Pediatric first time non-febrile seizure with focal manifestations: is emergent imaging indicated?

PURPOSE: To assess the prevalence of clinically urgent intra-cranial pathology among children who had imaging for a first episode of non-febrile seizure with focal manifestations. METHODS: We performed a cross sectional study of all children age 1 month to 18 years evaluated for first episode of non-febrile seizure with focal manifestations and having neuroimaging performed within 24h of presentation at a single pediatric ED between 1995 and 2012. We excluded intubated patients, those with known structural brain abnormality and trauma. A single neuro-radiologist reviewed all cranial computed tomography and/or magnetic resonance imaging performed. We defined clinically urgent intracranial pathology as any finding resulting in a change of initial patient management. We performed univariate analysis using χ(2) analysis for categorical data and Mann-Whitney U test for continuous data. RESULTS: We identified 319 patients having a median age of 4.6 years [IQR 1.8-9.4] of which 45% were female. Two hundred sixty-two children had a CT scan, 15 had an MR and 42 had both. Clinically urgent intra-cranial pathology was identified on imaging of 13 patients (4.1%; 95% CI: 2.2, 7.0). Infarction, hemorrhage and thrombosis were most common (9/13). Twelve of 13 were evident on CT scan. Persistent Todd's paresis and age ≤ 18 months were predictors of clinically urgent intracranial pathology. Absence of secondary generalization and multiple seizures on presentation were not predictive. CONCLUSIONS: Four percent of children imaged with first time, afebrile focal seizures have findings important to initial management. Children younger than ≤ 18 months are at increased risk.

A controlled family study of children with DSM-IV bipolar-I disorder and psychiatric co-morbidity.

BACKGROUND: To estimate the spectrum of familial risk for psychopathology in first-degree relatives of children with unabridged DSM-IV bipolar-I disorder (BP-I). METHOD: We conducted a blinded, controlled family study using structured diagnostic interviews of 157 children with BP-I probands (n=487 first-degree relatives), 162 attention deficit hyperactivity disorder (ADHD) (without BP-I) probands (n=511 first-degree relatives), and 136 healthy control (without ADHD or BP-I) probands (n=411 first-degree relatives). RESULTS: The morbid risk (MR) of BP-I disorder in relatives of BP-I probands (MR=0.18) was increased 4-fold [95% confidence interval (CI) 2.3-6.9, p<0.001] over the risk to relatives of control probands (MR=0.05) and 3.5-fold (95% CI 2.1-5.8, p<0.001) over the risk to relatives of ADHD probands (MR=0.06). In addition, relatives of children with BP-I disorder had high rates of psychosis, major depression, multiple anxiety disorders, substance use disorders, ADHD and antisocial disorders compared with relatives of control probands. Only the effect for antisocial disorders lost significance after accounted for by the corresponding diagnosis in the proband. Familial rates of ADHD did not differ between ADHD and BP-I probands. CONCLUSIONS: Our results document an increased familial risk for BP-I disorder in relatives of pediatric probands with DSM-IV BP-I. Relatives of probands with BP-I were also at increased risk for other psychiatric disorders frequently associated with pediatric BP-I. These results support the validity of the diagnosis of BP-I in children as defined by DSM-IV. More work is needed to better understand the nature of the association between these disorders in probands and relatives.

The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study.

BACKGROUND: A better understanding of the long-term scope and impact of the co-morbidity with oppositional defiant disorder (ODD) and conduct disorder (CD) in attention deficit hyperactivity disorder (ADHD) youth has important clinical and public health implications. METHOD: Subjects were assessed blindly at baseline (mean age=10.7 years), 1-year (mean age=11.9 years), 4-year (mean age=14.7 years) and 10-year follow-up (mean age=21.7 years). The subjects' lifetime diagnostic status of ADHD, ODD and CD by the 4-year follow-up were used to define four groups (Controls, ADHD, ADHD plus ODD, and ADHD plus ODD and CD). Diagnostic outcomes at the 10-year follow-up were considered positive if full criteria were met any time after the 4-year assessment (interval diagnosis). Outcomes were examined using a Kaplan-Meier survival function (persistence of ODD), logistic regression (for binary outcomes) and negative binomial regression (for count outcomes) controlling for age. RESULTS: ODD persisted in a substantial minority of subjects at the 10-year follow-up. Independent of co-morbid CD, ODD was associated with major depression in the interval between the 4-year and the 10-year follow-up. Although ODD significantly increased the risk for CD and antisocial personality disorder, CD conferred a much larger risk for these outcomes. Furthermore, only CD was associated with significantly increased risk for psychoactive substance use disorders, smoking, and bipolar disorder. CONCLUSIONS: These longitudinal findings support and extend previously reported findings from this sample at the 4-year follow-up indicating that ODD and CD follow a divergent course. They also support previous findings that ODD heralds a compromised outcome for ADHD youth grown up independently of the co-morbidity with CD.

Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder: a MRI study of brain volumes.

BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders. METHOD: Morphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm(3)) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. RESULTS: When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. CONCLUSIONS: Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

The CBCL as a screen for psychiatric comorbidity in paediatric patients with ADHD.

AIMS: To examine the informativeness of the Child Behavior Checklist (CBCL) as a screening tool to identify comorbid and non-comorbid cases of attention deficit hyperactivity disorder (ADHD) in a paediatrically referred population. It was hypothesised that specific scales of the CBCL would help identify specific comorbidities within ADHD cases in the primary care setting. METHODS: The sample consisted of children and adolescents 6-17 years old of both genders with ADHD (n = 121). A receiver operating curve (ROC) approach was used to determine which CBCL scales best differentiated between ADHD cases with and without its comorbidities with conduct, anxiety, and mood disorders. RESULTS: ROC analysis showed that the CBCL Delinquent Behavior and Aggressive Behavior scales predicted the structured interview derived diagnoses of conduct and bipolar disorder, the Anxious/Depressed and Aggressive Behavior scales predicted major depression, and the Anxious/Depressed and Attention problems scales predicted anxiety disorders. CONCLUSIONS: These results extend to a paediatrically referred population with previously reported findings in psychiatric samples documenting good convergence between structured interview diagnoses and syndrome congruent CBCL scales. These findings support the utility of the CBCL as a screening tool for the identification of psychiatric comorbidity in ADHD youth in the primary care setting.

Specificity in the familial aggregation of overt and covert conduct disorder symptoms in a referred attention-deficit hyperactivity disorder sample.

BACKGROUND: To examine the familial associations of overt and covert antisocial behavior within the diagnosis of conduct disorder (CD) in families ascertained by referred children with attention-deficit hyperactivity disorder (ADHD), and to test if these familial associations differed between male and female probands. METHOD: Subjects were clinically-referred male and female ADHD children (n = 273) and their first-degree biological relatives (n = 807). Scores for overt and covert conduct problems were calculated by summing the DSM-III-R conduct disorder symptoms, as derived from structured diagnostic interviews. Familial aggregation analyses were conducted with multivariate regression modeling methodology. RESULTS: Proband overt scores significantly predicted the overt scores of their relatives, and proband covert scores significantly predicted the covert scores of their relatives. There was no evidence of covert symptom scores predicting overt scores or vice versa. There was some evidence that the aggregation of covert symptoms was stronger in the families of female probands. CONCLUSIONS: These results provide preliminary evidence that overt and covert conduct disorder symptoms are independently transmitted through families and may represent distinct familial syndromes.

Impact of exposure to parental attention-deficit hyperactivity disorder on clinical features and dysfunction in the offspring.

BACKGROUND: Although genes are known to influence the aetiology of ADHD, the impact of exposure to parental ADHD has received limited scientific scrutiny. This study investigated the impact of exposure to parental ADHD on clinical features and dysfunction in offspring. METHODS: We studied 1099 offspring (53% male, mean age 12.4 years) of non-ADHD, remitted ADHD, and persistent ADHD parents, using structured diagnostic interviews and a battery of cognitive and psychosocial measures. Offspring across these three groups were compared on clinical, cognitive and psychosocial outcomes, adjusting for exposure to other parental psychopathology, offspring ADHD status and social class. RESULTS: Parental ADHD was associated with an increased risk for ADHD in offspring relative to no parental ADHD, but no significant differences were found between children of remitted versus persistent ADHD parents. Exposure to parental ADHD predicted higher levels of family conflict and lesser levels of family cohesion relative to families without parental ADHD, independent of other psychopathological conditions in parents or ADHD status. Significant interactions were detected in which parental ADHD had a deleterious impact on measures of school performance in offspring without ADHD but not in those with the disorder. CONCLUSIONS: These results find no support for the hypothesis that exposure to parental ADHD increases the risk for ADHD in children beyond that conveyed by the liability associated with the diagnosis in the parent. However, since exposure to parental ADHD was associated with a disruptive family environment, the identification and treatment of adults with ADHD may be an important component of the treatment plan of youth with ADHD.

