Original Research

Psychiatric Comorbidities in Adolescents With Attention-Deficit Hyperactivity Disorder and Their Siblings
Li-Kuang Yang, MD1; Chi-Yung Shang, MD2; Susan Shur-Fen Gau, MD, PhD3
Objective: Despite high psychiatric comorbidities in adolescents with clinical diagnosis of attentiondeficit hyperactivity disorder (ADHD), little is known about psychiatric comorbidities in their siblings. We investigated the psychiatric comorbid conditions in adolescents with ADHD, their siblings, and healthy control subjects from their school. Method: The sample included 136 adolescent probands with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostic criteria; 136 siblings (47 affected and 89 unaffected) and 136 age- and sex-matched healthy school control subjects. All participants and their parents received the structured psychiatric interviews for current and lifetime DSM-IV psychiatric disorders of the participants. Results: The rate of ADHD (34.6%) in the siblings of probands with ADHD was about 7 times higher than in the general population. Probands with ADHD were significantly more likely than unaffected siblings (OR 6.38; 95% CI 3.43 to 11.88) and healthy school control subjects (OR 9.60; 95% CI 5.31 to 17.34) to have a DSM-IV psychiatric disorder, including oppositional defiant disorder (ODD), conduct disorder (CD), tic disorders, major depressive disorder, specific phobia (more than control subjects only), nicotine use disorder, and sleep disorders. The affected siblings were significantly more likely than healthy school control subjects to have ODD, CD, specific phobia, and to have consumed alcohol (ORs ranging from 2.30 to 20.16). Conclusions: Our findings suggest that siblings of probands with ADHD have increased risks for ADHD and that the affected siblings have more psychiatric comorbidities than healthy school control subjects. It warrants early identification of ADHD symptoms and other psychiatric comorbid conditions as well in siblings of adolescents with ADHD. Can J Psychiatry. 2011;56(5):281292. Clinical Implications High sibling recurrent risk for ADHD implies the need for screening for ADHD in siblings of adolescents with ADHD. Only affected siblings of patients with ADHD, rather than unaffected siblings, had increased psychiatric comorbidities. It warrants early recognition of comorbid conditions to offset future adverse outcomes among adolescents with ADHD and their siblings. There is questionable external validity for possible selection bias derived from clinic-based samples, and only probands with siblings were included. Although we conducted structured interviews of mothers and participants to confirm the clinical diagnosis of ADHD in probands and to make ADHD diagnosis of siblings, the possible recall bias might exist to confirm the presence of ADHD symptoms in adolescents aged 7 years and younger.

Limitations

Key Words: attention-deficit hyperactivity disorder, sibling, comorbidity, adolescence

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Original Research

DHD, characterized by inattention, hyperactivity, and impulsivity, is a common1,2 childhood-onset neuropsychiatric disorder. Literature has documented high levels of psychiatric comorbidity in children and adolescents with ADHD,3 including ODD,4 CD,4 anxiety disorders,5 MDD,5 SUDs,6 and tic disorders.4 Adolescents with subthreshold ADHD may also have high rates of psychiatric comobidity.3

internalizing, inattention, and hyperactivity symptoms,20 and impaired social function.18 However, data are limited as to whether increased psychiatric conditions in the siblings are related to ADHD or to other factors. Despite the large number of studies on ADHD comorbidities in Western populations, few have been conducted in Asian populations,4 and none of them have investigated the comorbidities in siblings of adolescents with ADHD. To fill the gap regarding our understanding of the rates of ADHD and other psychiatric disorders in the siblings of children and adolescents with ADHD, we investigated the current and lifetime psychiatric comorbidities among probands with ADHD and their affected and unaffected siblings, compared with healthy school control subjects. We hypothesized that siblings of ADHD probands, particularly affected siblings, were more likely to have other comorbid psychiatric disorders.

Psychiatric comorbidity in children with ADHD is associated with increased risks of ADHD in adulthood,7 decreased pharmacological8 and psychosocial9 treatment response, increased symptom severity,10,11 and impaired psychosocial functioning.12 Specifically, comorbidity with ODD and (or) CD predicts later illicit drug use6 and alcohol dependence.13 ADHD is one of the most heritable complex disorders with a mean heritability of 76%.14 The sibling recurrence risk ratio () for ADHD is around 9.0,15 with a greater figure (for example, = 26.2) for siblings of children with ADHD and comorbid psychiatric conditions, compared with siblings of healthy school control subjects without ADHD.16 In addition, relatives of children with ADHD also showed increased rates of other psychiatric disorders, such as CD, MDD, and bipolar disorders, implying the familial co-aggregation of ADHD and other psychiatric disorders.16 Children with ADHD have impaired relationships with their parents and siblings.17 Most studies involving siblings as a control group18 have demonstrated that patients with ADHD usually functioned worse than their siblings. However, the siblings may be influenced by the symptoms of children with ADHD and associated dysfunctional family and parental processes. For example, the siblings are more likely to have remedial tutoring, repeated grades, placement in special classes,18 and neuropsychological dysfunctioning such as executive dysfunction.19 The few studies focusing on the psychiatric comorbid conditions of the siblings18,20 have shown that siblings of children and adolescents with ADHD were at increased risks for psychopathology,18 symptoms of Abbreviations used in this article
ADHD CD DSM K-SADS-E attention-deficit hyperactivity disorder conduct disorder Diagnostic and Statistical Manual of Mental Disorders Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version major depressive disorder oppositional defiant disorder substance use disorder

