ad en Adolescentes Con Tdah y Sus Hermanos

281The Canadian Journal of Psychiatry, Vol 56, No 5, May 2011 W

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 attention-deficit 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):281–292.

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.

Limitations• 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.

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

282 W La Revue canadienne de psychiatrie, vol 56, no 5, mai 2011

Original Research

ADHD, 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

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 (λ) for ADHD is around 9.0,15 with a greater figure (for example, λ = 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

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.

Method

ParticipantsThe 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.

MeasuresThe 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

Abbreviations used in this articleADHD attention-deficit hyperactivity disorder

CD conduct disorder

DSM Diagnostic and Statistical Manual of Mental Disorders

K-SADS-E Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children— Epidemiologic Version

MDD major depressive disorder

ODD oppositional defiant disorder

SUD substance use disorder

WISC Weschler Intelligence Scale for Children, Third Edition



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.

ProceduresThe 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 well-trained 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.

Data AnalysisWe conducted the data analysis using SAS software, version 9.1 (SAS Institute Inc, Cary, NC). The comparison groups were: patients with ADHD, affected siblings,

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 DescriptionTable 1 presents the distribution of the demographics, full-scale 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.

Comparisons of ADHD SymptomsThere 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,


Original Research

Table 1 Sample description: demographics and medical history Siblings Statistics

Variable

1. ADHDn =136

2. Affected

n = 47

3. Unaffected

n = 89

4. Control subjectsn = 136

χ2 or F (df)

P

Sex, n (%) χ2 = 81.82 (3) <0.001

Male 116 (85.3) 27 (57.5) 33 (37.1) 116 (85.3)

Female 20 (14.7) 20 (42.5) 56 (62.9) 20 (14.7)

IQ, mean (SD)a

Full-scale 105.14 (11.91) 105.37 (11.91) 102.76 (10.35) 112.02 (9.30) F = 15.32 (3,404) <0.001

Verbal 102.96 (10.62) 105.24 (11.46) 103.75 (11.21) 111.81 (9.31) F = 17.67 (3,404) <0.001

Performance 107.30 (14.33) 105.30 (14.02) 101.56 (12.25) 110.84 (11.53) F = 9.08 (3,404) <0.001

Age, years, mean (SD)

Child 12.78 (1.61) 11.51 (2.42) 13.12 (3.37) 12.39 (1.00) F = 6.89 (3,404) <0.001

Father 45.49 (4.73) 45.86 (4.55) F = 0.40 (1,270) 0.53

Mother 42.46 (4.28) 43.29 (3.89) F = 2.53 (1,270) 0.11

Education, %

Father χ2 = 18.93 (2) <0.001

≥College 58.2 83.3

Senior high school 30.2 12.5

≤Junior high school 11.6 4.2

Mother χ2 = 10.62 (2) 0.005

≥College 49.2 69.4

Senior high school 40.9 24.8

≤Junior high school 9.9 5.8

Job type, %

Father χ2 = 2.23 (2) 0.33

Professional 17.6 23.4

Technical personnel 80.0 72.1

Nontechnical personnel 2.4 4.5

Mother χ2 = 3.91 (2) 0.14

Professional 4.0 8.0

Technical personnel 60.0 66.1

Nontechnical personnel 36.0 25.9

Household, % χ2 = 0.87 (1) 0.35

With 2 parents 91.7 94.9

Others 8.3 5.1

Age of onset of ADHD, mean (SD) 4.37 (1.50) 4.76 (2.03) ― ― F = 1.93 (1,181) 0.17

Age of first psychiatric visit, mean (SD) (n = 135) (n = 25)

7.37 (2.72) 8.96 (2.54) ― ― F = 7.34 (1,158) 0.008

Methylphenidate, n (%)

Current use 72 (52.9) 14 (29.8) ― ― χ2 = 7.52 (1) 0.006

Ever used 120 (88.2) 20 (42.6) ― ― χ2 = 40.56 (1) <0.001

(n = 115) (n = 19)

Duration, months, mean (SD) 22.88 (21.54) 11.76 (12.89) ― ― F = 4.76 (1,132) 0.03a 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



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 ConditionsTable 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

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).

DiscussionOur 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.

