I have just returned from a three day conference given by Lilly (the maker of Strattera) to doctors that they hope will lecture on their behalf. I have not yet decided on that but these are my initial opinions based on what I heard and what I think. Naturally I reserve the right to change my opinions as my own experience with this new drug widens and more data accumulates.

On the matter of the conference givers:

This is an interesting issue because the conference was given by the company making strattera so it is plausible to assume that they will present their medication in the best light possible. That being said, however, I think that a few things have to be understood. The conference was attended by around 250 doctors all of whom where specialists or in some way deeply involved in the use of medications to treat ADHD. Everyone that I met there was genuinely interested in learning about the medications. Certainly we were wined and dined but this was serious business. No one there was going to go home and prescribethis medication just because lunch was terrific.

About the conference:

There are a number of things that struck me as being different about this type of a drug rollout.

It is impossible to not be impressed with the enormity of the marketing campaign. It made a lot of us at the conference very uneasy. On the other hand I can honestly say that the company seems so convinced of the fact that this drug is the best thing since sliced bread that they appeared to be very open to the most difficult questions the doctors could ask. They stated what they thought were the good points about the Strattera and admitted when they did not know about something and when some things about the medication were not perfect.

I will add to this as I get more experience with it and as the new studies are completed and I will report it here:

My opinions on the drug up to this point are the following.

This medicine has been comparatively well studied: It has been tested on about 5000 patients and the studies are ongoing. This is a lot of patients for this type of a drug. It is clear that this company has really done its homework on this drug. I was very impressed with this.

It is safe: The data that they presented is compelling. There are very few side affects and the main ones are not very toxic and consist of things like nausea and stomach ache and went away with discontinuation of the medication. Also it appears that it is almost impossible to overdose accidentally. While it looks safe one has to remember that it is still new.

It is a medication meant to treat ADHD holistically. By that I mean that it is meant for the patients that have needs around the clock such as evenings which impacts on the entire family, as well as, the mornings when lots of people need help with getting organized. This is very good thing for many patients but the patients that may need to take Ritalin like drugs only occasionally(such as for exams or to do homework occasionally) are probably not the right patients for this drug.

It appears to work for attention and hyperactivity.

It probably has some antidepressant activity, though the company does not openly proclaim this.

Sexual dysfunction is apparently better that the SSRI'S (Prozac, paxil etc.)

Bipolar safety:This drug appears to be safe in bipolar people: it does not cause mania. This is always a big issue for me because sometimes it is hard separate a bipolar from ADHD.

It works relatively fast: The company said that you need to give it a few weeks but privately many of the doctors who treated large number of patients said they felt it worked in just a few days. Personally I think the mechanism of action is similar to the SSRI's and while the companies that make Prozac, paxil Zoloft etc. say that those drugs often take weeks to work, it has been obvious to me and other doctors that they work in a matter of hours. Only time will tell if that is true with strattera.

It is hard not to be impressed by the stories told by some of the investigators (doctors) about the miraculous affects this medicine had on many of their patients.

CEO Rises Above Severe Dyslexia from USA TODAY -- by Del Jones

Don Winkler, 52, has what the experts call "deep" dyslexia, more severe than the mild or surface varieties. More than 60 percent of prison inmates have learning disabilities. "Dyslexia is a disease," Winkler says, and he figures most adults afflicted this badly are behind bars or living with their parents, dysfunctional products of being dismissed as slow or retarded since first-grade reading class.

Winkler, driven to success by the daggers of his childhood and the desire to prove to dyslexic children that they can succeed, heads a 19,000-employee company that makes more auto loans than GMAC or any other.

The price he pays is a 3 a.m. alarm each morning, a head start on a world that thinks so differently. Winkler's day begins with 20 minutes of mental "warm-ups" that could be mistaken for first-grade homework.

He tunes his focus by staring at squares on his computer screen, zooming in and out, changing the background back and forth from white to black. He stares at the letters "C" and "F," clicking his mouse to flip them sideways and upside down. He excelled in calculus in school, but one of the math problems he does at 4 a.m. is 4 + 1 = 5. He studies a long list of "trigger" words, such as "get" or "it" that he stumbles on because he can't visualize them like he can more difficult words such as elephant.

Winkler has a reputation for making great speeches, but he can't make a simple one without exhaustive practice. E-mails arrive written entirely in uppercase because he reads block letters more easily. Without speed dial he would constantly be calling the wrong number. Contractions are roadblocks to his mind, so "can't" will be the last one that appears in this story.

Tears well in Winkler's eyes aboard a corporate jet as he recalls being 7 and unable to spell the word "red" in front of big brother Dickie's friends. He says he still hears snickering in the sanctuary of the First Presbyterian Church in Phillipsburg, N.J., when he sang "praise dog from whom all blessings flow" instead of "praise God."

The memories, 45 years old, will keep him awake tonight, he says.

About 25 million Americans have dyslexia. Albert Einstein and Winston Churchill were among the D-students whose minds would stumble on the letters "b" and "d," and silent vowels.

Many dyslexics, including Tom Cruise and Whoopi Goldberg, gravitate to the arts. But a new era of intellectual property in business is unearthing creativity from the dyslexic minds of CEOs Craig McCaw, Charles Schwab and Cisco Systems' John Chambers.

Though they have never met, Chambers shares a bond with Winkler. "I tried to read in third grade and everybody laughed," Chambers says. Like Winkler, he wants "to let people know they are in charge of their own destiny."

Strategies For Focusing

It is 4 a.m. when Winkler arrives at his Dearborn, Mich., office. There is a video camera mounted in front of his desk, the kind other executives use for teleconferencing. For Winkler it is a tool to keep his mind from racing in a thousand directions. When talking on the phone he projects a live video of himself on a big-screen TV and looks himself squarely in the eye.

