In the United States, Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common causes of referrals in family practice, pediatric, neurology, and child psychiatry clinics. Epidemiologic studies indicate that about five percent of children have ADHD, with boys being a large majority of these; the disorder persists into adult years in a substantial minority of cases.

Although we do not know from what specific parts of the brain ADHD arises, current hypotheses associate it with abnormalities of connections in the outermost layer at the front of the brain; it may involve faulty regulation of certain brain chemical messenger systems, predominantly those that use dopamine and norepinephrine.

The cardinal features of this syndrome are inattentiveness, impulsivity and motoric overactivity. These symptoms start during early gradeschool years; they are persistent and impair the child socially and educationally. Based on the type of symptoms that predominate, psychiatrists now diagnose ADHD by its "subtype," as "predominantly inattentive," "predominantly hyperactive," or "combined."

Recently, we completed a double-blind, family-genetic study of 140 boys diagnosed with ADHD and, as controls, 120 boys without the disorder. These groups had 454 and 368 first degree (parent, brother, sister) biological relatives, respectively.

In an earlier study, we had established three key facts: that other psychiatric disorders frequently co-occur with ADHD, that ADHD is familial, and that ADHD is associated with environmental adversity and social disability.

The phenomenon of finding more than one psychiatric disorder in a patient (the medical term for this is "comorbidity") was well established for some adult psychiatric disorders, but had been controversial for child psychiatry. By using structured psychiatric interviews, we had documented that ADHD frequently co-occurred with conduct, mood, anxiety and learning disorders.

Our next step was to test the validity of the apparent risk factors. We waited four years and then conducted a follow-up study of our ADHD group. This study confirmed and extended our initial findings pertaining to comorbidity. By mid-adolescence, ADHD children originally diagnosed with comorbid psychiatric disorders had markedly elevated rates of antisocial, mood and anxiety disorders, more impaired intellectual and achievement scores than ADHD-only children, and high rates of social disability.

We also found that the original diagnoses of comorbidity predicted impaired functioning and outcomes consistent with the other disorders found with ADHD: Conduct disorder in childhood predicted an antisocial diagnosis as well as alcohol and drug dependence at followup; major depression in childhood predicted the emergence of mania at followup; and severe anxiety in childhood predicted more anxiety disorders at followup than in other ADHD children.

Finding that comorbidity is an important predictor of impaired outcome provides clinicians with a basis for reaching a medium-term prognosis in ADHD children and underscores the importance of recognizing co-occurring disorders early in order to develop prevention and early intervention strategies.

In addition, the findings have helped make progress in the problem of predicting whether or not ADHD will persist or remit. They document that comorbidity with conduct, mood and anxiety disorders, familial ADHD and psychosocial adversity is likely to mean that the child's ADHD will persist into mid-adolescence.

The MGH study was the first double-blind study to clearly show not only that ADHD is familial, but also that the way the illness clusters in families is most consistent with the effects of a single gene of modest effect. We were able to dismiss other explanations such as sociocultural factors.

By examining family members for patterns of familial transmission of the comorbid disorders as well, we saw evidence that ADHD and major depression are variable expressions of shared underlying risk factors and that ADHD with conduct disorder might be a distinct familial subtype of the disorder. However, anxiety and learning disorders were not tied to ADHD familially; instead, when those disorders co-occur with ADHD in families, they appear to be transmitted independently

We also evaluated psychosocial adversity as a risk factor and found ADHD and its common complications to be associated with low social class, large family size, paternal antisocial personality, and maternal mental disorder. We also found that chronic family conflict, family disunity, and exposure of children to parents' mental illness were frequent in ADHD families.

Notably, chronic family conflict had a more pernicious impact on the exposed child than exposure to parental psychopathology -- compelling evidence for the critical importance of psychosocial adversity as a risk factor for ADHD that argues for intervention strategies aimed at reducing such adversity.

In the brain, ADHD is commonly associated with malfunction of frontal networks, but research on its underlying neuropsychology has so far failed to produce consistent results. Our studies found that boys with ADHD were significantly more impaired on neuropsychological tests that explore frontal lobe functioning, and those with a family history of ADHD were most impaired.

The ADHD children performed worse on various tasks of attention, executive function, learning and memory. ADHD children with learning disabilities showed motor impairment and had extremely slow reading speed, suggesting irregularities in communication between brain structures that deal with reading material. These neuropsychological impairments in the children we studied could not be attributed to co-morbid psychiatric conditions, learning disabilities or medication, and we concluded that they were features of ADHD and not of its complications.

For many years ADHD was considered a childhood diagnosis that was outgrown in adulthood. However, in recent years many adults have sought help for ADHD. Unfortunately, their effective treatment has been hindered by concerns about the validity of retrospectively-diagnosed ADHD in adults.

To address this issue, we demonstrated the validity of adult ADHD by showing: 1) that its psychiatric and neuropsychological features mirror the well known correlates of childhood ADHD; 2) that the children of ADHD adults are at very high risk for ADHD; and 3) that in carefully designed studies, adult ADHD shows the same therapeutic response to ADHD medications as does the childhood form.

In summary, our child and adult studies furnish converging evidence that ADHD is a persistent disorder associated with multiple impairments. We are beginning to learn about its cause and to trace it in the brain, but more work is needed to determine how genes and environment interact to create brain dysfunction in ADHD. *

Dr. Biederman is Chief, Joint Program, and Dr. Faraone is Director of Research, Pediatric Psychopharmacology at Massachusetts General Hospital.