Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue2.2000:
ORIGINAL ARTICLES
Attention-Deficit Disorder and Conduct Disorder in
Girls: Evidence for a Familial Subtype
Stephen V. Faraone, Joseph Biederman, and Michael C. Monuteaux
Background: The frequent comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct
disorder (CD) raises the possibility that ADHD1CD is a
distinct and separate condition.
Methods: We tested hypotheses about patterns of familial
association between ADHD, CD, oppositional defiant
disorder (ODD) and adult antisocial personality disorder
(ASPD). Using family study methodology in a sample of
girls, we found 11 children with diagnoses of ADHD1CD,
39 with ADHD1ODD, and 90 with ADHD only. These
were compared with 122 non-ADHD, non-CD control
probands. Familial risk analysis was utilized.
Results: Relatives of each ADHD proband subgroup were
at significantly greater risk for ADHD, and the relatives of
ADHD-only subjects were at a greater risk of ODD than
relatives of control subjects. Also, rates of CD were
elevated among relatives of ADHD1CD probands only,
and the coaggregation of ADHD and the antisocial disorders could not be accounted for by marriages between
ADHD and antisocial spouses. Both ADHD and antisocial
disorders occurred in the same relatives more often than
expected by chance.
Conclusions: These findings suggest that ADHD with and
without antisocial disorders may be etiologically distinct
disorders and provide evidence for the nosologic validity
of ICD-10 hyperkinetic conduct disorder. Biol Psychiatry 2000;48:21–29 © 2000 Society of Biological
Psychiatry
Key Words: ADHD, conduct disorder, oppositional defiant disorder, family– genetic, risk factors
Introduction
A
n obstacle to the successful classification of attentiondeficit/hyperactivity disorder (ADHD) is the frequently reported comorbidity between ADHD and conduct
From Pediatric Psychopharmacology Unit, Psychiatry Service, Massachusetts
General Hospital (SVF, JB, MCM), the Department of Psychiatry, Harvard
Medical School (SVF, JB), Harvard Institute of Psychiatric Epidemiology and
Genetics, Department of Psychiatry, Harvard Medical School at Brockton–
West Roxbury Veterans Affairs Medical Center and Massachusetts Mental
Health Center (SVF), and the Department of Epidemiology, Harvard School of
Public Health (MCM), Boston, Massachusetts.
Address reprint requests to Stephen V. Faraone, Ph.D., Harvard Medical School,
Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, Fruit Street, Boston MA 02114.
Received April 7, 1999; revised December 17, 1999; accepted December 22, 1999.
© 2000 Society of Biological Psychiatry
disorder (CD; Caron and Rutter 1991). This overlap has
been consistently found in clinical samples in studies of
children with ADHD and children with CD (Biederman et
al 1987, 1991c; Hinshaw 1987; Loeber et al 1990; Milich
et al 1987; Schachar and Tannock 1995) and in follow-up
studies of ADHD children (Gittelman et al 1985). Taylor
(1994) noted that the comorbidity between ADHD and CD
raises a key nosologic question: Are these two disorders
best seen as co-occurring yet separate entities or, does
their consistent co-occurrence signal the presence of a
separate category of disorder? The former approach was
taken by the American DSM-IV (American Psychiatric
Association 1994), whereas the latter has been recognized
with the separate category of hyperkinetic conduct disorder used by the World Health Organization’s ICD-10
(World Health Organization 1988). The differences between the two systems underscore the need for further
nosologic research.
As discussed in detail by Caron and Rutter (1991),
comorbidity can occur for many reasons. It can be an
artifact in clinical samples, because people with multiple
disorders are more likely to seek help than those with only
one disorder. In epidemiologic studies, screening tests can
exaggerate comorbidity, because comorbid disorders are
more likely to exceed the test’s threshold for detection.
Comorbidity may also signal errors in the nosology used
to define the disorders. If two disorders are actually the
extremes of dimensional traits, then the choice of the
threshold for defining the disorders will influence the
degree of observed comorbidity. Also, overlapping diagnostic criteria can lead to spurious comorbidity. Our
empirical study of this latter issue, however, suggests that
this effect cannot account for most comorbidity in ADHD
(Milberger et al 1995). Comorbidity might also indicate
that a nosologic subdivision of syndromes is not appropriate or that one disorder is an early manifestation or a
component of the other.
Elsewhere, we have argued that methods from genetic
epidemiology can clarify the etiologic relationships
among comorbid disorders (Biederman et al 1990b,
1991a, 1991b; Faraone et al 1991a, 1991b). In previous
work, we first showed that the familial coaggregation of
DSM-III-defined attention deficit disorder (ADD) and
CD was consistent with the ICD-10 formulation of
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22
BIOL PSYCHIATRY
2000;48:21–29
hyperkinetic conduct disorder (Faraone et al 1991b).
We then replicated that result in an entirely different
sample of children using DSM-III-R criteria (Faraone et
al 1995, 1997, 1998).
Data from other groups also favored a familial distinction between ADHD with CD (ADHD1CD) and other
ADHD children. Stewart et al (1980) found alcoholic or
antisocial disorders to be more frequent among fathers of
unsocialized, aggressive, hyperactive boys compared with
fathers of boys who were only hyperactive. Lahey et al
(1988) reported higher rates of antisocial disorders, depression, and substance abuse among relatives of
ADHD1CD probands compared to other ADHD probands. In another study, the mothers of ADHD1CD
children were found to have higher rates of psychopathology than the mothers of ADHD children (Lahey et al
1989). In a study by Frick et al (1991), parents of
ADHD1CD children had higher rates of childhood hyperactivity, CD, and substance use than parents of ADHD
children. August and Stewart (1983) reported that, among
hyperactive children, a family history of hyperactivity
predicted more symptoms of CD in the child and a greater
risk of CD to siblings.
Notably, Szatmari et al (1993) confirmed the familial
coaggregation of ADHD and CD in a population based,
epidemiologic, family study, as did Silberg et al (1996) in
a population-based twin study. The twin study found that
the genes influencing variation in hyperactivity scores
were also responsible for variation in conduct problems.
Between 76% and 88% of the correlation between hyperactivity and conduct scores were attributed to genes. It
further concluded that the results were consistent with the
existence of a biologically based group of children who
manifest both hyperactivity and conduct disturbances.
Further evidence that the ADHD1CD subgroup may be
etiologically meaningful comes from a study showing
differences in serotonergic functioning between aggressive and nonaggressive ADHD children (Halperin et al
1994).
Overall, these data suggest that, from a familial perspective, ADHD children with CD may be etiologically distinct from those without CD. Although persuasive, these
prior studies have examined predominantly male samples.
Thus, we do not know if prior finds generalize to female
ADHD patients. We cannot assume generalizability, given
that CD is known to have gender-specific features in
ADHD children. Notably, a meta-analysis by Gaub and
Carlson (1997) suggested that, compared with boys, girls
with ADHD tend to have lower rates of conduct disorder.
We recently confirmed that in a large case-control study of
girls (Biederman et al 1999).
The main hypothesis of this report posits ADHD1CD
to be a distinct familial subtype (i.e., an entirely separate
S.V. Faraone et al
condition from ADHD without CD as regards familial risk
factors). This hypothesis predicts high rates of ADHD in
relatives of both ADHD1CD and ADHD without CD
children, but that CD should be increased only among
relatives of ADHD1CD children. It also predicts that
ADHD and CD should cosegregate among the relatives of
ADHD1CD children (i.e., among relatives of children
with ADHD1CD, the presence of one disorder should
predict the other; cases of ADHD without CD and CD
without ADHD should be rare).
We focus on this main hypothesis because it has been
supported in our prior studies of ADHD and CD among
families ascertained through boy probands (Faraone et al
1991b, 1995, 1997, 1998). Our prior studies also ruled out
alternative hypotheses that must be considered in genetic
epidemiologic studies (Faraone et al 1999; Faraone and
Tsuang 1995; Pauls et al 1986a, 1986b; Reich et al 1972,
1979). Thus, we also sought to see if the alternative
hypotheses could be ruled out in our sample of girl
probands.
