In the pipeline: non-stimulant ADHD MEDS: stimulant side effects drive development of alternative medications.
Article Type: Report
Subject: Attention-deficit hyperactivity disorder (Risk factors)
Attention-deficit hyperactivity disorder (Drug therapy)
Attention-deficit hyperactivity disorder (Research)
Antipsychotic drugs (Dosage and administration)
Author: Glazer, William M.
Pub Date: 01/01/2010
Publication: Name: Behavioral Healthcare Publisher: Vendome Group LLC Audience: Academic; Trade Format: Magazine/Journal Subject: Health; Health care industry; Psychology and mental health Copyright: COPYRIGHT 2010 Vendome Group LLC ISSN: 1931-7093
Issue: Date: Jan, 2010 Source Volume: 30 Source Issue: 1
Topic: Event Code: 310 Science & research
Product: SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 220203608
Full Text: Attention-deficit hyperactivity disorder (ADHD) has some-times devastating effects in the daily lives of the 25 million, or five percent of the U.S. population, who suffer from it. Children with ADHD are at greater risk than children without ADHD for substance abuse and delinquency. And, 65 percent of those diagnosed with childhood ADHD have symptoms as adults.

ADHD treatment requires a multi-modal approach: medication, behavior modification, lifestyle changes, and therapy. While stimulants such as methylphenidate and amphetamine are thought to be most effective in treating ADHD, concerns about sudden unexplained death, adverse psychiatric effects, addiction, and abnormal growth have driven the introduction of "non-stimulant" therapies.

Both stimulant and non-stimulant ADHD medications appear to reduce the neurotransmission of dopamine and norepinephrine. While Strattera (atomoxetine) was the first non-stimulant ADHD drug approved by the FDA, another was approved in September and more are in the pipeline. Non-stimulant medications are needed for ADHD patients who do not respond to stimulants, who are subject to insomnia, or who fail to adhere to medication schedules.

Non-stimulant options: Alpha 2 adrenergic agonists

The alpha 2 adrenergic agonists clonidine and guanfacine were developed 30 years ago to treat hypertension, but have been used off-label to treat Tourette's syndrome, developmental disorders, substance abuse, and ADHD. Animal studies of clonidine and guanfacine have led researchers to believe that they reduce arousal by reducing the activity of noradrenaline neurons in the locus ceruleus area of the brain.

Intuniv (guanfacine hydrochloride)

In September, Shire received approval for Intuniv (guanfacine hydrochloride), an oral, extended-release tablet containing the selective alpha-2A-adrenoceptor agonist guanfacine. Intuniv provides another non-stimulant alternative to amphetamines and methylphenidate that is not a controlled substance and does not have a known mechanism for abuse or dependence. The FDA's September ruling approved it for use in children and adolescents aged six to 17.

Guanfacine is already available in a short-acting formulation (Tenex) for the treatment of hypertension and has been used off-label for ADHD treatment. However, Intuniv differs from Tenex because its extended-release formulation makes adherence much easier.

Lee Cohen, MD, Assistant Professor of Clinical Psychiatry at Columbia University College of Physicians and Surgeons, sees Intuniv as "a drug for individuals who fail a stimulant, as an add-on to stimulants, or as a 'go to' drug if tics are a concern." Dr. Cohen, who acts as a consultant to Shire and other companies, thinks that Intuniv will work well for those patients who present with "aggression or hyperactivity."

Theresa Cerulli, MD, a clinical instructor at Harvard University School of Medicine and a consultant to Shire, observes that "the data for Intuniv is positive not only for behavioral problems but also for cognitive problems. Clinicians will need to attend to this benefit because they often niche guanfacine as simply a behavioral agent." Dr. Cerulli noted that the "higher doses ... might [be found] comparable in efficacy to the stimulants."

