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 - 29th Annual Conference of the Canadian Academy of Child and Adolescent Psychiatry

Toronto, Ontario / November 12-14, 2009

Attention-deficit/hyperactivity disorder (ADHD) is typically diagnosed in children who experience significant academic difficulties and fail to learn. Yet its manifestation is not confined to the school environment. “ADHD goes way beyond an academic focus—it gets into social interactions, extracurricular activities, home life and relationships with parents and other members of the family and any other activity where attention is required such as driving,” stated Dr. Declan Quinn, Associate Professor of Psychiatry, University of Saskatchewan, Saskatoon.

When comparing functional deficits among those with ADHD vs. controls, those with ADHD are far more likely to repeat school years, drop out before grade 12, abuse substances, get into serious road and other accidents, be arrested and incarcerated or laid off from work. “Patients with ADHD also do not have a good relationship with their parents,” Dr. Quinn added, even though parents can “make or break” the life of a child with ADHD, he noted.

Management of ADHD thus must be focused on improving quality of life (QoL) across all domains by helping children learn to concentrate on the task at hand, improve their ability to learn on a day-to-day basis, sharpen their ability to problem-solve and, importantly, help them adhere to their medication.

Assessing QoL in ADHD

In treating children and adolescents with ADHD, Dr. Quinn favours the Clinical Global Impression (CGI) tool to evaluate the overall degree of ADHD impairment on a patient’s life before and after treatment. This simple evaluation tool asks the child, the parent and even the teacher to rate how much better the child is doing on treatment and typically, all arrive at the same degree of improvement without hesitation, he noted.

Dr. Quinn suggested that the 10 questions from the Swanson, Nolan and Pelham (SNAP)-IV questionnaire are phrased to assess the child’s performance and interaction in the classroom but could easily be adapted to apply to the home and extracurricular activities to judge the full extent of the treatment’s effect on the patient’s QoL. Another tool evaluating treatment effect on overall QoL is the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) component.

“The objective of ADHD treatment is to improve overall QoL for patients—to enjoy healthy relationships at home and to interact successfully with friends and peers in extracurricular groups, not just to perform adequately in school or in the workplace,” Dr. Quinn stressed.

Effect Sizes

Both the amphetamine and methylphenidate (MPH) formulations are approved for the treatment of ADHD but whether one type of stimulant offers greater symptom control over another is not clear. To that end, investigators under Dr. Stephen Glatt, Assistant Professor of Psychiatry, Neuroscience and Physiology, State University of New York-Upstate Medical University, Syracuse, conducted a meta-analysis of 23 trials involving 11 medications and 19 outcome measures of ADHD behaviours. They compared the effect sizes (treatment response vs. comparator) for both short- and long-acting MPH and amphetamine products, expressed as a standardized mean difference (SMD) between the two.

For all ADHD symptoms, the unadjusted overall SMD for studies of amphetamines was greater at 1.03 than that for studies of MPH at 0.77. The difference between the amphetamines and MPH preparations was still statistically significant after controlling for potentially confounding design features at 1.1 for amphetamines vs. 0.79. (Consider that the effect size for antidepressants is about 0.5 while the effect size for atypical antipsychotics is 0.25. The effect size of lisdexamfetamine [LDX] dimesylate is 1.2.) Consistent with the SMD analyses, the number needed to treat for ADHD total scores was smaller for the amphetamines (2) than for MPH (3).

As Dr. Glatt explained in an interview, the net effect of both drugs is to increase dopaminergic concentrations in the synapse. However, MPH is a dopamine transport blocker that inhibits dopamine reuptake into the synapse, thereby increasing dopamine levels where they are needed. The amphetamines cause the synapse to be “leaky” so dopamine leaks into the synapse where it can act on the next neuron down the line. “We are making an assumption that the sets of studies we compared were equivalent, but if it holds true that the amphetamines have a larger effect on reducing symptoms of ADHD than MPH, it suggests that amphetamines offset the faulty machinery of ADHD better than MPH,” stated Dr. Glatt.

Evaluating Treatment Delivery and Duration

North American guidelines recommend that practitioners use a long-acting stimulant as first-line therapy as these preparations extend the medication coverage and help those with ADHD better cope outside the academic setting. In Canada, the non-stimulant preparation atomoxetine is also recommended as a first-line choice.

As pointed out here at the CACAP by Dr. Frank Lopez, Director, Children’s Developmental Center, Winter Park, Florida, in 1992, there was a call for safer stimulants less likely to be misused, abused and diverted, leading to the introduction of extended-release mixed amphetamine salts (MAS XR).

Currently, there are four long-acting stimulant delivery systems (not all available in Canada): MAS XR is delivered via a beaded dual-pulse capsule system; MPH is delivered via a multi-layer release system or by an osmotic-controlled release oral system (OROS); and LDX, which is the first prodrug stimulant ever created and is delivered via Carrierwave technology.