Alternative hypothesis one posits that ADHD and CD
are etiologically independent but co-occur because of
nonrandom mating. This explains comorbidity by assuming that the spouses of ADHD individuals have higher
rates of CD than spouses of non-ADHD individuals. If that
were true, then children of ADHD parents would be at
increased risk for CD. This hypothesis differs from our
main hypothesis, because it predicts that ADHD and CD
should not cosegregate among the relatives of
ADHD1CD probands and that there should be an association between ADHD diagnoses in one parent and CD
diagnoses in the other parent.
Additional alternative hypotheses assume that the familial transmission of ADHD and CD follows a multifactorial
polygenic (MFP) model. The MFP model assumes that
both disorders arise from the same pool of familially
transmissible etiologic factors (e.g., genes, familial adversity; Faraone et al 1999). Alternative hypothesis two states
that ADHD1CD requires more familially transmissible
etiologic factors (e.g., genes, familial adversity) for its
expression compared with ADHD without CD. It predicts
that relatives of ADHD1CD probands will have higher
rates of ADHD and higher rates of CD (Faraone et al
1999). This would be consistent with the idea that
ADHD1CD is a severe form of ADHD. For example, if a
polygenic system (or a series of adverse familial environmental events) causes these disorders, then alternative
hypothesis two would predict that the number of genes (or
familial adverse events) required to express ADHD1CD
is greater than the number required to express other cases
of ADHD.
The MFP model also underlies alternative hypothesis
three, which assumes that ADHD1CD and ADHD
ADHD and Conduct Disorder
without CD share common familial etiologic factors;
but, in contrast to alternative hypothesis two, alternative
hypothesis three assumes that the two groups differ
because of nonfamilial environmental effects. This
predicts similar rates of ADHD and CD among the
relatives of ADHD1CD and other ADHD probands.
For example, if a polygenic system (or a series of
adverse familial environmental events) causes these
disorders, then an equal risk to relatives across subgroups would suggest that the number of genes (or
familial adverse events) required for each subgroup is
the same. If that is so, then differences between groups
must be owing to nonfamilial causes.
The primary goal of this report is to test our main
hypothesis and the alternatives listed above. Also, any
examination of the association between ADHD and CD
must also consider that some ADHD children have oppositional defiant disorder (ODD) but not CD. Lahey et al’s
review of longitudinal studies showed that ODD is a
heterogeneous condition (Lahey et al 1994). Some ODD
children progress to CD, but others do not (Loeber and
Keenan 1994). For example, our follow-up study described two subtypes of ODD associated with ADHD—
one that is prodromal to CD and another that was not
likely to progress into CD in later years (Biederman et al
1996). These ODD subtypes had different correlates,
course, and outcome.
Our prior family studies of the association between
ADHD, CD, and ODD provided ambiguous evidence for
the status of ADHD1ODD boys who did not have CD
(Faraone et al 1991b,1997). Our family study of boys with
DSM-III ADD showed that the relatives of ADD1ODD
probands were at a higher risk for ADD and for one or
more antisocial disorders than the relatives of ADD
probands but at a lower risk than the relatives of
ADD1CD probands (Faraone et al 1991b). This suggested
that the ADHD1ODD boys were, in terms of familial risk,
intermediate between ADHD-only and ADHD1CD boys.
In contrast, our larger study of DSM-III-R ADHD boys
showed that as regards the prevalence of ADHD, CD, and
ODD among relatives, the ADHD1ODD boys were more
similar to the ADHD-only boys than the ADHD1CD boys
(Faraone et al 1997). These data suggested that
ADHD1ODD children who did not onset with CD before
adolescence were nosologically different from those who
develop CD.
Given these uncertainties about the nosological status of
ADHD children who have ODD but not CD, in this report
we stratified our ADHD sample into three groups:
ADHD1CD, ADHD1ODD, and ADHD only. This allowed for comparisons among relative groups that would
determine if, from a familial perspective, ADHD1ODD
was more similar to ADHD1CD or ADHD only.
BIOL PSYCHIATRY
2000;48:21–29
23
Methods and Materials
Subjects
An overview of this sample has been previously published
(Biederman et al 1999). Female children and adolescents 6 –18
years of age were eligible for the study. We studied two groups
of index girls: 140 ADHD probands and 122 non-ADHD
comparisons. These groups had 417 and 369 first degree biological relatives, respectively. No ethnic or racial groups were
excluded from the study. Potential girl probands were excluded
if they had been adopted, or if their nuclear family was not
available for study. We excluded girls if they had major sensorimotor handicaps (paralysis, deafness, blindness), psychosis,
autism, inadequate command of the English language, or a Full
Scale IQ less than 80. All of the ADHD girls met full DSM-III-R
diagnostic criteria for ADHD at the time of the clinical referral;
at the time of recruitment they all had active symptoms of the
disorder. All subjects older than 12 gave written informed
consent for participation. Parents gave written informed consent
for participation of children under 12, and these children participated only if they assented to the study procedures.
We identified psychiatrically referred females from lists of
consecutive ADHD patients from the pediatric psychopharmacology clinic at the Massachusetts General Hospital (MGH).
Pediatrically referred ADHD females were identified from lists
of children having evidence of ADHD in the computerized
medical record of a health maintenance organization (HMO).
Within each setting, we selected normal control subjects from
lists of outpatients at pediatric medical clinics.
Procedures
Because this study had begun prior to the finalization of DSM-IV
criteria for ADHD, we used DSM-III-R– based structured interviews to ascertain and diagnose subjects but supplemented our
interviews with questions that would allow us to make DSM-IV
diagnoses. Psychiatric assessments of probands and their siblings
were made with the Kiddie Schedule for Affective Disorders and
Schizophrenia (epidemiologic version [Kiddie-SADS-E]; Orvaschel 1985). Diagnoses were based on independent interviews
with the mothers and direct interviews with the child. Children
younger than 12 years of age were not interviewed directly.
Diagnostic assessments of parents were based on direct interviews with each parent using the Structured Clinical Interview
for DSM-III-R (SCID; Spitzer et al 1990). To assess childhood
diagnoses in the parents, we administered an addition to the
SCID, consisting of unmodified modules from the KiddieSADS-E covering childhood DSM-III-R diagnoses.
All assessments were made by raters who were blind to the
proband’s diagnosis (ADHD or control) and ascertainment site
(MGH or HMO). All efforts were made to 1) sequence the
mothers’ interviews about their children after the direct interview
with the mother about herself and 2) have different raters conduct
the direct interviews of siblings and the interviews with mothers
about their children. Interview data were collected on all siblings
in both the ADHD and control families. When a parent was not
available for interviewing, information was obtained by administering the SCID about the absent parent to the available one. All
24
S.V. Faraone et al
BIOL PSYCHIATRY
2000;48:21–29
Table 1. Demographic Characteristics of Sample at Baseline
ADHD1CD
Probands
(n 5 11)
Relatives
(n 5 40)
Age of proband
Age of parents
Age of siblings
SES
Intact families
Number of brothers
Number of sisters
ADHD1ODD
Probands
(n 5 39)
Relatives
(n 5 117)
ADHD Only
Probands
(n 5 90)
Relatives
(n 5 260)
Control subjects
Probands
(n 5 122)
Relatives
(n 5 369)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
p value
Test statistic
13.9
41.4
14.8
2.4
n
9
9
9
3.7
7.4
6.7
1.3
%
81.8
50.0
50.0
11.6
42.0
12.9
1.9
n
28
21
19
3.1
5.1
4.5
0.9
%
71.8
52.5
47.5
11.6
42.4
14.3
1.8
n
64
54
31
3.4
6.4
5.5
0.9
%
71.1
63.5
36.5
12.7
44.2
13.8
1.7
n
100
75
56
3.0
5.7
4.8
0.8
%
82.0
57.3
42.8
.015
.002
.956
.346
F (261) 5 3.53
F (509) 5 4.96
F (190) 5 0.00
x2 (3) 5 3.31
.245
.559
.559
x2 (3) 5 4.16
x2 (3) 5 2.07
x2 (3) 5 2.07
Age of proband and parents by one-way analysis of variance; age of siblings by linear regression with Huber’s Correction for correlated data; socioeconomic status (SES)
by Kruskal–Wallis Equality of Populations Rank Test; intact families, number of brothers and number of sisters by x2 test. ADHD, attention-deficit/hyperactivity disorder;
CD, conduct disorder; ODD, oppositional defiant disorder.
parents signed a written consent form for participation in the
study.
