Sage Journals: Discover world-class research

Abstract

Objectives: The aims of the present study were to examine the current psychiatric comorbidity among children and adolescents with and without persistent attention-deficit hyperactivity disorder (ADHD) as compared to school controls, and to determine the factors predicting psychiatric comorbidity.

Method: The sample included 296 patients (male, 85.5%), aged 11–17, who were diagnosed with DSM-IV ADHD at the mean age of 6.7 ± 2.7 years and 185 school controls. The ADHD and other psychiatric diagnoses were made based on clinical assessments and confirmed by psychiatric interviews. The ADHD group was categorized into 186 patients (62.8%) with persistent ADHD and 110 (37.2%) without persistent ADHD.

Results: Compared to the controls, the two ADHD groups were more likely to have oppositional defiant disorder (ODD), conduct disorder (CD), tics, mood disorders, past and regular use of substances, substance use disorders and sleep disorders (odds ratios (ORs) = 1.8–25.3). Patients with persistent ADHD had higher risks for anxiety disorders, particularly specific phobia than the controls. Moreover, patients with persistent ADHD were more likely to have ODD than their partially remitted counterparts. Advanced analyses indicated that more severe baseline ADHD symptoms predicted ODD/CD at adolescence; longer methylphenidate treatment duration was associated with an increased risk for tics and ODD/CD at adolescence; and older age predicted higher risks for mood disorders and substance use disorders.

Conclusion: Reduced ADHD symptoms at adolescence may not lead to decreased risks for psychiatric comorbidity, and identification of severe ADHD symptoms at childhood and age-specific comorbid patterns throughout the developmental stage is important to offset the long-term adverse psychiatric outcomes of ADHD.

Keywords

adolescence attention-deficit hyperactivity disorder comorbidity methylphenidate

Attention-deficit hyperactivity disorder (ADHD) is a common, early-onset, lifetime-impairing neuropsychiatric disorder [1] affecting 5–10% school-age children in Western countries [2] and 7.5% in Taiwan [3]. Literature has documented high psychiatric comorbidity in ADHD [4,5] including oppositional defiant disorder (ODD) [6], conduct disorder (CD) [6], mood disorders [7–9], anxiety disorders [10,11], learning disorder [12], tic disorder [13], initial use [14] and regular use of substances [14], and substance use disorders [15]. There is a lack of information, however about whether adolescents without persistent ADHD also have increased risks for other psychiatric disorders. Also, previous reports about ADHD and psychiatric comorbidity were mainly based on cross-sectional data [16] and only some have investigated psychiatric comorbidity longitudinally [6,17].

The predictors for comorbid substance use disorder in ADHD patients are CD [18], childhood CD/ODD symptoms [17], hyperactive/impulsive symptoms [14,19], childhood inattentive symptoms [17,19] and persistence of ADHD [17]. Childhood hyperactive/impulsive symptoms [20,21] and current ADHD symptoms [22] are associated with comorbid ODD/CD in ADHD patients. Comorbidity of tics is related to medications including methylphenidate [23,24] and atomoxetine [25]. Comorbid internalizing disorders are associated with an earlier age of onset of ADHD [26], more severe ADHD symptoms [26] and family loading for anxiety, depression and adversity [27].

Despite the extensive studies on ADHD comorbidity in Western populations, few have been conducted in Asian populations [28,29] and none of them has investigated predictors for comorbidity at adolescence or adulthood. To fill in the gap in the understanding of ADHD comorbidity in ethnic Chinese populations and to investigate the association between partially remitted ADHD and psychiatric comorbidity, the aim of the present study was to examine current psychiatric comorbidity among probands with and without persistent ADHD as compared to children and adolescents without lifetime ADHD; and to determine the factors predicting the risks of psychiatric comorbid conditions among adolescents with childhood diagnosis of DSM-IV ADHD.

Methods

Participants

We recruited 296 patients (male, 85.5%) aged 11–17, who had had overt ADHD symptoms since the mean age of 4.2 ± 1.6, and were clinically diagnosed with DSM-IV ADHD at the mean age of 6.7 ± 2.7, consecutively mainly from National Taiwan University Hospital (n = 242). Their lifetime and current (past 6 months) ADHD and other psychiatric diagnoses were confirmed by psychiatric interviews with the participants and their parents using the Chinese version of the Kiddie Epidemiologic Version of the Schedule for Affective Disorders and Schizophrenia (Chinese K-SADS-E) at the participants’ mean age of 12.9 ± 1.6. The patients who had psychosis disorders, autism spectrum, or a full-scale IQ < 80 were excluded. The ADHD subtype distributions at baseline were 221 (74.7%) for combined type, 65 (22.0%) for predominantly inattentive type, and 10 (3.3%) for predominantly hyperactive-impulsive type.

The school comparison participants (school controls), who were assessed without ADHD at the ages of 6-8 and at adolescence using the Chinese K-SADS-E interview at the mean age of 12.9 ± 1.5, were recruited from the same school districts as the patients with ADHD, yielding 185 school controls (male, 72.4%).

Measures

Chinese K-SADS-E

The Chinese K-SADS-E is a semi-structured interview scale for the systematic assessment of both past and current episodes of mental disorders in children and adolescents. The development of the Chinese K-SADS-E has been described elsewhere in detail [3,30]. The Chinese K-SADS-E is a reliable and valid instrument to assess DSM-IV child and adolescent psychiatric disorders, and has been used extensively in clinic-based [31] and community-based studies [32].

