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 - Canadian Academy of Child and Adolescent Psychiatry (CACAP) & American Academy of Child and Adolescent Psychiatry (AACAP)

Toronto, Ontario / September 26-28, 2010 & New York, New York / October 26-31, 2010

Data presented during the CACAP and AACAP conferences have expanded the evidence that attention-deficit hyperactivity disorder (ADHD) can be effectively controlled in most children and adolescents. While a holistic approach is needed to address the effects of ADHD on daily life, pharmacotherapy is the cornerstone. A variety of agents with a related stimulant mechanism of action have been effective, but these drugs are not interchangeable. One of the most important differences is duration of action, but poor response to one agent does not preclude a good response to another. The critical issue in selecting either the first-line agent or a subsequent switch strategy is recognizing that improvement in overall functioning, not just school performance, must be part of the definition of a fully effective treatment program.

“It is essential for the clinician to have a thorough understanding of the current stimulant medications available, including understanding the role of the new-generation drugs,” stated Dr. Don Duncan, Clinical Director, British Columbia Interior ADHD Clinic, Kelowna, at the CACAP meeting. He indicated that the newer longer-acting therapies have greatly expanded options for symptom control. It is unclear whether one agent is more effective than another in every child with ADHD, but the agents may differ in their ability to control symptoms outside of classroom activities, and this may be important to the control of the cycle of symptoms which affect a more global set of behaviours.

Novel Agents of Extended Duration

The most important advance in the recent history of ADHD drug development has been the creation of agents with extended duration of action. It was once hypothesized that a 6-hour window of activity might be sufficient, particularly when change in classroom function was the only goal, but ADHD symptoms produce morbidity across waking hours. Families often express their greatest concern about school performance. Yet the adverse effects on relationships with peers and family and the obstacles to extracurricular activity are at least as important, as they create a sense of well-being that is critical to an overall reversal of symptoms, including those affecting school performance.

The new-generation agents have focused on longer duration of activity to provide more comprehensive control of symptoms. These have incorporated a variety of slow-release technologies to extend stimulant activity. One of the newest agents, lisdexamfetamine (LDX), is a prodrug that is active for approximately 13 hours. Relative to the slow-release technologies that are dependent on gastric transit time or pH-sensitive dissolution of the capsule, the prodrug is inactive until broken down into d-amphetamine by peptidase enzymes after the drug has already been absorbed. This avoids the potential problems of delayed-release strategies subject to interindividual differences in variables affecting pill dissolution.

Adverse Impact of Impaired Social Relationships

There is a strong rationale for predicting better outcome from a longer duration of effect relative to a shorter one in ADHD. Abundant evidence indicates that much of the adverse impact of ADHD on patient quality of life and satisfaction is derived from impaired social and family relationships that diminish self-esteem. However, there are also data to indicate that these drugs are not interchangeable. At the recent AACAP meeting in New York, a compilation of evidence from 2 studies evaluating the effect of an ADHD medication administered to those who had previously failed another demonstrated very robust rates of response with the second medication. It was the most recent in a series of studies suggesting that children with persistent symptoms on 1 drug can respond to another.

In the analysis presented at the AACAP, on which Dr. Duncan served as a senior author, 150 children aged 6 to 12 years who were not well controlled on their previous stimulant medication were started on LDX. Examinations such as the ADHD Rating Scale IV (ADHD-RS-IV), Swanson, Kotkin, Agler, M-Flynn and Pelham Deportment (SKAMP-d), Behaviour Rating Inventory of Executive Function (BRIEF) and Clinical Global Impressions-Improvement (CGI-I) assessments were administered in 1 or both studies to evaluate response. One study, with 83 patients, was open-label; the other, with 67 patients, was double-blind and placebo-controlled with a crossover design.

While the open-label study associated LDX with a clinical response in almost 90% of patients, many of whom were previous methylphenidate (MPH) failures, on multiple assessment tools, the double-blind crossover study demonstrated a difference between active therapy and placebo in assessments taken 1.5 hours and 13 hours after dosing. The observer-rated assessment included improvement in validated rating scales for deportment, attention-to-task and ability to stay on task. Parent-completed BRIEF also recorded an improvement in executive function and a reduction in behavioural impairments. Adverse events on LDX were consistent with those previously associated with stimulant therapy.

On the ADHD-RS-IV (Figure 1), the average scores at baseline in both studies were approximately 42, which correspond to moderately severe symptomatology with upper confidence intervals (CIs) extending into the severe range. At the end of each study, average scores fell into the norms for age and upper CIs did not extend past moderate symptom scores. In the placebo group of the controlled study, mean scores also fell modestly, but upper CIs included scores in the severe symptom ranges. The reduction of approximately 25 points from baseline in the ADHD-RS-IV assessment tool underscored a large treatment benefit despite failure on previous therapy. Similar findings from this study were also presented at the American Psychiatric Association meeting earlier this year by Dr. Rakesh Jain, R/D Clinical Research, Inc., Lake Jackson, Texas.

Figure 1.

The Role of Stimulants

The efficacy of stimulants in controlling ADHD has been documented since 1937, but a plausible explanation for the mechanism of action has evolved more recently with more sophisticated methods of brain imaging and tracking of neurobiological activities. In comparing ADHD patients to healthy controls, differences in the prefrontal cortex, which appears to be the single most important area of the brain responsible for mediating attention, have been observed. Although the systems are complex and remain incompletely understood, upregulation of the dopamine required to produce focused attention is believed to be irregular. Stimulant medications are known to excite pathways of dopamine and norepinephrine release to achieve a more normal neurochemical environment (Arnsten et al. CNS Drugs 2009;23(suppl 1):33-41).

