Research in Developmental Disabilities 33 (2012) 419–425

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Research in Developmental Disabilities

What can ADHD without comorbidity teach us about comorbidity?

Toshinobu Takeda a,d,*, Paul J. Ambrosini c, Rachel deBerardinis b, Josephine Elia a,b

a Children’s Hospital of Philadelphia, Philadelphia, PA, United Statesb University of Pennsylvania, Philadelphia, PA, United Statesc Drexel University, Philadelphia, PA, United Statesd Ryukoku University, Kyoto, Japan

A R T I C L E I N F O

Article history:

Received 22 September 2011

Received in revised form 23 September 2011

Accepted 26 September 2011

Available online 24 November 2011

Keywords:

ADHD

Comorbidity

FIGS

Parental neuropsychiatric disorders

A B S T R A C T

Neuropsychiatric comorbidity in ADHD is frequent, impairing and poorly understood. In

this report, characteristics of comorbid and comorbid-free ADHD subjects are investigated

in an attempt to identify differences that could potentially advance our understanding of

risk factors.

In a clinically-referred ADHD cohort of 449 youths (ages 6–18), age, gender, IQ, SES and

ADHD symptoms were compared among ADHD comorbid free subjects and ADHD with

internalizing and externalizing disorders. Logistic regression analyses were also carried

out to investigate the relationship between comorbidity and parental psychiatric status.

Age range was younger in the ADHD without comorbidity and older in ADHD + in-

ternalizing disorders. No significant difference in IQ or SES was found among ADHD

comorbid and comorbid-free groups. ADHD with internalizing disorder has a significantly

greater association with paternal psychiatric conditions. After matching by age, gender, IQ

and SES, ADHD with externalizing disorders had significantly higher total ADHD,

hyperactivity/impulsivity score and single item score of difficulty awaiting turn than

ADHD without comorbidity and ADHD with internalizing disorders.

Older age ranges, ADHD symptom severity and parental psychopathology may be risk

factors for comorbidity.

� 2011 Elsevier Ltd. All rights reserved.

1. Introduction

ADHD, one of the most frequent psychiatric disorders in children and adolescents is well-known for its high-rate ofcomorbidities which occur in over 2/3 of cases (Jensen et al., 2001). Comorbid disorders include externalizing disorders suchas oppositional defiant and conduct disorders reported in 30–50%, and internalizing disorders such as anxiety and mooddisorders reported respectively in 25% and 15–75% of clinical samples of ADHD children and adolescents (Biederman,Newcorn, & Sprich, 1991; Brown et al., 2001; Cantwell, 1996; Elia, Ambrosini, & Berrettini, 2008; Hinshaw, 1992; Jensen,Martin, & Cantwell, 1997; Schatz & Rostain, 2006; Spencer, 2006; Wilens et al., 2002).

The causes of comorbidity are unclear. It does not appear to be due to referral bias, expected in clinical samples, sinceepidemiological samples of children and adolescents also report significant comorbidity between behavioral disorders,anxiety and depression (Angold, Costello, & Erkanli, 1999; Caron & Rutter, 1991; Costello, Foley, & Angold, 2006).

The co-morbid relationship between ADHD and anxiety is bi-directional with high levels of ADHD (16–24%) also reportedin children with anxiety disorder (Anderson, Williams, McGee, & Silva, 1987). Risk for anxiety disorders among family

* Corresponding author at: Ryukoku University, Shichijo-Omiya, Shimogyou-ku, Kyoto, Japan. Tel.: +81 75 343 3311; fax: +81 75 343 4302.

E-mail address: t-tak@let.ryukoku.ac.jp (T. Takeda).

0891-4222/$ – see front matter � 2011 Elsevier Ltd. All rights reserved.

doi:10.1016/j.ridd.2011.09.024

T. Takeda et al. / Research in Developmental Disabilities 33 (2012) 419–425420

members of patients with ADHD is higher than in the relatives of normal comparison (Biederman et al., 1991). However, therate of anxiety disorders was found elevated only in relatives of children with ADHD/anxiety and not in ADHD alonesuggesting that ADHD and anxiety are separate disorders inherited independently of each other (Biederman et al., 1991; Last,Perrin, Hersen, & Kazdin, 1996).

