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FIGURE 43.1. ADHD in relatives of ADHD and controls children. A: ADHD in siblings. B: ADHD in fathers. C: ADHD in mothers.

is familial. Moreover, studies of more distant relatives are consistent with this idea as well (76).

Family studies of ADHD suggest that its psychiatric comorbidities may help to clarify its genetic heterogeneity. The Harvard/Massachusetts General Hospital (Boston) ADHD family project studied two independent samples of children with attention-deficit disorder (ADD) as defined by the DSM-III (74) and ADHD as defined by the DSM- III-R (77). These data show that (a) ADHD and major depression share common familial vulnerabilities (78,79), (b) children with ADHD who have conduct (80,81) and bipolar (82,83) disorders may comprise a distinct familial subtype of ADHD, and (c) ADHD is familially indepen- dent of anxiety disorders (84) and learning disabilities (85). Thus, stratification by conduct and bipolar disorders may cleave the universe of children with ADHD into more famil- ially homogeneous subgroups. In contrast, major depression may be a nonspecific manifestation of different ADHD subforms. In a sample of 132 ADHD sib-pair families, Smalley et al. reported further evidence that ADHD with conduct disorder is a distinct subtype (86). These investiga- tors also examined comorbidity with learning disability, but these data produced equivocal results.

Chapter 43: Pathophysiology of ADHD


Faraone et al. proposed that stable or persistent ADHD may be a useful subtype of ADHD for genetic studies (87). These investigators reasoned that cases that remit before adolescence could have a smaller genetic component to their disorder than persistent cases. Evidence supporting this hy- pothesis derives from several studies. In a prospective follow- up study, Biederman et al. showed that by midadolescence, 85% of boys with ADHD continued to have ADHD; 15% remitted (88). The prevalence of ADHD among parents was 16.3% for the persistent ADHD probands and 10.8% for the remitted ADHD probands. For sibs, the respective prevalences were 24.4% and 4.6%. Thus, these data suggest that children with persistent ADHD have a more familial form of ADHD than those whose ADHD remits by adoles- cence.

Consistent with this finding, Biederman et al. showed that children of parents with clinically referred, childhood- onset, ADHD were at high risk of meeting diagnostic crite- ria for ADHD: 84% of the adults with ADHD who had children had at least one child with ADHD, and 52% had two or more children with ADHD (89). The 57% rate of ADHD among children of adults with ADHD was much higher than the more modest 15% risk for ADHD in sib- lings of referred children with this disorder. These findings were consistent with a prior study by Manshadi et al. (72). They studied the siblings of 22 alcoholic adult psychiatric patients who met DSM-III criteria for ADD, residual type. The authors compared these patients with 20 patients matched for age and comorbid psychiatric diagnoses. Forty- one percent of the siblings of the adult ADD probands were diagnosed with ADHD compared with 0% of the non- ADHD comparison siblings.

In another retrospective study, Biederman et al. com- pared adolescents with ADHD having retrospectively re- ported childhood-onset ADHD with children with ADHD (90). These investigators found that the relatives of adoles- cent probands had higher rates of ADHD compared with the relatives of child probands. Thus, a prospective study of children and retrospective studies of adolescents and adults suggested that, when ADHD persists into adolescence and adulthood, it is highly familial. This idea is consistent with one of Ernst’s explanations for the finding that frontal dopa- minergic hypoactivity is stronger in adult ADHD compared with adolescent ADHD; that is, frontal dopaminergic hypo- activity may be associated with persistent ADHD.

Twin and Adoption Studies

Although family studies provide much useful information, they cannot disentangle genetic from environmental sources of transmission. To do so, we must turn to twin and adop- tion studies. There are two types of twins: identical or monozygotic twins share 100% of their genes in common. In contrast, fraternal or dizygotic twins are no more geneti- cally alike than siblings and therefore share only 50% of

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