(Laurie Barclay, MD, May 2004)

Attention Deficit/Hyperactivity Disorder (ADHD) is now the most often diagnosed neurological and behavioral disorder in childhood, and the fastest growing psychiatric disorder in adults. Since 1990, the number of US children diagnosed with ADHD has increased from 900,000 to more than 5.5 million. Meanwhile, the use of stimulant medications for treatment has increased sevenfold, causing critics of the diagnosis to label young patients as "Generation Rx" and ADHD as "the pediatric diagnosis of the decade."

The core symptoms of attention deficit/hyperactivity disorder (ADHD) are inattention, impulsivity and hyperactivity, usually appearing by age seven and often resulting in chronic impairment.

The American Psychiatric Association recognizes three subtypes of ADHD. The inattentive subtype, formerly known as attention deficit disorder (ADD), is characterized by inability to pay attention to details, a tendency to make careless errors, difficulty with sustained attention and with following instructions, problems with organizing tasks and activities, avoidance or dislike of tasks requiring mental effort, a tendency to lose needed items, distractibility, and forgetfulness causing difficulties with daily activities.

The hyperactive-impulsive subtype has signs including fidgeting or squirming, difficulty remaining seated or staying still, excessive running or climbing, difficulty playing quietly, excessive talking, increased activity levels, and impulsive behaviors including blurting out answers, difficulty waiting, interrupting and intruding. In the combined subtype, behaviors include those from both of the other subtypes, although hyperactivity is not a prerequisite.

Diagnostic criteria for ADHD include onset before age seven, behaviors lasting for at least six months, and negative impact of behaviors in at least two settings, such as school, home, daycare, or relationships.

Estimates of the prevalence of ADHD range from 3% to 12% in school-age children and from 2% to 4% in adults, and about 15% to 20% of children have transient symptoms suggesting ADHD. Recognition of ADHD persisting into adulthood is a relatively recent phenomenon, and is is one with important implications for work performance and societal adjustment. About half to two-thirds of children diagnosed with ADHD have persistent symptoms as adults that significantly interfere with academic, vocational or social functioning. The male to female ratio is approximately 3:1 in children and 2:1 or lower in adults.

Although the cause of ADHD is unknown, genetic predisposition; smoking, alcohol or other substance use during pregnancy; premature delivery, significantly low birth weight, and exposure to lead or other toxins may play some causative role. Earlier theories that excessive sugar intake, food additives, TV viewing, or poor upbringing might cause ADHD have fallen out of favor.

Genetic factors in families with several members suffering from ADHD may involve abnormalities in dopamine and norepinephrine neurotransmission. Low dopamine signaling in patients with ADHD may be related to failure of the dopamine receptors to respond to dopamine, or to enhanced dopamine re-uptake, preventing it from binding to its receptor.

Postnatal injury to the prefrontal regions of the brain may also increase risk for ADHD. PET scanning and other neuroimaging may reveal about a 5% to 10% decrease in size and activity of select brain regions, namely the the frontal lobes and basal ganglia, in children with ADHD. Because there are no clear biological markers, however, diagnosis rests largely on history, behavioral observation, and psychiatric interview.

Nearly half of all children with ADHD also have oppositional defiant disorder, with symptoms of stubbornness, temper outbursts, and defiant acts. Other common comorbidities include depression and other mood disorders, and specific learning disabilities. Tourette’s syndrome accompanies ADHD in a very small percentage of cases.

Although there is no cure for ADHD, many treatments can help manage the symptoms, including education of adults with ADHD and caregivers of children with the disorder, cognitive-behavioral therapy, psychotherapy, social skills training, and support groups. Research suggests that the greatest symptomatic improvement is from treatment with stimulant medication combined with counseling.

Currently available stimulants which seem to be most effective in both children and adults are methylphenidate (Ritalin), dextroamphetamine (Dexedrine or Dextrostat), and pemoline (Cylert). These drugs typically reduce hyperactivity and improve attention in about 90% of individuals with ADHD, and they may also ameliorate physical incoordination and impulsivity.

Most stimulants are short-acting and must be given several times per day, although a few longer-acting preparations of methylphenidate and dextroamphetamine with amphetamine, which last up to 12 hours, are now available.

Pemoline may cause serious adverse effects on the liver and is therefore not recommended as a first-line therapy for ADHD.

Side effects of stimulants in some children may include weight loss, reduced appetite, temporary growth retardation, and problems falling asleep. Although stimulant drugs can be addictive in teenagers and adults, they are not thought to be addictive in children. However, about 80% of children needing medication for ADHD still need it as teenagers, and 50% still need it as adults.

