The calls started coming several months ago: When will it be here? When will you have it? For some parents the wait seemed interminable. They kept the phones ringing until the release date finally arrived.
This may sound like the launch of the new Harry Potter book. It's not. But if research and clinical trials prove correct, the newly released drug Strattera, the object of the callers' questions, will help many children with attention-deficit hyperactivity disorder (ADHD) concentrate while they read that soon-to-be bestseller.
(courtesy of Eli Lilly and Co)
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"Parents called and begged to put their kids on it," says Larry B. Silver, a clinical professor of psychiatry at Georgetown University Medical Center who specializes in treating ADHD.
Why the excitement? Strattera, which hit pharmacy shelves Jan. 14, is the first new type of medication for treating ADHD that the Food and Drug Administration (FDA) has approved since 1975. Developed by Eli Lilly and Co., it is also the only non-stimulant approved to treat the disorder.
Though stimulants have proven effective for managing the disorder's symptoms, not everyone responds well to them. Some don't respond at all; others have serious side effects, such as a difficult "rebound" effect, when symptoms return in force between doses or at the end of the day during which symptoms return at a greater level. And Strattera, unlike most stimulants, is taken only once a day. These factors make it a much-welcomed option for many doctors, parents and patients.
"In medicine," says Joseph Biederman, a professor of psychiatry at Harvard, "we are always looking for alternatives."
ADHD affects an estimated 3 to 7 percent of school-age children, and it often continues into adulthood. The disorder is marked by an inability to concentrate, overly impulsive behavior and, frequently though not always, physical hyperactivity. Untreated, ADHD can wreak havoc at school, at work and in social lives. Behind the wheel of a car, the distraction that is a hallmark of the disorder can be deadly.
Fortunately, the disorder is highly treatable. Stimulants, such as Ritalin and Dexedrine, have been used to treat ADHD for half a century. These drugs are often the first line of treatment after the disorder is diagnosed, and they work for perhaps 70 percent of those who take them. But what about the others?
In some cases, stimulants have little or no effect, while in some others, the side effects outweigh the benefits. In searching for alternatives, researchers have looked at, and doctors have prescribed, a variety of other drugs. Clonidine, a blood pressure medication, has shown some effectiveness, as has the antidepressant buproprion, marketed as Wellbutrin. Of the various alternatives, an older class of antidepressants known as tricyclics held the most promise; but possible side effects included damage to the heart, making prescribing it for children unacceptable.
In the mid-1990s, while Harvard's Biederman was exploring tricyclics as a treatment for ADHD, Lilly researchers were testing Strattera (then known as tomoxetine, now called atomoxetine) as an antidepressant. But studies showed the drug to be ineffective against depression, and the company halted testing and development.
"In the normal course of events," says David Michelson, medical director of Lilly's Strattera project, "it would have died there." But staff psychiatrist John Heiligenstein speculated that atomoxetine had potential for treating ADHD. To him, the drug appeared to work in much the same way as the tricyclics but without the potentially harmful side effects. Michelson says Heiligenstein, an ADHD specialist, "worked very hard to get the company to do pilot work." (Lilly, citing a need to protect its creative process, declined to make Heiligenstein available for an interview.)
The first studies Heiligenstein conducted were done with Biederman and Thomas Spencer, an associate professor of psychiatry at Harvard, in 1996. According to Michelson, they were "done under the gun before the last lots of the drug expired. [The results] looked good, so that opened some eyes."
That study, which was conducted on adults, was published in 1998. It would take four more years and more than 4,000 child and adult test subjects to bring the drug to pharmacy shelves.
Now, How to Use It?
Spencer recalls that when results of the first test were presented to Lilly, "no one knew how to set the dose or how long it lasted or how safe it would be for kids." Researchers now know the answers to many questions regarding Strattera's efficacy and safety. (For example, Biederman says the safety data on the drug are among "the largest in pediatrics.")
But they still can't say precisely how it works. This is not surprising, given that much about ADHD itself remains a mystery. Research suggests that the symptoms of the disorder result, at least in part, from malfunctioning of the brain's neurotransmitters, or chemical messengers, including dopamine and norepinephrine.