In detailing the attributes of the various technologies, Dr. Lopez noted that the beaded delivery system—the idea of which is to mimic the effect of giving two to four doses of the medication with 4 to 6 hours in between—has a rapid onset of action and extended duration of coverage. The preparation may also be sprinkled on food, an advantage for younger children who cannot swallow pills. However, the Tmax of the beaded delivery system can be affected by certain foods and the medication is affected by pH changes in the gastric pouch. “If you have a patient who is secreting a lot of acid in the morning, you have rapid release of both the immediate-release and the long-acting preparation,” Dr. Lopez explained. Preparations delivered by a beaded pulse delivery system may also have significant interpatient variability and may require multiple daily doses, he added.

The OROS delivery system releases 22% of the medication immediately and the remainder is gradually released over 5 to 9 hours. While absorption of this preparation is not affected by food, differences in gastric transit times between and within individual patients may lead to variable bioavailability and absorption. Because the OROS capsule must also be swallowed whole, “this does present a problem for some of the smaller kids who have not learned to swallow pills,” Dr. Lopez noted.

Prodrug delivery systems have already been used for other pharmacologic agents including some antibiotics, proton pump inhibitors and antihypertensive agents. The attributes of prodrug delivery systems are multiple: the technology increases solubility and therefore availability of the medication for absorption in the gut; it renders medication more resistant to degradation or metabolism; and it allows for drugs to be targeted to the desired site of action, reducing toxicity by allowing for slow release of the medication. Most importantly, prodrugs prolong systemic availability of the drug following biological conversion to its active metabolite.

The extent of prodrug technology efficacy has been demonstrated in studies involving LDX. In a pivotal study involving children treated with the prodrug, the mean decrease in symptoms as reported by parents was 51.7% from baseline (prior to 7:30-8:00 am when the medication was taken) at 10:00 am. The same magnitude of reduction in symptoms was maintained at 2:00 pm and even at 6:00 pm, typically the hour when medication wears off. Parents still reported a 46% reduction in symptoms some 10 hours after the agent had been given. “Because this is a prodrug, LDX is not affected by pH nor by gastric transit time,” Dr. Lopez told delegates, “and the C_max and the T_max is very tight at between 4.5 and 6 hours, so the consistency and predictability of this drug is very good.”

In another analogue classroom trial comparing the prodrug against MAS XR and placebo, children on both active drugs performed equally well on math test scores up to about three hours’ post-dose, after which children treated with the prodrug outperformed those on MAS XR out to 12 hours, and significantly so between 10 and 12 hours, Dr. Lopez noted.

In another classroom analogue study that lasted 13 hours, investigators found that improvement in attention as measured by the SKAMP attention scale persisted out to 13 hours following LDX administration. Importantly, the most commonly reported adverse events (AEs) over a four-week, forced-dose titration trial included decreased appetite, abdominal pain, insomnia and irritability; yet as the dose of LDX was increased from 30 to 50 to 70 mg a day, the incidence of the same AEs gradually decreased—contrary to what might be expected, as Dr. Lopez observed, with dose uptitration (Figure 1).

“If patients with ADHD are not treated, they will tell you that they can’t succeed no matter what they do,” he remarked.

Figure 1.

Questions and Answers

The following section is based on discussions with Dr. Frank Lopez, Director, Children’s Developmental Center, Winter Park, Florida, and Dr. Ann Childress, Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada.

Q: Did you observe any cardiovascular effects with the prodrug?

Dr. Lopez: We have data that go up to over a year now and there were no issues with QTcF [the QT interval corrected for heart rate]. We saw nothing that alarmed us and nothing that raised a red flag [for] the FDA. As with all stimulant medications, there can be some variability in blood pressure but we saw the expected, not the unexpected.

Q: What do you think are the most important findings from the clinical trial program evaluating LDX?

Dr. Lopez: [First of all], the onset time is comparable to that of MAS XR but more importantly, its effect on attention is longer and the child’s attention is much more easily redirectable even after 12 hours in the classroom. Even in a 13-hour analog classroom, it is possible to redirect a child despite them being fidgety, which is in contrast to MAS XR. I also like the reproducibility of the drug’s effects within each patient, so physicians can tell patients, ‘You can expect this drug to work the same way every day’—and it will.

Q: Why is duration of coverage so important with stimulant medications?

Dr. Childress: Children have long days. School may be only six hours but they often take their medication before they leave for school, and if they don’t, I’ve had children who have been kicked off the bus because they haven’t taken their medication yet and they are disruptive. After school, there are also sports and other activities; if their parents aren’t picking them up until 6:00 pm, it’s a really long day for these children and if their medication has worn off, they are not going to get their homework done, they are going to get into trouble at home, so duration of effect makes a huge difference.