|
||||||||
|
PSYCHIATRY New Fronts in ADHD Drug WarsScience Shifts Ground as Researchers Wrestle with Controversy over Best Therapy On December 1 and 2, researchers from across the country and abroad gathered at the NIH in Bethesda, Md., to pick each other's brains about the status of drug therapy for attention deficit–hyperactivity disorder (ADHD). Convened by Steven Hyman, director of the National Institute of Mental Health, the research workshop asked invited scientists to address persistent questions about the long-term safety and effectiveness of using stimulant medications such as methylphenidate (Ritalin) and amphetamines to treat this common neurobehavioral disorder. In part, it is with events like this that researchers are responding to charges, voiced in popular books last year, that stimulants can lead adolescents with ADHD to abuse their medications or take street drugs. While these claims rest mostly on two individual cases published in the scientific literature, they have put pressure on scientists to allay these and related fears with solid, long-term evidence to the contrary. Beyond these controversies, however, ADHD research has made important strides in the past year, says Timothy Wilens, HMS associate professor of psychiatry at Massachusetts General Hospital, who presented data on ADHD therapy and the risk for drug abuse at the workshop. These advances include studies on novel treatments, early work on possible genetic components of the disease, and a budding effort to develop a biologically based diagnosis for the disorder (see sidebars).
ADHD is the most common cognitive, emotional, and behavioral disorder treated in children. About 25 epidemiological studies in different countries estimate its prevalence at about 4 percent of children and adolescents. Medication, mostly with stimulant drugs and tricyclic antidepressants, is a mainstay of ADHD treatment along with psychotherapy and behavior modification. A common misperception, says Wilens, holds that ADHD is overtreated. Fueling this concern are isolated cases, such as a well-publicized study in September that found almost one in five white male fifth-graders to be on medication in one Virginia district. As a public health issue, however, Wilens believes that ADHD remains undertreated, especially in light of recent data shoring up the usefulness of drug therapy. For instance, Massachusetts Medicaid records indicate that less than one percent of children in the program receive ADHD medication, he adds. Working with Joseph Biederman, HMS professor of psychiatry, and other researchers at the MGH pediatric psychopharmacology unit, Wilens is studying the effects of many psychiatric drugs in children, adolescents, and adults. Just this month, the scientists describe in the American Journal of Psychiatry initial results of a clinical trial for a new kind of drug to treat ADHD. Though the biological cause of ADHD remains unclear, most research points to insufficient dopamine action in the frontal cortex and striatum areas of the brain. Indeed, most medications used for ADHD target the dopamine system. The new drug is different. Developed by Abbott Laboratories, which supported the MGH researchers, it is a chemical relative of nicotine. Promised as a kind of "designer nicotine," it stimulates attention without exerting the dangerous effects of the real McCoy. Wilens says the compound intrigued him because teenagers with ADHD smoke at twice the rate of the general population. Wilens and his colleagues at MGH tested the compound in 29 adults with ADHD in a double-blind, placebo-controlled trial. After six weeks, 40 percent of those receiving the test substance and 13 percent of those on placebo were "much" or "very much" improved. Patients with the inattentive subtype of ADHD did better on the drug than those with more hyperactivity. Scientifically, this compound breaks new ground because it acts through a different arm of the brain's chemistry. Broadly speaking, the brain has two major neurotransmitter systems: the catecholaminergic system, which includes dopamine, and the cholinergic system, in which so-called nicotinic receptors are one of two major recipients of the neurotransmitter acetylcholine. Nicotine binds these receptors, as does the new compound. The drug presumably mediates cross talk between the two systems. "This is one of the first times that a cholinergic agent proved in a clinical trial to be effective for ADHD. This new class of agent is worth investigating in larger studies, because it helps with some of the symptoms that do not respond well to the standard ADHD medications," says Wilens. Even if confirmed in larger studies, do these results carry any meaning for ADHD in children? Wilens says he feels increasingly confident about extrapolating from adults to youngsters. That is because he and his colleagues have extensive new data showing that people with ADHD respond to medications similarly throughout their lifetime. Touching on another controversial point, that of ADHD among adults, Wilens adds, "this drug responsiveness data is solid evidence that whatever brain defect we are talking about in children really is continuous into adulthood." Brain Imaging Promises Objective Diagnosis for Attention Deficit–Hyperactivity DisorderTell the truth: which of the following symptoms describe you sometimes? Fails to pay close attention to details; has difficulty organizing tasks; loses things; is forgetful in daily activities; interrupts or intrudes on others. Does pleading guilty to these failings mean you have attention deficit–hyperactivity disorder (ADHD)? Probably not. This smattering of the 18 ADHD symptoms listed in the diagnostic manual DSM-IV illustrates how easily local pockets of overdiagnosis can occur, belittling this real and often devastating condition. "We would love to have a biologically based diagnosis," says Timothy Wilens, a Harvard psychiatrist (see main story). He may soon get his wish. In a paper due out in Lancet, Harvard scientists describe how an imaging method they developed to diagnose Parkinson's disease may also be able to reveal ADHD. Alan Fischman, HMS associate professor of radiology at Massachusetts General Hospital, worked with Bertha Madras, HMS professor of psychobiology in the Department of Psychiatry at the New England Regional Primate Research Center, to test a SPECT imaging agent that can detect and quantify in a person's brain a protein called the dopamine transporter. This transporter can do diagnostic double-duty because it disappears as dopamine neurons die in Parkinson's yet is elevated in people with ADHD. Incidentally, the transporter is the target for the drug Ritalin and has been implicated as a cause of ADHD. This initial trial included only six adults with previously diagnosed ADHD. The results were clear, however. All six had dopamine transporter levels in their striatum roughly 70 percent higher than did controls, and there was no overlap between cases and controls. Further trials are being planned, says Madras. Even if all goes well, the test will take several more years to bring to the market. The researchers received support from Boston Life Sciences, Inc., and the National Institute on Drug Abuse. Jury Still Out on ADHD GenesMost ADHD research occurs amid controversy, so it is fair to assume that passionate debate about what defines a person's behavior will greet emerging genetics data on ADHD once it becomes better known. Four scientific groups have independently implicated the dopamine receptor 4 gene in the disorder. This past May, Steven Faraone, HMS associate professor of psychology in the Department of Psychiatry, and others at Massachusetts General Hospital's Pediatric Psychopharmacology Unit described in the American Journal of Psychiatry how they, too, found that the presence of a certain allele of this gene predicted the disorder in 27 triads of an ADHD adult, his or her spouse, and an affected child. Intriguingly, researchers in Arizona last year cast suspicion on a polymorphism of the dopamine transporter, a channel that removes excess transmitter from the synaptic cleft. This protein is imaged in the diagnostic study described in the sidebar above. It is important to remember, however, that in psychiatry many attempts to link genes to diseases have subsequently been refuted. Remember alcoholism? Schizophrenia? With the dopamine receptor, too, researchers elsewhere report that they cannot replicate the connection. |