Lawrence Scahill, MSN, PhD, Professor of Nursing & Child Psychiatry at Yale University School of Nursing and Child Study Center and a pharmaceutical consultant, voiced concern about the relatively brief (six-week) duration of Intuniv studies. While he agrees with Dr. Cerulli's observation of a possible dose-response effect, he is concerned about the side effect signal that emerged when the higher doses were prescribed. "In the Shire study," he explained, "they raised the dose of Intuniv over three to four weeks and then only observed the subjects for two weeks." In his clinical and research experience, Dr. Scahill says, he has found that "sedation and sleep disturbance are factors unless doses of guanfacine are carefully titrated upward." Intuniv's dosing is based on the child's weight.

While it is unclear how any medication works to treat ADHD, Intuniv's mechanism of action differs from the stimulants as well as from Strattera. No comparative studies are yet available to differentiate the clinical effectiveness of these compounds. Studies of effectiveness in patients with comorbid depression, anxiety, or substance abuse are also needed.

Clonicel (clonidine hydorchloride)

The next addition to the ADHD treatment regime could well be Clonicel (clonidine), a long-acting version of clonidine hydrochloride. According to Addrenex Pharmaceuticals, Clonicel is in Phase III clinical trials and, reportedly, has benefit in treating ADHD symptoms, especially when combined with a stimulant medication like Ritalin (methylphenidate).

Dr. Scahill says, "Preclinical data suggest that clonidine and guanfacine may differ in their affinity for alpha-2 receptors in the prefrontal cortex, which may have yet-to-be-defined relevance to clinical outcomes." Individual variability in patient response to these two medications would be expected. Both are associated with sedation, fatigue, and somnolence. Reductions in heart rate and blood pressure also occur, but have rarely led to discontinuation of treatment across studies.

Dr. Cerulli has not had experience with Clonicel, but has prescribed clonidine off- label as an adjunctive medication for ADHD. She also uses it for sleep in patients who exhibit hyperactivity, impulsivity, or for comorbid ADHD with tic disorders. "I'm interested to see data on monotherapy with Clonicel," she says.

Dr. Scahill says that mono-therapy studies of clonidine versus placebo in ADHD have not been impressive, while Dr. Cerulli adds, "The sedation with the short-acting form of clonidine can be problematic, so I am hoping that the long-acting form will be better tolerated." Dr. Cohen believes that the once-daily formulation of clonidine will offer advantages over the earlier three-times-per-day medication.

Dr. Scahill referred to two controlled trials suggesting that monotherapy with clonidine is well tolerated in typically developing children with ADHD. "The benefits are modest and appear slightly better for children with ADHD with tic disorders than children with ADHD without a tic disorder," he adds. "Both trials showed additive benefit with the combination of clonidine and methylphenidate."

Future medications

Nicotinic medications may help in treating cognitive dysfunction associated with Alzheimer's disease, schizophrenia, and ADHD. Evidence from pharmacological, clinical, and animal studies suggests that cholinergic transmission, particularly involving neuronal nicotinic acetylcholine receptors, may play a role in the pathophysiology of ADHD.

Interest in the possible role of nicotinic cholinergic systems in ADHD has risen, in part, from observations that smoking rates are higher among adolescents and adults with ADHD than among non-ADHD populations. Harvard's Timothy Wilens, MD, is optimistic about studies aimed at developing nicotinic agonists for ADHD. He hopes that these compounds could have cognitive effects that reduce ADHD symptoms without addictive liabilities.

Another potential ADHD medication may be Abilify (aripiprazole), the partial dopamine D2 and 5-HT 1A receptor agonist and 5-HT 2A receptor antagonist labeled for treatment of schizophrenia, bipolar disorder, and depression. It is rumored that Otsuka Pharmaceuticals and Bristol--Myers Squibb may be seeking an ADHD indication for Abilify.


William M. Glazer, MD, is President of Glazer Medical Solutions ( of Key West, Fla., and Menemsha, Mass. He is a clinician, researcher, lecturer, and consultant and has been a member of faculty of the Departments of Psychiatry at the Yale and Harvard schools of medicine. Dr. Glazer has served as a consultant to Eli Lilly, Schering-Plough, and AstraZeneca. To contact him, call (305) 293-3555 or email
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