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 >90% agreement on all mental disorders assessed by the Chinese K-SADS-E (range = 98.25 ± 1.91–99.38 ± 1.06) against the rating of each item in the Chinese K-SADS-E by the first author for 30 clinical subjects before study implementation. The interrater reliability of the Chinese K-SADS-E among the first author and the four interviewers using 12 subjects was satisfactory for all mental disorders, with generalized kappa for each diagnosis ranging from 0.86 to 1.00. Their Chinese K-SADS-E interviews were audio-taped periodically and monitored by the first author, who was blind to the personal information of the participants, to ensure the quality of interviews.

Best-estimate diagnoses

The first author, trained in best estimate [33] for diagnoses during her doctoral study at Yale, was blind to the diagnostic status and name of the participant and was not involved in the direct Chinese K-SADS-E interview of any of the participants or their parents at follow-up. The first author made all the best estimates of each psychiatric diagnosis according to the data from the Chinese K-SADS-E interviews of participants and their mothers [34], 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 half or no functional impairment), possible (some symptoms but no impairment), and no diagnosis. For mental disorders other than ADHD, those patients who received a rating as definite or probable on the best estimate were categorized as having a particular mental disorder.

Persistent and non-persistent ADHD

Patients with a childhood diagnosis of ADHD were categorized into (i) patients with persistent ADHD (186, 62.8%) if their current symptoms reached the definite category (meeting all DSM-IV ADHD diagnostic criteria including impairment) based on the best estimate; and or (ii) patients without persistent ADHD (110, 37.2%).

Procedures

The Research Ethics Committee of National Taiwan University Hospital approved the present study prior to implementation. We obtained written informed consent from both the participants and their parents. The Wechsler Intelligence Scale for Children–3rd edition was administered to all the participants to exclude those who had an IQ < 80. All the adolescent participants and their parents were interviewed independently by individual well-trained interviewers for the DSM-IV psychiatric diagnoses at baseline first to confirm childhood diagnosis, followed by current psychiatric assessments separately, using the Chinese K-SADS-E. Medication information was obtained by interviews and validated by medical records of prescription. All the interview data were cross-checked by research team members independently and the best estimate of psychiatric diagnosis of each participant was made by the first author blindly and independently.

Data analyses

Data analysis was conducted using SAS 9.1 (SAS Institute, Cary, NC, USA). The comparison groups were (i) patients with persistent ADHD; (ii) patients with non-persistent ADHD; and (iii) school controls without a lifetime diagnosis of ADHD. We used a logistic regression model to compare the rates of psychiatric disorders among the three groups controlling for age, sex, parental educational level, and current treatment with methylphenidate. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed. For all the analyses, we started from the four-way interactions (age × sex × medication × group). We found that there was neither four-way nor three-way interactions for the group differences in psychiatric comorbid conditions. For the majority of statistical models, there were no two-way interactions between age, sex, medication, and the group (ADHD vs control) on the psychiatric comorbid conditions except that there was an interaction of age × group for ODD (regression coefficient, β = 0.19, p = 0.02). Therefore, we did not stratify by sex and age in all the analyses. We also tested the linear trend across the three groups from unaffected controls, to non-persistent ADHD, and persistent ADHD after model comparisons indicated that the group variable can be treated as a linear variable in the logistic regression model using the goodness of fit tests. The alpha was pre-selected at the level of p < 0.05.

Results

Sample description

Table 1 presents the demographic data, and medication and clinical history of the three groups. The two ADHD groups had a higher proportion of male participants and lower parental educational levels. Patients with persistent ADHD were found to have overt ADHD symptoms at a younger age than those without. There was no difference in maternal (p = 0.282) and paternal (p = 0.121) job types, age of clinical diagnosis of ADHD or medication history (Table 1).

Table 1.

Subject characteristics

	Persistent ADHD	Non-persistent ADHD	Control	Statistics
	(n = 186)	(n = 110)	(n = 185)	χ²/F	p
Male, n (%)	160 (86.0)	93 (84.6)	134 (72.4)	χ² ₂ = 12.41	0.002
Age (years), mean ± SD	12.78 ± 1.47	12.99 ± 1.68	12.91 ± 1.46	F = 0.74	0.476
Father's education (%)
College and above	57.8	64.1	77.1
Senior high school	31.7	26.2	17.5	χ² = 14.88	0.005
Junior high school and below	10.5	9.7	5.4
Mother's education (%)
College and above	46.5	56.1	64.5
Senior high school	43.8	35.5	28.9	χ² ₄ = 11.49	0.022
Junior high school and below	9.7	8.4	6.6
Household with two parents (%)	89.2	88.6	96.1	χ² ₂ = 5.62	0.060
Age of overt ADHD symptoms (years)	3.95 ± 1.46	4.66 ± 1.76	—	F = 14.02	<0.001
Age of clinical diagnosis of ADHD (years)	6.65 ± 2.63	6.90 ± 2.71	—	F = 0.51	0.474
Use of methylphenidate, n (%)
Current	96 (51.6)	57 (51.8)	—	χ² ₁ = 0.01	0.973
Ever	163 (87.6) (n = 156)	96 (87.3) (n = 91)	—	χ₁ ² = 0.08	0.928
Duration (months) (mean ± SD)	20.28 ± 21.51	19.57 ± 21.72		F = 0.06	0.804

ADHD, attention-deficit hyperactivity disorder.

