Quality of Life and Treatment Outcomes With Once-Daily Medications for ADHD: An Expert Interview With Joseph Biederman, MD Expert Interview:Editor’s Note – The standard of care for treating ADHD has shifted such that when a clinician prescribes a psychostimulant, the choice should be a once-daily preparation, in most cases. The number of such medications has grown markedly, and familiarity with their characteristics will help prescribers make rational choices among the options. Medscape’s Randall F. White, MD, FRCPC, discussed the advantages of and differences among the longer-acting formulations with Joseph Biederman, MD, Professor of Psychiatry, Harvard Medical School and Chief of Pediatric Psychopharmacology, Massachusetts General Hospital, Boston.
The clinician who treats patients with attention-deficit/hyperactivity disorder (ADHD) now has a variety of once-daily stimulant medications to choose from. What preparations of methylphenidate are available and what are their most salient pharmacologic characteristics?
Joseph Biederman, MD: The most salient characteristics that distinguish these formulations are the duration of effect and how they are designed to reach the brain. The prototype of the second-generation, long-acting methylphenidate agents is OROS methylphenidate (Concerta). It was specifically designed to replace 3 administrations of immediate-release methylphenidate given 4 hours apart, to cover 12 hours of the day. This approach recognizes that ADHD is a life problem and not just a school problem, and that it’s as important to manage after-school hours as school hours.
Subsequent to OROS methylphenidate, extended-release methylphenidate (Metadate CD) and long-acting methylphenidate (Ritalin LA) came to market. These medications were developed to replace 2 administrations of immediate-release methylphenidate given 4 hours apart so that children can avoid taking medication at school. Essentially they were designed to cover the school day, not the after-school day.
There is a subtle difference between the preparations. Extended-release methylphenidate is made up of 30% short-acting beads and 70% long-acting beads. It was designed with the idea that acute tachyphylaxis or tolerance occurs, and in order to have a continued effect, levels of the medication have to rise during the day. In other words, higher concentrations of medication are required in the afternoon, hence the 70% long-acting beads. The delivery of extended-release methylphenidate in many ways is similar to the delivery of OROS methylphenidate, which also has a slow, ascending curve, whereas long-acting methylphenidate has 50% short-acting beads and 50% long-acting beads. Long-acting methylphenidate emulates 2 doses of immediate-release methylphenidate given 4 hours apart, so it comes closest to the way clinicians dose immediate-release methylphenidate.
Medscape: More recently released is a preparation of once-daily dexmethylphenidate.
Dr. Biederman: Yes, dexmethylphenidate (Focalin) is a purified optic isomer of methylphenidate that is considered the molecule responsible for the medicinal effect. This medication also is available in short- and long-acting preparations. Dexmethylphenidate has a little longer duration of action, about 6 hours, than racemic methylphenidate, which works for about 4 hours. Therefore, as a long-acting preparation that releases 2 pulses, the estimated duration of effect is 10-12 hours. It and OROS methylphenidate are considered long-acting, whereas extended-release and long-acting methylphenidate are medium-acting.
Medscape: What about once-daily preparations of amphetamines?
Dr. Biederman: The one that has been formulated is extended-release mixed amphetamine salts (MAS-XR; Adderall XR), which releases 2 pulses of drug. Immediate-release MAS works for about 6 hours, so the 2 pulses in the once-daily formulation are expected to cover about 10-12 hours.
Medscape: And some nonstimulants can also be taken once a day as well.
Dr. Biederman: Yes, but the only nonstimulant approved for ADHD is atomoxetine (Strattera), a noradrenergic-specific reuptake inhibitor. It can be given once or twice a day.
Medscape: You discussed a new agent, methylphenidate transdermal system (MTS; Daytrana), at the recent APA meeting in Toronto. What do you think the therapeutic niche for this product will be?
Dr. Biederman: Transdermal methylphenidate is administered through the skin so it is not metabolized the traditional way, which is through the hepatic circulation. The MTS is designed to be applied for 9 hours and it works for about 12 hours. It’s one of the longest-acting compounds that we have today.