Long-term stability of the Child Behavior Checklist in a clinical sample of youth with attention deficit hyperactivity disorder.

Evaluated the long-term stability of the Child Behavior Checklist (CBCL) in a longitudinal clinical sample of youth with attention deficit hyperactivity disorder (ADHD), testing the hypothesis that the CBCL scales will show stability over time. Participants were 105 Caucasian, non-Hispanic boys with ADHD between the ages of 6 and 17 assessed at baseline and at a 4-year follow-up. Stability of CBCL scales were computed for dimensional (intraclass correlation coefficients [ICCs], Pearson correlations) and dichotomized scale scores (kappa coefficients and odds ratios [ORs]). Evidence was found for stability of the categorical and dimensional types of scores, as demonstrated by statistically significant stability of the Pearson correlation coefficients, kappas, and ORs. The robust findings obtained from ICCs and kappa coefficients document substantial stability for CBCL scales over time within individuals with ADHD. These results support the informativeness of the CBCL as a useful measure of longitudinal course in clinical samples of youth with ADHD.

Social impairment in girls with ADHD: patterns, gender comparisons, and correlates.

OBJECTIVE: To investigate social impairment in girls with attention-deficit/hyperactivity disorder (ADHD), compare the social functioning of boys and girls with ADHD, and explore the association between social dysfunction and conditions comorbid with ADHD. METHOD: Four groups of index children were studied: 267 children (127 girls) with ADHD and 234 non-ADHD comparison children (114 girls). Groups were compared on social functioning, psychopathology, and demographic characteristics. RESULTS: Girls with ADHD manifested significant deficits in interpersonal functioning compared with girls without ADHD and evidenced a similar degree of social impairment compared with boys with ADHD. ADHD and associated comorbid disorders were significant correlates of specific domains of social dysfunction in boys and girls with ADHD. CONCLUSIONS: Interpersonal deficits are a major correlate of ADHD, irrespective of gender, and appear to stem from the behaviors associated with ADHD as well as behaviors characteristic of conditions comorbid with ADHD.

Heterogeneity of childhood conduct disorder: further evidence of a subtype of conduct disorder linked to bipolar disorder.

BACKGROUND: Although a small literature suggests that conduct disorder (CD) co-occurs with bipolar disorder (BPD), little is known about this overlap. Thus, we investigated the familial association of antisocial disorders (CD and/or antisocial personality disorder (ASPD)) and BPD among the first degree relatives of children with CD with and without comorbid BPD. METHODS: We compared relatives of four proband groups defined by the presence or absence of CD and BPD in the proband: (1) CD+BPD (N=26 probands, 92 relatives; (2) BPD without CD (BPD) (N=19 probands, 53 relatives); (3) CD without BPD (CD) (N=16 probands, 58 relatives); and (4) controls without BPD or CD (N=102 probands, 338 relatives). All subjects were evaluated with structured diagnostic interviews. Diagnoses of relatives were made blind to the diagnoses of probands. RESULTS: The results show high rates of antisocial disorders and BPD in relatives of children with CD+BPD. Moreover, antisocial disorders and BPD cosegregated among the relatives of children with CD+BPD. While relatives of both CD proband groups with and without BPD had high rates of CD/ASPD, the combined condition CD/ASPD+BPD was found exclusively among relatives of probands with CD+BPD. LIMITATIONS: Since we pooled two datasets, subjects were not all evaluated at the same time. Also, the lack of direct psychiatric interviews with children younger than 12 may have decreased the sensitivity of some diagnoses. CONCLUSIONS: These family-genetic findings suggest that CD and BPD represent separate disorders. Furthermore, they suggest that the comorbid condition of CD+BPD may be a distinct nosological entity. This suggests that clinicians treating CD or BPD children should consider the treatment implications of this comorbid condition.

