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High risk studies and developmental antecedents of anxiety disorders.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:99 – 117 (2008)
A R T I C L E
High Risk Studies and Developmental
Antecedents of Anxiety Disorders
DINA R. HIRSHFELD-BECKER,* JAMIE A. MICCO, NICOLE A. SIMOES, AND AUDE HENIN
The past two decades have witnessed significant growth in our understanding of the developmental antecedents
of anxiety disorders. In this article, we review studies of offspring at risk for anxiety disorders, longitudinal studies
of the course of anxiety disorders in clinical, epidemiologic, and at-risk samples, studies of hypothesized
temperamental risk factors for anxiety, and give a brief overview of the literature on environmental risk factors.
Clear developmental antecedents to anxiety disorders identified include (1) childhood anxiety disorders [in
particular, separation anxiety and overanxious disorder/general anxiety disorder (GAD)], (2) behavioral inhibition
which predicts later social phobia, (3) anxiety sensitivity which predicts later panic disorder, and (4) negative
affectivity, which predicts a spectrum of psychopathology including anxiety disorders. Further prospective studies
are needed to examine the roles of environmental factors such as parenting practices, peer influences, stressful
life events, and perinatal stressors. Future studies could benefit from (1) beginning earlier in development
and following individuals into adulthood, (2) assessing the overlap between multiple temperamental constructs,
(3) greater use of observational measures of temperament and of parent–child and peer interactions, (4) greater
attention to parental psychopathology which may confound associations noted, (5) exploration of other features
of anxiety disorders (neurofunctional correlates, cognitive features, other aspects of emotional regulation) as
potential precursors, and (6) intervention studies exploring whether modifying developmental antecedents can
alter the course of anxiety disorders. ß 2008 Wiley-Liss, Inc.
KEY WORDS: anxiety disorders; antecedents; temperament; high-risk studies; behavioral inhibition
How to cite this article: Hirshfeld-Becker DR, Micco JA, Simoes NA, Henin A. 2008. High risk studies and
developmental antecedents of anxiety disorders. Am J Med Genet Part C Semin Med Genet 148C:99–117.
INTRODUCTION
The ability to identify early in life
individuals at highest risk for anxiety
disorders would enhance efforts to
understand the genetic and neurobiological underpinnings and developmental
psychopathology of the disorders, as well
as efforts to intervene preventively. Over
the past two decades, information about
the early risk factors for anxiety has
burgeoned. In the following review, we
provide a detailed overview of high-risk
studies, early diagnostic predictors, and
temperamental antecedents, and a broad
summary of the environmental factors
associated with onset of anxiety disorders;
discuss the strengths and limitations of
these studies; and highlight areas for
further inquiry.
In reviewing this literature, several
methodological issues warrant consideration. First, the category ‘‘anxiety
disorders’’ is extremely broad, encompassing no fewer than eight separate
DSM-IV disorders, yet many studies
Dina Hirshfeld-Becker, Ph.D. is Director of High Risk Studies and Anxiety Research in the CRPPP,
and is Associate Professor of Psychiatry at the Harvard Medical School.
Jamie Micco, Ph.D. is a researcher in the High Risk Studies Program in the CRPPP and an
Instructor in Psychiatry at the Harvard Medical School.
Nicole Simoes, M.A. is a graduate of Tulane University who serves as research coordinator of an
NIMH-funded longitudinal study of children at risk for anxiety disorders.
Aude Henin, Ph.D. is the Director of Cognitive Behavior Therapy Research in the CRPPP, an
Instructor of Psychiatry at the Harvard Medical School, and a co-investigator and project director
of an NIMH-funded longitudinal study of children at risk for anxiety disorder.
*Correspondence to: Dina R. Hirshfeld-Becker, Ph.D., MGH Clinical and Research Program in
Pediatric Psychopharmacology, 185 Alewife Brook Parkway, Suite 2000, Cambridge, MA 02138.
E-mail: dhirshfeld@partners.org
DOI 10.1002/ajmg.c.30170
ß 2008 Wiley-Liss, Inc.
treat these disorders as a unitary construct. Arguments for considering the
anxiety disorders as a single category
include considerable comorbidity between the disorders, evidence from twin
and family studies suggesting shared
genetic variability for several, and similarities in brain regions underlying the
disorders and in effective treatment
approaches (cognitive-behavioral as
well as pharmacological). Arguments
for regarding the anxiety disorders as
discrete entities include their distinct
ages of onset, courses, phenomenologies, and, in some cases, distinct
patterns of association. In the present
review, we include studies of risk for
anxiety disorders in general, as well as
more detailed consideration of the
antecedents of several well-studied discrete disorders.
Second, of the different methodologies used to study developmental
antecedents of anxiety disorders, prospective longitudinal designs are the
most informative. Capitalizing on the
100
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
moderate heritability of the anxiety
disorders, offspring-at-risk studies recruit
young children of parents affected with
an anxiety disorder of interest and a
contrast group of offspring of unaffected
parents, and follow them prospectively
to examine early disorders, symptom
constellations, and biological or temperamental markers and relate these to onset
and course of psychopathology. Such
studies ensure high rates of the outcome
of interest with a relatively small initial
sample. In contrast, studies of unselected epidemiologic or community samples
examine large cohorts of children for
hypothesized early risk factors and
link these prospectively to outcomes of
interest. Such studies eliminate the bias
introduced by clinical referral of parent
probands but require very large samples
to ensure sufficient representation of the
disorders studied. Longitudinal studies
of selected samples begin with children
chosen on the basis of the presence
or absence of a hypothesized risk factor,
without regard to parental psychopathology, and then examine the children’s outcomes over time. These
studies enable the study of factors with
relatively low prevalence without introducing bias inherent in beginning with
clinically-referred parents.