Psychiatric comorbidity

Table 2 summarizes the rates and ORs with the 95%CIs of having other psychiatric disorders among the three groups. The ADHD groups were significantly more likely than the controls to have had any psychiatric disorders at adolescence including ODD, CD, tic disorder, mood disorders (major depression, bipolar disorders), ever use of nicotine, alcohol, betel nut, regular use of nicotine, substance use disorders (mainly nicotine use disorder), and sleep disorders (ORs = 1.84–25.34, Table 2). The significance of these results remained after further controlling for other comorbidities.

Table 2.

Psychiatric disorders at adolescence

	Persistenl ADHD		Non-persistent ADHD		Control			OR (95%CI)
	n	(%)	n	(%)	n	(%)	Persistent ADHD vs control	Non-persistent ADHD vs control	Persistent ADHD vs non-persistent
	(n = 186)		(n = 110)		(n = 185)
Psychiatric diagnoses
Oppositional defiant disorder∗∗∗∗	119	(64.3)	50	(45.5)	17	(9.2)	17.82 (9.95-31.90)	8.24 (4.41-15.37)	2.16 (1.34-3.50)
Conduct disorder∗∗∗∗	46	(24.9)	18	(16.4)	2	(1.1)	30.27 (7.23-126.83)	17.90 (4.07-78.78)	1.69 (0.92-3.10)
Tic disorder∗	14	(7.5)	7	(6.4)	3	(1.6)	4.94 (1.40-17.48)	4.12 (1.04-16.29)	1.20 (0.47-3.07)
Mood disorders∗	23	(12.4)	19	(17.3)	10	(5.4)	2.47 (1.14-5.35)	3.65 (1.63-8.18)	0.68 (0.35-1.31)
Dysthymic disorder	4	(2.2)	3	(2.7)	4	(2.2)	1.00 (0.25-4.04)	1.27 (0.28-5.78)	0.78 (0.17-3.57)
Major depression	13	(7.0)	10	(9.1)	5	(2.7)	2.71 (0.94-775)	3.60 (1.20-10.82)	0.75 (0.32-1.78)
Bipolar disorder	6	(3.2)	6	(5.5)	1	(0.5)	6.13 (0.73-51.52)	10.61 (1.26-89.31)	0.58 (0.18-1.84)
Anxiety disorders∗	59	(31.7)	25	(22.7)	38	(20.5)	1.80 (1.12-2.88)	1.14 (0.64-2.01)	1.58 (0.92-2.72)
Generalized anxiety disorder	5	(2.7)	2	(1.8)	1	(0.5)	5.11 (0.59-44.18)	3.41 (0.31-38.02)	1.50 (0.29-787)
Specific phobia∗∗	37	(20.0)	12	(10.9)	19	(10.3)	2.18 (1.20-3.96)	1.07 (0.50-2.30)	2.04 (1.02-4.11)
Social phobia	17	(9.2)	8	(7.3)	10	(5.4)	1.77 (0.79-3.98)	1.37 (0.53-3.59)	1.29 (0.54-3.10)
Separation anxiety disorder∗	7	(3.8)	2	(1.8)	1	(0.5)	7.24 (0.88-59.40)	3.41 (0.31-38.02)	2.12 (0.43-10.41)
Panic disorder	7	(3.8)	5	(4.6)	4	(2.2)	1.78 (0.51-6.19)	2.16 (0.57-8.20)	0.83 (0.26-2.67)
Agoraphobia	1	(0.5)	0	(0)	0	(0)	0.500‡	—	0.627‡
Obsessive-compulsive disorder	10	(5.4)	2	(1.8)	8	(4.3)	1.26 (0.49-3.28)	0.41 (0.09-1.97)	3.08 (0.66-14.34)
Substance use disordersf	4	(2.2)	5	(4.6)	0	(0)	0.062‡	0.007‡	0.46 (0.12-1.76)
Nicotine
Ever used∗∗∗∗	32	(17.2)	15	(13.6)	6	(3.2)	6.20 (2.53-15.22)	4.71 (1.77-12.54)	1.32 (0.68-2.56)
Regular use†	8	(4.4)	7	(6.4)	0	(0)	0.004‡	<0.001‡	0.67 (0.24-1.90)
Abuse/Dependence†	4	(2.2)	4	(3.6)	0	(0)	0.062‡	0.019‡	0.58 (0.14-2.38)
Alcohol
Ever used∗∗∗	121	(65.1)	61	(55.5)	86	(46.5)	2.14 (1.41-3.25)	1.43 (0.89-2.30)	1.50 (0.92-2.42)
Regular use ‡	1	(0.5)	3	(2.7)	0	(0)	0.500‡	0.051‡	0.19 (0.02-1.89)
Abuse/Dependence†	0	(0)	2	(1.8)	0	(0)	—	0.138‡	0.139‡
Betel nut
Ever used∗	8	(4.3)	4	(3.6)	0	(0)	0.004‡	0.019‡	1.19 (0.35-4.05)
Regular use	0	(0)	1	(0.9)	0	(0)	—	0.373‡	0.372‡
Abuse/Dependence	0	(0)	1	(0.9)	0	(0)	—	0.373‡	0.210‡
Adjustment disorders	6	(3.2)	1	(0.9)	6	(3.2)	0.99 (0.32-3.14)	0.27 (0.03-2.30)	3.63 (0.43-30.58)
Sleep Disorders∗∗∗	53	(28.8)	26	(23.6)	23	(12.4)	2.85 (1.66-4.89)	2.18 (1.17-4.05)	1.31 (0.76-2.25)
Eating Disorders	3	(1.6)	0	(0)	0	(0)	0.124‡	—	0.245‡
Psychosis	2	(1.1)	0	(0)	0	(0)	0.249‡	—	0.394‡
Any psychiatric disorder∗∗∗∗	151	(81.2)	77	(70.0)	64	(34.6)	8.16 (5.07-13.13)	4.41 (2.65-7.33)	1.85 (1.07-3.20)

ADHD, attention-deficit hyperactivity disorder; Cl, confidence interval; OR, odds ratio. †The three groups across the persistent ADHD, non-persistent ADHD, and healthy controls cannot be treated as a linear variable. ‡Fisher's exact test p. Significance levels of the linear trend of the group effects by treating the three groups as a linear variable: ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001.