Some tricyclic antidepressants may reduce symptoms of ADHD as well as comorbid symptoms of mood disorder and anxiety. Other therapeutic options may include antihistamines, bupropion (Wellbutrin), or clonidine, the last being especially helpful for people with both ADHD and Tourette's syndrome.

CenterWatch has identified a pipeline of 11 drugs in various phases of development for ADHD. These include stimulants in different formulations and delivery systems, and novel neurochemicals affecting various central neurotransmitter systems.

Noven Pharmaceuticals has submitted an new drug application (NDA) for MethyPatch/methylphenidate, a once-daily transdermal methylphenidate (Ritalin) system. They have received a non-approvable letter from the Food and Drug Administration (FDA), but further trials are planned.

Results were positive in a Phase III, four-week clinical trial comparing MethyPatch to placebo patch in 212 children, ages 6 to 12 years, meeting DSM-IV criteria for ADHD. Compared with placebo, MethyPatch, worn for approximately 12 hours per day, was associated with improved teacher, parent and clinician ratings of patient behavior and attention (P < 0.0001). There were no serious adverse events, but the most common adverse events were reduced appetite, insomnia, abdominal pain and headache.

D-methylphenidate, the more active d-isomer of Ritalin, is already FDA-approved, but Celgene/Novartis is now in Phase III testing of Focalin, an extended release formulation. Focalin was safe and effective in two double-blind, parallel-group, placebo-controlled trials in subjects ages six to 17 years old with a DSM-IV diagnosis of ADHD.
Adverse events included abdominal pain, fever, anorexia and nausea, and the drug is contraindicated in patients with glaucoma, motor tics, Tourette's syndrome, known hypersensitivity to the drug, or use of monoamine oxidase inhibitors.

The mechanism of action of Focalin is central nervous system stimulation by inhibiting reuptake of norepinephrine and dopamine into the presynaptic neuron and increasing the release of these monoamines into the extraneuronal space.

Cephalon has completed Phase II testing for Provigil (modafinil), a dopamine-releasing agent that increases excitatory glutamatergic transmission. This drug is the first in a new class of stimulants believed to activate the brain cortex through the sleep-wake centers. In the United Kingdom, Cephalon has received marketing approval to include the treatment of excessive sleepiness in patients with narcolepsy, obstructive sleep apnea/hypopnea syndrome and moderate to severe chronic shift work sleep disorder.

Another glutaminergic agent is CX-516 (SPD-420, Org-24292), in Phase II testing by Cortex Pharmaceuticals. This ampakine (AMPA)-receptor agonist is thought to enhance the neuronal use of glutamate. Although a double-blind, placebo-controlled study failed to meet the primary endpoint in patients with mild cognitive impairment, development is ongoing in ADHD.

NeuroSearch is in Phase II development of NS-2359, a monoamine (MAO) reuptake inhibitor. In preclinical testing, this compound appears to improve function of dopamine, noradranaline and serotonin in brain regions involved in attention, concentration and memory. In five Phase I studies in 125 healthy volunteers, NS-2359 was well tolerated, and in a study with 54 volunteers, the drug was associated with increased attention and verbal recall.

An ongoing Phase II trial at three clinical US centers is scheduled to enroll 100 adult patients with ADHD and to randomize them to 0.5 mg of NS2359 once a day or to placebo for eight weeks, with the principal aim being to evaluate efficacy in the treatment of ADHD symptoms.

ABT-089, in Phase II testing by Abbott Laboratories, is a selective neuronal cholinergic channel modulator. In adult monkeys, this central nicotinic receptor agonist appears to reduce distractibility without nicotinic-mediated side effects.

Altropane, in Phase II development by Boston Life Sciences, is a radioactive (123 I-based) SPECT imaging agent which binds to dopamine transporters in the brain to allow more accurate diagnosis of ADHD by measuring the number of these transporters. In a recent study, subjects meeting strict criteria for diagnosis of ADHD had two- to fourfold the normal number of dopamine transporters in the midbrain. Single intravenous injections of Altropane were safe and well tolerated in Phase I and II clinical trials with no serious adverse events or significant abnormalities in laboratory test results, vital signs, ECG parameters, or physical or neurologic examination findings.

Most therapeutic agents now in development for ADHD appear to address the core symptom of inattention by manipulation of neurotransmitter systems involved in vigilance. New formulations may allow longer duration of action, but adverse effects including excessive stimulation and potential dependence on these new agents still remains to be determined.

Exploiting the known reduction in dopamine transporters in ADHD as a biological marker will hopefully allow more accurate diagnosis, which should facilitate clinical therapy as well as future drug trials.