The most striking niche is for people who don’t want to take pills. Another niche comes from its flexible duration of effect, which is contingent on how long you keep the patch on the skin. If you remove the patch, activity continues for about 3 hours. If you have a short day and you don’t need coverage for 12 hours, you can remove it earlier. If you have a long day and you want to do homework in the evening, you can keep the patch on. It offers a more individualized duration of effect.
Medscape: What are the compelling reasons to use a long-acting psychostimulant medication instead of an immediate-release medication?
Dr. Biederman: There are many reasons. The main one is that patients are symptomatic all day long, but taking medication multiple times a day including at school and work is not convenient. Any time you ask patients to take multiple doses of any medication, compliance goes down. Once-daily preparations enhance compliance and clinical control and allow people to normalize life.
In addition to the issue of compliance, the problem of immediate-release medication is that between doses, symptoms may come back. A patient may consequently have a very uneven clinical course, such that symptoms are controlled for 2-3 hours in the morning, but later the child’s performance deteriorates in school until the second dose. Symptoms reemerge later until another dose. This kind of yo-yo effect is clinically unwise and certainly does not allow stable clinical control.
Medscape: Under what circumstance is an immediate-release medication still a worthwhile treatment?
Dr. Biederman: The immediate release medication is often used when children have problems tolerating long-acting medication. Some children have side effects that make a long-acting drug unattractive, so a clinician may use pulses of minimal exposure to reduce adverse effects. But clinicians need a very good reason not to start a patient on long-acting compounds given that we have excellent ones on the market.
Medscape: You were an investigator in a 24-month study of MAS-XR in children. What were the findings on the effectiveness of the medication?
Dr. Biederman: The main finding was that the effect was maintained for the duration of the trial, but the caveat is that it was an open-label study and many subjects dropped out. Considering how large a study it was, even with all the dropouts, we showed that the benefits were maintained and the side effects were well tolerated.
Medscape: Of 568 subjects, about half completed the trial. What led to attrition during the 24 months?
Dr. Biederman: The most common reason for people to drop out from the study was the study itself — that is, the requirement to come back for the lengthy visits the study demanded. The drug was available through community physicians, so patients didn’t really need to come back to obtain the prescription from us. That was the most common reason for dropping out, not side effects.
Medscape: Among the patients who discontinued because of side effects, the most frequently cited causes were weight loss and anorexia. What were the overall findings regarding growth over the course of 24 months of treatment?
Dr. Biederman: They were not dramatic. The statistics on growth showed that, in this young sample, the height and weight loss were very modest, with evidence of compensation over time.
In a naturalistic study published some years ago, we noticed that boys with ADHD who were not treated with stimulants tended to have a delay in the tempo of growth as they went into adolescence. This suggests that a slowing of growth may occur when patients are taking medication, but it may be independent of the medication and eventually will go away. We see very little evidence that final height is compromised.
Height and weight are very measurable outcomes, and if at any point clinicians are concerned, they can consult a primary-care physician or an endocrinologist to evaluate whether a child’s development is compromised. In medicine, we always weigh risks and benefits. All medications are associated with some risk; risk occurs when you cross the street and when you drive. The benefits of treating ADHD are much larger than the risks.
Medscape: The actions of the US Food and Drug Administration (FDA) have made clinicians and parents concerned about the cardiovascular effects of stimulants. What is known about these effects with extended-release formulations?
Dr. Biederman: The extended-release preparations, like the short-acting medications, have a remarkable record of safety. In healthy people, those without any history of cardiac disease, an enormous amount of data indicate that they produce very small changes in blood pressure and pulse but no effects on the electrocardiogram. In healthy people, they are considered extremely safe.
As for reported cases of sudden death, it appears that the rate associated with these drugs does not exceed the rate expected in the population. The FDA required a black-box warning for MAS that urges clinicians to be careful in patients with known structural cardiac anomalies. The FDA has not pursued the black box warning for cardiovascular effects of methylphenidate compounds.
