerability) evaluation is a prospective, open-label investigation of MAS XR 10 mg to 60 mg/day in adults with ADHD treated in a community practice setting. In a 10-week interim analysis of this ongoing trial, Jeanne Landgraf, Vice-President and Chief Scientific Officer, Healthact, Boston, was among several investigators to demonstrate how significant a response to MAS XR therapy can be even at 10 weeks.

Having developed an adult version of the ADHD Impact Module (AIM-A), treatment response to MAS XR was evaluated among Qu.E.S.T. patients according to their treatment status: no previous treatment (naive, n=378); previous stimulant treatment (Pre Stim, n=272); and previous non-stimulant treatment (Previous Non-stim, n=52). Intent-to-treat (ITT) analysis of this cohort demonstrated that patients in all treatment categories exhibited similar, statistically significant improvements on all six AIM-A quality-of-life domains (P<0.0001).

“Improvements emerged within two weeks following initiation of MAS XR treatment and were maintained or gradually increased up to study week 10,” investigators reported. The most robust improvements were seen within the performance and functioning domain, bothersomeness and concern domain, and daily interference domain, again in all treatment groups, they added. Changes from baseline to study end point in other AIM-A domains including living with ADHD; general well-being, relationships and communication also reached statistical significance for all groups (P<0.001). “When we developed this measure, we talked to adults—married, unmarried, divorced, different backgrounds, different severity and duration of ADHD—to get an understanding of how ADHD affects their relationships, how they feel about themselves, how they are performing at work, at school, and with other adults at work,” Landgraf explained in an interview, “and the level of interference that people experience from their symptoms and the degree of bothersomeness their symptoms create in everyday life is phenomenal. So what this study is suggesting is that you have to go beyond safety and efficacy issues when treating adults with ADHD and understand that the drug is having a significant impact on the lives of these patients.”

This theme was echoed in several other related interim analyses of the Qu.E.S.T study, again carried out at 10 weeks. In the ITT population of 702 participants, data were collected on the 36-item Short Form (SF) Health Survey and scores were compared with 1998 SF-36 US normative data.

At baseline, the mean mental component summary score for ADHD adults was 1 standard deviation (SD) below the 1998 US norm, investigators reported. Ten weeks after treatment with MAS XR, the same summary score was significantly greater than at baseline (P<0.0001) and comparable to the US norm. Significant improvements from baseline were also seen in the physical functioning and general health subdomains, while body pain scores remained comparable to those seen at baseline. The mean physical component summary score for the study group was similarly comparable to the 1998 US norm at baseline and at week 10.

As investigators noted, fewer than 7% of the cohort withdrew from the study due to adverse events over the 10-week interval, the most common being decreased appetite, dry mouth, insomnia and headache. “This is quite an amazing study because patients were all scoring 1 SD below the US norm on general quality-of-life measures and after 10 weeks of therapy, they are back to the levels of the normal population,” commented Dr. Declan Quinn, Associate Professor of Psychiatry, University of Saskatchewan College of Medicine, Saskatoon, in an interview. “This does not happen in any other psychiatric disorder, so this is a very effective, once-a-day, long-acting stimulant for adults with ADHD and cost-wise, MAS XR is cheaper than long-acting MPH, especially at higher doses.”

Adult Patient Satisfaction

Another analysis of the 10-week interim data from Qu.E.S.T. evaluated patient satisfaction with MAS XR therapy. Since it is known that long-term compliance with stimulant medication is an issue in ADHD patients and that this has an effect on symptom management, patient satisfaction with their treatment becomes an important factor to consider. As explained in an interview by lead author Dr. Margaret Weiss, Director of Research, Division of Child Psychiatry, Children’s and Women’s Health Centre of British Columbia, Vancouver, “One of the problems with short-acting medications is that an adult has to take it four to five times a day and that is just outside the realm of what anyone can do, never mind someone with ADHD.”

She presented the results from 77 adults who had previously been treated with a short-acting stimulant. They were then switched to MAS XR and were asked to rate their level of satisfaction with the long-acting formulation compared with the short-acting agent.

“After 10 weeks of treatment, 72.8% expressed overall satisfaction with MAS XR,” Dr. Weiss and co-investigators reported, while 87% indicated they were satisfied with once-daily dosing. Close to 88% of individuals also indicated that they rarely missed a dose once switched to the long-acting stimulant. While on short-acting amphetamine therapy, some 48% of adults indicated that they were satisfied with the frequency of daily dosing requirements, while 39% indicated that they rarely missed a dose.

Dr. Weiss told delegates, “What you see here—and it is statistically significant on all levels—is that patients found the long-acting medication easier to take; they were more compliant on it; they were satisfied with the duration of effect; and they were also pleased with the effect the medication had on their behaviour. So the two medications might have similar efficacy, but the effect the medication has in terms of whether it is taken, how long it is taken for and how it affects self-esteem is going to be different with the longer-duration stimulants like MAS XR than for short-acting stimulants.”

Driving Simulation Results

The MAS XR formulation has been shown to significantly improve both speed and accuracy of response in adolescents and young adults during a simulated driving test carried out as a two-way crossover design. Patients received active treatment and placebo according to one of two treatment sequences. “What was interesting about this study was that when subjects crossed over to placebo, they did not drop back down to the level of their placebo performance, so it seems that they gain more from a practice effect [from the first test] because we did not see this practice effect among those who started on placebo,” observed Dr. Gary Kay, President, Washington Neuropsychological Institute, and Associate Clinical Professor of Neurology, Georgetown University School of Medicine, Washington, DC, in an interview. “How long this lasts, we don’t know, but at least three weeks later, they still showed a benefit.”

New Developments

Dr. Wilens briefly discussed future options for the treatment of ADHD, one of which is a novel transdermal formulation of MPH. The patch is approved in the US for a nine-hour “wear-time,” during which interlude it is estimated that patients receive anywhere from 10 to 30 mg of active drug, depending on the size of the patch.

The amphetamine prodrug NRP-104 that appears to be comparable to MAS XR for effect and duration of effect breaks down into active treatment after oral administration. As well, the modafinil film-coated tablet—an arousal system modulator (under review for approval in the US)—has a response rate that appears to range between 50 and 60%, although there may be a slight delay in full onset in patients who have previously responded to modafinil, Dr. Wilens observed.

Questions and Answers

This question-and-answer session is based on an interview with Dr. Margaret Weiss, Director of Research, Division of Child Psychiatry, Children’s and Women’s Health Centre of British Columbia, Vancouver.

Q: Once ADHD is diagnosed, how do you decide which treatment will be best for the patient?

Dr. Weiss: First-line medications for ADHD in Canada are MAS XR, MPH and atomoxetine. The guidelines do not recommend any hierarchy between the three, they only say optimal medication depends on the individual needs of the patient. If their main problem is first thing in the morning, MAS XR might have an advantage because MPH releases more medication late in the day. When their impairment is mainly in the late afternoon, MPH might be a first choice; however, if a patient is anxious, has tics and most of [parents’] problems are putting their child to bed late at night, atomoxetine may be a first-line option. So each of these medications has a slightly different profile which you can explain to patients and which allows them to participate in the choice of therapy.