Both patients with and without persistent ADHD had higher risks for ODD, CD, tic disorder, mood disorders, ever and regular use of nicotine, ever use of betel nut, and sleep disorders than the controls (Table 2). In addition, patients with persistent ADHD were more likely than the controls to have anxiety disorders, particularly specific phobia (Table 2). Patients without persistent ADHD were more likely than the controls to have major depression, bipolar disorders, substance use disorder (nicotine abuse/dependence). Moreover, patients with persistent ADHD were more likely to have ODD, specific phobia, and any psychiatric disorders than their partially remitted counterparts (Table 2).

We found that the three groups were suitable to be treated as a linear variable in the majority of models except those having substance use disorder, regular use of nicotine, nicotine abuse/dependence, regular use of alcohol, and alcohol abuse/dependence (p < 0.05 for model comparisons). There were significant linear trends from the three groups on their prediction of any psychiatric disorders, ODD, CD, tics, anxiety disorders (particularly, specific phobia and separation anxiety), sleep disorders, ever use of nicotine, alcohol, and betel nut.

Correlates for psychiatric comorbid conditions

We further examined the factors influencing the risks for five major significant psychiatric comorbidities (Table 3). These predictors included childhood ADHD core symptoms, age of overt observable ADHD symptoms, treatment with methylphenidate, and demographics (sex, age, parental education as senior high school or below, household without two parents). Analyses indicated that inattention, hyperactivity, and impulsivity symptoms at childhood, and longer duration of treatment with methylphenidate significantly predicted ODD/CD. Ever treatment with methylphenidate significantly decreased and longer treatment duration of methylphenidate significantly increased the risk for tics. Older age and comorbidity with CD significantly predicted the risk for mood disorders and substance use disorders. Female gender and longer duration of methyl phenidate treatment significantly increased the risk for specific phobia.

Table 3.

Prediction of baseline ADHD symptoms, medication, and demographics of adolescent psychiatric outcomes

		ODD/CD			Tic disorder			Mood disorder			Specific phobia		Substance use disorder
	No	Yes	OR	No	Yes	OR	No	Yes	OR	No	Yes	OR	No	Yes	OR
	Mean ±	SD/n (%)	(95%CI)	Mean ±	SD/n (%)	(95%CI)	Mean ±	SD/n (%)	(95%CI)	Mean ±	SD/n (%)	(95%CI)	Mean ±	SD/n (%)	(95%CI)
Baseline ADHD	(n = 119)	(n = 176)		(n = 275)	(n = 21)		(n = 254)	(n = 42)		(n = 246)	(n = 49)		(n = 287)	(n = 9)
symptoms
Inattention	11.5 (4.7)	13.24 (3.6)	1.1 (1.1-1.2)	12.4 (4.3)	14.0 (2.6)	1.1 (0.9-1.3)	12.4 (4.3)	13.2 (3.5)	1.1 (0.9-1.1)	12.6(4.2)	12.4 (4.1)	1.0 (0.9-1.7)	12.5 (4.2)	14.8 (3.6)	1.2 (0.9-1.2)
Hyperactivity	6.2 (3.7)	8.0 (2.9)	1.2 (1.1-1.3)	7.2 (3.4)	7.6(3.1)	1.0 (0.9-1.2)	7.2 (3.3)	7.9 (3.6)	1.1 (0.9-1.2)	7.3 (3.4)	7.3 (3.3)	1.0 (0.9-1.1)	7.2 (3.4)	8.6 (3.1)	1.1 (0.9-1.4)
Impulsivity	2.4 (2.1)	3.89 (2.0)	1.4 (1.3-1.6)	3.3 (2.2)	3.3(2.1)	1.0 (0.8-1.2)	3.2(2.1)	3.5 (2.3)	1.1 (0.9-1.2)	3.2 (2.2)	3.5 (2.0)	1.1 (0.9-1.2)	3.2 (2.2)	3.8 (1.8)	1.1 (0.8-1.6)
Age onset of	4.4 (1.7)	4.1 (1.56)	0.9	4.2 (1.6)	4.0 (1.4)	0.9	4.2 (1.7)	4.10 (1.2)	1.0	4.3 (1.6)	3.9 (1.5)	0.8	4.2 (1.6)	3.8 (1.4)	0.8
ADHD			(0.8-1.0)			(0.7-1.2)			(0.8-1.2)			(0.7-1.0)			(0.5-1.3)
Use of methy-Iphenidate
Ever use	104 (87.4)	154 (87.5)	1.0 (0.5-2.0)	244 (88.7)	15 (71.4)	0.3 (0.1-0.9)	226 (89.0)	33 (78.6)	0.5 (0.2-1.1)	214(870)	44 (89.8)	1.3 (0.5-3.6)	250 (87.1)	9 (100.0)	0.3‡
Current use	61 (51.3)	92 (52.3)	1.0 (0.7-1.7)	146 (53.1)	7 (33.3)	0.4 (0.2-1.1)	136 (53.5)	17 (40.5)	0.6 (0.3-1.2)	123 (50.0)	29 (59.2)	1.5 (0.8-2.7)	149 (51.9)	4 (44.4)	0.7 (0.2-2.8)
Duration of use	16.8 (19.0)	22.3 (23.0)	1.0 (1.0-1.1)	19.23 (20.9)	32.6(28.2)	1.0 (1.0-1.1)	20.8 (22.0)	14.1 (16.9)	1.0 (0.9-1.0)	18.0(19.8)	29.4 (26.8)	1.0 (1.0-1.1)	20.0 (21.5)	19.3 (24.3)	1.0 (0.9-1.0)
Demographics
Male	98 (82.4)	155 (88.1)	1.6 (0.8-3.1)	234(85.1)	19 (90.5)	1.7 (0.4-7.4)	219 (86.2)	34 (81.0)	0.7 (0.3-1.6)	216(878)	36 (73.5)	0.4 (0.2-0.8)	244 (85.0)	9 (100.0)	0.2t
Child age	12.7 (1.5)	13.0 (1.6)	1.1 (0.9-1.3)	12.9 (1.6)	12.6 (1.5)	0.9 (0.6-1.2)	12.8 (1.5)	13.5 (1.7)	1.3 (1.1-1.7)	12.9 (1.6)	12.6 (1.4)	0.9 (0.7-1.1)	12.8 (1.5)	15.5 (1.4)	3.3 (1.9-5.7)
Lower parent education	39 (21.8)	61 (35.5)	1.1 (0.7-1.9)	92 (34.0)	8 (38.1)	1.2 (0.5-3.0)	870 (34.5)	13(32.5)	0.9 (0.5-1.9)	79 (32.5)	21 (42.9)	1.6 (0.8-2.9)	97 (34.2)	3 (37.5)	1.2 (0.3-4.9)
Household without both parents	9 (7.6)	23 (13.5)	1.9 (0.9-4.3)	28 (10.4)	4 (20.0)	2.2 (0.7-6.9)	31 (12.4)	1 (2.5)	0.2 (0.1-1.4)	22 (9.1)	10 (20.4)	2.6 (1.1-5.8)	31 (11.0)	1 (12.5)	1.2 (0.1-9.7)