Does anxiety occur more frequently in different ADHD subtypes? Increased rates were noted in children withouthyperactivity vs those with hyperactivity by some investigators (Lahey, Schaughency, Hynd, Carlson, & Nieves, 1987).Decreased impulsivity on CPT (Continuous Performance Test) has been reported in ADHD children with anxiety than thosewithout anxiety (Newcorn et al., 2001; Pliszka, 1992) however this finding was noted only in males in one study and femalesin the MTA study (Newcorn et al., 2001).

Severity of ADHD has been associated with comorbid anxiety and mood (Jensen, Shervette, Xenakis, & Richters, 1993;Jensen et al., 1997), while other data suggest that comorbidity between ADHD and internalizing disorders may notnecessarily be indicative of more severe ADHD (August, Realmuto, MacDonald, Nugent, & Crosby, 1996; Pliszka, 1992). Whilesome studies mentioned only about higher total ADHD severity in ADHD and comorbid CD (Kuhne, Schachar, & Tannock,1997),

Psychiatric comorbidities have been reported to be similar in ADHD children with normal and high IQ rates (Antshel et al.,2007) as well as across the IQ spectrum (Katusic et al., 2011).

Subjects with ADHD plus CD have been reported to have a lower verbal IQ than those with either disorder alone (Barkley,2006) however t his was contradicted by another study indicating that psychiatric comorbidity had limited influence on IQ(Faraone et al., 1993).

Depressive disorders, antisocial behaviors and substance abuse are more common in the parents of children with ADHDand CD/ODD than in parents of children with non-comorbid ADHD (Faraone, Biederman, Jetton, & Tsuang, 1997). It is well-known that high rate of parents of children with ADHD have ADHD, however, to what extent parental ADHD exerts effect oncomorbidity is still unclear.

Socio-economic factors have also been shown to differ with adolescents with ADHD free of comorbidity living in familieswith higher SES than those with comorbidity (Hurtig et al., 2007).

Follow-up studies of children with ADHD consistently have indicated poorer outcome of comorbid ADHD (Rutter, 1989).Thus, gaining a better understanding of risk factors for comorbidities is important since it may allow earlier identificationand prevention. In this study, we compare subjects with comorbidity and those free of comorbidity in an attempt ofidentifying differentiating characteristics.

2. Methods

2.1. Subjects

This sample was recruited in an ongoing ADHD genetic study that includes probands ages 6–18 and their parents. Allsubjects were of European descent. Individuals of other ancestries were not included because ADHD candidate genehaplotype frequencies varies substantially across major world populations (Chang, Kidd, Livak, Pakstis, & Kidd, 1996),lowering power of the study to detect genetic association for ADHD if multiple ethnic groups were included. The study wasapproved by the Institutional Review Boards of The Childrens Hospital of Philadelphia (Protocol #2003-1-3125) and theUniversity of Pennsylvania, School of Medicine (Protocol #707843). After complete description of the study to the subjects,written informed consent was obtained.

2.2. Procedures and exclusionary criteria

Families were recruited from pediatric and behavioral health clinics in the Philadelphia area. Phone screenings wereconducted to determine age range of 6–18, presence of ADHD symptoms, ancestry, availability and willingness to participatein a genetic study from both biological parents. Exclusionary criteria included gestational age <36 weeks, IQ scores <75,inability to understand and complete K-SADS, major medical (excluding asthma), neurological (e.g. seizures, fetal alcoholsyndrome, plumbism), and neuropsychiatric disorders (pervasive developmental disorder, bipolar disorder, majordepressive disorder with symptoms starting prior to ADHD or where ADHD symptoms were found to occur primarily duringdepressed episodes, psychotic disorders). Disruptive behavioral disorders, other mood disorders and anxiety disorders werenot excluded.