Method
Participants
The sample consisted of 136 adolescent probands (male, 85.3%; mean age 12.8 years, SD 1.6) with clinical diagnosis of ADHD according to the DSM-IV diagnostic criteria. Adolescent probands were recruited consecutively from the child psychiatric clinic of the National Taiwan University Hospital if they had at least one biological sibling. We drafted the sibling whose age was closest to the probands with ADHD, if there were more than one biological sibling in the family. ADHD and other psychiatric diagnoses of the participants were confirmed by the Chinese K-SADS-E interview of the participants and the control subjects. The siblings were divided into the affected group (n = 47; boys, 57.5%; mean age 11.5 years, SD 2.4) and unaffected group (n = 89; boys, 37.1%; mean age 13.1 years, SD 3.4) based on clinical diagnosis and the Chinese K-SADS-E interview. The healthy school control subjects consisted of 136 subjects (male 85.3%) without lifetime ADHD based on the assessments of ADHD symptoms at age 6 years and currently using the Chinese K-SADS-E at the mean age of 12.4 years (SD 1.0). The healthy school control subjects were recruited from the same school districts according to the distribution of age and sex of probands with ADHD rather than by advertisement. The exclusion criteria of all of the participants were those who had a clinical diagnosis of psychotic disorders or autism spectrum disorders, or who had a full-scale IQ of less than 80 measured by the WISC. The Chinese K-SADS-E. The K-SADS-E is a semi-structured interview for the systematic assessment of both current and lifetime episodes of mental disorders in children and adolescents.21 The development of the Chinese K-SADS-E has been described elsewhere in detail.2,22 Previous studies have shown that the Chinese K-SADS-E is a reliable and valid instrument to assess DSM-IV child and adolescent
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Measures

MDD ODD SUD

WISC

Weschler Intelligence Scale for Children, Third Edition

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Psychiatric Comorbidities in Adolescents With Attention-Deficit Hyperactivity Disorder and Their Siblings

psychiatric disorders,23 and it has been used extensively in various clinic-based23 and community-based22,24 studies. Interviewer Training. Four interviewers, who had undergone 1 year of intensive clinical and research training in child psychiatry before the Chinese K-SADS-E interview training, reached over 90% agreement on all mental disorders assessed by the Chinese K-SADS-E (ranging from 98.25, SD 1.91 to 99.38, SD 1.06) against the rating of each item in the K-SADS-E by the corresponding author for 30 clinical subjects before study implementation. The interrater reliability of the Chinese K-SADS-E among the corresponding author and the 4 interviewers using 12 subjects was satisfactory for all mental disorders, with generalized kappa for each diagnosis ranging from 0.86 to 1.00. Their K-SADS-E interviews were audiotaped periodically and monitored by the corresponding author, who was blind to the personal information of the participants, to ensure the quality of the interviews. Best Estimate Diagnoses. The corresponding author was blind to the diagnostic status and name of the participant and was not involved in the direct K-SADS-E interviews. The corresponding author made all of the best estimates of each psychiatric diagnosis according to the data from the K-SADS-E interviews of participants and their mothers,25 medical records, and other self-administered questionnaires reported by the participants, parents, and teachers. The diagnostic coding was categorized into definite (meeting all DSM-IV diagnostic criteria), probable (either not meeting all DSM-IV symptoms criteria but more than one-half or no functional impairment), possible (some symptoms but no impairment), and no diagnosis. The participants who received a rating as definite or probable by best estimate were categorized as having a particular mental disorder.

unaffected siblings, and healthy school control subjects without a lifetime diagnosis of ADHD. The descriptive results regarding the differences in demographics and medical history among the 4 groups are presented by frequency and percentage for categorical variables using chi-square statistics for significant test, and by mean and SD for continuous variables using 1-way ANOVAs for significant test. We used a multilevel model with random and fixed effects to address the lack of independence of the probands with ADHD and their siblings within the same family and the lack of independence between the proband and matched healthy school control subjects. The Proc Glimmix procedure with binomial distribution and logit link for the nonlinear mixed model was used to compare the rates of psychiatric disorders among the 4 groups and compute the odds ratios and 95% confidence intervals. We used a linear multilevel model to compare the mean scores of ADHD symptoms rated by different informants. The Bonferroni method was used to adjust P values in post hoc analysis owing to multiple comparisons. We controlled for sex, age, full-scale IQ, use of methylphenidate, and parental educational levels in the statistical model.

Results
Sample Description
Table 1 presents the distribution of the demographics, fullscale IQ, and medical history for 4 groups. Among the siblings, 34.6% (47 of 136) were diagnosed with DSM-IV ADHD, giving a sibling a recurrence risk ratio of 7 as compared with the average rate of the school-age general population (5%). ADHD probands and their affected siblings had a higher proportion of male participants than the unaffected siblings. Affected siblings were younger and were more likely to be male than unaffected siblings. The healthy school control subjects had higher full-scale IQ, performance IQ, and verbal IQ than the other 3 groups. There were no significant IQ differences among probands with ADHD, affected siblings, and unaffected siblings except lower performance IQ in unaffected siblings than probands with ADHD. Parental educational levels were found to be lower among the ADHD families. Compared with the affected siblings, despite no difference in the age of onset of ADHD symptoms observed by the parents, ADHD probands had the first psychiatric visit at a younger age, were more likely to have been treated with methylphenidate previously or currently, and had longer treatment duration. There was no difference in paternal and maternal job types and households between the ADHD and control families.

Procedures

The Research Ethics Committee of the National Taiwan University Hospital approved our study prior to its implementation. We obtained written informed consent from both the participants and their parents. The WISC was administered to all participants to exclude those who had an IQ of less than 80. All of the 408 participants and their parents were interviewed independently by individual welltrained interviewers for the diagnosis of ADHD and other psychiatric disorders according to the DSM-IV diagnostic criteria by using the Chinese K-SADS-E. Medication information was obtained by interviews and validated by medical records of prescription. All interview data were cross-checked by research team members independently and the best estimate of the psychiatric diagnosis of each participant was made by the corresponding author blindly and independently.