Attention deficit hyperactivity disorder with bipolar disorder in girls: further evidence for a familial subtype?

BACKGROUND: To clarify the nosologic status of girls with attention deficit hyperactivity disorder (ADHD) who also satisfy diagnostic criteria for bipolar disorder (BPD). METHODS: Using blind raters and structured psychiatric interviews, we examined 140 girls with ADHD, 122 non-ADHD comparisons and their 786 first degree relatives. Analyses tested specific hypotheses about the familial relationship between ADHD and bipolar disorder in girls. RESULTS: After stratifying our ADHD sample into those with and without BPD, we found that: (1) relatives of both ADHD subgroups were at significantly greater risk for ADHD than relatives of non-ADHD controls, (2) the two subgroups did not significantly differ in their relatives' risk for ADHD; (3) an elevated risk for bipolar disorder was observed among relatives when the proband child had BPD but not ADHD alone; (4) weak evidence of cosegregation between ADHD and BPD, and (5) no evidence of a trend for random mating between ADHD parents and those with mania. LIMITATIONS: Limitations of this study include the lack of direct interviewing of probands and the limited number of ADHD/BPD probands available. CONCLUSIONS: These findings extend to girls what was previously documented in boys and suggest that comorbid ADHD with BPD in girls is familially distinct from other forms of ADHD and may be related to what others have termed childhood onset BPD. Future work could determine if this subgroup has a characteristic course, outcome and response to treatment.

A controlled clinical trial of bupropion for attention deficit hyperactivity disorder in adults.

OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials demonstrating the effectiveness of compounds used in treatment, particularly nonstimulants. The authors report results from a controlled investigation to determine the anti-ADHD efficacy of bupropion in adult patients with DSM-IV ADHD. METHOD: This was a double-blind, placebo-controlled, randomized, parallel, 6-week trial comparing patients receiving sustained-release bupropion (up to 200 mg b.i.d.) (N=21) to patients receiving placebo (N=19). The authors used standardized structured psychiatric instruments for diagnosis of ADHD. To measure improvement, they used separate assessments of ADHD, depression, and anxiety symptoms at baseline and each weekly visit. RESULTS: Of the 40 subjects (55% male) enrolled in the study, 38 completed the study. Bupropion treatment was associated with a significant change in ADHD symptoms at the week-6 endpoint (42% reduction), which exceeded the effects of placebo (24% reduction). In analyses using a cutoff of 30% or better reduction to denote response, 76% of the subjects receiving bupropion improved, compared to 37% of the subjects receiving placebo. Similarly, in analyses using Clinical Global Impression scale scores, 52% of the subjects receiving bupropion reported being "much improved" to "very improved," compared to 11% of the subjects receiving placebo. CONCLUSIONS: These results indicate a clinically and statistically significant effect of bupropion in improving ADHD in adults. The results suggest a therapeutic role for bupropion in the armamentarium of agents for ADHD in adults, while further validating the continuity of pharmacological responsivity of ADHD across the lifespan.

Methodological complexities in the diagnosis of major depression in youth: an analysis of mother and youth self-reports.

OBJECTIVE: Considering the well-documented low level of agreement between youth and parent reports on the diagnosis of major depressive disorder (MDD), uncertainties remain as to the informativeness of discrepant youth and parent reports in clinical studies. To this end we evaluated whether morbidity and functional correlates on the diagnosis of MDD in youth vary by informant source. METHODS: The sample consisted of 186 pairs of independently assessed mother and youth self-reports on the diagnosis of MDD using structured diagnostic interviews ascertained in a large study of youth with and without attention deficit hyperactivity disorder of both genders. Subjects were also assessed on measures of interpersonal, school, and family functioning as well as prior treatment history. RESULTS: The diagnosis of MDD endorsed by youth self-report only when compared with that reported by the mother was characterized by significantly: shorter duration episode, later age at onset, milder depression-associated impairment, less impairment in interpersonal functioning, lower rates of comorbid disorders, and decreased likelihood to receive any course of treatment for depression. The morbidity and dysfunction associated with MDD varied significantly by informant source, and followed a dose-response association with the highest morbidity associated with the concurrent reports of the youth and the mothers, followed by mother report alone, with the least morbidity and dysfunction when endorsed by youth alone. CONCLUSIONS: These findings suggest that exclusive reliance on youth self-reports may identify a mild form of depression associated with limited morbidity and disability compared with that identified by parental reports.

