Choose Nonstimulants With Care in ADHD


NEW YORK – Options are available for children with attention-deficit hyperactivity disorder who do not respond to treatment with stimulants or are troubled by side effects, but they must be chosen and used carefully, Laurence L. Greenhill, M.D., said at a psychopharmacology update sponsored by the American Academy of Child and Adolescent Psychiatry.

First the diagnosis should be reviewed, as many conditions that will not respond to stimulants can overlap or mimic ADHD. These include oppositional defiance disorder, anxiety problems, depression, occasionally bipolar disorder, and psychotic conditions.

“And don't forget substance abuse disorder, which is a pretty good neutralizer of some stimulant treatments,” said Dr. Greenhill, who is professor of clinical psychiatry at Columbia University, New York, and director of research for the pediatric psychopharmacology unit at the New York State Psychiatric Institute.

The preferred second-line drug is atomoxetine (Strattera), a nonstimulant, highly specific norepinephrine reuptake inhibitor. This is not a controlled substance, so it also is useful for parents who are uncomfortable giving their child a schedule II drug, he said.

As a 24-hour drug, atomoxetine significantly improves behavior and activities in both evening and early morning.

“The most important thing you can do for your patients is to start this drug slowly and give it twice a day when you are titrating it,” Dr. Greenhill said. Patients are much less likely to experience severe somnolence if the drug is titrated over a week, despite the fact that the labeling says upward titration to a full dose of 1.2 mg/kg per day can begin after 3 days on the initial dose of 0.5 mg/kg per day.

If the full dose is given rapidly, there is a good chance that a formerly disruptive ADHD child will fall asleep in class. “As much as that might be a refreshing change for a teacher who's been battling the noise, nothing gets a parent out of work faster than the school nurse calling and saying, 'We can't keep your son awake–come and get him.' That only has to happen once and the parents will stop the atomoxetine really fast, because they've never had this problem before,” Dr. Greenhill said.

Third-line treatments include the α-2 agonists and bupropion. Clonidine (Catapres) may be useful in treating very hyperactive or aggressive patients, but it may take several weeks to take effect and does not improve inattention symptoms. There also are risks of cardiovascular adverse effects, depression, and decreased glucose tolerance.

Guanfacine (Tenex) is a longer acting α-2 agonist that has a more favorable side effect profile than clonidine, but it has been studied only in open trials. Studies of this drug in primates suggest that it acts more on postsynaptic α-2 receptors in the prefrontal cortex than in the brainstem where clonidine works. This may prove helpful, but there's much more work to be done, Dr. Greenhill said.

Bupropion may be useful for comorbidities and is not a controlled substance, but the effect size of this drug appears to be limited. Adverse effects include irritability, insomnia, and tics.

The usual effective dose is about 300 mg/day, but seizures can result if the dose exceeds 450 mg/day. “So make sure the patient hasn't been prescribed Zyban, the other form of bupropion, for smoking cessation,” he said.

Dr. Greenhill disclosed that he has relationships with several manufacturers of drugs used to treat ADHD, including Eli Lilly & Co., the manufacturer of atomoxetine.

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