Table 2 Comparison of symptoms of inattention, hyperactivity, and impulsivity among adolescents with ADHD, affected siblings, unaffected siblings, and healthy school control subjects

Sibling Statistics Symptoms

1. ADHD Mean (SD)

2. Affected Mean (SD)

3. Unaffected Mean (SD)

4. Control subjects Mean (SD)

Fa

Bonferroni adjustment

Child report n = 136 n = 47 n = 89 n = 136

Inattention 8.21 (4.62) 8.53 (5.52) 1.35 (2.26) 0.93 (1.72) 137.96 1, 2 > 3, 4

Hyperactivity 4.70 (3.28) 5.60 (4.28) 0.73 (1.71) 0.64 (1.31) 89.14 2 > 1 > 3, 4

Impulsivity 2.24 (2.00) 2.53 (2.39) 0.25 (0.79) 0.24 (0.70) 63.00 1, 2 > 3, 4

Total score 15.13 (8.09) 16.66 (10.12) 2.33 (3.60) 1.81 (2.86) 157.65 1, 2 > 3, 4

Mother report n = 136 n = 47 n = 89 n = 124

Inattention 12.44 (4.60) 8.89 (7.05) 0.94 (2.10) 1.63 (3.12) 201.18 1 > 2 > 3, 4

Hyperactivity 5.92 (3.65) 4.68 (4.33) 0.52 (1.45) 0.59 (1.43) 110.61 1 > 2 > 3, 4

Impulsivity 3.51 (2.13) 2.38 (2.37) 0.32 (0.81) 0.52 (1.25) 95.21 1 > 2 > 3, 4

Total score 21.86 (7.87) 15.96 (11.92) 1.79 (3.46) 2.80 (5.09) 229.04 1 > 2 > 3, 4a df = 3,130, P < 0.001


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 OR (95% CI) Psychiatric diagnosis

1. ADHD n =136 n (%)

2. Affected n = 47 n (%)

3. Unaffected n = 89 n (%)

4. Control subjects n = 136 n (%)

1 compared with 4

2 compared with 4

1 compared with 3

2 compared with 3

ODD

Current 89 (65.9) 20 (42.6) 7 (8.2) 11 (8.1) 21.99 (10.72–45.10) 8.41 (3.59–19.76) 21.56 (9.13–50.92) 8.25 (3.11–21.88)

Lifetime 102 (75.6) 21 (44.7) 10 (11.4) 13 (9.6) 29.25 (14.53–58.88) 7.64 (3.37–17.32) 24.11 (11.12–52.26) 6.30 (2.61–-15.22)

CD

Current 40 (29.6) 6 (12.8) 1 (1.2) 1 (0.7) 56.75 (7.50–429.24) 20.16 (2.30–176.69) 35.92 (4.74–272.37) 12.76 (1.45–112.37)

Lifetime 76 (56.3) 10 (21.3) 2 (2.3) 4 (2.9) 42.54 (14.66–123.46) 9.15 (2.66–31.42) 56.45 (13.15–242.31) 12.14 (2.48–59.35)

Tic disorder

Current 10 (7.4) 3 (6.4) 0 (0) 3 (2.2) 0.03a 0.14a 0.007a 0.04a

Lifetime 11 (8.1) 4 (8.5) 0 (0) 4 (2.9) 0.04a 0.09a 0.004a 0.02a

Dysthymic disorder

Current 8 (5.9) 1 (2.1) 1 (1.1) 2 (1.5) 4.19 (0.86–20.38) 1.46 (0.13–16.81) 5.50 (0.66–45.62) 1.91 (0.11–32.10)

Lifetime 19 (14.0) 1 (2.1) 5 (5.9) 3 (2.2) 7.19 (2.05–25.30) 0.96 (0.10–9.71) 2.60 (0.92–7.33) 0.35 (0.04–3.14)

MDD

Current 18 (13.2) 3 (6.4) 2 (2.4) 3 (2.2) 6.76 (1.92–23.81) 3.02 (0.58–15.76) 6.33 (1.41–28.42) 2.83 (0.45–17.88)

Lifetime 30 (22.1) 5 (10.6) 7 (8.2) 14 (10.3) 2.46 (1.22–4.98) 1.04 (0.35–3.15) 3.19 (1.32–7.73) 1.35 (0.39–4.65)