Eye contact is crucial to focus, he explains, even when face to face. Later on he demands "a little eye contact here" at a breakfast meeting over a mushroom omelet with Ford Credit North America President Greg Smith when Smith loiters over his notes.

An innocent consequence of lost focus is the monologues Winkler habitually launches into, think-alouds that are laden with insight about everything except the subject at hand. "Quite a walk down the garden path," says communications Vice President Walter Jennings, who says it is acceptable to interrupt the boss and steer him back on course.

A less innocent consequence is what Winkler calls his debilitating slides into "the world of insecurity, or worse, the world of anxiety."

When he is at the top of his game, Winkler is the ultimate CEO-coach who wins healthy productivity from the troops, says Ken Clark, Winkler's chief of staff. Beth Acton, Ford Credit's chief financial officer, says she has received more useful advice from Winkler in the eight months he has been on the job than she has had in 17 years at Ford.

But when Winkler slides, and everyone around him has seen it, he loses confidence and "rants and yells" in anger like the definitive insecure boss, Clark says.

"If you do not keep the discipline, you tend to go off into other worlds," Winkler says.

The best way to handle Winkler, Clark says, is to let him blow off steam. "Then I ask for some coaching" on what seems to have angered him because, above all, Winkler sees himself as a teacher, Clark says.

Winkler requires a lot of attention from his troops. At a recent board meeting, Acton says she was concentrating on her part of a presentation and failed Winkler by not providing enough eye contact and nods of support as he spoke.

"He became very nervous and talked way too fast to be clear," Acton says. "He needed feedback from me."

Ford Credit officers say Winkler often does not "get it" until they go reluctantly to an easel to draw pictures so that, for example, Winkler can visualize what Ford customers experience when their leases expire. MBA types are usually linear thinkers and have not so much as doodled since grade school. But they say a few crude stick figures can switch light bulbs on in Winkler's brain, and he then takes their ideas to depths and angles never considered, a process he calls "upgrading."

"Don's brain has created a compensatory pathway," says Sam Marks, an organizational psychologist and longtime friend. "He has changed his brain."

Help From Technology

A drive from Winkler's office to his 4,000-square-foot condominium is short. "2.7 minutes," he says, long enough for a quick story about how he met his second wife, Deborah. "I dated her 18 times over 18 weeks before we kissed for the first time."

"I had to ask," Deborah says.

"I had never dated before," Winkler says. He fell in love with his first wife, Carol, at 13. "She was my best friend, my high school sweetheart," but the marriage collapsed under the weight of Winkler's high maintenance. Carol was a straight-A student who gave up college and career ambitions to put Winkler through Northrop University, raise two children and be his one-woman support system. She proofread every report and letter he wrote on his way up.

Winkler says he remains close friends with his first wife and is determined not to lean on Deborah the same way. Technology is his nanny, and he owns the latest in gadgetry, from the most expensive PalmPilot to a Quicktionary reading pen that scans written words, defines them in writing and speaks the pronunciation into an earpiece. His house is littered with recording devices into which he dictates ideas.

"He will give you 100 ideas. Your job is to pick out the best three or go crazy trying to do all 100," says Barrett Burns, Ford Credit's executive vice president of global risk management, who worked with Winkler at Banc One Credit and Citibank.

Winkler joined Ford Credit in October, recruited by Ford CEO Jacques Nasser. Winkler replaced Phillipe Paillart, who was forced out after 13 months. Paillart became caught up in the transitional crossfire when Nasser replaced former CEO Alex Trotman, Winkler says.

"Don is enormously creative and has that rare ability to mobilize people to come up with new ideas that generate results," Nasser says. "In just eight months, Don has engineered new initiatives that have increased our customer satisfaction as well as our revenues."

Organizing Daily Life

Aboard a hotel treadmill at 5 a.m., Winkler says his pre-dawn regimen fills him with confidence, and "as the day goes on, I get more stable, more powerful." Waking at 3 a.m. means he must get to sleep by 9 p.m., and he makes an art of disappearing at dinner functions.

Winkler charts everything. He inputs into a computer program today's breakfast: skim milk, coffee, raisins, a half cup each of Cheerios and Special K. He inputs his body temperature, cholesterol level, hours of TV. Today he judges his mood, self-esteem, anxiety level, even his sex drive to be all above average.

"They call it anal-retentive," Winkler says, but it allows him to see his life visually and plot graphs to see if, say, what he eats might be influencing his focus.

His daily calendar is mapped out three weeks in advance by Clark, and the first block of time -- 3 a.m. to 5 a.m. -- is always set aside for thinking about a single business challenge. Never two things. "It is always one," Clark says.

One day recently between 3 a.m. and 5 a.m. he thought about his first face-to-face meeting in eight days with Chambers, the dyslexic CEO of Cisco Systems. Winkler will plan 3 a.m. thinking sessions as much as a year in advance when he considers it important, and he hopes to get Chambers and Schwab together in January for a dyslexic "summit to help kids."

Winkler is a casual dresser, and acquaintances tell him he looks like actor Jackie Gleason. He blames the resemblance on his weight. It has ballooned from 185 pounds to 250 since he got married and gave up running five years ago.

Winkler's two grown children are both dyslexics. Winkler himself never knew he had dyslexia, had never even heard the word, until he was a 19-year-old electrical engineering student studying twice as hard as his classmates to keep from flunking out. Today he has his own Web site (www.cyberwink.com) largely dedicated to helping dyslexic children.

His boyhood friends remember him for his perseverance and creativity, sometimes suggesting trick plays to the high school football coach, says Joe Lissi, now a special education teacher.