Comparisons of ADHD Symptoms

Data Analysis

We conducted the data analysis using SAS software, version 9.1 (SAS Institute Inc, Cary, NC). The comparison groups were: patients with ADHD, affected siblings,
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There were significant differences in the severity of current ADHD symptoms reported by the participants and their mothers across the 4 groups (all P values < 0.001; Table 2). In general, for both child and mother reports, ADHD probands had the highest current inattention, hyperactivity, and impulsivity symptoms, followed by affected siblings,
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Table 1 Sample description: demographics and medical history

Siblings 4. Control subjects n = 136
116 (85.3) 20 (14.7) 112.02 (9.30) 111.81 (9.31) 110.84 (11.53) 12.39 (1.00) 45.86 (4.55) 43.29 (3.89) F = 15.32 (3,404) F = 17.67 (3,404) F = 9.08 (3,404) F = 6.89 (3,404) F = 0.40 (1,270) F = 2.53 (1,270) 2 = 18.93 (2) 58.2 30.2 11.6 49.2 40.9 9.9 83.3 12.5 4.2 2 = 10.62 (2) 69.4 24.8 5.8 2 = 2.23 (2) 17.6 80.0 2.4 4.0 60.0 36.0 91.7 8.3 4.37 (1.50) (n = 135) 7.37 (2.72) Methylphenidate, n (%)
Current use Ever used Duration, months, mean (SD)
a

Statistics

Variable Sex, n (%)

Male Female

1. ADHD n =136
116 (85.3) 20 (14.7) 105.14 (11.91) 102.96 (10.62) 107.30 (14.33) 12.78 (1.61) 45.49 (4.73) 42.46 (4.28)

2. Affected n = 47

3. Unaffected n = 89

2 or F (df) = 81.82 (3)

2

P <0.001

27 (57.5) 20 (42.5) 105.37 (11.91) 105.24 (11.46) 105.30 (14.02) 11.51 (2.42)

33 (37.1) 56 (62.9) 102.76 (10.35) 103.75 (11.21) 101.56 (12.25) 13.12 (3.37)

IQ, mean (SD)a

Full-scale Verbal Performance

<0.001 <0.001 <0.001 <0.001 0.53 0.11 <0.001

Age, years, mean (SD)

Child Father Mother

Education, %
Father College Senior high school Junior high school Mother College Senior high school Junior high school

0.005

Job type, %
Father Professional Technical personnel Nontechnical personnel Mother Professional Technical personnel Nontechnical personnel

0.33

23.4 72.1 4.5 2 = 3.91 (2) 8.0 66.1 25.9 2 = 0.87 (1) 94.9 5.1 F = 1.93 (1,181) F = 7.34 (1,158) 2 = 7.52 (1) 2 = 40.56 (1) F = 4.76 (1,132) 0.17 0.008 0.006 <0.001 0.03 0.35 0.14

Household, %
With 2 parents Others

Age of onset of ADHD, mean (SD) Age of first psychiatric visit, mean (SD)

4.76 (2.03) (n = 25) 8.96 (2.54) 14 (29.8) 20 (42.6) (n = 19) 11.76 (12.89)

72 (52.9) 120 (88.2) (n = 115) 22.88 (21.54)

Using Bonferroni methods to adjust for multiple comparisons: for full scale IQ, control subjects > ADHD, affected siblings, unaffected siblings: for verbal IQ, control subjects > ADHD, affected siblings, unaffected siblings; for performance IQ, control subjects > ADHD, affected siblings, unaffected siblings; ADHD > unaffected siblings

= no data

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Psychiatric Comorbidities in Adolescents With Attention-Deficit Hyperactivity Disorder and Their Siblings

Table 2 Comparison of symptoms of inattention, hyperactivity, and impulsivity among adolescents with ADHD, affected siblings, unaffected siblings, and healthy school control subjects
Sibling
Symptoms Child report
Inattention Hyperactivity Impulsivity Total score

Statistics 4. Control subjects Mean (SD)

n = 136 0.93 (1.72) 0.64 (1.31) 0.24 (0.70) 1.81 (2.86) n = 124 1.63 (3.12) 0.59 (1.43) 0.52 (1.25) 2.80 (5.09) 201.18 110.61 95.21 229.04 1 > 2 > 3, 4 1 > 2 > 3, 4 1 > 2 > 3, 4 1 > 2 > 3, 4 137.96 89.14 63.00 157.65 1, 2 > 3, 4 2 > 1 > 3, 4 1, 2 > 3, 4 1, 2 > 3, 4 Fa Bonferroni adjustment

1. ADHD Mean (SD)

n = 136 8.21 (4.62) 4.70 (3.28) 2.24 (2.00) 15.13 (8.09) n = 136 12.44 (4.60) 5.92 (3.65) 3.51 (2.13) 21.86 (7.87)

2. Affected Mean (SD) n = 47 8.53 (5.52) 5.60 (4.28) 2.53 (2.39) 16.66 (10.12) n = 47 8.89 (7.05) 4.68 (4.33) 2.38 (2.37) 15.96 (11.92)

3. Unaffected Mean (SD) n = 89 1.35 (2.26) 0.73 (1.71) 0.25 (0.79) 2.33 (3.60) n = 89 0.94 (2.10) 0.52 (1.45) 0.32 (0.81) 1.79 (3.46)

Mother report
Inattention Hyperactivity Impulsivity Total score
a

df = 3,130, P < 0.001

then unaffected siblings and healthy school control subjects, with the exception of the following. Based on child reports, affected siblings had the highest current hyperactivity symptoms, followed by ADHD probands, who both scored higher than unaffected siblings and healthy school control subjects.