ADHD, attention-deficit hyperactivity disorder; CD, conduct disorder; Cl, confidence interval; ODD, oppositional defiant disorder; OR, odds ratio. Conduct disorder predict mood disorders (OR = 2.31, 95%CI = 1.14–4.68, p = 0.020) and substance use disorders (OR = 7.86, 95%CI = 1.91-32.39, p = 0.004). ‡Fisher exact test p.

We then used backward elimination in the model selection to identify the most associated correlates for the following comorbid conditions. We found that childhood hyperactivity (OR = 1.09, 95%CI = 1.01–1.25; p = 0.004) and impulsivity (OR = 1.29, 95%CI = 1.14–1.47, p < 0.001) significantly predicted ODD/CD. Longer duration of methylphenidate treatment (OR = 1.03, 95%CI = 1.01–1.05, p = 0.018) and younger age (OR = 0.60, 95%CI = 0.39–0.93, p = 0.023) predicted the risk for tic disorder. Older age (OR = 1.35, 95%CI = 1.08–1.70, p = 0.009), and comorbidity with CD (OR = 2.31, 95%CI = 1.12–4.80, p = 0.024) increased and ever treatment with methylphenidate (OR = 0.42, 95%CI = 0.19–0.97, p = 0.043) decreased the risk for mood disorders. Male gender (OR = 0.39, 95%CI = 0.19–0.82, p = 0.013) decreased and having a household without both parents (OR = 2.70, 95%CI = 1.18–6.22, p = 0.019) increased the risk for specific phobia. Older age (OR = 3.31, 95%CI = 1.81–6.06, p < 0.001) and comorbidity with CD (OR = 12.24, 95%CI = 1.99–75.25, p = 0.007) were associated with an increased risk for substance use disorders.

Discussion

Many Western studies have reported high rates of psychiatric comorbidity in ADHD, but this is the first to investigate the psychiatric outcomes at adolescence in an Asian population. Similar to Western studies in children and adolescents with ADHD [4,5,35,36], the present major findings are that a childhood diagnosis of ADHD was significantly associated with the risks for ODD, CD, tics, mood disorders, and ever and regular use of tobacco and betel nut, regardless of persistent ADHD. Although Biederman et al. reported that psychiatric comorbidity is related to persistent ADHD [37], the present study demonstrated that these psychiatric disorders except anxiety disorders also present in children and adolescents without persistent ADHD. This suggests that psychiatric comorbid conditions at adolescence cannot be fully explained by the persistence of ADHD symptoms. There was a significant linear trend in the order of school controls, non-persistent ADHD, and persistent ADHD in terms of the prediction of any psychiatric disorders, ODD/CD, tics, anxiety disorders, sleep disorders, ever use of nicotine, alcohol, and betel nut. The novel finding is the increased risk for specific phobia in adolescents with persistent ADHD.