Winkler had his electrician's license at 16, and Phillipsburg parents started pointing to the slow learner as someone whose future was secure because he would always make a good living. Winkler could fix anything and admits to tapping 200 phones about town. His favorite eavesdropping target was the quarterback and his girlfriends, Lissi says.

He grew up with four brothers, all at least 10 years older, in an apartment above the family-run Dick's Store in Phillipsburg.

Winkler says he is unable to read a list of names at a graduation ceremony. Yet, using pictures for notes and reading from a TelePrompTer marked with backslashes for \\\emphasis\\\, underscores to alert him to trigger words and punctuation like ''!!!'' and ''???'' at the beginning of sentences, he often emotionally moves audiences.

In his days as a banking executive, he says he transferred more than $300 billion a day on the job, yet has no recollection of his dyslexia ever causing him to make a costly mistake.

Really?

He promises to think about it. The next morning at 5 a.m. he confesses that "those ballistic missiles I launched" had slipped his unconventional mind.

School Nurses Struggle to Keep Up with Students' Meds

from Reuters Health -- by Suzanne Rostler

Nearly half of all school nurses make mistakes when administrating medication to children, results of a survey suggest.

The most common error was missing a dose, but other mistakes included giving a double dose, giving students the wrong medication and administering medication without authorization, according to a report published in the November issue of the Journal of School Health.

An increase in the number of children who rely on prescription medication has caused nurses to delegate some of their responsibilities to unlicensed assistants, most often the nearest secretary. This trend might have contributed to mistakes.

"Part of the reason more children in schools are taking medication is the improved care and survival of children with significant health problems and the inclusion of these children in the schools," lead study author Dr. Ann Marie McCarthy, of the University of Iowa in Iowa City, told Reuters Health.

"I think the major implication of having children in the schools who require medications during the day is the need for more nurses in the schools," she added.

The survey found that just over 24% of nurses dispensed all of the medications in their schools while more than 75% rely on assistants such as secretaries, health aides, teachers and other students. Errors were more than three times more likely to occur with the use of assistants, the survey found.

According to the study, the National Association of School Nurses recommends that one licensed nurse oversee every 750 school children. But in the US, one nurse is responsible for anywhere from 1,300 to 1,400 children.

The results are based on information from 649 registered nurses who work in schools. More than 5% of children receive medication in school, with about 3% receiving medication for attention-deficit/hyperactivity disorder (ADHD).

"It is essential that the current practice of school nurses be clarified to develop realistic guidelines to ensure the safe use of medications in schools," the authors conclude.

An estimated 10% to 15% of children have a chronic health condition with 1% having a serious health condition such as AIDS (news - web sites) or cancer. (Journal of School Health 2000;70:371-376.)

"Once-Daily Strattera (Atomoxetine) Effective in Children with Attention Deficit Hyperactivity Disorder"

By Paula Moyer Special to DG News SAN FRANCISCO, CA -- October 25, 2002 -- A new once-daily formulation of atomoxetine (Strattera), an investigative agent, appears to be a safe and effective for treatment of attention-deficit/hyperactivity disorder (ADHD). Dr. David Michelson, medical director of Lilly Research Laboratories in Indianapolis, Indiana, United States, and colleagues presented their data here October 24 at the 49th annual meeting of the American Academy of Child and Adolescent Psychiatry (ACAAP). "The once-daily formulation appears to be as effective as twice-daily atomoxetine treatment," said Dr. Michelson. "Treatment effects were seen into the evening, with dosing in the morning." Noting the universal popularity of once-daily dosing of treatments for a variety of conditions, Dr. Michelson and his colleagues conducted a randomised, double-blind, placebo-controlled study to assess the efficacy of this formulation of atomoxetine in children and adolescents, six to 16 years (average approximately 10 years), diagnosed with ADHD. The investigators randomised 85 children to treatment with once-daily atomoxetine and 86 to placebo. To evaluate response to treatment, they used the investigator-rated ADHD Rating Scale (ADHD-RS), the Conners' Parent Rating Scale-Revised (CPRS-R) and the Conners' Teacher Rating Scale-Revised (CTRS-R), as well as parent-rated diaries and Clinical Global Impressions of Severity (CGIS). Subjects in the atomoxetine arm had significantly superior outcomes to those in the placebo arm (p<0.001 for ADHD-RS). Treatment effect size (0.71) was similar to those observed in previous atomoxetine studies in which the twice-daily formulation was used. The parent diaries suggested that atomoxetine-specific effects were seen late in the day after a morning dosing. In both groups less than three percent of subjects discontinued due to adverse events. Dr. Michelson said his team observed no serious safety concerns. "These findings add to our knowledge about atomoxetine as an effective treatment for ADHD," he said. "We are continuing to study this medication." Atomoxetine differs from other ADHD medications because it is a norepinephrine reuptake inhibitor, rather than a stimulant. The study was funded by Eli Lilly, which received an approvable letter from the U.S. Food and Drug Administration for Strattera (atomoxetine) in April 2002.

FDA Approves Adderall XR (Amphetamine Product) For Once-Daily Treatment Of Attention Deficit/Hyperactivity Disorder URL: http://www.pslgroup.com/dg/2088CA.htm Doctor's Guide October 12, 2001

FLORENCE, KY -- October 12, 2001 -- Shire Pharmaceuticals Group plc announced today that the U.S. Food and Drug Administration approved Adderall XR™ (mixed salts of a single-entity amphetamine product) for the treatment of attention deficit/hyperactivity disorder (ADHD). Adderall XR, a novel, extended-release formulation of Shire's well tolerated and effective ADHD treatment Adderall®(1)(2)(3), is designed to provide symptom control in the morning and throughout the day with just one morning dose -- an increasingly important benefit for children with ADHD and their caregivers.

The DSM-IV, the leading diagnostic manual for psychiatrists, underscores the pervasive nature of ADHD, defining it as a disorder that occurs in multiple settings throughout the course of a day.