Psychiatric Comorbid Conditions

Table 3 summarizes the rates and odds ratios with 95% confidence intervals of having psychiatric disorders among the 4 groups. ADHD probands were significantly more likely than unaffected siblings (OR 6.38; 95% CI 3.43 to 11.88) and healthy school control subjects (OR 9.60; 95% CI 5.31 to 17.34) to have a DSM-IV psychiatric disorder including ODD, CD, tic disorder, MDD, lifetime separation anxiety disorder, and sleep disorders. Moreover, ADHD probands were more likely than healthy school control subjects to have ODD, CD, MDD, specific phobia, SUDs (mainly nicotine use disorder), and sleep disorders. The significance of these results remained after further controlling for confounding factors and other comorbid conditions as mentioned above. The affected siblings were significantly more likely than healthy school control subjects to have a DSM-IV psychiatric disorder (OR 5.38; 95% CI 2.50 to 11.60) including ODD, CD, specific phobia, and ever use of alcohol (ORs ranging from 2.30 to 20.16). The affected siblings were significantly more likely than the unaffected siblings to have a DSM-IV psychiatric disorder (OR 3.58; 95% CI 1.61 to 7.98) including ODD, CD, and tic disorder. The significance of these results remained after further controlling for other comorbidities. There were no significant differences in the rates of psychiatric disorders between probands and affected
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siblings, and between unaffected siblings and healthy school control subjects with the following exceptions. ADHD probands were more likely than affected siblings to have ODD (current, OR 2.61; 95% CI 1.32 to 5.18; lifetime, OR 3.83; 95% CI 1.90 to 7.73), CD (current, OR 2.82; 95% CI 1.09 to 7.26; lifetime, OR 4.65; 95% CI 2.11 to 10.25), and current sleep disorders (OR 2.43; 95% CI 1.08 to 5.50). Unaffected siblings were significantly more likely than healthy school control subjects to have subthreshold ADHD (OR 3.71; 95% CI 1.34 to 10.25) and to have consumed alcohol (OR 2.20; 95% CI 1.27 to 3.82). Our study is among the few studies18,20 that employed clinical and psychiatric interviews of the adolescent participants and their parents to investigate the psychiatric comorbidity of the siblings of ADHD probands. In accordance with the diagnostic categorization, the ADHD probands had significantly higher symptom scores than the affected siblings, who in turn had significantly higher scores than the unaffected siblings and healthy school control subjects, except the child-reported current hyperactivity symptoms. Despite extensive studies on psychiatric comorbidity in ADHD in Western populations, our study is the first to investigate the comorbidity of probands with ADHD and their siblings in one study in the Asian population. Similar to previous studies,26 we found that ADHD probands and their affected siblings were significantly associated with the risks for ODD, CD, MDD, specific phobia, and any DSM-IV psychiatric disorder. Moreover, ADHD probands had higher rates of ODD, CD, and sleep problems than their affected siblings. The hypothesis of increased psychiatric comorbid conditions in the siblings was partially supported in our study as only siblings diagnosed with ADHD rather than unaffected siblings had increased psychiatric comorbidities.
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Discussion

Original Research

Table 3 Lifetime and current diagnosis of psychiatric disorders among probands with ADHD, affected siblings, unaffected siblings, and healthy school control subjects
Sibling
1. ADHD n =136 n (%) 89 (65.9) 102 (75.6) 40 (29.6) 76 (56.3) 10 (7.4) 11 (8.1) 8 (5.9) 19 (14.0) 18 (13.2) 30 (22.1) 5 (3.7) 5 (3.7) 28 (20.7) 31 (23.0) 11 (8.2) 17 (12.6) 8 (5.9) 20 (14.8) 7 (6.2) 9 (6.7) 2. Affected n = 47 n (%) 20 (42.6) 21 (44.7) 6 (12.8) 10 (21.3) 3 (6.4) 4 (8.5) 1 (2.1) 1 (2.1) 3 (6.4) 5 (10.6) 1 (2.1) 2 (4.3) 13 (27.7) 13 (27.7) 3 (6.4) 3 (6.4) 1 (2.1) 2 (4.3) 1 (2.1) 1 (2.1) 3. Unaffected n = 89 n (%) 7 (8.2) 10 (11.4) 1 (1.2) 2 (2.3) 0 (0) 0 (0) 1 (1.1) 5 (5.9) 2 (2.4) 7 (8.2) 0 (0) 1 (1.2) 14 (16.5) 15 (17.7) 6 (7.1) 6 (7.1) 2 (2.4) 3 (3.5) 4 (4.7) 4 (4.7) 4. Control subjects n = 136 n (%) 11 (8.1) 13 (9.6) 1 (0.7) 4 (2.9) 3 (2.2) 4 (2.9) 2 (1.5) 3 (2.2) 3 (2.2) 14 (10.3) 1 (0.7) 1 (0.7) 15 (11.0) 18 (13.2) 7 (5.2) 9 (6.6) 1 (0.7) 6 (4.4) 2 (1.5) 5 (3.7)

Psychiatric diagnosis ODD

Current Lifetime

CD
Current Lifetime

Tic disorder
Current Lifetime

Dysthymic disorder
Current Lifetime

MDD
Current Lifetime

Generalized anxiety disorder

Current Lifetime

Specific phobia
Current Lifetime

Social phobia
Current Lifetime

Separation anxiety disorder

Current Lifetime

Panic disorder
Current Lifetime

Consistent with many studies, ADHD probands in our study were found to have increased risks for a wide range of psychiatric disorders. The rates of ODD and CD in ADHD probands reported by previous research were in the ranges of 32%29 to 77%,30 and as 12%29 to 50%,27 respectively. Our findings supported the notion that ADHD, ODD, and CD were the most frequently co-occurring diagnoses.27,29 Owing to the higher comorbidity, more severe symptomatology and more adverse outcome, ADHD comorbid with CD has been suggested to constitute a distinct subtype of ADHD.8
2628

Psychiatric Comorbidities in ADHD Probands

ranging from 10.9%32 to 33%.3 In line with previous studies,28 we found that children and adolescents with ADHD were at higher risk for depressive disorders (MDD and dysthymic disorder) ranging from 6% to 22%, indicating an overlap between ADHD and depression. This assumption is supported by a recent report of common genes conferring liability to inattentive, hyperactive, and depressive symptoms in children and adolescents.33 The rate of anxiety disorders in ADHD in our study was similar to those reported in epidemiologic and clinical samples of ADHD, ranging from 25%27 to 33%.25 Consistent with Gau et al4,34 and a Korean study,35 we found that ADHD was related to phobic disorders such as specific phobia and separation anxiety disorder. Although the magnitude of
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In our study, ADHD is associated with tic disorder, with a similar rate in the Japanese population.31 However, the rate of tic disorders was lower than in Western populations,
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OR (95% CI)

