1) ADHD Treatment, Research Advances Lead AACAP to Revise Practice Guide

Aaron Levin

Psychiatry News April 6, 2007 Volume 42, Number 7, page 2

The American Academy of Child and Adolescent Psychiatry (AACAP) has issued a new "practice parameter" for evaluating and treating attention-deficit/hyperactivity disorder (ADHD).

Based on a review of more than 5,000 papers published since 1996, the document is a "major statement by the academy on ADHD and how to treat it," said the paper's lead author, Steven Pliszka, M.D., a professor of psychiatry and chief of the Division of Child and Adolescent Psychiatry at the University of Texas Health Sciences Center in San Antonio.

"A parameter is a detailed discussion of the current state of the science," said Pliszka in an interview. "It's more specific than a guideline and addresses screening, diagnosis, the best medical and nonmedical treatments, side effects, and patient monitoring systems."

The ADHD parameter was last revised in 1997, but advances in research and clinical experience make an updated version helpful today, said James McGough, M.D., a professor of clinical psychiatry and director of the ADHD treatment program at the University of California at Los Angeles Semel Institute.

"We now have a greater understanding of the disorder, new clinical trials, new medications, and new long-term drug formulations that are changing the way we treat patients," said McGough, who was not involved in writing the AACAP document, in an interview with Psychiatric News.

Besides the new developments in treatment, the intervening years have also seen a better understanding of the underlying neurobiology and genetics of ADHD. Genetics is now believed to play an important role in the origins of the disease, said Pliszka. "There's no debate [among psychiatrists] on whether it exists or its neurological basis."

The practice parameter sets out 13 recommendations, each graded by the level of evidence available to support it. It begins by recommending that screening should be a part of every young patient's mental health assessment, since ADHD is the most common psychiatric disorder of childhood.

Evaluation, and eventually monitoring, should draw on a wide variety of information sources besides the child—parents, teachers, and other caregivers, for example. ADHD depends on a clinical diagnosis drawing upon the patient's and the family's history. Expensive neurological or psychological tests add little or no information to what the clinician learns from interviewing the patient, parents, and teachers and reviewing the "patient's medical, social, and family history," according to the guideline, unless ruling out neurological comorbidities is necessary. Neuroimaging, however, has no scientific justification regarding ADHD, said McGough.

Behavioral treatment may be indicated for milder cases or as an adjunct to medication, but the latter has proven safe in most cases. Treatment should always begin with an FDA-approved drug and proceed to off-label agents only if standard drug treatment fails or cannot be tolerated, according to the parameter.

Treatments that fall outside the medical mainstream, like dietary supplements or homeopathy, should not be considered, said McGough. "Within the ballpark of treatment, you have a lot of flexibility, but anything outside is on the fringe."

He also concurred with AACAP's recommendation to monitor drug treatment as one would do with other psychotropic medications, although side effects are uncommon. In light of concerns about cardiac side effects, physicians should ask and document information about heart problems with regard to both patients and their families, as they would when clearing a young athlete to play sports.

Patients who have a structural cardiac defect; a history of syncope, fainting while exercising, or a seizure of cardiac origin; or a family history of sudden cardiac death should be referred to a pediatric cardiologist, said McGough.

While primarily intended for child and adolescent psychiatrists, the practice parameter will also be useful for primary care physicians and general psychiatrists, who are frequently called upon to treat ADHD patients in their practices, said Pliszka.

A condensed version of the practice parameter, designed as a pocket card for clinicians, is available from AACAP.

2) Novel Drug for ADHD Wins FDA Approval

Jim Rosack

Psychiatry News April 6, 2007 Volume 42, Number 7, page 1

Shire and its newly acquired subsidiary—New River Pharmaceuticals—won final approval from the U.S. Food and Drug Administration (FDA) last month to market lisdexamfetamine (Vyvanse) for treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 12.

Shire CEO Matthew Emmens said in a press release that the new medication should start showing up on pharmacy shelves in the second quarter of 2007.

Lisdexamfetamine is a prodrug composed of the amino acid L-lysine bound to the amino group of the therapeutically active ingredient d-amphetamine. When taken orally, the therapeutic effects characteristic of amphetamine are blocked by the conjugated amino acid. However, when the prodrug is absorbed from the gastrointestinal tract, it must go through the patient's liver to undergo first-pass metabolism. During first-pass metabolism the conjugated L-lysine is removed, and the d-amphetamine regains its therapeutic potential.

In theory, as a prodrug, Vyvanse should carry less liability for diversion and abuse because of the necessity to metabolize the drug before it can become active. If someone tried to open a Vyvanse capsule and snort the powdered ingredients, for example, or tried to dissolve the powder in water and inject it, the result should be significantly reduced potential for the "high" associated with amphetamine formulations.

Shire and New River said that when the prodrug was administered orally and intravenously in two clinical human drug abuse studies, it "produced subjective responses on a scale of 'Drug Liking Effects' (DLE) that were less than d-amphetamine, at equivalent doses." The DLE scale is commonly used to measure abuse potential of a medication when given to a study population of known substance abusers.