Interviews were conducted by raters with undergraduate degrees in psychology who had been trained to high levels of
inter-rater reliability. The training consisted of familiarization
with psychiatric nosology and the structured interviews. Ratersin-training first observed interviews carried out by experienced
raters and clinicians. Raters were supervised by the principal
investigator (JB). Kappa coefficients of agreement were computed between raters and three experienced psychiatrists, each
board certified in both child and adult psychiatry, who listened to
audiotaped interviews made by the raters. Based on 173 interviews, the median k was 0.86. The ks were 0.99 for ADHD, 0.93
for conduct disorder, 0.80 for multiple anxiety disorders, 0.83 for
major depression, and 0.94 for bipolar disorder.
A committee of three psychiatrists, each board certified in both
child and adult psychiatry, chaired by the principal investigator
(JB) resolved all diagnostic uncertainties. The committee members were blind to the subjects’ ascertainment group, ascertainment site, all data collected from other family members, and all
nondiagnostic data (e.g., psychological tests). Diagnoses were
considered positive if, based on the interview results, DSM-III-R
criteria were unequivocally met to a clinically meaningful
degree. As suggested by others (Gershon et al 1982), we
diagnosed major depression only if the depressive episode was
associated with marked impairment. Because the anxiety disorders comprise many syndromes with a wide range of severity, we
used two or more anxiety disorders as a useful summary variable.
For children older than 12, data from direct and indirect interviews were combined by considering a diagnostic criterion
positive if it was endorsed in either interview.
In addition to psychiatric data, we assessed socioeconomic
status (SES), with the Hollingshead–Redlich scale (Hollingshead
1975) and family intactness (divorce or separation of parents in
family of origin).
Our analyses of sibling data avoided the statistical problems
associated with correlated family data by using Huber’s (1967)
formula as implemented in STATA (Stata Corporation 1992).
The formula is a “theoretical bootstrap” that produces robust
statistical tests for both linear and logistic regression. To reduce
the Type I error rate, all statistical tests were two tailed; we used
the .01 level of statistical significance. Differences that were
significant at the .05 level are discussed as marginally significant
trends.
Results
Sociodemographic and Clinical Characteristics
We defined a subject as having a lifetime history of illness
if a disorder was reported at the time of assessment. There
were 11 girls with ADHD1CD, 39 with ADHD1ODD,
and 90 with ADHD only. These were compared with 122
non-ADHD, non-CD control girls. There were 10 children
with comorbid CD as well as ODD. These girls were
included in the ADHD1CD group.
The groups did not significantly differ in age of probands, age of siblings, SES, intactness of family, number
of brothers or number of sisters (Table 1). There was a
significant difference in the age of the parents, but
pairwise comparisons between groups failed to yield any
significant findings.
Familial Association between Antisocial Disorders
and ADHD
Relatives of the ADHD, ADHD1ODD, and ADHD1CD
proband subgroups were at significantly greater risk for
ADHD compared with relatives of controls (Table 2).
Also, relatives of the ADHD subgroup were at significantly greater risk for ODD compared to control subjects.
There were trends toward differences in the rates of ODD
between the relatives of the ADHD1CD and
ADHD1ODD subgroups and the relatives of controls, but
ADHD and Conduct Disorder
BIOL PSYCHIATRY
2000;48:21–29
25
Table 2. Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) among Relatives of Attention-Deficit/Hyperactivity
Disorder (ADHD) Girl Probands
Proband’s diagnosis
ADHD1CD
n 5 40
All relatives
ADHD
ODD
CD
Antisocial personality disorder
CD or antisocial disorder
Parents
ADHD
ODD
CD
Antisocial personality disorder
CD or antisocial disorder
Siblings
ADHD
ODD
CD
Antisocial personality disorder
CD or antisocial disorder
n
a
%
9
23
6
15
7a,c
18
3
11
9b,c
23
n 5 22
4b
18
2
10
2
10
2
9
3
14
n 5 18
5
28
4
22
5
28
1
17
6a,c,d
33
ADHD1ODD
n 5 117
%
n
b
24
13
10
7
14
21
11
9
9
12
n 5 77
17b
9a
9
7
13
23
12
12
9
17
n 5 40
7
4
1
0
1
18
10
3
NA
3
ADHD only
n 5 260
Control subjects
n 5 369
%
n
%
p value
Test statistic
69
27
29a
11
12
5
12
6
22
8
n 5 175
39b
22
13
8
8
5
11
6
17
10
n 5 85
30
35
16
19
4
5
1
6
5
6
23
18
16
9
19
7
5
4
3
5
,.001
.001
.007
.013
,.001
Z (1) 5 4.8
Z (1) 5 3.3
Z (1) 5 2.7
Z (1) 5 2.5
Z (1) 5 4.0
5
6
11
9
14
2
3
5
4
6
,.001
.012
.087
.286
.027
x2 (3) 5 45.8
x2 (3) 5 11.0
x2 (3) 5 6.6
x2 (3) 5 3.8
x2 (3) 5 9.2
18
12
5
0
5
n 5 131
14
9
4
NA
4
.097
.236
.041
.049
.009
n
b
n 5 238
Z (1) 5 1.7
Z (1) 5 1.2
Z (1) 5 2.0
Z (1) 5 2.0
Z (1) 5 2.6
Tests on all relatives and siblings by logistic regression with Huber’s Correction for correlated data; tests on Parents by x2. NA, not applicable.
a
p # .01 vs. control subjects.
b
p # .001 vs. control subjects.
c
p # .01 vs. ADHD only.
d
p # .01 vs. ADHD 1 ODD.
they were not significant (p 5 .021 and p 5 .013,
respectively). Furthermore, compared with control subjects, only relatives of CD probands had increased rates of
CD and the combined category CD or antisocial personality disorder (CD/ASPD). There was a difference in the
rates of CD/ASPD between the ADD1ODD relatives and
the control relatives, but it was not significant (p 5 .013).
There were no significant differences found in the rates of
ASPD alone among the relatives of the four subgroups.
The relatives of ADHD1ODD and ADHD-only probands did not differ in rates of ADHD, ODD, CD, or
ASPD. In contrast, relatives of ADHD1CD probands had
higher rates of CD and CD/ASPD compared with the
ADHD only subgroup.
As Table 2 indicates, the pattern of results observed for
the entire sample was also observed when the data were
analyzed separately for parents and siblings. Because of
the smaller sub-samples for these latter analyses, however,
some comparisons did not attain statistical significance.
Nonrandom Mating and Cosegregation of ADHD,
ODD, and CD
Our finding that the increased risk for CD among relatives
was limited to families of ADHD1CD probands could
occur if ADHD individuals had an increased likelihood of
marriage with CD individuals. Rates of CD were similar
among fathers whose spouses did and did not have ADHD
[12% vs. 10%; x2(1) 5 0.21, p 5 .65]. Rates of CD were
higher among mothers if their spouse had ADHD (7% vs.
2%), but the difference was not statistically significant
[x2(1) 5 3.0, p 5 .08]. Fathers whose spouse had ADHD
had lower rates of ADHD, but this difference was not
significant [6% vs. 12%, x2(1) 5 1.0, p 5 .31]. Rates of
ASPD in mothers were higher in those whose spouse has
ADHD (4% vs. 1%), but again this was not a statistically
significant difference [x2(1) 5 3.2, p 5 .08].
If ADHD1CD probands carried two unrelated risk
factors, one for ADHD and one for CD, ADHD and CD
should be independently transmitted in the families of
ADHD1CD probands. That is, relatives with ADHD
should be at no greater risk for CD than those without
ADHD. If, however, in the families of ADHD1CD
probands, the degree of comorbidity in the relatives is
greater than expected by chance, we use the term “cosegregate” to indicate that the disorders are transmitted
together, not independently (Pauls et al 1986a, 1986b).
That was the case in our data; there was a substantial
degree of cosegregation. Among relatives of ADHD1CD
probands, 56% of the relatives diagnosed as ADHD also
had CD, compared to 7% of the relatives who did not have
ADHD [x2(1) 5 11.2, p 5 .001].
Our cosegregation findings are consistent with an addi-
26
BIOL PSYCHIATRY
2000;48:21–29
tional finding: There were higher rates of CD among the
nine ADHD relatives of ADHD1CD probands (56%),
compared with the 93 ADHD relatives of other ADHD
probands [13%; x2(1) 5 10.7, p 5 .001] or the 23 ADHD
relatives of control probands [9%; x2(1) 5 8.3, p 5 .004].