1 compared with 4 21.99 (10.7245.10) 29.25 (14.5358.88) 56.75 (7.50429.24) 42.54 (14.66123.46) 0.03a 0.04
a

2 compared with 4 8.41 (3.5919.76) 7.64 (3.3717.32) 20.16 (2.30176.69) 9.15 (2.6631.42) 0.14a 0.09
a

1 compared with 3 21.56 (9.1350.92) 24.11 (11.1252.26) 35.92 (4.74272.37) 56.45 (13.15242.31) 0.007a 0.004
a

2 compared with 3 8.25 (3.1121.88) 6.30 (2.61-15.22) 12.76 (1.45112.37) 12.14 (2.4859.35) 0.04a 0.02a 1.91 (0.1132.10) 0.35 (0.043.14) 2.83 (0.4517.88) 1.35 (0.394.65) 0.36a 3.73 (0.3243.29) 1.94 (0.824.61) 1.78 (0.764.20) 0.89 (0.213.82) 0.91 (0.213.93) 0.87 (0.0710.49) 1.22 (0.197.75) 0.44 (0.054.14) 0.44 (0.054.14) continued

4.19 (0.8620.38) 7.19 (2.0525.30) 6.76 (1.9223.81) 2.46 (1.224.98) 0.09a 5.19 (0.5945.98) 2.11 (1.064.19) 1.95 (1.033.72) 1.63 (0.604.41) 2.02 (0.854.81) 8.17 (0.9768.77) 3.77 (1.449.87) 3.66 (0.7418.24) 1.87 (0.605.80)

1.46 (0.1316.81) 0.96 (0.109.71) 3.02 (0.5815.76) 1.04 (0.353.15) 0.38a 6.00 (0.5269.32) 3.08 (1.337.16) 2.51 (1.115.67) 1.25 (0.305.14) 0.96 (0.243.82) 2.72 (0.1647.04) 0.96 (0.185.04) 1.46 (0.1316.82) 0.57 (0.065.11)

5.50 (0.6645.62) 2.60 (0.927.33) 6.33 (1.4128.42) 3.19 (1.327.73) 0.08a 3.23 (0.3628.72) 1.33 (0.652.71) 1.39 (0.702.78) 1.17 (0.413.32) 1.91 (0.715.13) 2.61 (0.5312.91) 4.78 (1.3616.84) 1.11 (0.313.95) 1.45 (0.434.91)

association between phobia and ADHD may decrease with age,36 this association was reported to last until adulthood.5 The rates of nicotine use were significantly higher in ADHD probands than in healthy school control subjects, ranging from 4.4% to 16.2%. ADHD has been recognized as one predictor for early initiation of cigarette smoking37 and nicotine use disorder24 at adolescence. However, the rate of nicotine use estimated in our study was lower than in Western data38 (for example, 46% of subjects with ADHD as daily smokers by age 17 years). Because substance use or abuse is a developmental phenomenon and increases linearly from early to late adolescence,39 a lower rate of nicotine use in our study may be accounted for by the relatively younger age at assessment and lower rate of SUD
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in Taiwan than in Western countries.24 Likewise, given that ADHD was associated with alcohol abuse or dependence found in our study, these 2 points can explain lower rates of alcohol abuse or dependence in the ADHD probands (3.7%) than in Molina and Pelhams6 report (15.5%). Both ADHD and sleep problems are the major concerns of the parents and in clinical practice.40 Findings4044 provide strong evidence to support the relation between ADHD and sleep problems. Studies40 showed that adolescents with a childhood diagnosis of ADHD, regardless of persistence of ADHD at adolescence or not, were more likely to have various sleep problems such as dyssomnia, sleepwake pattern disturbance, and breathing-related sleep problems. ADHD symptoms were positively associated with the
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Table 3 continued
Sibling 1. ADHD n =136 n (%)
1 (0.7) 2 (1.5) 6 (4.4) 12 (8.9) 22 (16.2) 10 (7.4) 6 (4.4)
9 (6.6)

Psychiatric diagnosis Agoraphobia

Current Lifetime

2. Affected n = 47 n (%) 0 (0) 0 (0) 1 (2.1) 2 (4.3) 2 (4.3) 0 (0) 0 (0)

0 (0)

3. Unaffected n = 89 n (%) 1 (1.2) 1 (1.2) 3 (3.5) 3 (3.5) 6 (7.1) 0 (0) 0 (0)

0 (0)

4. Control subjects n = 136 n (%) 0 (0) 0 (0) 6 (4.4) 8 (5.9) 5 (3.7) 0 (0) 0 (0)
0 (0)

Obsessivecompulsive disorder
Current Lifetime

Nicotine
Ever use Regular use Current abuse or dependence

Lifetime abuse or dependence Alcohol

Ever use Regular use Current abuse or dependence Lifetime abuse or dependence

65 (47.8) 4 (3.0) 2 (1.5) 5 (3.7) 8 (5.9) 49 (36.6) 74 (55.2) 112 (82.4)

29 (61.7) 0 (0) 0 (0) 0 (0) 2 (4.3) 9 (19.2) 14 (29.8) 34 (72.3)

54 (60.7) 0 (0) 0 (0) 0 (0) 1 (1.2) 11 (12.9) 16 (18.8) 38 (42.7)

56 (41.2) 0 (0) 0 (0) 0 (0) 0 (0) 17 (12.5) 32 (23.5) 45 (33.1)

Use of betel nut Sleep disorders

Current Lifetime

Any psychiatric disorder

a

Fisher exact test P value; = neither the OR (95% CI) nor P by Fisher exact test owing to zero observation

risks for sleep problems in children41 and young adults.42 Similarly, our study indicated that ADHD probands had higher rates of sleep problems than those without ADHD.