2.3. Measures

A child psychiatrist (JE) assessed diagnostic status by administering a K-SADS P-IVR interview to the parent(s) and childseparately. This semi-structured interview provides diagnoses occurring within the last twelve months of the presentepisode (PE) and for the last week (LW). The (IVR version) rates each symptom on a graded severity scale thus allowing for acomposite severity rating score (Ambrosini, 2000). Permission to videotape K-SADS interviews was included in the informedconsent and a subset of the videotapes were randomly chosen and reliability maintained with K-SADS trainer (PA). Cognitiveability was assessed by reviewing reports of IQ assessments completed prior to participation in this study. The WASI IQ

T. Takeda et al. / Research in Developmental Disabilities 33 (2012) 419–425 421

assessment was administered to children not previously tested. Other children, included but not formally tested, wereworking up to grade level academically and were able to understand and complete the K-SADS. Socioeconomic status wasmeasured by the Hollingshead Scale.

Family history of psychiatric disorders was derived from clinical history and self-reported questionnaires (FIGS)(Maxwell, 1992).

Parents also completed an 18-question World Health Organization ADHD Self-Report Scale (ASRS). This screener assessesthe presence of ADHD symptoms in the subjects parents based on a numerical rating of 18 symptoms on a scale of 0–4(0 = Never, 4 = Very Often). The questions are divided in two parts, Part A assessing symptoms of inattention and Part Bassessing hyperactivity and impulsivity. The scale has been validated (Kessler et al., 2005, 2007) and a score of 21 or over onPart A or B was accepted as criteria for positive parental ADHD.

2.4. Data analysis

K-SADS-P-IVR data was used to determine ADHD diagnosis. Consistent with DSM-IV criteria, subjects with 6 or moresymptoms of inattention (severity scores �3) but fewer than 6 symptoms of hyperactivity and impulsivity were identified asinattentive subtype. Subjects with 6 or more hyperactive-impulsive symptoms (severity scores �3) and fewer than 6symptoms of inattention were categorized as Hyperactive-Impulsive subtype and subjects with 6 or more symptoms in bothdimensions were categorized as combined subtypes. Age of onset was not used in determining ADHD diagnoses.

For comorbid mood and anxiety disorder, The K-SADS-P IVR diagnostic domain is keyed to the Research DiagnosticCriteria (RDC) (Spitzer, Endicott, & Robins, 1978) for those syndromes similar in youths and adults. All other diagnoses areDSM IV-TR based and were made excluding the DSM hierarchical requirements.

2.5. Statistical analysis

Comparisons of the demographic variables was done among 4 groups [i.e. ADHD free of comorbidity (ADHD-only), ADHDwith internalizing disorders alone (ADHD-in), ADHD with externalizing disorders alone (ADHD-ex), and ADHD with bothinternalizing and externalizing disorders (ADHD-both)] using x2 analysis and ANOVA. If there is any significant difference inANOVA, post hoc Tukey analysis was completed. To determine the relative contribution of parental psychiatric disorders tocomorbidity in children, logistic regression was conducted, using non-comorbid ADHD as the control group. ADHD severityis determined by the sum of ADHD symptom severity points.

To examine the difference in ADHD symptoms among four groups, a group matching procedure by age, gender, SES,IQ was carried out before the 4 group comparison by ANOVA, since generally symptom severity of hyperactivity/impulsivity decreases with age (Biederman, Mick, & Faraone, 2000). Post hoc Tukey analysis was administered if thereare any significant results in ANOVA. Bonferroni corrections for multiple comparisons were adopted in the analysis ofeach item in ADHD symptoms. All tests were two-tailed. All data were entered and analyzed by using SPSS 16.0 (SPSS,Inc., Chicago, IL).