"Once-a-day medications, such as Adderall XR, are an important new option for parents and patients, and represent the future of ADHD therapy," said Dr. Joseph Biederman, Professor of Psychiatry at Harvard Medical School, who led a study of Adderall XR. "ADHD is an all-day disorder, affecting children as they study, play, and participate in sports and other extracurricular activities. Adderall XR provides the long-acting treatment children with ADHD need, helping them achieve their full potential inside and outside the classroom."

The FDA based its approval of Adderall XR on results of two studies representing classroom and naturalistic/home settings that found that the medication dramatically helps reduce hyperactivity and impulsivity in children with ADHD, and improves their ability to work, focus, and learn. The American Academy of Pediatrics treatment guidelines, released in early October, confirm that ADHD is a persistent and chronic disorder that often is best treated to maximize function across multiple domains, including schoolwork, home work, social stigma and peer-to-peer interaction. Studies show the effects of Adderall XR last throughout the afternoon, a time when many children participate in after-school activities or do homework, and thus need a long- acting treatment.

Most other ADHD medications must be taken during the school day, or immediately after school, making school personnel or the child responsible for the midday dose. But many schools lack school nurses, which often puts the responsibility of dispensing medication on people with no medical background, such as school secretaries, parent aides, and teachers.

"Avoiding having to take medication in school is an important benefit, as it eases the burden on school nurses who have a variety of responsibilities, including tending to sick students and conducting health education programs in the classroom," said Dr. Judith Vessey, Professor of Nursing at Boston College and research consultant to the National Association of School Nurses. "Once- daily dosing with long-acting medications does not just benefit the child, but also the people who support the child in his or her treatment."

"By eliminating the need for children to bring their medication to school, the convenient dosing regimen of Adderall XR decreases social stigma issues, as well as the risk of medication misuse," added Dr. Biederman.

The benefits of Adderall XR have been demonstrated in two well-controlled trials with more than 600 patients at more than 50 sites.

A laboratory classroom study found that Adderall XR provides longer-lasting symptom control than original Adderall. In the study, a single morning dose of Adderall XR 30mg demonstrated statistically significant superiority in ADHD symptom control, compared with placebo, at all observed time points from 1.5 hours to 12 hours post dose. The symptom control continued after the benefit of a single dose of conventional Adderall would have expired.

In a second clinical study involving more than 500 children with ADHD, Adderall XR demonstrated statistically significant improvement in attention and behavior in children with ADHD, as measured by parents and teachers. The improvement in symptom control observed at 4 p.m. was comparable to the significant improvement observed at 10 a.m. earlier the same day.

The most commonly observed side effects in the studies were consistent with those typically seen with psychostimulant medications and included anorexia, insomnia, abdominal pain, emotional lability, and nervousness. The majority of these side effects were mild and did not escalate. In clinical studies, fewer patients given Adderall XR had an adverse event that led to discontinuation of treatment, compared with those given placebo.

"Adderall XR is a welcome new treatment option for families affected by ADHD because the symptoms of the disorder do not stop when the school day ends," said Dr. Alex Michaels, Vice President of Medical Affairs at Shire Pharmaceutical Development. "The approval of Adderall XR represents our commitment toward providing the best in ADHD treatment and support -- including working to ensure that parents are in control of their children's medication."

ADHD is considered the most commonly diagnosed psychiatric disorder among school-aged children.(4) Children with ADHD often are inattentive, impulsive, and hyperactive -- difficulties serious enough to interfere with their ability to function normally in academic or social settings. Up to 66 percent of children with ADHD will continue to show symptoms into adulthood.(5)

Although there is no "cure" for ADHD, physicians, parents, teachers, nurses, and advocates are finding ways to help people with the condition learn to adapt to their academic, social, and work settings. ADHD usually can be successfully managed with a combination of treatments, including educational approaches, psychological and behavioral therapies, and medication. A recent government-sponsored clinical trial found that therapies that include carefully monitored medication are more effective than those that do not, such as behavioral therapy alone.(6) Medication should be considered part of an overall multimodal treatment plan for ADHD. Shire supports the use of Adderall XR only after a thorough assessment and diagnosis of ADHD by a physician.

References

(1) Manos MJ, Short EJ, Findling RL. Differential Effectiveness of Methylphenidate and Adderall(R) in School-Age Youths with Attention Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 1999;38(7):1-7.

(2) Pelham WE, Aronoff HR, Midlam JK, et al. A Comparison of Ritalin and Adderall: Efficacy and Time-course in Children with Attention-deficit/Hyperactivity Disorder. Pediatrics. 1999;103:1-14.

(3) Swanson JM, Wigal S, Greenhill LL, Browne R, et al. Analog Classroom Assessment of Adderall in Children with ADHD. J Am Acad Child Adolesc Psychiatry. 1998;37:519-526.

(4) Cantwell DP. Attention Deficit Disorder: A Review of the Past 10 Years. J Am Acad Child Adolesc Psychiatry. 1996;35:978-987.

(5) Weiss G, Hechtman L, Milroy T, Perlman T. Psychiatric Status of Hyperactives as Adults: A Controlled Prospective 15-Year Follow-up of 63 Hyperactive Children. J Am Acad Child Adolesc Psychiatry. 1985;24:211-220.

(6) The MTA Cooperative Group. A 14-Month Trial of Treatment Strategies for Attention-Deficit/Hyperactivity Disorder. Arch Gen Psychiatry. 1999;56:1073-1086.

