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Objective: A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. Method: First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. Results: ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD probands with comorbid alcohol dependence. In addition, ADHD in the proband predicted drug dependence in relatives, and drug dependence in comparison probands increased the risk for ADHD in relatives. Both alcohol dependence and drug dependence bred true in families without evidence for a common risk between these disorders. Conclusions: Patterns of familial risk analysis suggest that the association between ADHD and drug dependence is most consistent with the hypothesis of variable expressivity of a common risk between these disorders, whereas the association between ADHD and alcohol dependence is most consistent with the hypothesis of independent transmission of these disorders. Findings also suggest specificity for the transmission of alcohol and drug dependence.

Objective: Diagnosing attention deficit hyperactivity disorder (ADHD) in adults is difficult when diagnosticians cannot establish an onset before the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve DSM's diagnosis threshold. Method: The authors addressed the validity of DSM-IV's age-at-onset and symptom threshold criteria by comparing four groups of adults: 127 subjects with full ADHD who met all DSM-IV criteria for childhood-onset ADHD, 79 subjects with late-onset ADHD who met all criteria except the age-at-onset criterion, 41 subjects with subthreshold ADHD who did not meet full symptom criteria for ADHD, and 123 subjects without ADHD who did not meet any criteria. The authors hypothesized that subjects with late-onset and subthreshold ADHD would show patterns of psychiatric comorbidity, functional impairment, and familial transmission similar to those seen in subjects with full ADHD. Results: Subjects with late-onset and full ADHD had similar patterns of psychiatric comorbidity, functional impairment, and familial transmission. Most children with late onset of ADHD (83%) were younger than 12. Subthreshold ADHD was milder and showed a different pattern of familial transmission than the other forms of ADHD. Conclusions: The data about the clinical features of probands and the pattern of transmission of ADHD among relatives found little evidence for the validity of subthreshold ADHD among such subjects, who reported a lifetime history of some symptoms that never met DSM-IV's threshold for diagnosis. In contrast, the results suggested that late-onset adult ADHD is valid and that DSM-IV's age-at-onset criterion is too stringent.

Objective: In a previous study, the authors found that, compared with referred boys with attention deficit hyperactivity disorder (ADHD), girls are less likely to manifest comorbid disruptive behavior disorders and learning disabilities--characteristics that could adversely affect identification of ADHD in girls. However, because referral bias can affect outcome, these findings require replication in nonreferred groups of ADHD subjects. Method: The authors evaluated gender effects in a large group of nonreferred siblings (N=577) of probands with ADHD and non-ADHD comparison subjects. Ninety-eight of the nonreferred siblings (N = 73 males, N = 25 females) met the criteria for diagnosis of ADHD, and 479 (N = 244 males, N = 235 females) did not meet those criteria. All siblings were systematically and comprehensively assessed with measures of emotional, school, intellectual, interpersonal, and family functioning. The assessment battery used for the siblings was the same as that used for the probands. Results: The nonreferred males and females with ADHD did not differ in DSM-IV subtypes of ADHD, psychiatric comorbidity, or treatment history. They also showed similar levels of cognitive, psychosocial, school, and family functioning. Conclusions: These findings suggest that the clinical correlates of ADHD are not influenced by gender and that gender differences reported in groups of subjects seen in clinical settings may be caused by referral biases.

Objective: The substantial discrepancy in the male-to-female ratio between clinic-referred (10 to 1) and community (3 to 1) samples of children with attention deficit hyperactivity disorder (ADHD) suggests that gender differences may be operant in the phenotypic expression of ADHD. In this study the authors systematically examined the impact of gender on the clinical features of ADHD in a group of children referred to a clinic. Method: The study included 140 boys and 140 girls with ADHD and 120 boys and 122 girls without ADHD as comparison subjects. All subjects were systematically assessed with structured diagnostic interviews and neuropsychological batteries for subtypes of ADHD as well as emotional, school, intellectual, interpersonal, and family functioning. Results: Girls with ADHD were more likely than boys to have the predominantly inattentive type of ADHD, less likely to have a learning disability, and less likely to manifest problems in school or in their spare time. In addition, girls with ADHD were at less risk for comorbid major depression, conduct disorder, and oppositional defiant disorder than boys with ADHD. A statistically significant gender-by-ADHD interaction was identified for comorbid substance use disorders as well. Conclusions: The lower likelihood for girls to manifest psychiatric, cognitive, and functional impairment than boys could result in gender-based referral bias unfavorable to girls with ADHD. (Am J Psychiatry 2002; 159:36-42)