3. Results

In our sample of 449 youths with ADHD, 145 (32.3%) had no comorbidity. The number with ADHD-in, ADHD-ex, andADHD-both is 103 (22.9%), 81 (18.0%), and 120 (26.7%), respectively. As summarized in Table 1, there was no significantdifference in the ratio of gender, SES, or IQ among four groups by comorbid pattern, while there was significant difference inage between ADHD-only and ADHD-in, between ADHD-only and ADHD-both.. The ADHD-only group and ADHD-ex werecomposed of younger subjects. There was significant difference in ratio of ADHD subtype among four groups.

The prevalence of comorbidities also appears to vary in the different age ranges. As summarized in Table 2, ADHD withoutcomorbidity was more notable in the younger cohorts. In the externalizing disorders, ODD occurred throughout the ageranges while CD was more notable in the older age ranges. Mood disorders also appear to occur more frequently in the olderage groups. GAD, OAD, OCD also increased with age while separation anxiety decreased.

Table 1

Sample characteristics.

ADHD-only n = 145 (32%) ADHD-in n = 103 (23%) ADHD-ex n = 81 (18%) ADHD-both n = 120 (27%)

Gender (male/female)1 111/34 69/34 63/18 86/34

Age (year) 9.37 (2.53)a,b 10.97 (3.42)a,c 9.70 (3.24)c 10.50 (3.32)b

ADHD subtype (IA/HI/C)2 48/12/85 42/8/38 15/7/58 23/7/90

SES (n = 413) 47.0 (10.2) 49.0 (10.6) 48.1 (11.1) 47.0 (11.6)

IQ (n = 313) 111.2 (13.6) 108.8 (15.5) 107.7 (13.5) 108.3 (13.0)

ADHD-in, ADHD with internalizing disorder alone; ADHD-ex, ADHD with externalizing disorder alone; ADHD-both, ADHD with both internalizing and

externalizing disorders.1 There is no significant difference in ratio of gender among 4 groups by Pearson chi-square test.2 There is significant difference in ratio of ADHD suptype among four groups by Pearson chi-square test (p = 0.00): a, p < 0.001; b,c, p < 0.05.

Table 2

Prevalence of comorbidities by age group.

Age group Comorbid-free

ADHD

Externalizing disorders Internalizing disorders

ODD CD SUD MDD DD MD GAD OAD SA SPD OCD SP

6–8 (n = 141) 54 (38%) 65 (46%) 0 (0%) 0 (0%) 2 (1%) 14 (10%) 11 (8%) 17 (12%) 12 (9%) 15 (11%) 11 (8%) 3 (2%) 1 (1%)

8–10 (n = 117) 31 (26%) 49 (42%) 1 (1%) 0 (0%) 3 (3%) 13 (11%) 11 (9%) 13 (11%) 17 (15%) 12 (10%) 11 (9%) 7 (6%) 3 (3%)

10–12 (n = 84) 26 (31%) 34 (40%) 0 (0%) 0 (0%) 6 (7%) 11 (13%) 12 (14%) 14 (17%) 15 (18%) 6 (7%) 6 (7%) 3 (4%) 3 (4%)

12–14 (n = 41) 16 (39%) 18 (44%) 1 (2%) 1 (2%) 2 (5%) 4 (10%) 1 (2%) 4 (22%) 4 (10%) 0 (0%) 1 (2%) 0 (0%) 1 (2%)

14–16 (n = 34) 11 (32%) 16 (47%) 2 (6%) 5 (15%) 5 (15%) 8 (24%) 6 (18%) 1 (3%) 3 (9%) 2 (6%) 0 (0%) 2 (6%) 0 (0%)

16–18 (n = 29) 7 (24%) 12 (41%) 2 (7%) 11 (38%) 5 (17%) 4 (14%) 7 (24%) 10 (34%) 6 (21%) 0 (0%) 0 (0%) 2 (7%) 2 (7%)

Note: Each disorder may overlap. Disorders with frequency over 10 except CD are displayed in the table (CYC = 2, PTSD = 7, PD = 8). ODD, oppositional defiant

disorder; CD, conduct disorder; SUD, SAB (substance abuse) + SD (substance dependence); MDD, major depressive disorder; DD, dysthymic disorder; MD,

minor depression disorder; GAD, generalized anxiety disorder; OAD, overanxious disorder; SA, separation anxiety disorder; SPD, social phobic disorder;

OCD, obsessive-compulsive disorder; SP: simple phobia.