Oppositional defiant/conduct disorders

The rate of ODD in the ADHD group (57.3%) has ranged from 32% [38] to 77% [37] across studies. The rate of CD (21.7%) is higher than that in epidemiological samples (12%) [38], but lower than that in clinical samples (30–50%) [4]. Consistent with previous studies [22], we also found a significant relationship between current ADHD symptom severity and current diagnosis of ODD/ CD. A gradient relationship across the three groups regarding the rate of ODD/CD suggests a dose-related linear relationship between current ADHD symptoms and an ODD/CD diagnosis, consistent with a recent study [39]. The present findings also indicate that a childhood diagnosis of ADHD predicts a higher risk for ODD/CD at adolescence [40], regardless of the persistence of ADHD. The present findings lend support to the notion that the severity of childhood hyperactive and impulsive symptoms is the most predictive factor for adolescent ODD/CD [20,21]. The significant effect of childhood inattention on adolescent ODD/CD, however, can be explained by hyperactive/impulsive symptoms.

Surprisingly, we found an association between longer duration of methylphenidate treatment and increased risks for ODD/CD at adolescence. Methylphenidate treatment was not designed to be randomized in the present study, so confounding self-selective factors such as ADHD symptom severity and comorbidity, may determine continued medication use [41]. Hence, treatment may indeed stand as a proxy for severity of ADHD [42,43]. Corresponding to previous studies, there were neither gender [44,45] nor age [3] differences in the risks for ODD/CD in ADHD.

Tic disorder

The rate of tic disorder in the ADHD group (7.1%) was lower than in previous reports, ranging from 10.9% (MTA study) [46] to 33% [47], with the average around 20% [36,48]. Unlike some [49] but corresponding to others [23,24], the present findings demonstrated that duration of methylphenidate treatment predicted tics, after taking confounding factors into consideration, suggesting that long-term use of methylphenidate may increase a risk for tics.

Mood disorders

The lower rate of bipolar disorder (4.1%) in the present report than in previous reports of 16% [8] to 23% [37] may be partially explained by the younger age of the present sample. Consistent with previous studies [35], ADHD is highly comorbid with major depression as a function of age [3], despite the fact that its rate is in the lower end of 3–75% [4]. The present findings, however, did not provide evidence to support an association between persistent ADHD and adolescent major depression [22], compared with non-persistent ADHD. Moreover, consistent with some studies, CD, not ODD, is associated with an increased risk for mood disorders [4]. Due to the relatively young age range and short follow-up period in the present study, further study of this sample with a longer follow-up period to clarify the prediction of ADHD to mood disorders is warranted. Identification of risk factors and correlates for mood disorders, which was not clarified significantly in the current study, will also be our next step.

Anxiety disorders

The rate of anxiety disorders in the ADHD group was similar to those reported in epidemiologic and clinical samples of ADHD, ranging from 25% [4] to 33% [50]. The magnitude of association, however, between persistent ADHD and anxiety disorders is not compatible with the estimate based on a meta-analysis (OR = 3.0, 95%CI = 2.1–4.3) [35]. One possible explanation is the higher prevalence rate of anxiety disorder in the control group (20.5%), which was higher than in Western (5–15%) [51] and Taiwanese epidemiological studies [3]. Despite the increased risk of anxiety disorders in adolescents with persistent ADHD, no such relationship was found in adolescents without persistent ADHD. This finding implies that anxiety disorders are likely to be related to current ADHD symptoms rather than a childhood diagnosis of ADHD [52].

Surprisingly, persistent ADHD is related to the risk for specific phobia, particularly in girls, a novel finding warranting further investigation. This finding is similar to some studies that girls are at a greater risk than boys regarding anxiety disorders [44,45] and separation anxiety disorder [45]. The present finding can also be explained by a higher prevalence rate of specific phobia in female gender [20]. The finding of an increased duration of methylphenidate treatment predicting specific phobia corresponds to some clinical trials showing that anxious and phobic symptoms are related to the adverse effects of methylphenidate [53]. Similar to earlier studies showing the relationship between parental divorce/ separation and comorbidity with anxiety disorder in ADHD [27], the present results indicate that a household without two parents predicts specific phobia.

Substance use

The present study not only lends evidence to support the prediction of persistence of ADHD to the risk for substance use in adolescence as shown in Western studies [17] and a Taiwan study [32], but also demonstrated an association between non-persistent ADHD and substance use in adolescents. This implies that a childhood diagnosis of ADHD may increase the risk for substance use, regardless of persistent ADHD at adolescence. Within the ADHD group, consistent with the majority of studies, older age [54] and comorbidity with CD [32], not ODD [32], were the predictors for substance use disorders. Lack of association between methylphenidate treatment and substance use disorder in adolescence is compatible to the findings of a 10 year follow-up study by Biederman et al. [55]. Unlike in several other studies [17,19], we did not find that childhood ADHD symptom severity predicted substance use disorders at adolescence. The relatively younger age at assessment in the present study than the other studies may have precluded a sound prediction of ADHD for substance use disorder at late adolescence or young adulthood.

Limitations

The major limitations of the present study were that questionable external validity needs to be examined further; that despite the clinical assessment of ADHD at childhood with detailed medical records, the Chinese K-SADS-E interview on childhood diagnoses were conducted at adolescence, resulting in possible recall bias; and that the follow-up period was not long enough to include more cases of mood disorders and substance use disorders for a more powerful examination of the prediction of ADHD and its comorbid conditions for these two disorders in adolescence and young adulthood.