The possibility of being able to prescribe a central nervous system stimulant medication for patients with ADHD that carried less potential for abuse, Shire said, should make the medication a sales blockbuster. The company had hoped that the U.S. Drug Enforcement Administration (DEA), which regulates controlled substances, would not list the drug as a Schedule II controlled substance (C-II), as it does with most other stimulants. Shire was hoping for a C-III or C-IV scheduling, in recognition of the theoretically reduced potential for abuse.

However, pending final approval of the medication, the FDA proposed to the DEA that lisdexamfetamine be listed as a C-II medication. In reviewing data on the drug, the DEA concurred with the FDA's recommendation and issued a proposed rule, listing lisdexamfetamine as a C-II controlled-substance medication.

According to Shire and New River, clinical trials they funded of lisdexamfetamine showed that it provided "significant efficacy compared with placebo." In phase II and III clinical trials the medication was associated with significant improvements in ADHD symptoms, compared with placebo. Efficacy was demonstrated at 30 mg per day, 50 mg per day, and 70 mg per day. In studies using a simulated school day in a classroom environment, significant benefits were associated with lisdexamfetamine compared with mixed amphetamine salts (Adderall XR). Significantly improved behavior as well as significantly improved academic performance were demonstrated in those taking lisdexamfetamine compared with study participants taking placebo.

As a stimulant medication, lisdexamfetamine will carry the same prominent label warnings regarding increased potential for cardiovascular risks and worsening or emergence of psychiatric symptoms, such as delusions or hallucinations, aggression, or agitation.

The most common side effects seen in clinical trials with children taking lisdexamfetamine were decreased appetite, difficulty falling asleep, stomachache, and irritability.

More information regarding Vyvanse, including full prescribing information, is posted at www.shireadhdtreatments.com/.

3) The global market for ADHD medications.

Scheffler RM, Hinshaw SP, Modrek S, Levine P.
Nicholas C. Petris Center on Health Care Markets and Consumer Welfare,
University of California, Berkeley, CA, USA. rscheff@berkeley.edu

Health Aff (Millwood). 2007 Mar-Apr;26(2):450-7.

Little is known about the global use and cost of medications for attention deficit hyperactivity disorder (ADHD). Global use of ADHD medications rose threefold from 1993 through 2003, whereas global spending (2.4 billion US dollars in 2003) rose ninefold, adjusting for inflation. Per capita gross domestic product (GDP) robustly predicted use across countries, but the
United States, Canada, and Australia showed significantly higher-than-predicted use. Use and spending grew in both developed and developing countries, but spending growth was concentrated in developed countries, which adopted more costly, long-acting formulations. Promoting optimal prescription and monitoring should be a priority.

4) Genes May Influence Methylphenidate-Induced Attention Improvement

Dr. Luis A. Rohde and colleagues
Archives of General Psychiatry, February, 2007.

There appears to be an association between the adrenergic alpha-2A receptor (ADRA2A) gene and methylphenidate-mediated improvement in inattentive symptoms in children and adolescents with attention-deficit/hyperactive disorder (ADHD), according to Brazilian researchers.
Several molecular genetic studies have suggested a role for the ADRA2A gene in ADHD, especially in the inattentive component. However, the effect of ADRA2A on the response to methylphenidate in humans has not been previously investigated.
To do so, the clinicians genotyped 106 children and adolescents with ADHD for the ADRA2A -1291C>G polymorphism. In total, 66 had the G allele. All study subjects were treated with short-acting methylphenidate in increasing doses until no further clinical improvement was detected or until limited side effects were observed.
According to the investigators, "A significant interaction effect between the presence of the G allele and treatment with methylphenidate over time on inattentive scores was detected during the 3 months of treatment." Such patients showed a greater reduction in inattentive symptoms.
Dr. Rohde, from Hospital de Clinicas de Porto Alegre, Rio Grande do Sul, noted that "this suggests that molecular biological mechanisms might be involved in the response to methylphenidate for attentional symptoms in ADHD patients."
"Traditionally, response to methylphenidate is associated with dopaminergic neurotransmission," Dr. Rohde added. "This study suggests that other brain neurotransmitters like noradrenalin might be involved in the response to methylphenidate."

5) Dexmethylphenidate extended-release capsules for the treatment of attention deficit hyperactivity disorder.

Kowalik S, Minami H, Silva R.
New York University School of Medicine, New York, USA.

Dexmethylphenidate is a chirally pure d-isomer of the racemic mixture of methylphenidate. The extended-release form of this compound was developed using proprietary Spheroidal Oral Drug Absorption System technology. The product is approved for the treatment of attention deficit hyperactivity disorder in individuals as young as 6 years old. It represents the first methylphenidate product approved for use in adults. The agent's delivery system is designed to provide an initial release of medication immediately after dosing, with a second release approximately 4 h later. Blood levels first peak at approximately 1.5 h, and the second peak is noted at an average of 6.5 h post-dose. Laboratory classroom studies have demonstrated clinically and statistically meaningful efficacy throughout a 12-h day. Pharmacokinetics, safety and efficacy data are reviewed.