SOURCE: Shire Pharmaceuticals Group plc

Drug Name: Adderall XR

The following information is obtained from various newswires, published medical journal articles, and medical conference presentations. Company: Shire Pharmaceuticals Group, Approval Status: Approved October 2001

Treatment for: Attention deficit/hyperactivity disorder (ADHD)

General Information

Adderall XR, an extended release formulation of Shire's previously approved ADHD treatment Adderall, has been approved for treatment of ADHD in children. This once-daily capsule provides all day treatment with one morning dose, unlike most ADHD treatments that require a midday dose. This dosing regimen eliminates the social stigma issues felt by children having to bring medication to school and decreases the possibility of medication misuse.

ADHD is the most commonly diagnosed psychiatric disorder among school-aged children. Symptoms include inattentive, impulsive and hyperactive behavior that interferes with a child's ability to properly function in academic and social settings.

Clinical Results

Approval of Adderall XR is based on two clinical studies, involving more than 600 pediatric subjects at over 50 sites. Results from a laboratory classroom study showed that Adderall XR provided longer-lasting symptom control than the original Adderall. Adderall XR demonstrated statistically significant superiority in symptom control over placebo at all times observed from 1.5 to 12 hours after dosing. Symptoms included hyperactivity, impulsivity and the inability to work, focus and learn.

In a second clinical study, including more than 500 ADHD diagnosed children, a morning administration of Adderall XR was shown to provide as significant an improvement in attention and behavior at 4 p.m. as was observed at 10 a.m.

Side Effects

Adverse events associated with the use of Adderall XR may include (but are not limited to) the following:

Anorexia

Insomnia

Abdominal pain

Emotional lability

Nervousness

Mechanism of Action

Adderall XR is an amphetamine product that acts as a stimulant to the central nervous system. It is unknown through which mechanism amphetamines produce mental and behavioral effects in children.

Additional Information

For additional information on attention deficit/hyperactivity disorder, please visit ADHD.com.

Long-Term Safety Of Atomoxetine In The Treatment Of Attention Deficit Hyperactivity Disorder

By Bruce Sylvester Special to DG News

YOKOHAMA, JAPAN -- August 29, 2002 -- Long-term use of atomoxetine in pediatric attention deficit hyperactivity disorder (ADHD) is safe and well-tolerated, researchers report.

The results of an open-label extension study led by M.Y. Hill of Eli Lilly and Company, Indianapolis, Indiana, United States, were presented at the 12th World Conference of Psychiatry in Yokohama, Japan.

Researchers enrolled 325 subjects, 266 males, 59 females, aged from seven to 17 years old. Only patients from previous atomoxetine trials were allowed to enroll in this long-term study. All met DSM-IV criteria for ADHD from their previous atomoxetine trial.

The ADHD subtype profile was: hyperactive/impulsive (4 or 1.2 percent), inattentive (62 or 19.1 percent) and combined (259 or 79.7 percent)

"The subjects had no serious medical illness, comorbid psychosis or bipolar disorder, history of seizure disorder, or ongoing use of psychoactive medications other than the study drug," the authors wrote.

The mean number of days on open-label, continuation therapy was 313. One hundred and forty two subjects completed one year.

The researchers assessed tolerability and safety of long-term treatment using data on discontinuations, adverse events, ECG data, weight, height, and vital signs.

A slight increase was noted from baseline to endpoint in mean diastolic blood pressure (3.6 mm Hg) and pulse (3.9 bpm). Mean weight increased (2.6 kg) from baseline to endpoint, as did mean height (4.4 cm).

The most commonly observed adverse events (headache, rhinitis, abdominal pain, pharyngitis and vomiting) and those associated with atomoxetine therapy (decreased appetite and weight loss) decreased over time. Twelve of the subjects (3.7 percent) left the trial due to an adverse event.

"A clinically nonsignificant decrease of 4.8msec in mean Fridericia corrected QT interval from baseline-to-endpoint was observed," the investigators reported.

The authors concluded that, "Overall, atomoxetine was well tolerated in this long-term clinical trial. In contrast to acute studies, this study revealed that during long-term therapy mean weight increased. Effects on ECG parameters were consistent with increased heart rate. No evidence for a drug related QTc prolongation was observed."

The research was funded by Lilly Research Laboratories.

ABT 089 (2-methyl-3-(2-(S) pyrrolidinylmethoxy) pyridine) from Abbott Laboratories is one of the two new drugs under study. It is a potent, selective neuronal cholinergic channel modulator that has shown cognition-enhancing activity in several animal paradigms.[1] Neuronal nicotinic acetylcholine receptors are a complex superfamily of pentmeric ligand gated ion channels that are activated by acetylcholine. On the basis of its biological activity, ABT 089 is being investigated for its potential ability to act at the neuronal nicotinic receptors to exert beneficial effects in ADHD.[2]

Timothy E. Wilens, M.D., and colleagues at Massachusetts General Hospital in Boston are conducting the Phase I clinical trials, but are not at liberty to disclose information about them at this time.

It is commonly known that nicotine possesses beneficial pharmacological actions. Michael A. Schwartz, M.D., clinical professor of psychiatry at Case Western Reserve University, says the cholinergic system, seen as a problem in the old days, is now appreciated as another neuromodulating system like the norepinephrine, dopamine and serotonin systems with broad effects on attention, alertness and specific effects on memory.

"This has particularly happened since the development of the dementia drugs, the cholinesterase inhibitors," says Schwartz. "And of course people who smoke cigarettes get alert and aroused and focused from the nicotinic effect. There's a high comorbidity between nicotine addiction and ADHD."

ARICEPT

The manufacturers of Aricept (donepezil), Eisai Inc., are seeking an indication for treatment of ADHD in children and adolescents ages 7 to 16. Donepezil is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. Schwartz says it is already being used for ADHD in children off-label by some clinicians.