Psychiatric Comorbidities in Affected Siblings

Our findings demonstrated that the affected siblings also had higher risks for ODD, CD, specific phobia, and ever use of alcohol. These findings showed that the affected siblings had a similar pattern of comorbid psychiatric disorders to ADHD probands. This provides converging evidence for the validity of their ADHD diagnoses and for the assertion that ADHD is a familial disorder.18 The comorbid rates of ODD and CD in affected siblings (44.7%, 12.8%) were significantly lower than the figures in the adolescent probands (75.6%, 29.6%). As ADHD probands had significantly more severe ADHD symptoms than affected siblings, the differences in ODD and CD comorbidity rates may be accounted for by the increased severity of ADHD symptoms in the proband group.11
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Compared with the proband group, affected siblings did not demonstrate as many psychiatric comorbid conditions as probands. As affected siblings had lower symptom severity than probands, the former may connect to clinical services less often or seek psychiatric service as they age. Our previous work45 has found that clinic-based children with ADHD had more developmental problems, comorbid conditions, and impaired function than community-based children with ADHD. In addition, previous studies have shown that severity of ADHD symptoms was associated with internalizing comorbid symptoms10 and SUDs,6 which may explain why there was no significant comorbidity with MDD or SUDs in the affected siblings group. However, because comorbidity with MDD and SUDs in ADHD is a function of age,2 follow-up of affected siblings with a longer period is warranted to clarify these associations.

Psychiatric Comorbidities in Unaffected Siblings

The unaffected siblings did not have higher rates of psychiatric disorders like the probands and affected siblings
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OR (95% CI)

1 compared with 4 0.498a 0.25a 1.01 (0.313.24) 1.56 (0.613.98) 5.04 (1.8213.98) <0.001a 0.02
a

2 compared with 4 0.47 (0.054.10) 0.71 (0.143.53) 1.19 (0.226.51)

1 compared with 3 0.48a 0.44a 1.27 (0.315.30) 2.67 (0.729.86) 2.58 (0.996.73) 0.007a 0.05
a

2 compared with 3 0.64a 0.64a 0.59 (0.066.01) 1.22 (0.197.67) 0.61(0.123.23)

0.002a

0.01a

1.31 (0.812.12) 0.06

a

2.30 (1.164.57) 0.06a 1.66 (0.684.06) 1.38 (0.652.94) 5.38 (2.5011.60)

0.59 (0.341.03) 0.14

a

1.04 (0.502.17) 0.24a 1.59 (0.604.22) 1.84 (0.804.28) 3.58 (1.617.98)

0.25a 0.03a 0.004a 4.04 (2.167.53) 4.01 (2.366.82) 9.60 (5.3117.34)

0.38a 0.09a 0.07a 3.88 (1.878.06) 5.34 (2.7910.22) 6.38 (3.4311.88)

in our study, suggesting psychiatric comorbidity was more likely to be related to the presence of ADHD symptoms. Previous studies have also shown that ADHD probands and their unaffected siblings reported differences in sibling interaction, parental treatment, and peer characteristics.46 In our study, there were few differences between unaffected siblings and healthy school control subjects, indicating that unaffected siblings are more like their typically developing counterparts.47 However, further follow-up of unaffected siblings is needed to determine whether a yet unexpressed vulnerability to psychopathology will emerge in their transition from adolescence into adulthood.18 The only exception was that unaffected siblings had an increased risk of ever use of alcohol. The link between ADHD and alcoholism has been seen in family members of children with ADHD, and ADHD with alcohol dependence predicts alcohol dependence in their relatives.48 Familial risk analyses suggest that the association between ADHD and alcohol dependence is consistent with independent transmission, and alcohol dependence in relatives is predicted by ADHD probands with comorbid alcohol
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dependence.48 Although our findings showed that the degree of alcohol use differed between the ADHD probands and their unaffected siblings, the risks of comorbid alcohol use were indeed higher in the affected families than in the healthy school control families, lending support to the notion that ADHD may be a familial predictor for alcohol use.

Limitations

There are 2 major limitations of our study. First, the questionable external validity needs to be examined further for possible selection bias (derived from a clinic-based sample). Only ADHD probands with siblings were included. Second, although we had carefully assessed childhood ADHD symptoms by using the Chinese K-SADS-E interview to confirm the diagnosis of ADHD according to the DSM-IV diagnostic criteria, the possible recall bias might still exist. The strengths of our study are an adequate sample size from a relatively less studied population; the comprehensive
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assessments of ADHD and other psychiatric disorders by clinical and psychiatric interviews of the participants and their parents. Next, we collected complete information about demographic data, IQ, lifetime and current ADHD and other psychiatric disorders, age at onset of ADHD, and medication treatment history, which were validated by detailed medical records. Lastly, a multilevel model was used for data analysis to control for lack of independence between probands and siblings within the same family and between probands and matched healthy control subjects.

Conclusions

Our findings suggest that although a proportion of siblings of probands with ADHD may not have as severe symptoms of ADHD as probands, or be as likely as the probands to be comorbid with some psychiatric disorders, they had a diagnosis of ADHD with a sibling recurrence risk ratio of 7. Hence health professionals are recommended to screen for ADHD and other psychiatric disorders as well among siblings of adolescents with ADHD and to provide appropriate psychosocial and pharmacological treatment for these disorders if needed. Such diagnosis and treatment procedures may improve family functioning and result in better outcome for ADHD probands and their affected siblings. Moreover, recognition of the comorbid patterns throughout the developmental stage is likely to be an important preventive strategy to offset the long-term adverse psychiatric outcomes among children with ADHD. Further, no increased comorbid conditions in unaffected siblings indicate no family aggregation of psychiatric comorbid conditions with ADHD, with the exception of use of alcohol.