Generalized anxiety disorder

Current 5 (3.7) 1 (2.1) 0 (0) 1 (0.7) 0.09a 0.38a 0.08a 0.36a

Lifetime 5 (3.7) 2 (4.3) 1 (1.2) 1 (0.7) 5.19 (0.59–45.98) 6.00 (0.52–69.32) 3.23 (0.36–28.72) 3.73 (0.32–43.29)

Specific phobia

Current 28 (20.7) 13 (27.7) 14 (16.5) 15 (11.0) 2.11 (1.06–4.19) 3.08 (1.33–7.16) 1.33 (0.65–2.71) 1.94 (0.82–4.61)

Lifetime 31 (23.0) 13 (27.7) 15 (17.7) 18 (13.2) 1.95 (1.03–3.72) 2.51 (1.11–5.67) 1.39 (0.70–2.78) 1.78 (0.76–4.20)

Social phobia

Current 11 (8.2) 3 (6.4) 6 (7.1) 7 (5.2) 1.63 (0.60–4.41) 1.25 (0.30–5.14) 1.17 (0.41–3.32) 0.89 (0.21–3.82)

Lifetime 17 (12.6) 3 (6.4) 6 (7.1) 9 (6.6) 2.02 (0.85–4.81) 0.96 (0.24–3.82) 1.91 (0.71–5.13) 0.91 (0.21–3.93)

Separation anxiety disorder

Current 8 (5.9) 1 (2.1) 2 (2.4) 1 (0.7) 8.17 (0.97–68.77) 2.72 (0.16–47.04) 2.61 (0.53–12.91) 0.87 (0.07–10.49)

Lifetime 20 (14.8) 2 (4.3) 3 (3.5) 6 (4.4) 3.77 (1.44–9.87) 0.96 (0.18–5.04) 4.78 (1.36–16.84) 1.22 (0.19–7.75)

Panic disorder

Current 7 (6.2) 1 (2.1) 4 (4.7) 2 (1.5) 3.66 (0.74–18.24) 1.46 (0.13–16.82) 1.11 (0.31–3.95) 0.44 (0.05–4.14)

Lifetime 9 (6.7) 1 (2.1) 4 (4.7) 5 (3.7) 1.87 (0.60–5.80) 0.57 (0.06–5.11) 1.45 (0.43–4.91) 0.44 (0.05–4.14)

Psychiatric Comorbidities in ADHD ProbandsConsistent with many studies,26–28 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

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,

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



continued

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

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 Pelham’s6 report (15.5%).

Both ADHD and sleep problems are the major concerns of the parents and in clinical practice.40 Findings40–44 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, sleep–wake pattern disturbance, and breathing-related sleep problems. ADHD symptoms were positively associated with the

Table 3 Lifetime and current diagnosis of psychiatric disorders among probands with ADHD, affected siblings, unaffected siblings, and healthy school control subjects

Sibling OR (95% CI) Psychiatric diagnosis

1. ADHD n =136 n (%)




1 compared with 4

2 compared with 4

1 compared with 3

2 compared with 3

ODD

Current 89 (65.9) 20 (42.6) 7 (8.2) 11 (8.1) 21.99 (10.72–45.10) 8.41 (3.59–19.76) 21.56 (9.13–50.92) 8.25 (3.11–21.88)

Lifetime 102 (75.6) 21 (44.7) 10 (11.4) 13 (9.6) 29.25 (14.53–58.88) 7.64 (3.37–17.32) 24.11 (11.12–52.26) 6.30 (2.61–-15.22)

CD

Current 40 (29.6) 6 (12.8) 1 (1.2) 1 (0.7) 56.75 (7.50–429.24) 20.16 (2.30–176.69) 35.92 (4.74–272.37) 12.76 (1.45–112.37)

Lifetime 76 (56.3) 10 (21.3) 2 (2.3) 4 (2.9) 42.54 (14.66–123.46) 9.15 (2.66–31.42) 56.45 (13.15–242.31) 12.14 (2.48–59.35)