"People have found that drugs like Aricept can sometimes help patients with ADHD, maybe more with memory than attention, but memory is a problem in ADHD, [as it relates to] organization, executive functioning," says Schwartz. "We now know that the anticholinergic drugs diminish your memory and cause a little confusion, and the drugs that promote the cholinergic system, the cholinesterase inhibitors, have the potential for increasing attention, memory and concentration and focus," Schwartz says.

Wilens and colleagues[3] identified five case studies in the literature of adjunctive donepezil treatment of ADHD in children ages 8 to 17, all of whom demonstrated improvement.

Effexor XR (venlafaxine extended release), from Wyeth Laboratories, is in Phase III trials for treatment of depression in children ages 8 to 16.

"I used that even before they had started the testing, and that tells something because I am extremely conservative," says Elizabeth B. Weller, M.D., professor of child and adolescent psychiatry and pediatrics at the University of Pennsylvania and Children's Hospital of Philadelphia.

"To me, Effexor is like cleaned-up tricyclics," Weller adds. "They have gotten rid of most of the side effects; you don't need to get scared about cardiac arrythmias and all that stuff. It's tolerated very nicely," Weller says. "I also like it for anxiety disorder and when children have comorbid conditions. ADHD is very common in the [child] population that we treat. I find it a lot more helpful than the SSRIs because they really do not help with the attentional problems of kids who have anxiety and ADHD, or depression and ADHD."

Schwartz says Effexor differs from the SSRIs in that, in addition to being a serotonin reuptake inhibitor -- as the dose increases -- it is also a norepinephrine reuptake inhibitor.

"Many studies show that it has at least 30 percent more capability to cause remission [in adults], which is getting to wellness, than single neurotransmitter drugs," says Schwartz. "What's limited its use in depression is that it's a novel medicine. Doctors are more familiar with SSRIs. Effexor can raise blood pressure but typically only in high doses. So, it will be good to have clinical trials. And it even has some possible benefits in comorbid ADHD."

[

A.D.D. WareHouse Medication Chart to Treat Attention Deficit Disorders

DRUG	FORM	DOSING	COMMON SIDE EFFECTS	DURATION OF BEHAVIORAL EFFECTS	PROS	PRECAUTIONS
CONCERTA® Methylphenidate	Tablet 18 mg 36 mg 54 mg	Start with 18mg once per day in the morning and increase as needed.	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache.	About 12 hours	Works quickly, lasts for 12 hours. No need for second dose during school or third, after school, dosing.	Use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome.
RITALIN® Methylphenidate	Tablet 5 mg 10 mg 20 mg	Start with a morning dose of 5 mg/day and increase up to 0.3-0.7 mg/kg of body weight. 2.5-60 mg/day*	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache.	About 3-4 hours	Works quickly(within 30-60 minutes): effective in 70% of patients; good safety record.	Use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome.
RITALIN-SR® Methylphenidate	Tablet 20 mg	Start with a morning dose of 20 mg and increase up to 0.3-0.7 mg/kg of body weight. Sometimes 5 or 10 mg standard tablet added in morning for quick start. Up to 60 mg/day*	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache.	About 7 hours	Particularly useful for adolescents with ADHD to avoid noontime dose; good safety record.	Slow onset of action (1 - 2 hours); use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome.
DEXEDRINE® Dextroamphetamine	Tablet 5 mg Spansules 5 mg 10 mg 15 mg	Start with a morning dose of 5 mg and increase up to 0.3-0.7 mg/kg of body weight. Give in divided doses2-3 times per day. 2.5-40 mg/day*	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache.	About 3-5 hours (tablet) About 7-10 hours (spansule)	Works quickly (within 30-60 minutes); may avoid noontime dose in spansule form; good safety record.	Use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome.
ADDERALL® Mixed salts of a single-entity amphetamine product.	Tablet 5 mg 10 mg 20 mg 30 mg	Start with a morning dose of 2.5 mg for 3-5 year olds. For 6 years and older start with 5 mg once or twice daily.	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache.	About 3-6 hours	Works quickly (within 30-60 minutes); may last somewhat longer than other standard stimulants.	Use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome.
ADDERALL XR® Mixed salts of a single-entity amphetamine product.	Tablet 10 mg 20 mg 30 mg	Once a day dosing in morning. Start with 10 mg and increase up to 30 mg.	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache.	About 12 hours	Works quickly (within 30-60 minutes); avoid needing a noon time or afternoon dose.	Use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome.
TOFRANIL® Imipramine; Hydrochloride NORPRAMIN® Desipramine Hydrochloride	TOFRANIL® Tablets 10 mg 25 mg 50 mg NORPRAMIN® Tablets 10 mg 25 mg 50 mg 75 mg 100 mg 150 mg	Start with a dose of 25 mg in evening if weight <50 lbs. and increase 25 mg every 3-5 days as needed. Given in single or divided doses, morning and evening. 25-150 mg/day. Do not skip days.	Dry mouth, decreased appetite, headache, stomachache, dizziness, constipation, mild tachycardia,tremor	12-24 hours	Helpful for ADHD patients with comorbid depression or anxiety; lasts throughout day.	May take 2-4 weeks for clinical response; to detect preexisting cardiac conduction defect, a baseline ECG may be recommended. Discontinue gradually.
METADATE CD® Methylphenidate	Capsule 20 mg	Once a day dosing in morning. Start with 20 mg and increase up to 60 mg or more if needed.	Insomnia, decreased appetite, weight loss, headache, irritability, stomachache	About 8-10 hours	Particularly useful for adolescents and adults to avoid needing a noon time dose; good safety record.	Use cautiously in patients with marked anxiety, motor tics or with family history of Tourette syndrome
CATAPRES® Clonidine Hydrochloride	Tablets .1 mg .2 mg .3 mg Patches TTS-1 TTS-2 TTS-3	Start with a dose of.025-.05 mg/day in evening and increase by similar dose every 3-7 days as needed. Given in divided doses 3-4 times per day. 0.15-.3mg/day*. Do not skip days	Sleepiness, hypotension, headache dizziness, stomach ache, nausea, dry mouth, localized skin reactions with patch.	3-6 hours (oral form) 5 days (skin patch)	Helpful for ADHD patients with comorbid tic disorder or severe hyperactivity and/or aggression.	Sudden discontinuation could result in rebound hypertension; to avoid daytime tiredness starting dose given at bedtime and increased slowly