Table 3

Associations between the risk for 3 types of comorbidities in ADHD by parental psychiatric status.

Parental psychiatric

status

ADHD-only ADHD-in ADHD-ex ADHD-both

n (total) % n (total) % OR (95% CI) n (total) % OR (95% CI) n (total) % OR (95% CI)

Any psychiatric

disorders in father

8 (85) 9.4 14 (65) 21.5 2.64 (1.03–6.75) 3 (41) 7.3 0.76 (0.19–3.03) 6 (68) 8.8 0.93 (0.31–2.83)

Any psychiatric

disorders in mother

13 (66) 19.7 15 (57) 26.3 1.46 (0.63–3.39) 6 (32) 18.8 0.94 (0.32–2.76) 15 (54) 27.8 1.57 (0.67–3.67)

ADHD in father 24 (112) 21.4 15 (74) 20.3 0.93 (0.45–1.92) 12 (63) 19.0 0.86 (0.40–1.87) 26 (92) 28.2 1.44 (0.76–2.74)

ADHD in mother 36 (119) 30.3 20 (82) 24.4 0.74 (0.39–1.41) 14 (66) 21.2 0.62 (0.31–1.26) 31 (99) 31.3 1.05 (0.59–1.87)

OR, odds ratio; 95% CI, 95% confidence interval; ADHD-in, ADHD with internalizing disorder alone; ADHD-ex, ADHD with externalizing disorder alone;

ADHD-both, ADHD with both internalizing and externalizing disorders.

Bold characters indicate significant difference.

T. Takeda et al. / Research in Developmental Disabilities 33 (2012) 419–425422

FIG data was available for 259 fathers and 31 reported a history of psychiatric disorders (20 mood, 6 anxiety, 1 psychosis,3 developmental disorders other than ADHD, 1 parent with multiple disorders). FIG data was available from 209 and 66reported a psychiatric disorder (45 mood, 14 anxiety, 5 developmental disorders other than ADHD, 2 SUB). ASRS dataindicates that 77 out of 341 fathers (22.6%) have ADHD and 101 out of 366 mothers (27.6%) have ADHD. Logistic regressionanalyses revealed significant association only between paternal psychiatric disorders and ADHD comorbid withinternalizing disorders. Parental ADHD status is not associated with either internalizing or externalizing comorbiditiesin ADHD probands (Table 3).

ADHD symptoms were investigated in a subgroup of the cohort that was matched for age, gender, SES and IQ. After age–gender–SES-IQ matching procedure, these variables in ADHD-only, ADHD-in, ADHD-ex, ADHD-both are the followingrespectively: age (mean 9.73, SD 3.15, range 6.0–17.2; mean 9.92, SD 2.88, range 6.0–17.8; mean 9.70, SD 3.23, range 6.0–18.7; mean 9.70, SD 3.29, range 6.0–17.8; F (323) = 0.09, p = 0.97), SES [mean 48.49, SD 9.50, (n = 73); mean 47.53, SD 10.54,(n = 74); mean 48.11, SD 11.14, (n = 73), mean 45.75, SD 11.47, (n = 74); F (293) = 0.95, p = 0.42), IQ [mean 109.00, SD 13.65,(n = 54); mean 107.76, SD 14.77 (n = 58); mean 107.67, SD 13.52, (n = 57); mean 108.98, SD 13.21, (n = 57); F (225) = 0.16,p = 0.92), gender (male 64, female 17; 23/58; 18/63; 19/62; Pearson chi-squire 1.41, df = 3, p = 0.70). There was significantdifference in the ratio of ADHD subtype between four groups [x2 (6) = 16.51, p = 0.01].

