• Effectiveness and Tolerability of Tomoxetine in Adults With Attention Deficit Hyperactivity Disorder

      Spencer, Thomas; Biederman, Joseph; Wilens, Timothy; Prince, Jeffry; Hatch, Mary; Jones, Janice; Harding, Margaret; Faraone, Stephen V.; Seidman, Larry (American Psychiatric Association Publishing, 1998-05)
      Objective: The authors assessed the experimental noradrenergic compound tomoxetine as an alternative treatment for adult attention deficit hyperactivity disorder (ADHD). Method: They conducted a double-blind, placebo-controlled, crossover study of tomoxetine in 22 adults with well-characterized ADHD. Results: Treatment with tomoxetine at an average oral dose of 76 mg/day was well tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall and sufficiently robust to be detectable in a parallel-groups comparison restricted to the first 3 weeks of the protocol. Eleven of 21 patients showed improvement after receiving tomoxetine, compared with only two of 21 patients who improved after receiving placebo. Significant tomoxetine-associated improvement was noted on neuropsychological measures of inhibitory capacity from Stroop tests. Conclusions: This preliminary study showed that tomoxetine was effective in treating adult ADHD and was well tolerated. These promising results provide support for further studies of tomoxetine over an extended period of treatment.
    • Environmental risk factors for attention‐deficit hyperactivity disorder

      Banerjee, Tania Das; Middleton, Frank; Faraone, Stephen V. (Wiley, 2007-06-15)
      Attention-deficit hyperactivity disorder (ADHD) is the most common cognitive and behavioural disorder diagnosed among school children. It is characterized by deficient attention and problem solving, along with hyperactivity and difficulty withholding incorrect responses. This highly prevalent disorder is estimated to affect 5–10% of children and in many cases, persists into adulthood, leading to 4% prevalence among adults. Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder. The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder. Family studies have identified a 2- to 8-fold increase in the risk for ADHD in parents and siblings of children with ADHD. Various twin and adoption studies have also highlighted the highly genetic nature of ADHD. In fact the mean heritability of ADHD was shown to be 0.77, which is comparable to other neuropsychiatric disorders such as schizophrenia or bipolar disorder. However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight. Many recent studies have specifically examined the relationships between ADHD and these extraneous factors. This review describes some of these possible risk factors.
    • Evidence for Similar Structural Brain Anomalies in Youth and Adult Attention-Deficit/Hyperactivity Disorder: A Machine Learning Analysis

      Zhang-James, Yanli; Helminen, Emily C; Liu, Jinru; Franke, Barbara; Hoogman, Martine; Faraone, Stephen V (Cold Spring Harbor Laboratory, 2019-02-11)
      Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children world-wide. Of these, two-thirds continue to have impairing symptoms of ADHD into adulthood. Although a large literature implicates structural brain differences of the disorder, it is not clear if adults with ADHD have similar neuroanatomical differences as those seen in children with recent reports from the large ENIGMA-ADHD consortium finding structural differences for children but not for adults. This paper uses deep learning neural network classification models to determine if there are neuroanatomical changes in the brains of children with ADHD that are also observed for adult ADHD, and vice versa. We found that structural MRI data can significantly separate ADHD from control participants for both children and adults. Consistent with the prior reports from ENIGMA-ADHD, prediction performance and effect sizes were better for the child than the adult samples. The model trained on adult samples significantly predicted ADHD in the child sample, suggesting that our model learned anatomical features that are common to ADHD in childhood and adulthood. These results support the continuity of ADHD’s brain differences from childhood to adulthood. In addition, our work demonstrates a novel use of neural network classification models to test hypotheses about developmental continuity.
    • Evidence for the multigenic inheritance of schizophrenia

      Freedman, Robert; Leonard, Sherry; Olincy, Ann; Kaufmann, Charles A.; Malaspina, Dolores; Cloninger, C. Robert; Svrakic, Dragan; Faraone, Stephen V.; Tsuang, Ming T. (Wiley, 2002-08-21)
      Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these ®endings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z ¼ 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the a7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z ¼ 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci.
    • Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies

      Faraone, Stephen V.; Biederman, Joseph; Wozniak, Janet (American Psychiatric Association Publishing, 2012-12)
      Objective: The existence of comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder. Method: The authors applied randomeffects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands. Results: These studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a significantly higher prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. The authors found no evidence of heterogeneity in the ADHD or bipolar family studies. Conclusions: The results suggest that ADHD plus bipolar comorbidity cannot be accounted for by misdiagnoses, but additional research is needed to rule out artifactual sources of comorbidity. More research is also needed to determine whether comorbidity of ADHD and bipolar I disorder constitutes a familial subtype distinct from its constituent disorders, which if confirmed would have implications for diagnostic nosology and genetic studies.
    • Familial Risk Analyses of Attention Deficit Hyperactivity Disorder and Substance Use Disorders

      Biederman, Joseph; Petty, Carter R.; Wilens, Timothy E.; Fraire, Maria G.; Purcell, Caitlin A.; Mick, Eric; Monuteaux, Michael C.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2008-01)
      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.
    • Family based association analysis of statistically derived quantitative traits for drug use in ADHD and the dopamine transporter gene

      Lasky-Su, Jessica; Biederman, Joseph; Doyle, Alysa E.; Wilens, Timothy; Monuteaux, Michael; Smoller, Jordan W.; Faraone, Stephen (Elsevier BV, 2006-06)
      Objective To determine whether SNPs within the dopamine transporter gene (DAT) are associated with quantitative phenotypes generated from drug frequency variables in an ADHD sample. Method 35 SNPs were genotyped in and around DAT. We developed a quantitative phenotype at each SNP by weighting the drug frequency variables. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, a screening procedure was used to select and test the SNPs with the greatest power to detect an association in DAT. Results No SNPs in DAT were associated with the quantitative phenotypes generated from the drug frequency variables after the multiple comparisons adjustment; however, some SNPs achieved nominal significance. A sliding window of analysis of 3 SNPs also resulted in only nominal associations. Conclusions SNPs in DAT do not appear to be associated with the phenotypes generated from drug frequency variables among individuals with ADHD.
    • Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3)

      Mick, Eric; Kim, Jang Woo; Biederman, Joseph; Wozniak, Janet; Wilens, Timothy; Spencer, Thomas; Smoller, Jordan W.; Faraone, Stephen V. (Wiley, 2008-10-05)
      Thedopaminetransportergene(SLC6A3) isacompelling candidate for pediatric bipolar disorder because (a) it has been associated with ADHD, (b) bipolar comorbidity with ADHD has been hypothesized to be an etiologically distinct familial subtype (c) blockade of the dopamine transporter with psychostimulants can induce mania in susceptible individualsand(d) previous studies have implicated the gene in bipolar disorder in adults. We conducted a family-based association study of SLC6A3 in 170 affected offspring trios defined by a child (12.9 5.3 years of age)with DSM-IV Bipolar-I disorder. Twenty-eight tag SNPs were chosen from the CEU (European) population of the International HapMap project (www.hapmap.org). Results indicated nominally positive association for 4 SNPs (rs40184, rs11133767, rs3776512, and rs464049), but only rs40184 survived correction formultiple statistical comparisons (P¼0.038). This is the first examination of the association with SLC6A3 and bipolar disorder in children and, like previous findings in adults with bipolar disorder, we found evidence of association with SNPs in the 30 region of the gene. These data provide suggestive evidence supporting a role for SLC6A3 in the etiology of pediatric bipolar disorder.
    • Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism

      Qian, Qiujin; Wang, Yufeng; Zhou, Rulun; Li, Jun; Wang, Bing; Glatt, Stephen; Faraone, Stephen V. (Wiley, 2003-03-04)
      Attention deficit hyperactivity disorder (ADHD) is the most common childhood-onset behavioral disorder. Boys are more often affected than girls. Family, twin, and adoption studies have supported a strong genetic basis. Some studies show that a catechol-O-methyltransferase (COMT) polymorphism affecting enzyme activity was associated with personality characteristics and diseases, such as novelty-seeking personality, substance abuse, and heroin addiction, whose features are similar to ADHD or are associated with ADHD. These findings suggest that the COMT gene may be a candidate gene for ADHD. TDT, HHRR, and case-control association studies were conducted within a sample of 202 nuclear ADHD families, 340 ADHD cases, and 226 controls in the Han Chinese population. Diagnoses and ADHD subtypes were ascertained according to DSM-IV criteria using American Clinical Diagnostic Interviewing Scales. The HHRR analysis suggested that the low enzyme-activity COMT Met allele was preferentially transmitted to ADHD boys (160 trios, χ2 = 3.858, P = 0.05, df = 1) but not girls. This association is particularly pronounced among male ADHD probands without any comorbidity (50 trios, HHRR: χ2 = 5.128, P = 0.024, df = 1; TDT: χ2 = 4.558, P = 0.033, df = 1), especially the ADHD-I subtype (32 trios, HHRR: χ2 = 5.792, P = 0.016, df = 1; TDT: χ2 = 5.333, P = 0.021, df = 1). The case-control study revealed that the Val allele was more frequent in females meeting ICD-10 or DSM-IV criteria for ADHD than in female controls (86 and 79.5%, respectively, χ2 = 4.059, P = 0.044, df = 1). Although these results suggest the COMT gene exerts some influence on the risk for ADHD in the Han Chinese population, given the potential for Type I error, these findings require replication before drawing definitive conclusions. © 2003 Wiley-Liss, Inc.
    • Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families