Tic disorder

Current 10 (7.4) 3 (6.4) 0 (0) 3 (2.2) 0.03a 0.14a 0.007a 0.04a

Lifetime 11 (8.1) 4 (8.5) 0 (0) 4 (2.9) 0.04a 0.09a 0.004a 0.02a

Dysthymic disorder

Current 8 (5.9) 1 (2.1) 1 (1.1) 2 (1.5) 4.19 (0.86–20.38) 1.46 (0.13–16.81) 5.50 (0.66–45.62) 1.91 (0.11–32.10)

Lifetime 19 (14.0) 1 (2.1) 5 (5.9) 3 (2.2) 7.19 (2.05–25.30) 0.96 (0.10–9.71) 2.60 (0.92–7.33) 0.35 (0.04–3.14)

MDD

Current 18 (13.2) 3 (6.4) 2 (2.4) 3 (2.2) 6.76 (1.92–23.81) 3.02 (0.58–15.76) 6.33 (1.41–28.42) 2.83 (0.45–17.88)

Lifetime 30 (22.1) 5 (10.6) 7 (8.2) 14 (10.3) 2.46 (1.22–4.98) 1.04 (0.35–3.15) 3.19 (1.32–7.73) 1.35 (0.39–4.65)

Generalized anxiety disorder

Current 5 (3.7) 1 (2.1) 0 (0) 1 (0.7) 0.09a 0.38a 0.08a 0.36a

Lifetime 5 (3.7) 2 (4.3) 1 (1.2) 1 (0.7) 5.19 (0.59–45.98) 6.00 (0.52–69.32) 3.23 (0.36–28.72) 3.73 (0.32–43.29)

Specific phobia

Current 28 (20.7) 13 (27.7) 14 (16.5) 15 (11.0) 2.11 (1.06–4.19) 3.08 (1.33–7.16) 1.33 (0.65–2.71) 1.94 (0.82–4.61)

Lifetime 31 (23.0) 13 (27.7) 15 (17.7) 18 (13.2) 1.95 (1.03–3.72) 2.51 (1.11–5.67) 1.39 (0.70–2.78) 1.78 (0.76–4.20)

Social phobia

Current 11 (8.2) 3 (6.4) 6 (7.1) 7 (5.2) 1.63 (0.60–4.41) 1.25 (0.30–5.14) 1.17 (0.41–3.32) 0.89 (0.21–3.82)

Lifetime 17 (12.6) 3 (6.4) 6 (7.1) 9 (6.6) 2.02 (0.85–4.81) 0.96 (0.24–3.82) 1.91 (0.71–5.13) 0.91 (0.21–3.93)

Separation anxiety disorder

Current 8 (5.9) 1 (2.1) 2 (2.4) 1 (0.7) 8.17 (0.97–68.77) 2.72 (0.16–47.04) 2.61 (0.53–12.91) 0.87 (0.07–10.49)

Lifetime 20 (14.8) 2 (4.3) 3 (3.5) 6 (4.4) 3.77 (1.44–9.87) 0.96 (0.18–5.04) 4.78 (1.36–16.84) 1.22 (0.19–7.75)

Panic disorder

Current 7 (6.2) 1 (2.1) 4 (4.7) 2 (1.5) 3.66 (0.74–18.24) 1.46 (0.13–16.82) 1.11 (0.31–3.95) 0.44 (0.05–4.14)

Lifetime 9 (6.7) 1 (2.1) 4 (4.7) 5 (3.7) 1.87 (0.60–5.80) 0.57 (0.06–5.11) 1.45 (0.43–4.91) 0.44 (0.05–4.14)


Original Research

Table 3 continuedSibling OR (95% CI)

Psychiatric diagnosis

1. ADHD n =136 n (%)




1 compared with 4

2 compared with 4

1 compared with 3

2 compared with 3

Agoraphobia

Current 1 (0.7) 0 (0) 1 (1.2) 0 (0) 0.498a — 0.48a 0.64a

Lifetime 2 (1.5) 0 (0) 1 (1.2) 0 (0) 0.25a — 0.44a 0.64a

Obsessive–compulsive disorder

Current 6 (4.4) 1 (2.1) 3 (3.5) 6 (4.4) 1.01 (0.31–3.24) 0.47 (0.05–4.10) 1.27 (0.31–5.30) 0.59 (0.06–6.01)