On total, IA, HI, there were no significant gender main effects (F = 2.65, p = 0.11; F = 1.44, p = 0.71; F = 3.23, p = 0.07,respectively) or gender � group interaction (F = 0.03, p = 0.99; F = 0.63, p = 0.60; F = 0.53, p = 0.66, respectively).

There were significant differences in total ADHD severity, hyperactivity/impulsivity severity, and the single itemdifficulty awaiting turn between pure ADHD and ADHD-ex, between ADHD-only and ADHD-both, between ADHD-in andADHD-ex, and between ADHD-in and ADHD-both. There were significant differences in the item difficulty playing quietlybetween ADHD-in and ADHD-both and in the item always on the go between ADHD-in and ADHD-ex. These significantresults in the single items remain significant even after Bonferroni correction (Table 4).

4. Discussion

In our sample of clinically-referred 449 youths (ages 6–18) with ADHD, 145 (32.3%) had no comorbidity. Comorbid-freeADHD subjects were youngest among four groups divided by comorbid pattern. ODD occurred throughout the age ranges.CD, GAD, OAD, OCD increased with age while SPD, separation anxiety decreased.

As for parental psychiatric history, paternal psychiatric disorders significantly increased the risk of the ADHD proband’sinternalizing disorders. There were significant differences in total ADHD severity, hyperactivity/impulsivity severity, and thesingle item ‘‘difficulty awaiting turn’’ between ADHD-only/ADHD-in and ADHD-ex/ADHD-both.

Table 4

Comparison of ADHD symptoms among age-gender-SES-IQ-matched 4 groups in terms of comorbidity pattern.

ADHD-only ADHD-in ADHD-ex ADHD-both F p

Total number (IA/IH/C) n = 81 (27/5/49) n = 81 (31/7/43) n = 81 (15/7/59) n = 81 (12/7/62)

Total 51.02 (7.02)a,b 50.70 (6.21)c,d 54.20 (6.65)a,c 54.80 (6.00)b,d 8.65 0.00

Inattention 27.27 (3.09) 27.47 (3.58) 27.60 (3.82) 28.09 (3.39) 0.81 0.49

Hyperactivity/impulsivity 23.75 (5.65)a,b 23.23 (5.04)c,d 26.55 (4.82)a,c 26.72 (4.56)b,d 10.63 0.00

Carelessness 3.06 (0.46) 3.04 (0.43) 3.02 (0.52) 3.11 (0.59) 0.46 0.70

Loses things 2.83 (0.63) 2.86 (0.69) 2.69 (0.77) 2.90 (0.75) 1.35 0.26

Fails to finish things 2.81 (0.64) 2.94 (0.64) 2.89 (0.71) 2.90 (0.66) 0.50 0.69

Doesn’t listen 3.19 (0.57) 3.19 (0.55) 3.32 (0.54) 3.40 (0.52) 2.95 0.03

Difficulty concentrating 3.07 (0.52) 3.27 (0.50) 3.20 (0.56) 3.19 (0.66) 1.71 0.17

Easily distracted 3.23 (0.48) 3.32 (0.54) 3.32 (0.57) 3.46 (0.53) 2.43 0.07

Difficulty organizing work 2.96 (0.66) 2.90 (0.74) 3.01 (0.66) 2.86 (0.72) 0.72 0.54

Avoids mental effort 3.09 (0.75) 2.96 (0.72 3.25 (0.70) 3.25 (0.72) 3.00 0.03

Forgetfullness 3.02 (0.67) 2.99 (0.78) 2.90 (0.80) 3.02 (0.76) 0.48 0.70

Fidgeting 3.11 (0.79) 3.06 (0.71) 3.17 (0.63) 3.22 (0.63) 0.83 0.48

Difficulty staying seated 2.75 (0.90) 2.78 (0.73) 3.02 (0.74) 3.09 (0.66) 4.03 0.01