Discussion
In a large set of families ascertained through ADHD girls,
we tested competing hypotheses about patterns of familial
association between DSM-III-R ADHD, CD, ODD, and
ASPD. After stratifying the ADHD sample into those with
CD (ADHD1CD), those with ODD (ADHD1ODD), and
those with neither (ADHD), familial risk analyses revealed
the following: 1) relatives of each ADHD proband subgroup were at significantly greater risk for ADHD than
relatives of normal control subjects, 2) rates of CD were
elevated among relatives of ADHD1CD probands only,
3) the coaggregation of ADHD and CD could not be
accounted for by marriages between ADHD and antisocial
spouses, and 4) both ADHD and CD occurred in the same
relatives more often than expected by chance alone.
Our results support our main hypothesis, which posits
that ADHD1CD is a familially distinct subtype. This
hypothesis is consistent with the ICD-10 decision to retain
hyperkinetic conduct disorder as a separate diagnostic
category (World Health Organization 1988). Our rejection
of the three alternative hypotheses generalizes the conclusions from our studies of ADHD boys (Faraone et al
1991b, 1995, 1997, 1998).
Because of the inferential limitations of family studies
(Faraone and Tsuang 1995), we cannot determine if the
familial etiology of ADHD1CD is genetic or environmental. Since both genes (Faraone and Biederman 1994) and
environment (Biederman et al 1995a, 1995b) have been
implicated in the etiology of ADHD, further work is
needed to see what role they might play in the familial
transmission of comorbidity between ADHD and CD.
Notably, our results reject the alternative hypothesis,
which attributes the differences between ADHD with and
without CD to environmental factors not transmitted in
families. This alternative incorrectly predicts equal rates of
conduct disorder among the relatives of the three ADHD
proband subgroups (Reich et al 1979). That is, if the
familial causes of CD were the same in type and degree
among ADHD subgroups, the familial risks to their
relatives should not differ, but they did.
Furthermore, although these familial risks did differ, the
pattern of differences rejected the idea that ADHD with
and without CD share a common pool of familial etiological factors such that ADHD1CD requires more familially
transmissible etiologic factors (e.g., genes, familial adversity) for its expression compared with ADHD alone. This
S.V. Faraone et al
idea incorrectly predicts greater rates of ADHD among
relatives of ADHD1CD probands. Although the lack of
group differences in rates of ADHD could be owing to low
statistical power (there were only 40 relatives in the
ADHD1CD group), the actual rates were very similar
(23% for relatives of ADHD1CD, 27% for relatives of
ADHD only).
The low risk for CD among relatives of ADHD probands without CD suggests that these probands are qualitatively distinct from the probands with comorbid antisocial disorders instead of quantitatively different as
assumed by the multifactorial model. That is, it may be the
case that the ADHD probands without CD share no
familial precursors with CD. This would further suggest
that ADHD in the presence of a comorbid CD represents
a distinct familial subtype of ADHD. If this is the case,
ADHD and CD should cosegregate (i.e., not be independently transmitted) in the families of ADHD probands
with antisocial disorders (Pauls et al 1986a, 1986b). That
is exactly what we found: In the relatives of ADHD1CD
probands, those with ADHD were at increased risk for
CD, and this level of comorbidity was significantly greater
than what was observed among the ADHD relatives of
other ADHD probands.
The subsample of ADHD1ODD girls provided some
intriguing results. We know from Lahey et al’s (1994)
literature review that, although a large majority of CD
children have prior histories of ODD, many ODD children
do not go on to develop CD. This raises a question: Are
there two types of ODD, one that progresses to CD and
one that does not? The present study found only one
statistically significant difference in familial rates of illness between ADHD1ODD probands and either
ADHD1CD or ADHD-only probands. The siblings of
ADHD1CD probands had greater rates of the combined
category CD or ASPD compared with siblings of
ADHD1ODD probands (p , .01).
For the comparisons with ADHD1CD probands, nonsignificant differences could reflect low statistical power,
given the small number of relatives in the ADHD1CD
group (n 5 40). For example, although not statistically
significant, there was a two-fold increase in the rate of CD
in relatives of ADHD1CD compared with ADHD1ODD
probands. For siblings, there was a nine-fold increase for
CD. These differences would likely have attained significance in a larger sample. By contrast, we had adequate
statistical power for comparisons between ADHD1ODD
and ADHD-only families (ns 5 117 and 260, respectively). This gives greater certainty to our finding of no
differences between these two groups.
Given the low power of some comparisons, any interpretation of the ODD results must be made cautiously.
Nonetheless, these results are consistent with the idea that
ADHD and Conduct Disorder
some of the ADHD1ODD children are similar to
ADHD1CD children, whereas others are similar to
ADHD-only children. Such heterogeneity in the ODD
group would tend to blur distinction between it and the
two other groups.
Because we did not examine a sample of CD children
without ADHD, our results cannot determine whether the
increased familial risk observed among relatives of
ADHD1CD probands is due to the antisocial component
of CD or to an interaction with the ADHD syndrome. The
work of Lahey et al (1988) suggests that the comorbidity
of ADHD and CD confers additional familial risk beyond
that of CD alone. Their results clearly indicate that the
risks for antisocial personality and substance abuse are
greater among fathers of ADHD1CD probands, compared
to those with either ADHD alone or CD alone. Children
with ADHD1CD have also been shown to have a greater
variety and severity of antisocial behaviors compared to
children with CD alone (Walker et al 1987). Another
group (Szatmari et al 1989) found that children with
ADHD1CD appeared to represent a true hybrid disorder
rather than one diagnosis or the other. Like ADHD
children, the mixed group had more developmental delays
than CD children, and like CD children, they had more
psychosocial disadvantage than ADHD children. A review
of the literature by Hinshaw (1993) concluded that children with ADHD1CD have an earlier age at onset of CD,
are more aggressive, and have more persistent CD than
other CD children.
The strength of our conclusions is further mitigated by
some methodological limitations. Notably, the number of
ADHD girls with CD was small, which limits the power of
our analyses, because there were only 40 family members
from ADHD1CD families, which were compared with the
117 members from ADHD1ODD families, the 260 members from ADHD-only families, and the 369 members
from control families.
Also, findings based on a clinical population should be
interpreted with caution, because they may not generalize
to other populations. Our diagnosis of ADHD, CD, and
ODD among parents of probands relied on retrospective
data, which may be subject to recall biases that may not be
independent of the proband diagnosis. Although relatively
little is known about the validity of these retrospective
diagnoses, several studies have shown it possible to
validly diagnose ADHD in adults (Biederman et al 1990a;
Cantwell 1985; Conners 1985; Varley 1985; Wender et al
1985).
Another methodological shortcoming pertains to our
assessments of psychopathology in children. Because they
used both interviews with mothers and direct interviews of
children, they may be subject to several potential confounds. First, similarities between children within a family
BIOL PSYCHIATRY
2000;48:21–29
27
could be exaggerated by using a common source of
information. The direct interview of a family member
could be biased if the reporter was aware of the proband’s
diagnoses. Second, a halo effect (i.e., a bias toward
reporting a second illness in the presence of another) could
lead to an overestimation of the comorbidity between
ADHD and antisocial disorders and the degree of
cosegregation.
Although we have tested seven hypotheses, these do not
exhaust the universe of plausible hypotheses. For example,
hypotheses six and seven are rejected only if the factors
that lead to a secondary disorder are independent of factors
leading to that disorder in the absence of the primary
disorder. Thus, our results should be interpreted cautiously. Replication by other groups would be very useful,
as would the testing of these hypotheses in a twin sample.
Despite these limitations, the data in this report can be
considered as suggestive of a useful working hypothesis:
that the combined syndrome of ADHD plus CD in girls
may be familially distinct from ADHD without CD. This
work generalizes findings from studies of boys and provides some evidence for the nosologic validity of the
ICD-10 category of hyperkinetic conduct disorder. Perhaps future revisions of the American DSM-IV should
consider including this comorbid condition as a separate
category.
This work was supported in part by Grants Nos. RO1 MH41314-07 (JB)
and R01MH57934-0 (SVF) from the National Institute of Mental Health,
Bethesda, Maryland.
