Attention deficit hyperactivity disorder (ADHD) has become crowded with companies stepping forward with products to take on Novartis AG's Ritalin and Ritalin SR (sustained release) methylphenidates. With a fresh FDA approval in hand, Alza Corp. is set to launch its Concerta extended release methlyphenidate, adding to the other approved generic methylphenidates and amphetamine-based treatments. On their heels are five companies that have filed NDAs for ADHD compounds or have products in Phase II or Phase III trials.

At the same time, recent reports in the August issue of the Journal of the American Academy of Child and Adolescent Psychiatry, have suggested that ADHD is over-diagnosed and over-treated in the U.S., while Europeans scoff that ADHD is an imaginary disease known only in America.

The debate over the rate of ADHD diagnosed in the U.S., and the absence of treatment in Europe, thus may provide mixed messages about the market opportunity. But physicians and psychiatrists who spoke to BioCentury generally believe that ADHD has been under-prescribed and blame misdiagnosis for inappropriate treatments with drugs for ADHD.

Defining ADHD

The clinical definition of ADHD is a neurobiological disorder with primary symptoms of hyperactivity, impulsivity, and the inability to maintain concentration. Patients must experience two or more of these symptoms in multiple settings, for example at home and at school. To be diagnosed with ADHD, a patient must display the symptoms for at least six months and not have related disorders, which could be contributory or a direct cause of the symptoms. The precise cause of the condition is unknown, although it is believed to be related to the rapid metabolism of dopamine and to a lesser extent norepinephrine, both of which are synaptic neurotransmitters.

The bulk of the products on the market, which include Ritalin from Novartis (SWX:NOVN, Basel, Switzerland), Methylin from Mallinckrodt Inc. (MKG, St. Louis, Mo.), and Concerta from Alza (AZA, Mountain View, Calif.), are based on methylphenidate. The mechanism of action of methylphenidate also is not fully understood, but it is believed to increase the output of both dopamine and norepinephrine.

The other marketed products are from Shire Pharmaceuticals Group plc (LSE:SHP; SHPGY, Andover, U.K.). Its Adderall is mixed salts of amphetamine while DextroStat is a single salt of amphetamine. Amphetamine is an adrenergic receptor agonist.

Other drugs besides stimulants are used to treat ADHD, including GlaxoWellcome's Wellbutrin (bupropion), a weak blocker of the neuronal uptake of norepinephrine that also inhibits to some extent the neuronal reuptake of dopamine. But they have drawbacks, such as a long onset of action and concerns about safety - bupropion lowers the seizure threshold in a dose-related fashion.