Medscape: How much data are available on treating adults with ADHD with long-acting psychostimulants?
Dr. Biederman: There is an emerging literature. We now have 2 stimulants that are approved for adults, dexmethylphenidate-XR and MAS-XR. We have conducted adult trials with methylphenidate, including immediate-release methylphenidate at high doses given 3 times a day, and with MAS-XR. Even though these trials do not involve millions of people, the cardiovascular data in this study showed what I said before: small changes in blood pressure and heart rate that were not related to dose and not associated with worrisome concerns.
Medscape: Where would readers find the dexmethylphenidate study?
Dr. Biederman: It has not been published, but it was submitted to the FDA and was the basis for the approval of dexmethylphenidate XR for adults with ADHD. I’m sure it will be published.
Medscape: The concern about stimulant diversion for illicit use sometimes makes psychiatrists more likely to use a nonstimulant for patients with a history of substance use disorder. Can you comment on the abuse liability of long-acting medications?
Dr. Biederman: There are 2 publics. In the public for whom we want to prescribe medication therapeutically, our struggle is to persuade them to take it. Most patients don’t want to take medication, and among people for whom it is prescribed, after 1 year the majority are no longer taking it.
The public that uses these medications to get high is different. They are not interested in the benefit, and they use this type of medication the same way they use cocaine or other illicit drugs. Addicts are not interested in oral administration; the cocaine addict snorts cocaine, injects it, or smokes it. The reason is that euphoria is achieved only if medication reaches the brain very sharply. People who abuse stimulants are interested in immediate-release preparations because they can crush and snort them. They cannot crush OROS methylphenidate or snort the beads of MAS-XR or dexmethylphenidate-XR. The new generation of drugs is safer and less likely to be diverted.
The second comment I want to make is that, on college campuses, students use the stimulants to study, not to get high. I don’t condone the custom, but I would make a distinction between using psychostimulants to study or cram for exams. Some people may have bona fide problems concentrating but are unable to secure medication from their physicians, so they improperly acquire them. The actual rate of diversion to get high represents a minority of the diversion. It turns out that the people who divert are using short-acting immediate-release preparations and often have conduct disorder. These are not your garden-variety children with ADHD.
Medscape: In counseling a patient who might be considering once-daily stimulant therapy, which could be relatively expensive compared with immediate-release medication, what benefits do you mention in terms of quality of life?
Dr. Biederman: The treatment may allow the patient to remain in therapy, to not forget to take the next dose, and to avoid the embarrassment of taking medication at school. Avoiding the ups and downs that I mentioned before provides superior clinical control. The patient can benefit for 6-12 hours, depending on what compound is used, and have peace of mind from knowing that the condition is well controlled.
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Medscape Psychiatry & Mental Health. 2006;11(1) ©2006 Medscape
Supported by an independent educational grant from McNeil Consumer and Specialty Pharmaceuticals.
Joseph Biederman, MD, Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts; Chief, Clinical and Research Programs in Pediatric Psychopharmacology, Massachusetts General Hospital, Boston, Massachusetts
Disclosure: Randall F. White, MD, FRCPC, has disclosed that he owns stock, stock options, or bonds in Roche Holdings AG, GlaxoSmithKline PLC, Novartis AG, Merck KGAA, sanofi-aventis, and Novo Nordisk.
Disclosure: Joseph Biederman, MD, has disclosed that he has received research support from Shire, Eli Lilly, Pfizer, McNeil, Abbott, Bristol-Myers Squibb, New River Pharmaceuticals, Cephalon, Janssen, Neurosearch, Stanley Medical Institute, Novartis, Lilly Foundation, Prechter Foundation, NIMH, NICHD, and NIDA. Dr. Biederman has also disclosed that he serves on the advisory board for Eli Lilly, Shire, McNeil, Janssen, Novartis, and Cephalon, and is on the speakers’ bureau for Shire, Lilly, McNeil, Cephalon, Novartis, and UCB Pharma, Inc.