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Attention-Deficit Disorder and Conduct Disorder in
Girls: Evidence for a Familial Subtype
Stephen V. Faraone, Joseph Biederman, and Michael C. Monuteaux
Background: The frequent comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct
disorder (CD) raises the possibility that ADHD1CD is a
distinct and separate condition.
Methods: We tested hypotheses about patterns of familial
association between ADHD, CD, oppositional defiant
disorder (ODD) and adult antisocial personality disorder
(ASPD). Using family study methodology in a sample of
girls, we found 11 children with diagnoses of ADHD1CD,
39 with ADHD1ODD, and 90 with ADHD only. These
were compared with 122 non-ADHD, non-CD control
probands. Familial risk analysis was utilized.
Results: Relatives of each ADHD proband subgroup were
at significantly greater risk for ADHD, and the relatives of
ADHD-only subjects were at a greater risk of ODD than
relatives of control subjects. Also, rates of CD were
elevated among relatives of ADHD1CD probands only,
and the coaggregation of ADHD and the antisocial disorders could not be accounted for by marriages between
ADHD and antisocial spouses. Both ADHD and antisocial
disorders occurred in the same relatives more often than
expected by chance.
Conclusions: These findings suggest that ADHD with and
without antisocial disorders may be etiologically distinct
disorders and provide evidence for the nosologic validity
of ICD-10 hyperkinetic conduct disorder. Biol Psychiatry 2000;48:21–29 © 2000 Society of Biological
Psychiatry
Key Words: ADHD, conduct disorder, oppositional defiant disorder, family– genetic, risk factors
Introduction
A
n obstacle to the successful classification of attentiondeficit/hyperactivity disorder (ADHD) is the frequently reported comorbidity between ADHD and conduct
From Pediatric Psychopharmacology Unit, Psychiatry Service, Massachusetts
General Hospital (SVF, JB, MCM), the Department of Psychiatry, Harvard
Medical School (SVF, JB), Harvard Institute of Psychiatric Epidemiology and
Genetics, Department of Psychiatry, Harvard Medical School at Brockton–
West Roxbury Veterans Affairs Medical Center and Massachusetts Mental
Health Center (SVF), and the Department of Epidemiology, Harvard School of
Public Health (MCM), Boston, Massachusetts.
Address reprint requests to Stephen V. Faraone, Ph.D., Harvard Medical School,
Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, Fruit Street, Boston MA 02114.
Received April 7, 1999; revised December 17, 1999; accepted December 22, 1999.
© 2000 Society of Biological Psychiatry
disorder (CD; Caron and Rutter 1991). This overlap has
been consistently found in clinical samples in studies of
children with ADHD and children with CD (Biederman et
al 1987, 1991c; Hinshaw 1987; Loeber et al 1990; Milich
et al 1987; Schachar and Tannock 1995) and in follow-up
studies of ADHD children (Gittelman et al 1985). Taylor
(1994) noted that the comorbidity between ADHD and CD
raises a key nosologic question: Are these two disorders
best seen as co-occurring yet separate entities or, does
their consistent co-occurrence signal the presence of a
separate category of disorder? The former approach was
taken by the American DSM-IV (American Psychiatric
Association 1994), whereas the latter has been recognized
with the separate category of hyperkinetic conduct disorder used by the World Health Organization’s ICD-10
(World Health Organization 1988). The differences between the two systems underscore the need for further
nosologic research.
As discussed in detail by Caron and Rutter (1991),
comorbidity can occur for many reasons. It can be an
artifact in clinical samples, because people with multiple
disorders are more likely to seek help than those with only
one disorder. In epidemiologic studies, screening tests can
exaggerate comorbidity, because comorbid disorders are
more likely to exceed the test’s threshold for detection.
Comorbidity may also signal errors in the nosology used
to define the disorders. If two disorders are actually the
extremes of dimensional traits, then the choice of the
threshold for defining the disorders will influence the
degree of observed comorbidity. Also, overlapping diagnostic criteria can lead to spurious comorbidity. Our
empirical study of this latter issue, however, suggests that
this effect cannot account for most comorbidity in ADHD
(Milberger et al 1995). Comorbidity might also indicate
that a nosologic subdivision of syndromes is not appropriate or that one disorder is an early manifestation or a
component of the other.
Elsewhere, we have argued that methods from genetic
epidemiology can clarify the etiologic relationships
among comorbid disorders (Biederman et al 1990b,
1991a, 1991b; Faraone et al 1991a, 1991b). In previous
work, we first showed that the familial coaggregation of
DSM-III-defined attention deficit disorder (ADD) and
CD was consistent with the ICD-10 formulation of
0006-3223/00/$20.00
PII S0006-3223(00)00230-4
22
BIOL PSYCHIATRY
2000;48:21–29
hyperkinetic conduct disorder (Faraone et al 1991b).
We then replicated that result in an entirely different
sample of children using DSM-III-R criteria (Faraone et
al 1995, 1997, 1998).
Data from other groups also favored a familial distinction between ADHD with CD (ADHD1CD) and other
ADHD children. Stewart et al (1980) found alcoholic or
antisocial disorders to be more frequent among fathers of
unsocialized, aggressive, hyperactive boys compared with
fathers of boys who were only hyperactive. Lahey et al
(1988) reported higher rates of antisocial disorders, depression, and substance abuse among relatives of
ADHD1CD probands compared to other ADHD probands. In another study, the mothers of ADHD1CD
children were found to have higher rates of psychopathology than the mothers of ADHD children (Lahey et al
1989). In a study by Frick et al (1991), parents of
ADHD1CD children had higher rates of childhood hyperactivity, CD, and substance use than parents of ADHD
children. August and Stewart (1983) reported that, among
hyperactive children, a family history of hyperactivity
predicted more symptoms of CD in the child and a greater
risk of CD to siblings.
Notably, Szatmari et al (1993) confirmed the familial
coaggregation of ADHD and CD in a population based,
epidemiologic, family study, as did Silberg et al (1996) in
a population-based twin study. The twin study found that
the genes influencing variation in hyperactivity scores
were also responsible for variation in conduct problems.
Between 76% and 88% of the correlation between hyperactivity and conduct scores were attributed to genes. It
further concluded that the results were consistent with the
existence of a biologically based group of children who
manifest both hyperactivity and conduct disturbances.
Further evidence that the ADHD1CD subgroup may be
etiologically meaningful comes from a study showing
differences in serotonergic functioning between aggressive and nonaggressive ADHD children (Halperin et al
1994).
Overall, these data suggest that, from a familial perspective, ADHD children with CD may be etiologically distinct from those without CD. Although persuasive, these
prior studies have examined predominantly male samples.
Thus, we do not know if prior finds generalize to female
ADHD patients. We cannot assume generalizability, given
that CD is known to have gender-specific features in
ADHD children. Notably, a meta-analysis by Gaub and
Carlson (1997) suggested that, compared with boys, girls
with ADHD tend to have lower rates of conduct disorder.
We recently confirmed that in a large case-control study of
girls (Biederman et al 1999).
The main hypothesis of this report posits ADHD1CD
to be a distinct familial subtype (i.e., an entirely separate
S.V. Faraone et al
condition from ADHD without CD as regards familial risk
factors). This hypothesis predicts high rates of ADHD in
relatives of both ADHD1CD and ADHD without CD
children, but that CD should be increased only among
relatives of ADHD1CD children. It also predicts that
ADHD and CD should cosegregate among the relatives of
ADHD1CD children (i.e., among relatives of children
with ADHD1CD, the presence of one disorder should
predict the other; cases of ADHD without CD and CD
without ADHD should be rare).
We focus on this main hypothesis because it has been
supported in our prior studies of ADHD and CD among
families ascertained through boy probands (Faraone et al
1991b, 1995, 1997, 1998). Our prior studies also ruled out
alternative hypotheses that must be considered in genetic
epidemiologic studies (Faraone et al 1999; Faraone and
Tsuang 1995; Pauls et al 1986a, 1986b; Reich et al 1972,
1979). Thus, we also sought to see if the alternative
hypotheses could be ruled out in our sample of girl
probands.