*Daily dose range

Treatment of ADHD usually includes medical management, behavior modification. counseling, and school or work accommodations. The medications charted above fall into three classes: stimulants (Ritalin, Dexedrine, Adderall, and Cylert), anti-depressants (Tofranil, Desipramine) and antihypertensives (Catapres). This is not a complete list as there are additional medications such as: Elavil, Wellbutrin, Effexor, Tenex, and others which have been shown to be helpful in the treatment of ADHD. Individuals respond in their own unique way to medication depending upon their physical make-up, severity of symptoms. associated conditions, and

other factors. Careful monitoring should be done by a physician in collaboration with the teacher, therapist. parents, spouse, and patient. Medications to treat ADHD and related conditions should only be prescribed by a physician. Information presented here is not intended to replace the advice of a physician. © 1997-2001 Harvey C. Parker, Ph.D.-Second Printing by Specialty Press, Inc. d/b/a A.D.D. WareHouse. All rights reserved.

ATomoxetine

Eli Lilly reported on October 26, 2000, positive results for early clinical testing of tomoxetine, a possible non-stimulant medication for ADHD. Tomoxetine is a noradrenergic compound that appears to have less cardiac effect than traditional stimulant medications like Ritalin or Adderall. (Noradrenergic means that it behaves like a stimulant in the body even though it is not an actual stimulant.) A recent study on the use of tomoxetine, which will likely be marketed as an antidepressant, in ADHD, shows promising results.

Don't expect this medication to challenge the stimulants seriously, as other existing antidepressants such as Effexor and Wellbutrin also have noradrenergic properties and have not significantly replaced the use of stimulants. Those medications have also shown to be more useful than placebo in well-controlled drug trials but, again, do not seem to be very efficacious in practice.

Expect an FDA supported indication for ADHD before placing much credence on isolated drug studies for tomoxetine.

If approved for use as an antidepressant, the medication should be available to the public by 2003 or 2004.

Atomoxetine, Eli Lilly's contribution to ADHD treatment, is the other new agent this year, although by now you've heard about it so much it can hardly seem new any longer (see the January issue of The Brown University Psychopharmacology Update). Atomoxetine is a non-stimulant, selective norepinephrine reuptake inhibitor (SNRI). The new drug application has been filed with the FDA and is under review. It could be on the market shortly. It has been shown to be very effective in four placebo-controlled studies, three in children and one in adults, said Schwartz. Weight loss is a side effect in 10 to 15 percent of patients.

"This medicine originally was a depression and anxiety medication, but the manufacturer realized norepinephrine is norepinephrine, whether it's coming from release and reuptake more rapidly with stimulants or more slowly with antidepressants," says Schwartz.

Medications Commonly Prescribed To Improve Behavior, Mood and Learning

CATEGORY	MEDICATIONS (Approved Age)	THERAPEUTIC (+) EFFECTS AND SIDE (-) EFFECTS
Psychostimulants	Ritalin® (6+) Dexedrine® (3+) Desoxyn® (3+) Adderall® (3+) Dextrostat® (3+) Cylert® (6+) (Note: Due to its potential for serious side effects affecting the liver, Cylert should not ordinarily be considered as first line drug therapy for ADHD)	(+) May reduce impulsivity, increase attentional strength, diminish motor activity, enhance certain memory functions (-) May cause tics, loss of appetite, growth delays, sleep problems, personality change; Cylert® may disrupt liver function
Tricyclic Antidepressants	Anafranil® (10+ for OCD) Effexor® (18+) Tofranil® (6+ for bedwetting) Sinequan® (12+)	(+) May reduce anxiety, depressive symptoms, aggression, overactivity, obsessive-compulsive signs (-) May cause sedation, changes in heart rhythm, gastrointestinal disturbance
Aminoketones	Wellbutrin® (18+)	(+) May reduce hyperactivity, anxiety and aggressive tendencies (-) May cause insomnia, headaches, gastrointestinal distress, seizures
Mood Stabilizing Medications	Lithium (12+) Eskalith® (12+) Depakote® (2+ for seizures) Tegretol® (Any age for seizures)	(+) May be effective in bipolar illness (Manic-depression); may also help in depression when other drugs fail (-) May cause gastrointestinal upset, tremor, weight gain, urinary symptoms, poor motor coordination
Serotonin Re-uptake Inhibitors	Prozac® (18+) Zoloft® (6+ for OCD) Paxil® (18+) Luvox® (8+ for OCD)	(+) May reduce anxiety, impulsivity, overactivity, obsessive-compulsive tendencies (-) May worsen attention deficits, cause nervousness, result in oversedation
Anti-psychotic Agents	Haldol® (3+) Mellaril® (2+) Seroquel® (18+) Zyprexa® (18+) Orap® (12+ for Tourette's- Data for age 2+ indicate similar safety profile)	(+) May help attention in low doses, reduce tics in Tourette Syndrome, lessen aggressive symptoms (-) May be overly sedative, interfere with cognition and learning, cause movement disorder (tardive dyskinesia)
Alpha-Adrenergic	Clonidine (Catapres®) Guanfacine (Tenex®) (The use of these drugs in children is off label. Safety in children has not been established)	(+) May increase frustration tolerance, reduce impulsivity, improve task oriented behaviors in children with motoric overactivity, lessen tics in Tourette Syndrome, improve sleep (-) May overly sedate, cause fall in blood pressure, induce depression or other mood disorder

Focalin

Dexmethylphenidate-Novartis/celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride.