Stimulant medications at the proper dosage appear to normalize dopamine levels. Strattera, according to Timothy Wilens, an associate professor of psychiatry at Harvard who works with Biederman and Spencer, "goes after norepinephrine." But as Lilly's own press release acknowledges, "it's not known precisely how Strattera reduces ADHD symptoms."
Treatment of ADHD is further complicated by the fact that the disorder can affect different people in different ways. For some, ADHD causes hyperactivity. For others, inattention is the primary indicator. This points to the possibility that different areas of the brain are affected in different people. This in turn could explain why certain medications work for some people but not others.
When prescribing drugs for ADHD, "we use trial and error based on probability," says Silver. Different medications at different doses are prescribed until the best drug at the best amount is found. This can take months, and success is never guaranteed.
While the researchers who studied Strattera are excited to see it become widely available, they caution that it is not a miracle drug that will replace stimulants in the treatment of ADHD. They also stress the need to find and stay with whatever medication works best.
"[Stimulants] are unequivocally highly effective," says Biederman. "It would be a terrible mistake to change treatments if [a patient] is doing well."
Current research can only suggest that Strattera and stimulants such as Ritalin are equally effective in countering the symptoms of ADHD. "The data," says Biederman, who worked on one study that compared the Strattera with Ritalin, "is not there to show definitively" how they match up.
Wilens, author of "Straight Talk about Psychiatric Medication for Kids" (Guilford Publications, 1998), has seen a nearly equal reduction in symptoms for patients taking either drug; Strattera, he notes, seems "slightly less effective than methylphenidate (Ritalin)."
Practitioners like Georgetown's Silver and Washington-based psychiatrist Nora Galil currently prescribe Strattera only for patients for whom stimulants are ineffective or intolerable.
Within a week of the new drug's release, Galil, who assisted in the study of Strattera, was writing two to three prescriptions a day for the new drug, mostly for patients who had tried stimulants. She is cautiously optimistic about Strattera's becoming a first-line treatment for ADHD.
Larry Sasich, a pharmacist and researcher with Public Citizen's Health Research Group, offers a warning to those who might get too enthused about Strattera. His group recommends that people wait for seven years after approval before trying any new drug "unless there is clear proof that it is more effective" for them than drugs currently available.
Laws governing the development and approval of new drugs, he explains, require that they prove to be more effective than a placebo but do not require that they be any safer or more effective than older medications -- leading, he feels, to a marketplace crowded with "endless alternatives . . . . With each new drug you use, the cost of health care goes up."
A CVS spokesman said a 30-day supply of Strattera costs $105, compared with $98 for 30 days' worth of Concerta, a once-a-day stimulant whose active ingredient is the same as Ritalin's. A month's standard dose of Ritalin costs $83 at CVS; a generic version of the drug costs half that half that. Adderall, a stimulant taken twice a day, is priced at $120, with the timed-release form of the drug costing $188.
Until there is strong evidence that Strattera is more effective than stimulants or that it works for people who don't respond well to stimulants, Sasich recommends a wait-and-see approach: "Lilly," he says, "has submitted nothing to indicate that [Strattera] is superior to other medications."
One advantage Strattera has over stimulants is that it is not a controlled substance, which means that prescriptions can be refilled over the phone. That appeals to many people; it may help patients stay on the medication. According to Wilens, studies have shown that people have stopped taking stimulant medication, which require a written prescription for each refill, due to the inconvenience. For people taking Strattera, he says, that problem is lessened "because there is an ease of use."
Like all medications prescribed for the disorder, however, Strattera comes with a laundry list of side effects. For children, these include decreased appetite, nausea, vomiting and tiredness. Adults can also experience sexual side effects, dry mouth and sleeping problems. According to Wilens, these side effects, which are similar to those of stimulants, seem to diminish with time. And, with more study, more will be learned about the long-term effectiveness of Strattera.
The immediate goal, Galil says, is to find a treatment that works, whether it is Strattera or one of the stimulants.
"I tell parents, 'You don't have much time. Your kids are developing now.' "•
Matt McMillen has written for Health about adult ADHD and about teens driving with the condition.