Alternative hypothesis one posits that ADHD and CD
are etiologically independent but co-occur because of
nonrandom mating. This explains comorbidity by assuming that the spouses of ADHD individuals have higher
rates of CD than spouses of non-ADHD individuals. If that
were true, then children of ADHD parents would be at
increased risk for CD. This hypothesis differs from our
main hypothesis, because it predicts that ADHD and CD
should not cosegregate among the relatives of
ADHD1CD probands and that there should be an association between ADHD diagnoses in one parent and CD
diagnoses in the other parent.
Additional alternative hypotheses assume that the familial transmission of ADHD and CD follows a multifactorial
polygenic (MFP) model. The MFP model assumes that
both disorders arise from the same pool of familially
transmissible etiologic factors (e.g., genes, familial adversity; Faraone et al 1999). Alternative hypothesis two states
that ADHD1CD requires more familially transmissible
etiologic factors (e.g., genes, familial adversity) for its
expression compared with ADHD without CD. It predicts
that relatives of ADHD1CD probands will have higher
rates of ADHD and higher rates of CD (Faraone et al
1999). This would be consistent with the idea that
ADHD1CD is a severe form of ADHD. For example, if a
polygenic system (or a series of adverse familial environmental events) causes these disorders, then alternative
hypothesis two would predict that the number of genes (or
familial adverse events) required to express ADHD1CD
is greater than the number required to express other cases
of ADHD.
The MFP model also underlies alternative hypothesis
three, which assumes that ADHD1CD and ADHD
ADHD and Conduct Disorder
without CD share common familial etiologic factors;
but, in contrast to alternative hypothesis two, alternative
hypothesis three assumes that the two groups differ
because of nonfamilial environmental effects. This
predicts similar rates of ADHD and CD among the
relatives of ADHD1CD and other ADHD probands.
For example, if a polygenic system (or a series of
adverse familial environmental events) causes these
disorders, then an equal risk to relatives across subgroups would suggest that the number of genes (or
familial adverse events) required for each subgroup is
the same. If that is so, then differences between groups
must be owing to nonfamilial causes.
The primary goal of this report is to test our main
hypothesis and the alternatives listed above. Also, any
examination of the association between ADHD and CD
must also consider that some ADHD children have oppositional defiant disorder (ODD) but not CD. Lahey et al’s
review of longitudinal studies showed that ODD is a
heterogeneous condition (Lahey et al 1994). Some ODD
children progress to CD, but others do not (Loeber and
Keenan 1994). For example, our follow-up study described two subtypes of ODD associated with ADHD—
one that is prodromal to CD and another that was not
likely to progress into CD in later years (Biederman et al
1996). These ODD subtypes had different correlates,
course, and outcome.
Our prior family studies of the association between
ADHD, CD, and ODD provided ambiguous evidence for
the status of ADHD1ODD boys who did not have CD
(Faraone et al 1991b,1997). Our family study of boys with
DSM-III ADD showed that the relatives of ADD1ODD
probands were at a higher risk for ADD and for one or
more antisocial disorders than the relatives of ADD
probands but at a lower risk than the relatives of
ADD1CD probands (Faraone et al 1991b). This suggested
that the ADHD1ODD boys were, in terms of familial risk,
intermediate between ADHD-only and ADHD1CD boys.
In contrast, our larger study of DSM-III-R ADHD boys
showed that as regards the prevalence of ADHD, CD, and
ODD among relatives, the ADHD1ODD boys were more
similar to the ADHD-only boys than the ADHD1CD boys
(Faraone et al 1997). These data suggested that
ADHD1ODD children who did not onset with CD before
adolescence were nosologically different from those who
develop CD.
Given these uncertainties about the nosological status of
ADHD children who have ODD but not CD, in this report
we stratified our ADHD sample into three groups:
ADHD1CD, ADHD1ODD, and ADHD only. This allowed for comparisons among relative groups that would
determine if, from a familial perspective, ADHD1ODD
was more similar to ADHD1CD or ADHD only.
BIOL PSYCHIATRY
2000;48:21–29
23
Methods and Materials
Subjects
An overview of this sample has been previously published
(Biederman et al 1999). Female children and adolescents 6 –18
years of age were eligible for the study. We studied two groups
of index girls: 140 ADHD probands and 122 non-ADHD
comparisons. These groups had 417 and 369 first degree biological relatives, respectively. No ethnic or racial groups were
excluded from the study. Potential girl probands were excluded
if they had been adopted, or if their nuclear family was not
available for study. We excluded girls if they had major sensorimotor handicaps (paralysis, deafness, blindness), psychosis,
autism, inadequate command of the English language, or a Full
Scale IQ less than 80. All of the ADHD girls met full DSM-III-R
diagnostic criteria for ADHD at the time of the clinical referral;
at the time of recruitment they all had active symptoms of the
disorder. All subjects older than 12 gave written informed
consent for participation. Parents gave written informed consent
for participation of children under 12, and these children participated only if they assented to the study procedures.
We identified psychiatrically referred females from lists of
consecutive ADHD patients from the pediatric psychopharmacology clinic at the Massachusetts General Hospital (MGH).
Pediatrically referred ADHD females were identified from lists
of children having evidence of ADHD in the computerized
medical record of a health maintenance organization (HMO).
Within each setting, we selected normal control subjects from
lists of outpatients at pediatric medical clinics.
Procedures
Because this study had begun prior to the finalization of DSM-IV
criteria for ADHD, we used DSM-III-R– based structured interviews to ascertain and diagnose subjects but supplemented our
interviews with questions that would allow us to make DSM-IV
diagnoses. Psychiatric assessments of probands and their siblings
were made with the Kiddie Schedule for Affective Disorders and
Schizophrenia (epidemiologic version [Kiddie-SADS-E]; Orvaschel 1985). Diagnoses were based on independent interviews
with the mothers and direct interviews with the child. Children
younger than 12 years of age were not interviewed directly.
Diagnostic assessments of parents were based on direct interviews with each parent using the Structured Clinical Interview
for DSM-III-R (SCID; Spitzer et al 1990). To assess childhood
diagnoses in the parents, we administered an addition to the
SCID, consisting of unmodified modules from the KiddieSADS-E covering childhood DSM-III-R diagnoses.
All assessments were made by raters who were blind to the
proband’s diagnosis (ADHD or control) and ascertainment site
(MGH or HMO). All efforts were made to 1) sequence the
mothers’ interviews about their children after the direct interview
with the mother about herself and 2) have different raters conduct
the direct interviews of siblings and the interviews with mothers
about their children. Interview data were collected on all siblings
in both the ADHD and control families. When a parent was not
available for interviewing, information was obtained by administering the SCID about the absent parent to the available one. All
24
S.V. Faraone et al
BIOL PSYCHIATRY
2000;48:21–29
Table 1. Demographic Characteristics of Sample at Baseline
ADHD1CD
Probands
(n 5 11)
Relatives
(n 5 40)
Age of proband
Age of parents
Age of siblings
SES
Intact families
Number of brothers
Number of sisters
ADHD1ODD
Probands
(n 5 39)
Relatives
(n 5 117)
ADHD Only
Probands
(n 5 90)
Relatives
(n 5 260)
Control subjects
Probands
(n 5 122)
Relatives
(n 5 369)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
p value
Test statistic
13.9
41.4
14.8
2.4
n
9
9
9
3.7
7.4
6.7
1.3
%
81.8
50.0
50.0
11.6
42.0
12.9
1.9
n
28
21
19
3.1
5.1
4.5
0.9
%
71.8
52.5
47.5
11.6
42.4
14.3
1.8
n
64
54
31
3.4
6.4
5.5
0.9
%
71.1
63.5
36.5
12.7
44.2
13.8
1.7
n
100
75
56
3.0
5.7
4.8
0.8
%
82.0
57.3
42.8
.015
.002
.956
.346
F (261) 5 3.53
F (509) 5 4.96
F (190) 5 0.00
x2 (3) 5 3.31
.245
.559
.559
x2 (3) 5 4.16
x2 (3) 5 2.07
x2 (3) 5 2.07
Age of proband and parents by one-way analysis of variance; age of siblings by linear regression with Huber’s Correction for correlated data; socioeconomic status (SES)
by Kruskal–Wallis Equality of Populations Rank Test; intact families, number of brothers and number of sisters by x2 test. ADHD, attention-deficit/hyperactivity disorder;
CD, conduct disorder; ODD, oppositional defiant disorder.
parents signed a written consent form for participation in the
study.