Method: Interviewers who were blind to diagnosis administered structured psychiatric interviews to 140 girls with ADHD and their 417 first-degree relatives and to 122 girls without ADHD and their 369 first-degree relatives. Results: The relatives of the ADHD girls had a significantly higher prevalence of ADHD, according to either the DSM-III-R or DSM-IV definition, than the relatives of the comparison girls. However, this did not differ from the prevalence the authors reported previously for families of boys with ADHD. Like the boys' families, the relatives of the girl probands also had significantly higher prevalences of antisocial, mood, anxiety, and substance use disorders, although the prevalence of familial antisocial disorders was lower than had been observed in the boys' families. There was no association between the DSM-IV subtypes of the probands and relatives. Conclusions: The familial transmission of ADHD and comorbid disorders generalizes to families of girls with ADHD. Neither proband gender nor subtype influences the familial transmission of ADHD.

The authors evaluated the association between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorders in adults with ADHD, attending to comorbidity with mood, anxiety, and antisocial disorders. It was hypothesized that psychiatric comorbidity would be a risk factor for psychoactive substance use disorders. Method: Findings for 120 referred adults with a clinical diagnosis of childhood-onset ADHD were compared with those for non-ADHD adult comparison subjects (N=268). All childhood and adult diagnoses were obtained by structured psychiatric interviews for DSM-III-R. Results: There was a significantly higher lifetime risk for psychoactive substance use disorders in the ADHD adults than in the comparison subjects (52% versus 27%). Although the two groups did not differ in the rate of alcohol use disorders, the ADHD adults had significantly higher rates of drug and drug plus alcohol use disorders than the comparison subjects. ADHD significantly increased the risk for substance use disorders independently of psychiatric comorbidity. Antisocial disorders significantly increased the risk for substance use disorders independently of ADHD status. Mood and anxiety disorders increased the risk for substance use disorders in both the ADHD and comparison subjects, but more demonstrably in the comparison subjects. Conclusions: Although psychiatric comorbidity increased the risk for psychoactive substance use disorders in adults with ADHD, by itself ADHD was a significant risk factor for substance use disorders. More information is needed to further delineate risk and protective factors mediating the development of substance use disorders in persons with ADHD.

Objective: Although well-documented in clinical and epidemiological studies of attention deficit hyperactivity disorder (ADHD) in children, the familial nature of the adult syndrome has not been well investigated. One approach to evaluate the familial nature of adult ADHD is through a high-risk design aimed at estimating the risk for the disorder in children of parents with childhood-onset ADHD. Method: Children at risk for ADHD were ascertained from the study group of 84 referred adults with clinical diagnoses of childhood onset of the disorder, confirmed by structured interviews. Diagnostic information on the disorder was derived from the ADHD module of the Schedule for Affective Disorders and Schizophrenia for School Age Children - Epidemiologic Version, supplemented with information regarding treatment for ADHD for the affected child and school history including repeated grades, placement in special classes, and tutoring. Results: Of the 84 children at risk, 48 (57%) met criteria for ADHD. The rate of the disorder in children of adults with the disorder was significantly higher than the previously reported rate of ADHD among siblings of children with the disorder. Of the 48 ADHD children of parents with the disorder, 36 (75%) were treated for it. The rates of school failure were almost identical to those previously reported in a group of referred children and adolescents with ADHD. Conclusions: These results support the validity of the adult diagnosis of ADHD and suggest that the adult form of this disorder may have stronger familial etiological risk factors than its pediatric form. If these results are confirmed, families selected through adult probands with ADHD might be especially useful for testing genetic hypotheses about the disorder.

Objective: Although attention deficit hyperactivity disorder is a common disorder of childhood, its status as a disorder in adults is not clear. The authors reasoned that if the adult diagnosis of the disorder is a valid clinical entity, it should be similar to the childhood disorder with regard to patterns of psychiatric and cognitive findings. Method: Eighty-four adults with a clinical diagnosis of childhood-onset attention deficit hyperactivity disorder confirmed by structured interview who were referred for treatment were studied. Findings were compared with those from a preexisting study group of referred children with attention deficit hyperactivity disorder, nonreferred adult relatives of those children who also had attention deficit hyperactivity disorder, and adults without the disorder who were relatives of normal children. Subjects were evaluated with a comprehensive battery of psychiatric, cognitive, and psychosocial assessments. Results: The referred and nonreferred adults with attention deficit hyperactivity disorder were similar to one another but more disturbed and impaired than the comparison subjects without the disorder. The pattern of psychopathology, cognition, and functioning among the adults with attention deficit hyperactivity disorder approximated the findings for children with the disorder. Conclusions: These results show that referred and nonreferred adults with attention deficit hyperactivity disorder have a pattern of demographic, psychosocial, psychiatric, and cognitive features that mirrors well-documented findings among children with the disorder. These findings further support the validity of the diagnosis for adults.