      Takahashi, Sakae; Cui, Yu-hu; Kojima, Takuya; Han, Yong-hua; Zhou, Ru-lum; Kamioka, Masashi; Yu, Shun-ying; Matsuura, Masato; Matsushima, Eisuyke; Wilcox, Marsha; et al. (Wiley, 2003-06-13)
      Several studies suggest that loci at chromosome 22q11.2-q13 might be linked to susceptibility to schizophrenia. Here we performed family-based association studies on chromosome 22q using 12 DNA microsatellite markers in African-American, European-American, and Chinese pedigrees. The marker D22S683 showed significant linkage and association with schizophrenia in not only the European-American sample but also in a combined sample (European-American and Chinese samples). Notably, D22S683 is located nearby and between D22S278 and D22S283, which have shown linkage and association to schizophrenia in prior reports. However, we found no significant association for the African-American sample. In conclusion, our data provide further support for the idea that the region around D22S683 contains a susceptibility gene for schizophrenia. © 2003 Wiley-Liss, Inc.
    • Further evidence of an association between maternal smoking during pregnancy and attention deficit hyperactivity disorder: Findings from a high-risk sample of siblings

      Milberger, Sharon; Biederman, Joseph; Faraone, Stephen V.; Jones, Janice (Informa UK Limited, 1998-09)
      The authors investigated the relationship between attentiondeficit/byperactivity disorder (ADHD) and cigarette smoking in siblings of ADHD and non-ADHD probands. They conducted a 4-year follow-up of siblings from ADHD and control-group families. In the siblings of ADHD probands, ADHD was associated with higher rates and earlier onset of cigarette smoking. There was also a significant positive association between cigarette smoking and conduct disorder, major depression, and drug abuse in the siblings, even after adjusting for confounding variables. Moreover, smoking was found to be familial among ADHD families but not control-group families. Our findings indicate that ADHD is a risk factor for early initiation of cigarette smoking in the high-risk siblings of ADHD probands
    • Further Evidence of Association Between Behavioral Inhibition and Social Anxiety in Children

      Biederman, Joseph; Hirshfeld-Becker, Dina R.; Rosenbaum, Jerrold F.; Hérot, Christine; Friedman, Deborah; Snidman, Nancy; Kagan, Jerome; Faraone, Stephen V. (American Psychiatric Association Publishing, 2001-10)
      Objective: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. Method: Behavioral inhibition, determined by using standard laboratory observations, was assessed in four groups of children (age 2–6 years): 129 children of parents with both panic disorder and major depression, 22 children of parents with panic disorder alone, 49 children of parents with major depression alone, and 84 comparison children of parents with neither panic disorder nor major depression. Psychopathology in children ≥5 years was compared between children with behavioral inhibition (N=64) and without (N=152). Results: Social anxiety disorder (social phobia or avoidant disorder) was significantly more likely to be found in the children with behavioral inhibition (17%) than in those without (5%). Noninhibited children were significantly more likely than inhibited children to have disruptive behavior disorders (20% versus 6%, respectively) and had higher scores on the attention problems scale of the Child Behavior Checklist (mean=52.1 versus 50.8). Conclusions: This study adds to the growing literature suggesting an association between behavioral inhibition and social anxiety disorder and an inverse relationship between inhibition and disruptive behavior disorders.
    • Further investigation of a chromosome 15 locus in schizophrenia: Analysis of affected sibpairs from the NIMH genetics initiative