The strengths of the current study were that the sample was of adequate sample size from a relatively less studied population; comprehensive assessments were done of ADHD and other psychiatric disorders at childhood and adolescence on clinical and psychiatric interviews of the participants and their parents; and collection was done of complete information about demographic data, baseline and current ADHD symptoms, age at onset of ADHD, and medication treatment history, which were validated by detailed medical records.

Conclusion

As in Western studies, Taiwanese adolescents with persistent ADHD are indeed more likely to have comorbid psychiatric disorders, and the onset of mood disorders and substance use disorders is a function of age, and comorbidity with CD. In addition, the increased likelihood of psychiatric comorbidity exists even in those without persistent ADHD, suggesting that the improvement of ADHD symptoms at adolescence may not result in decreased risks for psychiatric comorbidity. The present findings imply that identifying and eliminating factors contributing to the pathway from ADHD to other psychiatric disorders such as ODD, CD, anxiety disorders, mood disorders, and substance use disorders and recognizing age-specific 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.

References

Zuddas

Ancilletta

Muglia

Cianchetti

. Attention-deficit/ hyperactivity disorder: a neuropsychiatric disorder with childhood onset. Eur J Paediatr Neurol 2000; 4:53–62.

Faraone

Sergeant

Gillberg

Biederman

. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2003; 2:104–113.

Gau

Chong

Chen

Cheng

. A 3-year panel study of mental disorders among adolescents in Taiwan. Am J Psychiatry 2005; 162:1344–1350.

Biederman

Newcorn

Sprich

. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991; 148:564–577.

Biederman

. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 2005; 57:1215–1220.

Biederman

Petty

Dolan

. The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study. Psychol Med 2008; 38:1027–1036.

Biederman

Faraone

Keenan

. Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 1992; 49:728–738.

Wozniak

Biederman

Kiely

. Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 1995; 34:867–876.

Vance

Harris

Boots

Talbot

Karamitsios

. Which anxiety disorders may differentiate attention deficit hyperactivity disorder, combined type with dysthymic disorder from attention deficit hyperactivity disorder, combined type alone? Aust N Z J Psychiatry 2003; 37:563–569.

10.

Bowen

Chavira

Bailey

Stein

. Nature of anxiety comorbid with attention deficit hyperactivity disorder in children from a pediatric primary care setting. Psychiatry Res 2008; 157:201–209.

11.

Vance

Costin

Barnett

Luk

Maruff

Tonge

. Characteristics of parent- and child-reported anxiety in psychostimulant medication naive, clinically referred children with attention deficit hyperactivity disorder, combined type (ADHD-CT). Aust N Z J Psychiatry 2002; 36:234–239.

12.

Pastor

Reuben

. Diagnosed attention deficit hyperactivity disorder and learning disability: United States, 2004–2006. Vital Health Stat 10 2008; 237:1–14.

13.

Erenberg

. The relationship between tourette syndrome, attention deficit hyperactivity disorder, and stimulant medication: a critical review. Semin Pediatr Neurol 2005; 12:217–221.

14.

Elkins

McGue

Iacono

. Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry 2007; 64:1145–1152.

15.

Arias

Gelernter

Chan

. Correlates of co-occurring ADHD in drug-dependent subjects: prevalence and features of substance dependence and psychiatric disorders. Addict Behav 2008; 33:1199–1207.

16.

Smalley

McGough

Moilanen

. Prevalence and psychiatric comorbidity of attention-deficit/hyperactivity disorder in an adolescent Finnish population. J Am Acad Child Adolesc Psychiatry 2007; 46:1575–1583.

17.

Molina

Pelham

Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD. J Abnorm Psychol 2003; 112:497–507.

18.

Disney

Elkins

McGue

Iacono

. Effects of ADHD, conduct disorder, and gender on substance use and abuse in adolescence. Am J Psychiatry 1999; 156:1515–1521.

19.

Kollins

McClernon

Fuemmeler

. Association between smoking and attention-deficit/hyperactivity disorder symptoms in a population-based sample of young adults. Arch Gen Psychiatry 2005; 62:1142–1147.

20.

Burns

Walsh

. The influence of ADHD-hyperactivity/impulsivity symptoms on the development of oppositional defiant disorder symptoms in a 2-year longitudinal study. J Abnorm Child Psychol 2002; 30:245–256.

21.

Monuteaux

Faraone

Michelle Gross

Biederman

. Predictors, clinical characteristics, and outcome of conduct disorder in girls with attention-deficit/hyperactivity disorder: a longitudinal study. Psychol Med 2007; 37:1731–1741.

22.

Hurtig

Ebeling

Taanila

. ADHD symptoms and sub-types: relationship between childhood and adolescent symptoms. J Am Acad Child Adolesc Psychiatry 2007; 46:1605–1613.

23.

Pollack

Cohen

Friedhoff

. Gilles de la Tourette's syndrome. Familial occurrence and precipitation by methylphenidate therapy. Arch Neurol 1977; 34:630–632.

24.

Golden

. Gilles de la Tourette's syndrome following methylphenidate administration. Dev Med Child Neurol 1974; 16:76–78.

25.

Parraga

Harris

. Tic exacerbation and precipitation during atomoxetine treatment in two children with attention-deficit hyperactivity disorder. Int J Psychiatry Med 2007; 37:415–424.

26.

Connor

Edwards

Fletcher

Baird

Barkley

Steingard

. Correlates of comorbid psychopathology in children with ADHD. J Am Acad Child Adolesc Psychiatry 2003; 42:193–200.