Excessive running 2.69 (0.96) 2.53 (0.84) 2.98 (0.74) 2.91 (0.84) 4.73 0.00

Difficulty playing quietly 2.40 (0.92) 2.22 (0.91)* 2.65 (0.82) 2.74 (0.86)* 5.94 0.00

Always on the go 2.75 (0.87) 2.64 (0.89)* 3.10 (0.77)* 3.05 (0.50) 6.30 0.00

Talks excessively 2.91 (0.83) 2.81 (0.91) 2.95 (0.85) 3.12 (0.75) 1.92 0.13

Blurts out answers 2.27 (1.05) 2.20 (0.94) 2.66 (0.90) 2.73 (0.95) 6.34 0.00

Difficulty awaiting turn 2.11 (0.87)e,f 2.20 (0.75)g,h 2.85 (0.79)e,g 2.72 (0.83)f,h 16.88 0.00

Interrupts and intrudes 2.75 (0.81) 2.79 (0.75) 3.14 (0.65) 3.14 (0.65) 6.96 0.00

Note: Boxes with the same letter (*, a–g) are statistically different at p = 0.05 (a–d) or p = 0.05/18 [Bonferroni correction (*, e–h)] level and represent pairwise

comparison between each box. ADHD-in, ADHD with internalizing disorder alone; ADHD-ex, ADHD with externalizing disorder alone; ADHD-both, ADHD

with both internalizing and externalizing disorders.

T. Takeda et al. / Research in Developmental Disabilities 33 (2012) 419–425 423

There were no significant difference between two genders in terms of symptom profile. This differs from the MTA studywhere ADHD girls were less symptomatic especially those with comorbid anxiety (Newcorn et al. 2001). However the MTAsample had a more limited age range (ages 7–9), included only combined subtype, excluded simple phobias and analyzedhyperactive and impulsive symptoms separately.

In our sample, some comorbidities such as ODD remained relatively constant while CD, mood and some anxiety disorderswere more prevalent in the older age ranges while separation anxiety and phobias occurred less frequently in the oldergroups. Our cross-sectional data appears to be consistent with successive comorbidity data from an epidemiologicallongitudinal sample by Costello et al. (2006) in a sample of children ages 9–16. In that study substance use and mooddisorders emerge later in childhood while anxiety disorders appear to remain stable or decrease. There is a significantcomorbidity among behavioral disorders and anxiety and depression. Sex differences include depression comorbidity withCD in girls and Substance Use Dependence (SUD) in boys. ADHD predicted later ODD and there appears to be a strongheterotypic continuity (continuity of disorder but a different diagnosis) from depression to anxiety.

Among parental psychiatric conditions, we found only any psychiatric disorders other than ADHD in father as havingsignificant association with the ADHD probands comorbid internalizing disorders, compared to ADHD-only. In contrast withtheories that comorbidity is simply a reflection of more severe psychopathology among children with ADHD, our resultssupport an association between parental and child internalizing disorders and between parental and child externalizingdisorders as suggested Pfiffner et al. (1999). As for parental ADHD, we already revealed that parental ADHD significantlyincreased probands ADHD (inattention) severity compared to probands without any ADHD parents, although there is nosimple linear relationship between parental and probands ADHD severity (Takeda et al., 2010). It seems that 12–20% of themothers and 9–54% of fathers of children with ADHD may also have ADHD themselves (Chronis et al., 2003). In our sample,the rate of maternal ADHD is little higher. To our knowledge, there are not any studies suggesting a strong influence ofparental ADHD on comorbid disorders in ADHD probands. In our sample also could not detect any significant relationshipsbetween parental ADHD and comorbidity in probands. Our results, combined with results from previous findings, suggestthat parental symptoms of ADHD, internalizing disorders and externalizing disorders may exert their effect primarily on theADHD child’s internalizing and externalizing disorders, respectively).