      Leonard, Sherry; Gault, Judith; Moore, Theodore; Hopkins, Jan; Robinson, Misi; Olincy, Ann; Adler, Lawrence E.; Cloninger, C. Robert; Kaufmann, Charles A.; Tsuang, Ming T.; et al. (Wiley, 1998-07-10)
      Linkage of a neurophysiological deficit associated with schizophrenia, i.e., the failure to inhibit the auditory P50 response, was previously reported at chromosome 15q14. The marker with the highest pairwise lod score, D15S1360, was isolated from a yeast artificial chromosome containing a candidate gene, the α7-nicotinic acetylcholine receptor gene. In the present study, this linkage was further investigated in a subset of the NIMH Genetics Initiative schizophrenia families. These families have not been studied neurophysiologically, as were the families in the original report. Therefore, the DSMIII-R diagnosis of schizophrenia was used as the affected phenotype. Twenty families fulfilled the criteria of at least one sibpair concordant for schizophrenia, along with their two parents or another affected relative outside the nuclear family, available for genotyping. Sibpair analysis showed a significant proportion of D15S1360 alleles shared identical-by-descent (0.58; P < 0.0024). The results further support the involvement of this chromosomal locus in the genetic transmission of schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:308–312, 1998. © 1998 Wiley-Liss, Inc.
    • Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder

      Mick, Eric; Neale, Benjamin; Middleton, Frank A.; McGough, James J.; Faraone, Stephen V. (Wiley, 2008-12-05)
      We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N¼135) male) with mean age 9.2 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 andrs11134178;P¼3 10 6) fell short of the threshold for a genome-wide significant association. The most intriguing association amongsuggestivefindings(rs3792452;P¼2.6 10 5) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P 1 10 2. These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.
    • Genome-wide search for schizophrenia susceptibility loci: The NIMH genetics initiative and millennium consortium

      Cloninger, C. Robert; Kaufmann, Charles A.; Faraone, Stephen V.; Malaspina, Dolores; Svrakic, Dragan M.; Harkavy-Friedman, Jill; Suarez, Brian K.; Matise, Tara C.; Shore, David; Lee, Hang; et al. (Wiley, 1998-07-10)
      chizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:275–281, 1998. © 1998 Wiley-Liss, Inc.
    • Heterogeneity and the genetics of bipolar disorder

      Faraone, Stephen V.; Tsuang, Ming T. (Wiley, 2003-10-30)
    • Impact of Psychometrically Defined Deficits of Executive Functioning in Adults With Attention Deficit Hyperactivity Disorder

      Biederman, Joseph; Petty, Carter; Fried, Ronna; Fontanella, Jessie; Doyle, Alysa E.; Seidman, Larry J.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2006-10)
      Objective: The association between deficits in executive functioning and functional outcomes was examined among adults with attention deficit hyperactivity disorder (ADHD). Method: Subjects were adults who did (N=213) and did not (N=145) meet DSMIV criteria for ADHD. The authors defined having deficits in executive functioning as having at least two measures of executive functioning with scores 1.5 standard deviations below those of matched comparison subjects. Results: Significantly more adults with ADHD had deficits of executive functioning than comparison subjects. Deficits of executive functioning were associated with lower academic achievement, irrespective of ADHD status. Subjects with ADHD with deficits of executive functioning had a significantly lower socioeconomic status and a significant functional morbidity beyond the diagnosis of ADHD alone. Conclusions: Psychometrically defined deficits of executive functioning may help identify a subgroup of adults with ADHD at high risk for occupational and academic underachievement. More efforts are needed to identify cost-effective approaches to screen individuals with ADHD for deficits of executive functioning.
    • Impact of Tic Disorders on ADHD Outcome Across the Life Cycle: Findings From a Large Group of Adults With and Without ADHD

      Spencer, Thomas J.; Biederman, Joseph; Faraone, Stephen; Mick, Eric; Coffey, Barbara; Geller, Daniel; Kagan, Jake; Bearman, Sarah Kate; Wilens, Timothy (American Psychiatric Association Publishing, 2001-04)
      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.
    • Influence of Gender on Attention Deficit Hyperactivity Disorder in Children Referred to a Psychiatric Clinic

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Braaten, Ellen; Doyle, Alysa; Spencer, Thomas; Wilens, Timothy E.; Frazier, Elizabeth; Johnson, Mary Ann (American Psychiatric Association Publishing, 2002-01)
      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