Learning disabilities and executive dysfunction in boys with attention-deficit/hyperactivity disorder.

The effect of comorbid reading or arithmetic learning disabilities (LDs) on neuropsychological function in attention-deficit/hyperactivity disorder (ADHD) was studied. Participants were young males diagnosed with ADHD, with and without LD, and non-ADHD, non-LD male controls of similar age. LD was defined by combined regression-based and low-achievement classifications. Analyses adjusted for the effect of psychiatric comorbidity, age, and socioeconomic status on neuropsychological function. Children who had both ADHD and LD were significantly more impaired on both executive and nonexecutive functions than ADHD children without LD. Neuropsychological performance was most impaired in ADHD with combined arithmetic and reading disability. These data indicate that comorbid LD, especially arithmetic disability, significantly increases the severity of executive function impairment in ADHD.

Assessing symptoms of attention deficit hyperactivity disorder in children and adults: which is more valid?

The assessment of attention deficit hyperactivity disorder (ADHD) in adults has been a source of controversy. The authors tested competing ideas by evaluating familial transmission among adult and nonadult relatives of ADHD children. They analyzed ADHD symptom data collected by structured interviews from the members of 280 ADHD and 242 non-ADHD families. For both past and current symptoms, both the boys' and girls' families showed significantly more familial aggregation for adult relatives than for nonadult relatives. The results were similar for inattentive and hyperactive-impulsive symptoms and for relatives with and without psychiatric comorbidity. The results provide further evidence for the validity of adult ADHD and support the intriguing idea that, from a familial perspective, the assessment of ADHD may be more valid in adults than in children. They do not support the idea that parents of ADHD children are biased to report ADHD symptoms in themselves because of their exposure to an ADHD child.

Parsing the association between bipolar, conduct, and substance use disorders: a familial risk analysis.

BACKGROUND: Bipolar disorder has emerged as a risk factor for substance use disorders (alcohol or drug abuse or dependence) in youth; however, the association between bipolar disorder and substance use disorders is complicated by comorbidity with conduct disorder. We used familial risk analysis to disentangle the association between the three disorders. METHODS: We compared relatives of four proband groups: 1) conduct disorder + bipolar disorder, 2) bipolar disorder without conduct disorder, 3) conduct disorder without bipolar disorder, and 4) control subjects without bipolar disorder or conduct disorder. All subjects were evaluated with structured diagnostic interviews. For the analysis of substance use disorders, Cox proportional hazard survival models were utilized to compare age-at-onset distributions. RESULTS: Bipolar disorder in probands was a risk factor for both drug and alcohol addiction in relatives, independent of conduct disorder in probands, which was a risk factor for alcohol dependence in relatives independent of bipolar disorder in probands, but not for drug dependence. The effects of bipolar disorder and conduct disorder in probands combined additively to predict the risk for substance use disorders in relatives. CONCLUSIONS: The combination of conduct disorder + bipolar disorder in youth predicts especially high rates of substance use disorders in relatives. These findings support previous results documenting that when bipolar disorder and conduct disorder occur comorbidly, both are validly diagnosed disorders.

Pemoline treatment of adolescents with attention deficit hyperactivity disorder: a short-term controlled trial.

BACKGROUND: Despite the increased recognition of attention deficit hyperactivity disorder (ADHD) in adolescents, few controlled studies have assessed treatments for this age group. Adolescent issues, such as embarrassment at receiving medication at school and experimentation with abusable substances, have accelerated efforts to find effective, well-tolerated treatments beyond traditional stimulants. Pemoline has been found effective for treating both children and adults with ADHD but has not been evaluated in adolescents with ADHD. METHODS: Twenty-one adolescents (mean age 14 years old) diagnosed with ADHD by structured and clinical interviews participated in a 10-week, double-blind crossover design study of pemoline. Dosing was optimized with robust doses up to 3 mg/kg/day in one to two doses. Clinical evaluations of ADHD, depression, anxiety, and oppositional defiant disorder (ODD) symptoms were assessed weekly. RESULTS: Adolescents with ADHD exhibited a marked response to pemoline treatment relative to placebo on the ADHD rating scale (p = 0.001), with an average reduction of 3.02 points per week of treatment. Sixty percent of adolescents responded to pemoline, compared to 11% treated with placebo. This response was independent of gender or lifetime psychiatric comorbidity. Pemoline was well tolerated, with patients averaging 2.88 mg/kg/day in two doses per day, with a mean dose at end of follow-up of 181.1 mg (SD 45.6, range 112.5-262.5 mg). Side effects were mild, and no adverse hepatic events occurred. CONCLUSIONS: These findings resemble those reported in children and adults with ADHD. This trial suggests pemoline is well tolerated and effective in adolescents and may be a particularly useful ADHD treatment for adolescents.