Acknowledgements

This work was supported by grants from the National Health Research Institute (NHRI-EX989407PC), Taiwan. The preparation of this manuscript was supported by the National Science Council (NSC962628-B-002069MY3), Taiwan. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. We warmly thank all of the participants and families for their contribution to our study.

References

1. Faraone SV, Sergeant J, Gillberg C, et al. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry. 2003;2(2):104113. 2. Gau SS, Chong MY, Chen TH, et al. A 3-year panel study of mental disorders among adolescents in Taiwan. Am J Psychiatry. 2005;162(7):13441350. 3. Kadesjo B, Gillberg C. The comorbidity of ADHD in the general population of Swedish school-age children. J Child Psychol Psychiatry. 2001;42(4):487492.

4. Gau SS, Ni HC, Shang CY, et al. Psychiatric comorbidity among children and adolescents with and without persistent attention-deficit hyperactivity disorder. Aust N Z J Psychiatry. 2010;44(2):135143. 5. Park S, Cho MJ, Chang SM, et al. Prevalence, correlates, and comorbidities of adult ADHD symptoms in Korea: results of the Korean epidemiologic catchment area study. Psychiatry Res. 2011;186(2-3):378383. Epub 2010 Aug 19. 6. Molina BS, Pelham WE Jr. Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD. J Abnorm Psychol. 2003;112(3):497507. 7. Lara C, Fayyad J, de Graaf R, et al. Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biol Psychiatry. 2009;65(1):4654. 8. Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry. 2001;40(2):147158. 9. Antshel KM, Remer R. Social skills training in children with attention deficit hyperactivity disorder: a randomized-controlled clinical trial. J Clin Child Adolesc Psychol. 2003;32(1):153165. 10. Connor DF, Edwards G, Fletcher KE, et al. Correlates of comorbid psychopathology in children with ADHD. J Am Acad Child Adolesc Psychiatry. 2003;42(2):193200. 11. Hurtig T, Ebeling H, Taanila A, et al. ADHD and comorbid disorders in relation to family environment and symptom severity. Eur Child Adolesc Psychiatry. 2007;16(6):362369. 12. Blackman GL, Ostrander R, Herman KC. Children with ADHD and depression: a multisource, multimethod assessment of clinical, social, and academic functioning. J Atten Disord. 2005;8(4):195207. 13. Knop J, Penick EC, Nickel EJ, et al. Childhood ADHD and conduct disorder as independent predictors of male alcohol dependence at age 40. J Stud Alcohol Drugs. 2009;70(2):169177. 14. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57(11):13131323. 15. Chen W, Zhou K, Sham P, et al. DSM-IV combined type ADHD shows familial association with sibling trait scores: a sampling strategy for QTL linkage. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(8):14501460. 16. Faraone SV, Biederman J, Monuteaux MC. Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder. Genet Epidemiol. 2000;18(1):116. 17. Mikami AY, Pfiffner LJ. Sibling relationships among children with ADHD. J Atten Disord. 2008;11(4):482492. 18. Faraone SV, Biederman J, Mennin D, et al. A prospective fouryear follow-up study of children at risk for ADHD: psychiatric, neuropsychological, and psychosocial outcome. J Am Acad Child Adolesc Psychiatry. 1996;35(11):14491459. 19. Gau SS, Shang CY. Executive functions as endophenotypes in ADHD: evidence from the Cambridge Neuropsychological Test Battery (CANTAB). J Child Psychol Psychiatry. 2010;51(7):838849. 20. Listug-Lunde L, Zevenbergen AA, Petros TV. Psychological symptomatology in siblings of children with ADHD. J Atten Disord. 2008;12(3):239247. 21. Puig-Antich J, Chambers W. The Schedule for Affective Disorders and Schizophrenia for School-Age ChildrenEpidemiologic Version (K-SADS-E). New York (NY): New York State Psychiatric Institute, Biometrics Research; 1978. 22. Gau SF, Soong WT. Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a casecontrol study. Aust N Z J Psychiatry. 1999;33(5):734739. 23. Gau SS, Huang YS, Soong WT, et al. A randomized, doubleblind, placebo-controlled clinical trial on once-daily atomoxetine in Taiwanese children and adolescents with attention-deficit/ hyperactivity disorder. J Child Adolesc Psychopharmacol. 2007;17(4):447460. W La Revue canadienne de psychiatrie, vol 56, no 5, mai 2011