Lifetime 12 (8.9) 2 (4.3) 3 (3.5) 8 (5.9) 1.56 (0.61–3.98) 0.71 (0.14–3.53) 2.67 (0.72–9.86) 1.22 (0.19–7.67)

Nicotine

Ever use 22 (16.2) 2 (4.3) 6 (7.1) 5 (3.7) 5.04 (1.82–13.98) 1.19 (0.22–6.51) 2.58 (0.99–6.73) 0.61(0.12–3.23)

Regular use 10 (7.4) 0 (0) 0 (0) 0 (0) <0.001a — 0.007a —

Current abuse or dependence

6 (4.4) 0 (0) 0 (0) 0 (0) 0.02a — 0.05a —

Lifetime abuse or dependence 9 (6.6) 0 (0) 0 (0) 0 (0) 0.002a — 0.01a —

Alcohol

Ever use 65 (47.8) 29 (61.7) 54 (60.7) 56 (41.2) 1.31 (0.81–2.12) 2.30 (1.16–4.57) 0.59 (0.34–1.03) 1.04 (0.50–2.17)

Regular use 4 (3.0) 0 (0) 0 (0) 0 (0) 0.06a — 0.14a —


2 (1.5) 0 (0) 0 (0) 0 (0) 0.25a — 0.38a —

Lifetime abuse or dependence

5 (3.7) 0 (0) 0 (0) 0 (0) 0.03a — 0.09a —

Use of betel nut 8 (5.9) 2 (4.3) 1 (1.2) 0 (0) 0.004a 0.06a 0.07a 0.24a

Sleep disorders

Current 49 (36.6) 9 (19.2) 11 (12.9) 17 (12.5) 4.04 (2.16–7.53) 1.66 (0.68–4.06) 3.88 (1.87–8.06) 1.59 (0.60–4.22)

Lifetime 74 (55.2) 14 (29.8) 16 (18.8) 32 (23.5) 4.01 (2.36–6.82) 1.38 (0.65–2.94) 5.34 (2.79–10.22) 1.84 (0.80–4.28)

Any psychiatric disorder 112 (82.4) 34 (72.3) 38 (42.7) 45 (33.1) 9.60 (5.31–17.34) 5.38 (2.50–11.60) 6.38 (3.43–11.88) 3.58 (1.61–7.98)

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 SiblingsOur 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

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 SiblingsThe unaffected siblings did not have higher rates of psychiatric disorders like the probands and affected siblings



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

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.

LimitationsThere 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

Table 3 continuedSibling OR (95% CI)

Psychiatric diagnosis

1. ADHD n =136 n (%)




1 compared with 4

2 compared with 4

1 compared with 3

2 compared with 3

Agoraphobia

Current 1 (0.7) 0 (0) 1 (1.2) 0 (0) 0.498a — 0.48a 0.64a

Lifetime 2 (1.5) 0 (0) 1 (1.2) 0 (0) 0.25a — 0.44a 0.64a

Obsessive–compulsive disorder

Current 6 (4.4) 1 (2.1) 3 (3.5) 6 (4.4) 1.01 (0.31–3.24) 0.47 (0.05–4.10) 1.27 (0.31–5.30) 0.59 (0.06–6.01)

Lifetime 12 (8.9) 2 (4.3) 3 (3.5) 8 (5.9) 1.56 (0.61–3.98) 0.71 (0.14–3.53) 2.67 (0.72–9.86) 1.22 (0.19–7.67)

Nicotine

Ever use 22 (16.2) 2 (4.3) 6 (7.1) 5 (3.7) 5.04 (1.82–13.98) 1.19 (0.22–6.51) 2.58 (0.99–6.73) 0.61(0.12–3.23)

Regular use 10 (7.4) 0 (0) 0 (0) 0 (0) <0.001a — 0.007a —


6 (4.4) 0 (0) 0 (0) 0 (0) 0.02a — 0.05a —

Lifetime abuse or dependence 9 (6.6) 0 (0) 0 (0) 0 (0) 0.002a — 0.01a —

Alcohol

Ever use 65 (47.8) 29 (61.7) 54 (60.7) 56 (41.2) 1.31 (0.81–2.12) 2.30 (1.16–4.57) 0.59 (0.34–1.03) 1.04 (0.50–2.17)