“Studies of families, twins, and molecular genetics all support a genetic component for risk of ADHD,” observed neurodevelopmental psychiatrist Dr. Donna Antonucci, The Children’s Hospital of Philadelphia, Pennsylvania, at the CACAP. She emphasized that there is strong evidence that neurotransmitter abnormalities in the frontal cortex explain the pathophysiology of ADHD, which is the most common psychiatric disorder in children. In some population surveys, up to 12% of male and 6% of female children between the ages of 6 and 12 meet diagnostic criteria for ADHD. The frequency with which ADHD persists from early childhood into adolescence and adulthood is also consistent with a fundamental biological disorder.

Symptom Control During Activities of Daily Living

The evidence that ADHD is a controllable pathophysiologic process is overwhelming, but the ability of physicians to employ this fundamental premise in treatment is critical to successful therapy. While behavioural therapy is likely to have important adjunctive benefits, particularly in older children who have already experienced a loss of confidence or self-esteem from persistent symptoms, it is essential to first control ADHD pharmacologically to permit supportive care, including academic tutoring or socialization programs, to be effective. Pharmacologic therapy is not typically sufficient but it is essential.

Generally acknowledged as the first-line therapies for ADHD, all of the long-acting agents, including LDX and the long-acting formulations of MPH, atomoxetine and amphetamine, are administered once-daily. In children, once-daily therapies are considered particularly important because of the difficulties of maintaining these patients on a more frequent schedule, which includes the potential stigma from being singled out to take medicine. Yet once-daily therapies must remain active through most if not all of the child’s waking hours for optimal benefit. Parents often seek care for their children because of poor school performance or complaints from individuals who supervise their children, but more serious consequences may stem from the impact of symptoms on peer or family relationships.

“Traditionally, treatment of ADHD has tended to focus on school performance, but ADHD has a very broad impact,” reported Dr. Antonucci, who suggested that this has been an important reorientation in effective management. Children with ADHD develop their sense of identity from a full array of activities, and difficulty in extracurricular settings, making and retaining friends, and getting along with siblings all have important implications for a sense of self-worth.

Again, medication is the first step toward controlling symptoms, but providing patients and their families with a comprehensive treatment plan that includes behavioural modification may be critical. Dr. Antonucci maintained that management of ADHD “is not a question of drive-through medication dispensing.” Once the diagnosis is established, she tries to help patients and their families recognize ADHD as a treatable disorder and set up a program that establishes milestones for appropriate changes in behaviour.

“I prefer to have at least one meeting with the whole family. It helps to hear the key issues for each of the family members so that everyone is on board [for the treatment plan],” Dr. Antonucci told delegates. Once patients have been placed on a therapy that modifies the key symptoms of ADHD, the specific goals regarding performing certain tasks of interacting with others must be individualized. Often some form of objective rating system for ADHD behaviours can be helpful for patients and families to identify problems and quantify progress.

Comorbid Psychiatric Conditions: Case Study

A baseline evaluation is critical. This includes a comprehensive questionnaire that includes both physical and mental complaints. One clinical pearl offered by Dr. Duncan is to inquire about the types of side effects that have been associated with stimulant medications, such as headaches and abnormalities in appetite or sleep, before initiating therapy. “If we have a good baseline record before we start the medications, we may be able to avoid blaming some adverse effects on the medicines that are not related to the therapy,” Dr. Duncan advised.

In fact, comorbid psychiatric conditions are commonly associated with ADHD, particularly in older children. In a case presentation at CACAP, Dr. Duncan assessed the challenges of intervening effectively in a 15-year-old girl whose previously untreated ADHD was linked to a variety of comorbid conditions or complicating character traits, including mood swings, mild substance abuse and belligerence. Although these traits can be indistinguishable from normal emotional lability in a teenager, the patient met criteria for ADHD on several standardized diagnostic tests. For this patient, medication was an essential step on which to build a treatment plan that included psychoeducation for the patient and her family, as well as milestones that the patient and the family could use to monitor improvements in well-being, according to Dr. Duncan.

In this case, which is not atypical, the patient, who was started on LDX 30 mg and received an uptitration to 50 mg, experienced a series of incremental improvements, including a resolution of ADHD symptoms on objective ADHD scoring tests such as BRIEF. Although the patient did not necessarily attribute her improved relationship with family and teachers to the medication, performance in many areas improved and many of the comorbidities, including the mood swings, diminished. School work had been an initial concern, and although the child’s grades improved, the more global effects were at least as important to the family who had been struggling with an increasingly alienated child.

ADHD has a complex and insidious effect on patient well-being. Although impaired school performance is one of the most obvious manifestations, it should not be the sole focus of therapy. Children who have difficulty forming bonds with peers and family because of their symptoms can experience disaffectation that permeates their sense of self-worth with persistent and perhaps lifelong consequences. The development of long-acting therapies that provide symptom control for the majority of waking hours has been an important advance in ADHD treatment.

Summary

Stimulant medications have been effectively employed for the control of ADHD for more than 60 years, but advances in recognizing the global impact of ADHD, coupled with important progress in understanding key components of the neurobiology of this disease, have provided better tools for effective treatment. One of the most important advances has been the development of long-acting agents. This includes a variety of extended-release strategies as well as the more recent development of a prodrug formulation that circumvents inter-individual differences in metabolism and has been associated with activity over periods of up to 13 hours. By extended control of symptoms, these agents provide the framework for treatment plans in which to alter behaviour and improve a sense of well-being that can improve a broad range of outcomes, including school performance.