Interviews were conducted by raters with undergraduate degrees in psychology who had been trained to high levels of
inter-rater reliability. The training consisted of familiarization
with psychiatric nosology and the structured interviews. Ratersin-training first observed interviews carried out by experienced
raters and clinicians. Raters were supervised by the principal
investigator (JB). Kappa coefficients of agreement were computed between raters and three experienced psychiatrists, each
board certified in both child and adult psychiatry, who listened to
audiotaped interviews made by the raters. Based on 173 interviews, the median k was 0.86. The ks were 0.99 for ADHD, 0.93
for conduct disorder, 0.80 for multiple anxiety disorders, 0.83 for
major depression, and 0.94 for bipolar disorder.
A committee of three psychiatrists, each board certified in both
child and adult psychiatry, chaired by the principal investigator
(JB) resolved all diagnostic uncertainties. The committee members were blind to the subjects’ ascertainment group, ascertainment site, all data collected from other family members, and all
nondiagnostic data (e.g., psychological tests). Diagnoses were
considered positive if, based on the interview results, DSM-III-R
criteria were unequivocally met to a clinically meaningful
degree. As suggested by others (Gershon et al 1982), we
diagnosed major depression only if the depressive episode was
associated with marked impairment. Because the anxiety disorders comprise many syndromes with a wide range of severity, we
used two or more anxiety disorders as a useful summary variable.
For children older than 12, data from direct and indirect interviews were combined by considering a diagnostic criterion
positive if it was endorsed in either interview.
In addition to psychiatric data, we assessed socioeconomic
status (SES), with the Hollingshead–Redlich scale (Hollingshead
1975) and family intactness (divorce or separation of parents in
family of origin).
Our analyses of sibling data avoided the statistical problems
associated with correlated family data by using Huber’s (1967)
formula as implemented in STATA (Stata Corporation 1992).
The formula is a “theoretical bootstrap” that produces robust
statistical tests for both linear and logistic regression. To reduce
the Type I error rate, all statistical tests were two tailed; we used
the .01 level of statistical significance. Differences that were
significant at the .05 level are discussed as marginally significant
trends.
Results
Sociodemographic and Clinical Characteristics
We defined a subject as having a lifetime history of illness
if a disorder was reported at the time of assessment. There
were 11 girls with ADHD1CD, 39 with ADHD1ODD,
and 90 with ADHD only. These were compared with 122
non-ADHD, non-CD control girls. There were 10 children
with comorbid CD as well as ODD. These girls were
included in the ADHD1CD group.
The groups did not significantly differ in age of probands, age of siblings, SES, intactness of family, number
of brothers or number of sisters (Table 1). There was a
significant difference in the age of the parents, but
pairwise comparisons between groups failed to yield any
significant findings.
Familial Association between Antisocial Disorders
and ADHD
Relatives of the ADHD, ADHD1ODD, and ADHD1CD
proband subgroups were at significantly greater risk for
ADHD compared with relatives of controls (Table 2).
Also, relatives of the ADHD subgroup were at significantly greater risk for ODD compared to control subjects.
There were trends toward differences in the rates of ODD
between the relatives of the ADHD1CD and
ADHD1ODD subgroups and the relatives of controls, but
ADHD and Conduct Disorder
BIOL PSYCHIATRY
2000;48:21–29
25
Table 2. Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) among Relatives of Attention-Deficit/Hyperactivity
Disorder (ADHD) Girl Probands
Proband’s diagnosis
ADHD1CD
n 5 40
All relatives
ADHD
ODD
CD
Antisocial personality disorder
CD or antisocial disorder
Parents
ADHD
ODD
CD
Antisocial personality disorder
CD or antisocial disorder
Siblings
ADHD
ODD
CD
Antisocial personality disorder
CD or antisocial disorder
n
a
%
9
23
6
15
7a,c
18
3
11
9b,c
23
n 5 22
4b
18
2
10
2
10
2
9
3
14
n 5 18
5
28
4
22
5
28
1
17
6a,c,d
33
ADHD1ODD
n 5 117
%
n
b
24
13
10
7
14
21
11
9
9
12
n 5 77
17b
9a
9
7
13
23
12
12
9
17
n 5 40
7
4
1
0
1
18
10
3
NA
3
ADHD only
n 5 260
Control subjects
n 5 369
%
n
%
p value
Test statistic
69
27
29a
11
12
5
12
6
22
8
n 5 175
39b
22
13
8
8
5
11
6
17
10
n 5 85
30
35
16
19
4
5
1
6
5
6
23
18
16
9
19
7
5
4
3
5
,.001
.001
.007
.013
,.001
Z (1) 5 4.8
Z (1) 5 3.3
Z (1) 5 2.7
Z (1) 5 2.5
Z (1) 5 4.0
5
6
11
9
14
2
3
5
4
6
,.001
.012
.087
.286
.027
x2 (3) 5 45.8
x2 (3) 5 11.0
x2 (3) 5 6.6
x2 (3) 5 3.8
x2 (3) 5 9.2
18
12
5
0
5
n 5 131
14
9
4
NA
4
.097
.236
.041
.049
.009
n
b
n 5 238
Z (1) 5 1.7
Z (1) 5 1.2
Z (1) 5 2.0
Z (1) 5 2.0
Z (1) 5 2.6
Tests on all relatives and siblings by logistic regression with Huber’s Correction for correlated data; tests on Parents by x2. NA, not applicable.
a
p # .01 vs. control subjects.
b
p # .001 vs. control subjects.
c
p # .01 vs. ADHD only.
d
p # .01 vs. ADHD 1 ODD.
they were not significant (p 5 .021 and p 5 .013,
respectively). Furthermore, compared with control subjects, only relatives of CD probands had increased rates of
CD and the combined category CD or antisocial personality disorder (CD/ASPD). There was a difference in the
rates of CD/ASPD between the ADD1ODD relatives and
the control relatives, but it was not significant (p 5 .013).
There were no significant differences found in the rates of
ASPD alone among the relatives of the four subgroups.
The relatives of ADHD1ODD and ADHD-only probands did not differ in rates of ADHD, ODD, CD, or
ASPD. In contrast, relatives of ADHD1CD probands had
higher rates of CD and CD/ASPD compared with the
ADHD only subgroup.
As Table 2 indicates, the pattern of results observed for
the entire sample was also observed when the data were
analyzed separately for parents and siblings. Because of
the smaller sub-samples for these latter analyses, however,
some comparisons did not attain statistical significance.
Nonrandom Mating and Cosegregation of ADHD,
ODD, and CD
Our finding that the increased risk for CD among relatives
was limited to families of ADHD1CD probands could
occur if ADHD individuals had an increased likelihood of
marriage with CD individuals. Rates of CD were similar
among fathers whose spouses did and did not have ADHD
[12% vs. 10%; x2(1) 5 0.21, p 5 .65]. Rates of CD were
higher among mothers if their spouse had ADHD (7% vs.
2%), but the difference was not statistically significant
[x2(1) 5 3.0, p 5 .08]. Fathers whose spouse had ADHD
had lower rates of ADHD, but this difference was not
significant [6% vs. 12%, x2(1) 5 1.0, p 5 .31]. Rates of
ASPD in mothers were higher in those whose spouse has
ADHD (4% vs. 1%), but again this was not a statistically
significant difference [x2(1) 5 3.2, p 5 .08].
If ADHD1CD probands carried two unrelated risk
factors, one for ADHD and one for CD, ADHD and CD
should be independently transmitted in the families of
ADHD1CD probands. That is, relatives with ADHD
should be at no greater risk for CD than those without
ADHD. If, however, in the families of ADHD1CD
probands, the degree of comorbidity in the relatives is
greater than expected by chance, we use the term “cosegregate” to indicate that the disorders are transmitted
together, not independently (Pauls et al 1986a, 1986b).
That was the case in our data; there was a substantial
degree of cosegregation. Among relatives of ADHD1CD
probands, 56% of the relatives diagnosed as ADHD also
had CD, compared to 7% of the relatives who did not have
ADHD [x2(1) 5 11.2, p 5 .001].
Our cosegregation findings are consistent with an addi-
26
BIOL PSYCHIATRY
2000;48:21–29
tional finding: There were higher rates of CD among the
nine ADHD relatives of ADHD1CD probands (56%),
compared with the 93 ADHD relatives of other ADHD
probands [13%; x2(1) 5 10.7, p 5 .001] or the 23 ADHD
relatives of control probands [9%; x2(1) 5 8.3, p 5 .004].