Regular use 4 (3.0) 0 (0) 0 (0) 0 (0) 0.06a — 0.14a —


2 (1.5) 0 (0) 0 (0) 0 (0) 0.25a — 0.38a —

Lifetime abuse or dependence

5 (3.7) 0 (0) 0 (0) 0 (0) 0.03a — 0.09a —

Use of betel nut 8 (5.9) 2 (4.3) 1 (1.2) 0 (0) 0.004a 0.06a 0.07a 0.24a

Sleep disorders

Current 49 (36.6) 9 (19.2) 11 (12.9) 17 (12.5) 4.04 (2.16–7.53) 1.66 (0.68–4.06) 3.88 (1.87–8.06) 1.59 (0.60–4.22)

Lifetime 74 (55.2) 14 (29.8) 16 (18.8) 32 (23.5) 4.01 (2.36–6.82) 1.38 (0.65–2.94) 5.34 (2.79–10.22) 1.84 (0.80–4.28)

Any psychiatric disorder 112 (82.4) 34 (72.3) 38 (42.7) 45 (33.1) 9.60 (5.31–17.34) 5.38 (2.50–11.60) 6.38 (3.43–11.88) 3.58 (1.61–7.98)

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


Original Research

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.

ConclusionsOur 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.

AcknowledgementsThis work was supported by grants from the National Health Research Institute (NHRI-EX98–9407PC), Taiwan. The preparation of this manuscript was supported by the National Science Council (NSC96–2628-B-002–069-MY3), 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.

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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.

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

3 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, Chung-Shan South Road, Taipei 10002 Taiwan; [email protected]


Original Research

Résumé : Les comorbidités psychiatriques chez les adolescents souffrant du trouble d’hyperactivité avec déficit de l’attention et chez leurs frères et sœurs

Objectif : Malgré les comorbidités psychiatriques élevées chez les adolescents ayant reçu un diagnostic clinique du trouble du déficit de l’attention avec hyperactivité (TDAH), nous en savons très peu sur les comorbidités psychiatriques chez leurs frères et sœurs. Nous avons recherché les affections psychiatriques comorbides chez les adolescents souffrant de TDAH, leurs frères et sœurs, et des sujets témoins en santé de leur école.

Méthode : L’échantillon comprenait 136 adolescent proposants souffrant de TDAH selon les critères diagnostiques du Manuel diagnostique et statistique des troubles mentaux, 4e édition (DSM-IV); 136 frères et sœurs (47 affectés et 89 non affectés) et 136 sujets témoins en santé de l’école assortis selon l’âge et le sexe. Tous les participants et leurs parents ont reçu les entrevues psychiatriques structurées pour les troubles psychiatriques actuels et de durée de vie du DSM-IV des participants.

Résultats : Le taux de TDAH (34,6 %) chez les frères et sœurs des proposants souffrant de TDAH était environ 7 fois plus élevé que dans la population générale. Les proposants souffrant de TDAH étaient significativement plus susceptibles que leurs frères et sœurs non affectés (RC 6,38; IC à 95 % 3,43 à 11,88) et que les sujets témoins en santé de l’école (RC 9,60; IC à 95 % 5,31 à 17,34) d’avoir un trouble psychiatrique du DSM-IV, notamment le trouble oppositionnel avec provocation (TOP), le trouble des conduites (TC), les troubles tics, le trouble dépressif majeur, une phobie spécifique (plus que les sujets témoins seulement), le trouble lié à la nicotine, et les troubles du sommeil. Les frères et sœurs affectés étaient significativement plus susceptibles que les sujets témoins en santé de l’école d’avoir un TOP, un TC, une phobie spécifique, et d’avoir consommé de l’alcool (RC 2,30 à 20,16).

Conclusions : Nos résultats suggèrent que les frères et sœurs des proposants souffrant de TDAH ont des risques accrus de TDAH et que les frères et sœurs affectés ont plus de comorbidités psychiatriques que les sujets témoins en santé de l’école. Cela justifie l’identification précoce des symptômes du TDAH et d’autres affections psychiatriques comorbides également chez les frères et sœurs des adolescents souffrant de TDAH.

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