27.

Biederman

Faraone

Keenan

Steingard

Tsuang

. Familial association between attention deficit disorder and anxiety disorders. Am J Psychiatry 1991; 148:251–256.

28.

Takahashi

Miyawaki

Suzuki

. Hyperactivity and comorbidity in Japanese children with attention-deficit/hyperactivity disorder. Psychiatry Clin Neurosci 2007; 61:255–262.

29.

Yang

Jong

Hsu

Tsai

. Psychiatric features and parenting stress profiles of subtypes of attention-deficit/hyperactivity disorder: results from a clinically referred Taiwanese sample. J Dev Behav Pediatr 2007; 28:369–375.

30.

Gau

Soong

. Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a case-control study. Aust N Z J Psychiatry 1999; 33:734–739.

31.

Gau

Chiang

. Sleep problems and disorders among adolescents with persistent and subthreshold attention-deficit/hyperactivity disorders. Sleep 2009; 32:671–679.

32.

Gau

Chong

Yang

Yen

Liang

Cheng

. Psychiatric and psychosocial predictors of substance use disorders among adolescents: longitudinal study. Br J Psychiatry 2007; 190:42–48.

33.

Leckman

Sholomskas

Thompson

Belanger

Weissman

. Best estimate of lifetime psychiatric diagnosis: a methodological study. Arch Gen Psychiatry 1982; 39:879–883.

34.

Gau

Soong

Chiu

Tsai

. Psychometric properties of the Chinese version of the Conners’ Parent and Teacher Rating Scales-Revised: Short Form. J Atten Disord 2006; 9:648–659.

35.

Angold

Costello

Erkanli

. Comorbidity. J Child Psychol Psychiatry 1999; 40:57–87.

36.

Spencer

Biederman

Coffey

Geller

Faraone

Wilens

. Tourette disorder and ADHD. Adv Neurol 2001; 85:57–77.

37.

Biederman

Faraone

Milberger

. 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; 35:343–351.

38.

August

Realmuto

MacDonald

Nugent

Crosby

. Prevalence of ADHD and comorbid disorders among elementary school children screened for disruptive behavior. J Abnorm Child Psychol 1996; 24:571–595.

39.

Hurtig

Ebeling

Taanila

. ADHD and comorbid disorders in relation to family environment and symptom severity. Eur Child Adolesc Psychiatry 2007; 16:362–369.

40.

Whittinger

Langley

Fowler

Thomas

Thapar

. Clinical precursors of adolescent conduct disorder in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007; 46:179–187.

41.

Epstein

Conners

Hervey

. Assessing medication effects in the MTA study using neuropsychological outcomes. J Child Psychol Psychiatry 2006; 47:446–456.

42.

Kessler

Adler

Barkley

. Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication. Biol Psychiatry 2005; 57:1442–1451.

43.

Vance

Maruff

Barnett

. Attention deficit hyperactivity disorder, combined type: better executive function performance with longer-term psychostimulant medication. Aust N Z J Psychiatry 2003; 37:570–576.

44.

Bauermeister

Shrout

Chavez

. ADHD and gender: are risks and sequela of ADHD the same for boys and girls? J Child Psychol Psychiatry 2007; 48:831–839.

45.

Levy

Hay

Bennett

McStephen

. Gender differences in ADHD subtype comorbidity. J Am Acad Child Adolesc Psychiatry 2005; 44:368–376.

46.

The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56:1073–1086.

47.

Kadesjo

Gillberg

. The comorbidity of ADHD in the general population of Swedish school-age children. J Child Psychol Psychiatry 2001; 42:487–492.

48.

Banaschewski

Neale

Rothenberger

Roessner

. Comorbidity of tic disorders and ADHD: conceptual and methodological considerations. Eur Child Adolesc Psychiatry 2007; 16 (Suppl 1):5–14.

49.

Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002; 58:527–536.

50.

Bird

Gould

Staghezza

. Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Am Acad Child Adolesc Psychiatry 1993; 32:361–368.

51.

Cohen

Kasen

. An epidemiological study of disorders in late childhood and adolescence: I. Age- and gender-specific prevalence. J Child Psychol Psychiatry 1993; 34:851–867.

52.

Geller

Donnelly

Lopez

. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry 2007; 46:1119–1127.

53.

Gau

Shen

Soong

Gau

. An open-label, randomized, active-controlled equivalent trial of osmotic release oral system methylphenidate in children with attention-deficit/hyperactivity disorder in Taiwan. J Child Adolesc Psychopharmacol 2006; 16:441–455.

54.

Wilens

Adamson

Sgambati

. Do individuals with ADHD self-medicate with cigarettes and substances of abuse? Results from a controlled family study of ADHD. Am J Addict 2007; 16 (Suppl 1):14–21.

55.

Biederman

Monuteaux

Spencer

Wilens

Macpherson

Faraone

. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry 2008; 165:597–603.

Psychiatric Comorbidity Among Children and Adolescents With and Without Persistent Attention-Deficit Hyperactivity Disorder

Abstract

Keywords

Methods

Participants

Measures

Chinese K-SADS-E

Interviewer training

Best-estimate diagnoses

Persistent and non-persistent ADHD

Procedures

Data analyses

Results

Sample description

Psychiatric comorbidity

Correlates for psychiatric comorbid conditions

Discussion

Oppositional defiant/conduct disorders

Tic disorder

Mood disorders

Anxiety disorders

Substance use

Limitations

Conclusion

References