Celgene has developed a chirally pure form of methylphenidate (Ritalin), called dexmethylphenidate [d-methylphenidate, d-methylphenidate hydrochloride, d-MPH; Focalin]. The drug has been launched in the USA and is undergoing registration in Canada for the treatment of children with attention-deficit hyperactivity disorder (ADHD). Dexmethylphenidate is the single isomer version of racemic methylphenidate (Ritalin), which contains the active d isomer of Ritalin. Dexmethylphenidate acts via the inhibition of reuptake of norepinephrine and dopamine. Research is ongoing to further clarify the mode of therapeutic action in ADHD. Dexmethylphenidate was developed with the aim of reducing drug load, adverse events and drug interactions. Dexmethylphenidate provides effective management of attention-deficit hyperactivity disorder at half the dose of Ritalin. In April 2000, worldwide rights (excluding Canada) to dexmethylphenidate were granted to Novartis. Celgene has also granted Novartis rights to all related intellectual properties and patents. Novartis will fund all remaining development and marketing expenses required for regulatory approval and commercialisation of dexmethylphenidate. Crystaal Corporation, the marketing division of Biovail Corporation International, has exclusive Canadian marketing rights for all formulations of dexmethylphenidate. Novartis launched dexmethylphenidate (Focalin) in the USA during Q1 2002. It is available as a D-shaped tablet (2.5, 5 and 10 mg doses). Novartis had planned to use the tradename Ritadex, however the FDA recommended an alternative name due to potential prescribing errors with Ritalin. The finalized tradename to be used is Focalin. In July 2001, a new drug submission was filed with Canada's Therapeutic Products Programme for dexmethylphenidate in the treatment of attention-deficit disorder and attention-deficit hyperactivity disorder. Novartis is also developing an extended-release version of chirally pure dexmethylphenidate. Dexmethylphenidate has been found to be effective and well tolerated in clinical trials, involving a total of 684 children with ADHD and in 15 healthy adult volunteers. Dexmethylphenidate is a schedule II drug.

PMID: 12455205 [PubMed - in process]

FDA Warns About ADHD Drug Strattera

By JOHN J. LUMPKIN, Associated Press WriterThu Sep 29, 8:33 PM ET

The Food and Drug Administration warned doctors Thursday about reports of suicidal thinking in some children and adolescents who are taking Strattera, a drug used to treat attention deficit hyperactivity disorder.

Manufacturer Eli Lilly & Co. announced that a black-box warning will be added to the drug's label in the United States. Such a warning is the most serious that can be added to a medication's label, and similar warnings will be added to the drug's labels in other countries. The company said a study showed instances of suicidal thinking were rare.

In a statement, the FDA said it "is advising health care providers and caregivers that children and adolescents being treated with Strattera should be closely monitored for clinical worsening, as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior, especially during the initial few months of therapy or when the dose is changed."

Eli Lilly said it provided the FDA results from Strattera clinical trials of 1,357 patients that found five youths taking the medication reported having suicidal thoughts, while none of 851 patients taking a placebo reported having any. One young person taking Strattera attempted suicide, but survived, company and FDA officials said.

There was no evidence of increased suicidal thoughts in adults taking Strattera, which also goes by the generic name atomoxetine, the Indianapolis-based company said.

"The actual risk is very low," said Dr. Thomas Laughren, head of the FDA's psychiatric drug unit. Despite the warning, he said, "FDA still views Strattera as an effective drug."

At the FDA's request, Eli Lilly will publish a guide for doctors and pharmacists to give to people who are prescribed Strattera.

The warning is the result of a larger FDA review of psychiatric drugs and their possible association with suicide, the agency said. Old drug studies are being reviewed for occurrences of suicides and suicidal thoughts. Last year, the FDA ordered warnings on all antidepressants that they "increase the risk of suicidal thinking and behavior" in children who take them.

Strattera won praise from some doctors and parents when it became available because, unlike Ritalin, it is not a stimulant, a class of drug that can be addictive. But its chemical makeup is similar to certain antidepressants.

A review of other ADHD drugs is continuing, Laughren said.

About 3.4 million patients — adults and children — have been prescribed Strattera since it became available, with Lilly officials saying about 75 percent of those taking the medication are children.

Dr. Harold Koplewisz, a professor of child and adolescent psychiatry at the New York University School of Medicine, said that 19 percent of all teenagers have suicidal thoughts, making "suicidal thoughts in adolescents part of the normal experience."

"There are 2,400 adolescents thinking about suicide for every one that commits suicide," he said in an e-mail. "We are talking about a medication that may make some children and teenagers uncomfortable, which is very different than a lethal situation like a gun in a house."

Still, he said, all children and teens taking psychiatric medication should be monitored.

Attention deficit hyperactivity disorder affects as many as 7 percent of school-aged children and 4 percent of adults in the United States.

Strattera's worldwide sales have dropped lately, falling 31 percent to $123.5 million during this year's second quarter from a year earlier.

Lilly warned doctors in December to stop using Strattera in patients with jaundice or who show signs of liver problems, and it placed a warning on the label and in prescribing information after at least two patients on the medication developed liver problems.

The company said Thursday it believes the drug is safe.

"While suicidal thinking was uncommon in patients on the medication during clinical trials, it is important for parents to be aware it can occur, and to discuss any unusual symptoms with a physician, " said Alan Breier, Lilly's chief medical officer, in a statement. "Lilly continues to view Strattera as a safe and effective treatment option, and those doing well on the medication should be able to continue their treatment with confidence."