Objective: The authors' goal was to investigate phosphatidylinositol and glutamatergic metabolism in the anterior cingulate cortex of children and adolescents with attention deficit hyperactivity disorder (ADHD) alone, children with ADHD plus bipolar disorder, and children with no axis I diagnosis. Method: Proton spectra were acquired from a 4.8-ml voxel placed in the anterior cingulate cortex of 30 subjects who were 6 to 13 years old. Fifteen subjects had ADHD and no comorbid disorder, eight had ADHD plus bipolar disorder, and seven were healthy comparison subjects. Results: Children with ADHD had a significantly higher ratio of glutamate plus glutamine to myo-inositoI-containing compounds than children with ADHD plus bipolar disorder and healthy children. Conclusions: myo-lnositoI-containing compounds may provide information on the action of antimanic treatments such as lithium, valproate, and carbamazepine. Glutamate and glutamine are measures of glutamatergic neurotransmission and thus may also reflect changes in serotonin and dopamine pathways.

Objective: Symptom decline in attention deficit hyperactivity disorder (ADHD) was examined with different definitions of remission. Method: Symptoms in 128 boys were measured five times over 4 years. The prevalences of syndromatic (less than full syndrome), symptomatic (less than subthreshold diagnosis), and functional (full recovery) remission were estimated as a function of age with multivariate logistic regression. Results: Age was significantly associated with decline in total ADHD symptoms and symptoms of hyperactivity, impulsivity, and inattention. Symptoms of inattention remitted for fewer subjects than did symptoms of hyperactivity or impulsivity. The proportion of subjects experiencing remission varied considerably with the definition used (highest for syndromatic remission, lowest for functional remission). Conclusions: These results indicate that differences in reported remission rates reflect the definition used rather than the disorder's course. They provide systematic support for the clinical observation that hyperactivity and impulsivity symptoms tend to decline at a higher rate than inattention symptoms.

Objective: The authors' goal was to explore the nature of attention deficit hyperactivity disorder (ADHD) in African American children, which has received scant attention by psychiatric researchers. Method: Subjects were 19 African American children with DSM-III-R ADHD and 24 African American children without ADHD. Ethnically sensitive methods were used to evaluate the children comprehensively. The findings were compared with those from an earlier study of Caucasian children with ADHD. Results: African American children with ADHD had higher levels of psychiatric disorders other than ADHD than did African American children who did not have ADHD. Conclusions: Among African American children, ADHD may be characterized by a narrower pattern of psychiatric comorbidity and dysfunction than has been observed in Caucasians. Given the small number of subjects studied, these findings are preliminary and must be replicated to confirm their validity.

Objective: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine [D.sub.4] receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain. Method: Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. Results: For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. Conclusions: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association. (Am J Psychiatry 2001; 158:1052-1057)

Objective: The impact of tic disorders on the outcome of attention deficit hyperactivity disorder (ADHD) remains a subject of high scientific and clinical interest. To evaluate the impact of comorbid ADHD and tic disorders from a lifespan perspective, the authors systematically examined data from adults with and without ADHD. Method: They comprehensively evaluated 312 consecutively referred adults with ADHD and 252 comparison subjects without ADHD. Tic disorders were characterized along with a wide range of neuropsychiatric correlates, including other comorbid disorders as well as indexes of function in the domains of school, cognition, and interpersonal functioning. Results: A significantly greater proportion of adults with ADHD (12%) than those without ADHD (4%) had tic disorders. Tic disorders followed a mostly remitting course and had little impact on functional capacities. In addition, tic disorders were not associated with stimulant use. Conclusions: These findings in adults with ADHD confirm and extend previous findings in young subjects with ADHD, documenting that although individuals with ADHD are at greater risk for tic disorders, the presence of tic disorders has a limited impact on ADHD outcome. (Am J Psychiatry 2001; 158:611-617)