Friday, September 22, 2023
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Editor's Note
More adults with ADHD seek treatment, and the variety of options for therapy is growing. Both stimulants and nonstimulants are available and have particular clinical uses, and new agents in each category are available or are in late-phase development. Controversies over the use of stimulant medication continue, however, especially in the realms of cardiovascular risk and abuse liability. To discuss these issues, Medscape's Randall F. White, MD, interviewed David W. Goodman, MD, Assistant Professor, Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, Maryland and Director, Adult Attention Deficit Disorder Center of Maryland.
Medscape: The standard of treatment for attention deficit-hyperactivity disorder (ADHD) now includes long-acting medications. Can you briefly discuss the advantages of these agents for treating children and adults with ADHD?
David W. Goodman, MD: Since ADHD is a disorder with symptoms and impairment that encompass the full day, it's necessary to have medications that effectively control symptoms throughout the day or for as long as possible. We also want to prescribe medications that are taken as infrequently as possible so that we don't ask patients who are inherently forgetful to take medications several times each day. That improves adherence to any medication therapy compared with 3 or 4 times-a-day dosing. Furthermore, by eliminating several doses during the course of the day, the ups and downs that accompany the wear-off effects of short-acting medications are eliminated. And long-acting medications are less likely to be diverted for misuse and abuse.
Medscape: Physicians who treat adults who have ADHD often use non-stimulants as well. What are the indications for those medications, and when do you find them most useful?
Dr. Goodman: Non-stimulants are effective, and atomoxetine is approved for children, adolescents, and adults. Its effect size is less than that of stimulant medications;[1] however, it still remains an effective option. In patients who have active substance abuse but whose ADHD is so severe that a physician wants to prescribe something, the clinician could choose a nonstimulant, which is not liable to abuse.
Medscape: Are any novel nonstimulants in development?
Dr. Goodman: Guanfacine extended-release (GXR) is an alpha-2 agonist, non-stimulant medication in phase III review by the US Food and Drug Administration (FDA) for treating children and adolescents.[2]
Medscape: The prodrug stimulant lisdexamfetamine is now approved for treating ADHD in adults and children. Can you describe what therapeutic niche it occupies?
Dr. Goodman: Lisdexamfetamine is approved for children, and it just received FDA approval for treatment of ADHD in adults. I see it as a primary first-line agent because it is a long-acting form of dextroamphetamine, the stimulant medication that we are familiar with. Lisdexamfetamine is unique because as a prodrug, it's therapeutically inactive until consumed by mouth and enzymatic reactions cleave off the amino acid lysine that's attached to dextroamphetamine. Its duration of action is 12 hours, and in a pediatric trial they now have a documentation of release out to 13 hours, which would make it the longest documented stimulant on the market.
It's also the only stimulant that has the issue of likeability addressed in its package insert. Trials with oral dosing have shown that it's less likable compared with an equivalent dose of dextroamphetamine.
Medscape: In other words, it causes less euphoria?
Dr. Goodman: Exactly. It causes less euphoria. Likeability is a concept that indicates whether a drug has potential for abuse. In trials with lisdexamfetamine and equivalent doses of dextroamphetamine, stimulant-addicted people rated dextroamphetamine as more likable than lisdexamfetamine.[3] Part of the reason for this is that after ingestion of ordinary dextroamphetamine, the blood concentration rises rapidly, whereas with lisdexamfetamine, it rises slowly because of the rate-limiting hydrolysis reaction. Euphoria is associated with rapid rise of amphetamine concentration. If you administer dextroamphetamine intravenously, the likeability effect is large. If you administer lisdexamphetamine intravenously, you get very little likeability.
Medscape: Abuse liability of stimulants is of concern to many clinicians; what are other ways to manage that?
Dr. Goodman: First of all, I prescribe long-acting, once-a-day stimulants for my adult and late adolescent patients whenever possible, and I minimize the availability of short-acting agents. I keep very good records on how often, when, and how many pills I'm dispensing. That gives a sense of adherence and whether people are looking for more pills or for fewer pills. I counsel my patients that giving away their pills and especially selling their pills is illegal, and that if I find out they're doing that, it may have serious ramifications. And I take a substance-use history to investigate the proclivities of a particular patient for abusing medications.
Medscape: What proportion of adult patients has a significant likelihood of abusing stimulant medications?
Dr. Goodman: About 10%-11% of people with substance-use disorders have ADHD.[4] If you look at the ADHD population, about 10% have an active substance-use problem, 40% have a history of a substance abuse or alcohol problem, and 50% have no such history. So the questions to ask are: Do you have a history of a substance-use disorder, and if so, are you in treatment, are you in recovery, and are you stable? Or do you have an active substance-abuse problem that I need to consider before prescribing medication?