290

Psychiatric Comorbidities in Adolescents With Attention-Deficit Hyperactivity Disorder and Their Siblings
24. Gau SS, Chong MY, Yang P, et al. Psychiatric and psychosocial predictors of substance use disorders among adolescents: longitudinal study. Br J Psychiatry. 2007;190:4248. 25. Bird HR, Gould MS, Staghezza BM. Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Am Acad Child Adolesc Psychiatry. 1993;32(2):361368. 26. Spencer T, Biederman J, Coffey B, et al. Tourette disorder and ADHD. Adv Neurol. 2001;85:5777. 27. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry. 1991;148(5):564577. 28. Angold A, Costello EJ, Erkanli A. Comorbidity. J Child Psychol Psychiatry. 1999;40(1):5787. 29. August GJ, Realmuto GM, MacDonald AW 3rd, et al. Prevalence of ADHD and comorbid disorders among elementary school children screened for disruptive behavior. J Abnorm Child Psychol. 1996;24(5):571595. 30. Biederman J, Faraone S, Milberger S, et al. Predictors of persistence and remission of ADHD into adolescence: results from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry. 1996;35(3):343351. 31. Ishii T, Takahashi O, Kawamura Y, et al. Comorbidity in attention deficit-hyperactivity disorder. Psychiatry Clin Neurosci. 2003;57(5):457463. 32. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56(12):10731086. 33. Cole J, Ball HA, Martin NC, et al. Genetic overlap between measures of hyperactivity/inattention and mood in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2009;48(11):10941101. 34. Gau SS, Lin YJ, Cheng AT, et al. Psychopathology and symptom remission at adolescence among children with attention-deficithyperactivity disorder. Aust N Z J Psychiatry. 2010;44(4):323332. 35. Kim SJ, Kim BN, Cho SC, et al. The prevalence of specific phobia and associated co-morbid features in children and adolescents. J Anxiety Disord. 2010;24(6):629634. 36. Marmorstein NR. Relationships between anxiety and externalizing disorders in youth: the influences of age and gender. J Anxiety Disord. 2007;21(3):420432. 37. Milberger S, Biederman J, Faraone SV, et al. ADHD is associated with early initiation of cigarette smoking in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1997;36(1):3744. 38. Lambert NM, Hartsough CS. Prospective study of tobacco smoking and substance dependencies among samples of ADHD and nonADHD participants. J Learn Disabil. 1998;31(6):533544. 39. Young SE, Corley RP, Stallings MC, et al. Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates. Drug Alcohol Depend. 2002;68(3):309322. 40. Gau SS, Chiang HL. Sleep problems and disorders among adolescents with persistent and subthreshold attention-deficit/ hyperactivity disorders. Sleep. 2009;32(5):671679. 41. Chiang HL, Gau SS, Ni HC, et al. Association between symptoms and subtypes of attention-deficit hyperactivity disorder and sleep problems/disorders. J Sleep Res. 2010;19(4):535545. 42. Gau SS, Kessler RC, Tseng WL, et al. Association between sleep problems and symptoms of attention-deficit/hyperactivity disorder in young adults. Sleep. 2007;30(2):195201. 43. Cortese S, Faraone SV, Konofal E, et al. Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies. J Am Acad Child Adolesc Psychiatry. 2009;48(9):894908. 44. Sung V, Hiscock H, Sciberras E, et al. Sleep problems in children with attention-deficit/hyperactivity disorder: prevalence and the effect on the child and family. Arch Pediatr Adolesc Med. 2008;162(4):336342. 45. Gau SS, Lin YJ, Shang CY, et al. Emotional/behavioral problems and functional impairment in clinic- and community-based children with attention-deficit/hyperactivity disorder in Taiwan. J Abnorm Child Psychol. 2010;38(4):521532. 46. Buschgens CJ, van Aken MA, Swinkels SH, et al. Differential family and peer environmental factors are related to severity and comorbidity in children with ADHD. J Neural Transm. 2008;115(2):177186. 47. Jones KB, Welsh RK, Glassmire DM, et al. Psychological functioning in siblings of children with attention deficit hyperactivity disorder. J Child Fam Stud. 2006;15:757763. 48. Biederman J, Petty CR, Wilens TE, et al. Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders. Am J Psychiatry. 2008;165(1):107115.

Manuscript received December 2010, revised, and accepted January 2011.

1

Child and Adolescent Psychiatry Fellow, Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; Child and Adolescent Psychiatry Fellow, Department of Psychiatry, Beitou Armed Forces Hospital, Taipei, Taiwan.

Staff Psychiatrist, Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; Instructor, Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan.

Professor and Chairperson, Department of Psychiatry, National Taiwan University and College of Medicine, Taipei, Taiwan; Professor, Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan; Professor, Graduate Institute of Occupational Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan.

Address for correspondence: Dr S S Gau, Department of Psychiatry, National Taiwan University Hospital, No. 7, ChungShan South Road, Taipei 10002 Taiwan; gaushufe@ntu.edu.tw

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Rsum : Les comorbidits psychiatriques chez les adolescents souffrant du trouble dhyperactivit avec dficit de lattention et chez leurs frres et surs
Objectif : Malgr les comorbidits psychiatriques leves chez les adolescents ayant reu un diagnostic clinique du trouble du dficit de lattention avec hyperactivit (TDAH), nous en savons trs peu sur les comorbidits psychiatriques chez leurs frres et surs. Nous avons recherch les affections psychiatriques comorbides chez les adolescents souffrant de TDAH, leurs frres et surs, et des sujets tmoins en sant de leur cole. Mthode : Lchantillon comprenait 136 adolescent proposants souffrant de TDAH selon les critres diagnostiques du Manuel diagnostique et statistique des troubles mentaux, 4e dition (DSM-IV); 136 frres et surs (47 affects et 89 non affects) et 136 sujets tmoins en sant de lcole assortis selon lge et le sexe. Tous les participants et leurs parents ont reu les entrevues psychiatriques structures pour les troubles psychiatriques actuels et de dure de vie du DSM-IV des participants. Rsultats : Le taux de TDAH (34,6 %) chez les frres et surs des proposants souffrant de TDAH tait environ 7 fois plus lev que dans la population gnrale. Les proposants souffrant de TDAH taient significativement plus susceptibles que leurs frres et surs non affects (RC 6,38; IC 95 % 3,43 11,88) et que les sujets tmoins en sant de lcole (RC 9,60; IC 95 % 5,31 17,34) davoir un trouble psychiatrique du DSM-IV, notamment le trouble oppositionnel avec provocation (TOP), le trouble des conduites (TC), les troubles tics, le trouble dpressif majeur, une phobie spcifique (plus que les sujets tmoins seulement), le trouble li la nicotine, et les troubles du sommeil. Les frres et surs affects taient significativement plus susceptibles que les sujets tmoins en sant de lcole davoir un TOP, un TC, une phobie spcifique, et davoir consomm de lalcool (RC 2,30 20,16). Conclusions : Nos rsultats suggrent que les frres et surs des proposants souffrant de TDAH ont des risques accrus de TDAH et que les frres et surs affects ont plus de comorbidits psychiatriques que les sujets tmoins en sant de lcole. Cela justifie lidentification prcoce des symptmes du TDAH et dautres affections psychiatriques comorbides galement chez les frres et surs des adolescents souffrant de TDAH.

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