Discussion
In a large set of families ascertained through ADHD girls,
we tested competing hypotheses about patterns of familial
association between DSM-III-R ADHD, CD, ODD, and
ASPD. After stratifying the ADHD sample into those with
CD (ADHD1CD), those with ODD (ADHD1ODD), and
those with neither (ADHD), familial risk analyses revealed
the following: 1) relatives of each ADHD proband subgroup were at significantly greater risk for ADHD than
relatives of normal control subjects, 2) rates of CD were
elevated among relatives of ADHD1CD probands only,
3) the coaggregation of ADHD and CD could not be
accounted for by marriages between ADHD and antisocial
spouses, and 4) both ADHD and CD occurred in the same
relatives more often than expected by chance alone.
Our results support our main hypothesis, which posits
that ADHD1CD is a familially distinct subtype. This
hypothesis is consistent with the ICD-10 decision to retain
hyperkinetic conduct disorder as a separate diagnostic
category (World Health Organization 1988). Our rejection
of the three alternative hypotheses generalizes the conclusions from our studies of ADHD boys (Faraone et al
1991b, 1995, 1997, 1998).
Because of the inferential limitations of family studies
(Faraone and Tsuang 1995), we cannot determine if the
familial etiology of ADHD1CD is genetic or environmental. Since both genes (Faraone and Biederman 1994) and
environment (Biederman et al 1995a, 1995b) have been
implicated in the etiology of ADHD, further work is
needed to see what role they might play in the familial
transmission of comorbidity between ADHD and CD.
Notably, our results reject the alternative hypothesis,
which attributes the differences between ADHD with and
without CD to environmental factors not transmitted in
families. This alternative incorrectly predicts equal rates of
conduct disorder among the relatives of the three ADHD
proband subgroups (Reich et al 1979). That is, if the
familial causes of CD were the same in type and degree
among ADHD subgroups, the familial risks to their
relatives should not differ, but they did.
Furthermore, although these familial risks did differ, the
pattern of differences rejected the idea that ADHD with
and without CD share a common pool of familial etiological factors such that ADHD1CD requires more familially
transmissible etiologic factors (e.g., genes, familial adversity) for its expression compared with ADHD alone. This
S.V. Faraone et al
idea incorrectly predicts greater rates of ADHD among
relatives of ADHD1CD probands. Although the lack of
group differences in rates of ADHD could be owing to low
statistical power (there were only 40 relatives in the
ADHD1CD group), the actual rates were very similar
(23% for relatives of ADHD1CD, 27% for relatives of
ADHD only).
The low risk for CD among relatives of ADHD probands without CD suggests that these probands are qualitatively distinct from the probands with comorbid antisocial disorders instead of quantitatively different as
assumed by the multifactorial model. That is, it may be the
case that the ADHD probands without CD share no
familial precursors with CD. This would further suggest
that ADHD in the presence of a comorbid CD represents
a distinct familial subtype of ADHD. If this is the case,
ADHD and CD should cosegregate (i.e., not be independently transmitted) in the families of ADHD probands
with antisocial disorders (Pauls et al 1986a, 1986b). That
is exactly what we found: In the relatives of ADHD1CD
probands, those with ADHD were at increased risk for
CD, and this level of comorbidity was significantly greater
than what was observed among the ADHD relatives of
other ADHD probands.
The subsample of ADHD1ODD girls provided some
intriguing results. We know from Lahey et al’s (1994)
literature review that, although a large majority of CD
children have prior histories of ODD, many ODD children
do not go on to develop CD. This raises a question: Are
there two types of ODD, one that progresses to CD and
one that does not? The present study found only one
statistically significant difference in familial rates of illness between ADHD1ODD probands and either
ADHD1CD or ADHD-only probands. The siblings of
ADHD1CD probands had greater rates of the combined
category CD or ASPD compared with siblings of
ADHD1ODD probands (p , .01).
For the comparisons with ADHD1CD probands, nonsignificant differences could reflect low statistical power,
given the small number of relatives in the ADHD1CD
group (n 5 40). For example, although not statistically
significant, there was a two-fold increase in the rate of CD
in relatives of ADHD1CD compared with ADHD1ODD
probands. For siblings, there was a nine-fold increase for
CD. These differences would likely have attained significance in a larger sample. By contrast, we had adequate
statistical power for comparisons between ADHD1ODD
and ADHD-only families (ns 5 117 and 260, respectively). This gives greater certainty to our finding of no
differences between these two groups.
Given the low power of some comparisons, any interpretation of the ODD results must be made cautiously.
Nonetheless, these results are consistent with the idea that
ADHD and Conduct Disorder
some of the ADHD1ODD children are similar to
ADHD1CD children, whereas others are similar to
ADHD-only children. Such heterogeneity in the ODD
group would tend to blur distinction between it and the
two other groups.
Because we did not examine a sample of CD children
without ADHD, our results cannot determine whether the
increased familial risk observed among relatives of
ADHD1CD probands is due to the antisocial component
of CD or to an interaction with the ADHD syndrome. The
work of Lahey et al (1988) suggests that the comorbidity
of ADHD and CD confers additional familial risk beyond
that of CD alone. Their results clearly indicate that the
risks for antisocial personality and substance abuse are
greater among fathers of ADHD1CD probands, compared
to those with either ADHD alone or CD alone. Children
with ADHD1CD have also been shown to have a greater
variety and severity of antisocial behaviors compared to
children with CD alone (Walker et al 1987). Another
group (Szatmari et al 1989) found that children with
ADHD1CD appeared to represent a true hybrid disorder
rather than one diagnosis or the other. Like ADHD
children, the mixed group had more developmental delays
than CD children, and like CD children, they had more
psychosocial disadvantage than ADHD children. A review
of the literature by Hinshaw (1993) concluded that children with ADHD1CD have an earlier age at onset of CD,
are more aggressive, and have more persistent CD than
other CD children.
The strength of our conclusions is further mitigated by
some methodological limitations. Notably, the number of
ADHD girls with CD was small, which limits the power of
our analyses, because there were only 40 family members
from ADHD1CD families, which were compared with the
117 members from ADHD1ODD families, the 260 members from ADHD-only families, and the 369 members
from control families.
Also, findings based on a clinical population should be
interpreted with caution, because they may not generalize
to other populations. Our diagnosis of ADHD, CD, and
ODD among parents of probands relied on retrospective
data, which may be subject to recall biases that may not be
independent of the proband diagnosis. Although relatively
little is known about the validity of these retrospective
diagnoses, several studies have shown it possible to
validly diagnose ADHD in adults (Biederman et al 1990a;
Cantwell 1985; Conners 1985; Varley 1985; Wender et al
1985).
Another methodological shortcoming pertains to our
assessments of psychopathology in children. Because they
used both interviews with mothers and direct interviews of
children, they may be subject to several potential confounds. First, similarities between children within a family
BIOL PSYCHIATRY
2000;48:21–29
27
could be exaggerated by using a common source of
information. The direct interview of a family member
could be biased if the reporter was aware of the proband’s
diagnoses. Second, a halo effect (i.e., a bias toward
reporting a second illness in the presence of another) could
lead to an overestimation of the comorbidity between
ADHD and antisocial disorders and the degree of
cosegregation.
Although we have tested seven hypotheses, these do not
exhaust the universe of plausible hypotheses. For example,
hypotheses six and seven are rejected only if the factors
that lead to a secondary disorder are independent of factors
leading to that disorder in the absence of the primary
disorder. Thus, our results should be interpreted cautiously. Replication by other groups would be very useful,
as would the testing of these hypotheses in a twin sample.
Despite these limitations, the data in this report can be
considered as suggestive of a useful working hypothesis:
that the combined syndrome of ADHD plus CD in girls
may be familially distinct from ADHD without CD. This
work generalizes findings from studies of boys and provides some evidence for the nosologic validity of the
ICD-10 category of hyperkinetic conduct disorder. Perhaps future revisions of the American DSM-IV should
consider including this comorbid condition as a separate
category.
This work was supported in part by Grants Nos. RO1 MH41314-07 (JB)
and R01MH57934-0 (SVF) from the National Institute of Mental Health,
Bethesda, Maryland.
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