Patterns of alcohol and drug use in adolescents can be predicted by parental substance use disorders.

OBJECTIVE: To examine the specificity of risk for alcohol or drug abuse or dependence (substance use disorders [SUDs]) in offspring exposed to particular subtypes of parental SUDs. METHODS: The original sample was derived from 2 groups of index children: 140 attention-deficit/hyperactivity disorder (ADHD) probands and 120 non-ADHD comparison probands. These groups had 174 and 129 biological siblings and 279 and 240 parents, respectively. RESULTS: Independent of familial risk, exposure to parental SUDs predicted SUDs in the offspring. Controlling for duration of exposure, we found that adolescence was a critical developmental period for exposure to parental SUDs. Because all our analyses controlled for social class, ADHD status, and parental lifetime history of SUDs, these results show that exposure to parental SUDs predicts offspring SUDs independently of these risk factors. CONCLUSIONS: These results support the critical importance of familial environmental risk factors for the development of SUDs in youth in general and particularly in those at high risk for these disorders. These results highlight adolescence as a critical period for the deleterious effects of exposure to parental SUDs, supporting the need to develop preventive and early intervention strategies targeted at adolescents at high risk for SUDs.

Attention-deficit disorder and conduct disorder in girls: evidence for a familial subtype.

BACKGROUND: The frequent comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) raises the possibility that ADHD+CD is a distinct and separate condition. METHODS: We tested hypotheses about patterns of familial association between ADHD, CD, oppositional defiant disorder (ODD) and adult antisocial personality disorder (ASPD). Using family study methodology in a sample of girls, we found 11 children with diagnoses of ADHD+ CD, 39 with ADHD+ODD, and 90 with ADHD only. These were compared with 122 non-ADHD, non-CD control probands. Familial risk analysis was utilized. RESULTS: Relatives of each ADHD proband subgroup were at significantly greater risk for ADHD, and the relatives of ADHD-only subjects were at a greater risk of ODD than relatives of control subjects. Also, rates of CD were elevated among relatives of ADHD+CD probands only, and the coaggregation of ADHD and the antisocial disorders could not be accounted for by marriages between ADHD and antisocial spouses. Both ADHD and antisocial disorders occurred in the same relatives more often than expected by chance. CONCLUSIONS: These findings suggest that ADHD with and without antisocial disorders may be etiologically distinct disorders and provide evidence for the nosologic validity of ICD-10 hyperkinetic conduct disorder.

Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder.

Converging evidence from family, twin, and adoption studies points to a substantial genetic component of the etiology of attention deficit hyperactivity disorder (ADHD). These data about ADHD have motivated molecular genetic studies of the disorder, which have produced intriguing but somewhat conflicting results. Some studies have reported associations with candidate genes and others not. Our review of the literature shows that one problem facing molecular genetic studies of ADHD is that its recurrence risk to first-degree relatives is only about five times higher than the population prevalence. This suggests that, to produce consistently replicated results, molecular genetic studies should either use much larger samples or should select those families in which genes exert the largest effect. Risch [(1990a) Am J Hum Genet 46:222-228; (1990b) Am J Hum Genet 46:229-241] proved that the statistical power of a linkage study increases with the magnitude of risk ratios (lambda's) computed by dividing the affection rate among each relative type to the rate of affection in the population. Our prior work suggests two dimensions of genetic heterogeneity that might be useful for selecting ADHD subjects for molecular genetic studies: comorbidity with conduct disorder and persistence of ADHD into adolescence. This paper shows that these sub-phenotypes are useful for molecular genetic studies because (1) they have much higher empirical lambda values and (2) they affect a substantial minority of ADHD patients.