Some clinicians view drug and alcohol use as self-medication for ADHD. In that case, treating the ADHD would lead to remission of the substance use. That, however, is not supported by the research.[4]
Medscape: Another concern that clinicians often have is the cardiovascular effects of stimulants. Would you comment on that?
Dr. Goodman: In 2007, the FDA reviewed the evidence and ordered a change in package inserts to urge caution among physicians in prescribing stimulants to patients who have cardiovascular abnormalities. But how do you discern whether your patient is at cardiovascular risk? I suggest 5 symptoms to ask patients to screen for cardiac risk: spontaneous syncope, exercise-induced syncope, exercise-induced chest pain, sudden death in family members age 30 years and younger, and a family history of structural or electrical abnormalities.
In April 2008, the American Heart Association (AHA) came out with a policy statement that recommends obtaining baseline electrocardiograms (ECGs) in children who will receive stimulant medications.[5] This recommendation is not based on any new research, and it is being challenged both by the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics, both of which rendered a statement in response to the AHA guidelines because most clinicians have not been doing screening ECGs. The abnormalities that one can find are relatively limited, those being primarily hypertrophic cardiomyopathy and long QT syndrome. Other abnormalities associated with sudden death are arrhythmogenic right ventricular dysplasia, aberrant coronary arteries, and Wolf-Parkinson-White syndrome.
The AHA recommendations have given the media another opportunity to heighten concern about treatment of ADHD, and it leaves parents and the general public even more anxious about having family members on stimulant medications. It reminds me of when the FDA put suicide warnings on antidepressants, following which was a drop in the prescribing of antidepressants by pediatricians and primary care physicians.[6] In 2007, the Centers for Disease Control and Prevention reported that the adolescent suicide rate had the largest increase since 1990 [Editor's note -- based on 2004 statistics; no causal association has been confirmed between these events].[7] I'm concerned that these recommendations will present an obstacle to clinicians and incite fear in patients, and we'll be treating fewer children and adolescents for ADHD. Yet we know that children and, even more so, adults are undertreated for this condition.
Medscape: Another adverse effect for some patients is insomnia. What are the considerations in managing insomnia?
Dr. Goodman: Patients may complain of sleep difficulties, primarily initial insomnia but sometimes middle insomnia, with stimulant medications or other treatments for ADHD. However, we also recognize that sleep symptoms are inherent to ADHD, especially a delay in sleep onset in children and adults. When subjects enter a medication trial, have they been assessed for sleep symptoms before the trial? Otherwise, how can we know if sleep problems during the trial are a reflection of adverse events from medication or a baseline sleep disturbance? Some might say that by simply comparing the active treatment group with the placebo group, if the trial is randomized and has enough power, you should be able to detect a difference from baseline.
In clinical practice, sleep complaints are generally dose-related; that is, as the dose increases, sleep problems are more likely for a particular patient. If you look at the aggregate data in a large group of patients, there isn't a dose relationship between sleep side effects and dose, whether in trials with dexmethylphenidate, lisdexamfetamine, or mixed amphetamine salts.
Medscape: What does your research on the sleep effects of lisdexamfetamine show?
Dr. Goodman: In our trial, we administered the Pittsburgh Sleep Quality Index at baseline and then during the course of the trial.[8] The Pittsburgh sleep inventory has 7 components: quality, latency, duration, efficiency, disturbances, hypnotic medication use, and daytime functioning. In 6 of 7 domains and in overall sleep quality, treatment with lisdexamfetamine showed no difference compared with placebo. In daily functioning, a statistically significant improvement occurred with lisdexamfetamine compared with placebo.
Despite these findings, patients reported insomnia on the adverse events (AE) profile. What is the meaning of the AE frequency report when no qualitative change in sleep is found? That leads to the issue of side effects in general: are reports in the AE profile of real clinical concern? Yet important to note is that 9 of 400 patients discontinued the active treatment as a function of sleep-related AEs.
Medscape: Is it consistent with your clinical experience that a small number of patients will find the medication intolerable?
Dr. Goodman: Yes, but in clinical practice, you can increase the dose slowly. Patients seldom drop out of treatment because of a sleep-related problem; the clinician will modify the dose according to the patient's tolerance of the medication.
Medscape: Can you comment on any generic forms of long-acting stimulants that might be on the horizon?
Dr. Goodman: I believe that Adderall XR [mixed amphetamine salts] is losing its patent protection in the summer of 2009.
Medscape: So are we expecting that a generic form of mixed amphetamine salts will come on the market?
Dr. Goodman: Yes, that might happen mid-year in 2009.
This activity is supported by an independent educational grant from Shire.