No significant difference in IQ was found among four groups supporting previous reports showing no effects oncomorbidities (Antshel et al., 2007; Katusic et al., 2011). There was also no significant difference in SES detected among ourfour groups. One study reported lower comorbidities in ADHD adolescents with higher SES (Hurtig et al., 2007) suggestingthat further study is needed to address the relationship between comorbid ADHD and family environment.

Our study confirmed the results in previous studies claiming that children with comorbid ADHD and CD/ODD appear tohave higher levels of impulsivity as well as total ADHD severity than children with only ADHD or with ADHD and an anxietydisorder (Connor et al., 2003; Kuhne et al., 1997; Lynam, 1998).

T. Takeda et al. / Research in Developmental Disabilities 33 (2012) 419–425424

Most striking result in our study is that ADHD-both is much more similar to ADHD-ex rather than to ADHD-in in terms ofADHD symptomatology, IQ, or parental status and furthermore, these two groups are so similar that ADHD-ex and ADHD-both cannot easily be differentiated by those parameters. ADHD-ex and ADHD-both may share symptomatology andetiology. Surprisingly, like total ADHD severity and hyperactivity/impulsivity severity, score of a single item ‘‘difficultyawaiting turn’’ is significantly higher in children with externalizing disorders than children without externalizing disorders.This result in hyperactivity/impulsivity is consistent with the results of MTA study (Newcorn et al., 2001). As for ‘‘difficultyawaiting turn’’, this single item could be as potent a marker for externalizing disorders in ADHD as total ADHD severity andhyperactivity/impulsivity severity. Biederman, Faraone, Milberger, and Doyle (1993) revealed that among fourteen DSM-III-R ADHD symptoms which are not so different from current DSM-IV-TR symptoms, ‘‘difficulty awaiting turn’’ is the secondleast rated items in parent ratings, the least rated items in teacher ratings. Combining these findings with ours, when theseitems are rated, it is likely that children with more severe ADHD symptoms may also have comorbid externalizing disorders.

5. Study limitations

Since this study required the participation of both biological parents who are limited to Caucasians, children with ADHDin our study did not represent typical clinic-referred samples. Moreover, our data set includes the broadest age rangecompared to other studies, which could be one of shortcomings in our study.

Since we place more importance on analyzing data set in age, gender, IQ and SES close-matching samples, there wassignificant difference in ratio of ADHD subtype among four groups. Similarly, to maintain statistical power, we get parentalpsychiatric disorders together as any psychiatric disorder.

Self-report questionnaire on psychiatric family history, FIGS may contribute to considerably lower rate of externalizingdisorders in parents than expected. Likewise, this study is also limited by the ability of the parents of subjects to self-reporttheir own symptoms per the ASRS, which may have an impact on higher rate of maternal ADHD. However, the pilot study hasshowed ASRS as reliable and valid (Adler et al., 2006).

6. Conclusion

Neuropsychiartic comorbidity in ADHD is frequent, impairing, however, factors which have an impact on it are poorlyunderstood. It has already revealed in the study with large enough sample that impulsivity and hyperactivity increase therisk of having comorbidity in ADHD. Moreover, internalizing or externalizing comorbidities in children with ADHD havebeen suspected to associate parents’ counterpart neuropsychiatric disorders (Pfiffner et al., 1999). In this study, the formerfindings were confirmed and as for the latter, a transgenerational effect in internalizing disorders from fathers to theirchildren was indicated. In addition, a single item in the ADHD criteria in DSM-IV ‘‘difficulty awaiting turn’’ would be a potentmarker for externalizing disorder. Further investigations with rigorous methodology may attempt to discern if there are anyrisk factors for comorbidities in ADHD.

Acknowledgments

This research is supported by NIMH (K23MH066275-01), UL1-RR-024134 from the National Center for ResearchResources and in part by a grant-in-aid from the Ministry of Health, Labor and Welfare, Japan (to TT). There is no conflict ofinterest or financial support for all authors. We want to thank all the families that have participated, the referring cliniciansand Tamika Scott, research coordinator.

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