Finally, we note that space limitations required us to prioritize which
information in this rapidly growing
field to include and which to exclude.
Because we reasoned that high-risk and
prospective longitudinal studies would
be most informative about the developmental antecedents of anxiety disorders,
we elected to present the most detailed
information about factors studied using
these methods; namely parental psychopathology, early diagnostic and temperamental markers, and anxiety sensitivity
(AS). Although retrospective studies of
affected adults and cross-sectional studies
of affected children can be useful in
hypothesis generation, they are subject
to confounds of biased recall or of
concurrent symptoms, which may have
overlap with behavioral and physiologic
precursors. Consequently, although we
sought to provide a broad overview of
factors associated with anxiety disorders
and to underscore in particular data from
prospective longitudinal studies where
available, we tended to de-emphasize
studies relying mainly upon crosssectional methodologies, particularly in
the case of environmental risk factors
(e.g., the bulk of the literature on
parenting factors). This is not to say that
cross-sectional studies cannot be invaluable in hypothesis generation and model
building for future prospective analyses,
only that we did not have room for them
in our review. We have therefore made
an effort to direct the reader to thorough
reviews of the areas to which we have
devoted less emphasis.
HIGH-RISK
OFFSPRING STUDIES
Fourteen studies have examined rates
of anxiety disorders among offspring of
parents with anxiety disorders. Most
included offspring of parents with panic
or agoraphobia [Weissman et al., 1984;
Sylvester et al., 1988; Biederman et al.,
1991, 2001a, 2004, 2006b; Warner et al.,
1995; Capps et al., 1996] or of combined
groups of parents with anxiety disorders
[Turner et al., 1987; Beidel and Turner,
1997; Merikangas et al., 1998a],
although some studied offspring of
parents with generalized anxiety disorder (GAD) [Johnson et al., 2006], animal
phobias [Unnewehr et al., 1998], or
obsessive-compulsive disorder [Black
et al., 2003] in particular. Rates of ‘‘any
anxiety disorder’’ or ‘‘two or more
anxiety disorders’’ between offspring of
parents with anxiety and offspring of
non-affected controls differed significantly in all but two of the studies
[Warner et al., 1995; Merikangas et al.,
1998a], with rates of ‘‘any anxiety
disorder’’ ranging from 21% to 68% in
the at-risk offspring as contrasted
with 0–26% in the control offspring.
Rates of ‘‘any anxiety disorder’’
or ‘‘two or more anxiety
disorders’’ between offspring of
parents with anxiety and
offspring of non-affected
ARTICLE
controls differed significantly in
all but two of the studies, with
rates of ‘‘any anxiety disorder’’
ranging from 21% to 68% in the
at-risk offspring as contrasted
with 0–26% in the
control offspring.
Combining all studies that reported the
rate of ‘‘any anxiety disorder’’ (comprising 1,371 children), the 465 offspring
of parents with anxiety disorders had
a rate of ‘‘any anxiety disorder’’ of
37%, compared with 15% among the
906 offspring of non-anxious controls
(Chi-square ¼ 83.96, P < 0.0001). In
addition, ‘‘bottom-up’’ studies suggest
that about half of parents of children
presenting clinically with anxiety meet
criteria for anxiety disorders themselves
[e.g., Last et al., 1991].
Evidence for specificity of transmission is mixed, with some studies
showing transmission of the same disorder from parent to child, for panic
disorder [Unnewehr et al., 1998; Biederman et al., 2001a, 2004, 2006b],
social phobia [Lieb et al., 2000; Biederman et al., 2006a] or specific phobia
[Unnewehr et al., 1998], but with
most also showing that parental anxiety
disorders confer risk for a spectrum
of disorders in the offspring. High
risk studies also suggest that comorbid
anxiety or mood disorders in the affected
parent increase the children’s risk for
anxiety disorder [Biederman et al.,
2005], as does having more than
one parent with an anxiety disorder
[Merikangas et al., 1998b]. Additionally,
an analysis of the effects of comorbid
parental disorders found that social
phobia and separation anxiety disorder
among offspring of parents with panic
were predicted by social phobia and
separation anxiety disorder in the
parents’ own histories, whereas agoraphobia and OCD in these offspring were
predicted by parental panic disorder,
even after controlling for the presence
of comorbid agoraphobia and OCD in
the parents [Biederman et al., 2006a].
ARTICLE
In addition, several studies have also
found elevated risk for anxiety disorders
among offspring of parents with major
depressive disorder [e.g., Weissman
et al., 2006] and bipolar disorder [e.g.,
Grigoroiu-Serbanescu et al., 1989],
although others have not. In complementary fashion, several studies found
elevated rates of depression among offspring of parents with anxiety disorders
[Sylvester et al., 1988; Biederman et al.,
1991; Beidel and Turner, 1997].
The studies reviewed in this section
should be interpreted in light of several
methodological limitations. First, most
focused on offspring of parents with
panic and agorphobia or combined
parental diagnostic groups, and most
did not analyze the effects of parental
comorbidity, especially within the
anxiety disorders. Second, some studies
did not report on all separate childhood
anxiety disorders. Third, as reflected
in Table I, the participants studied
were mainly Caucasians, which limits
the generalizability of findings. Finally,
the offspring included were within the
age of risk for onset of psychopathology,
even for childhood psychopathology.
Future studies could benefit from
directly comparing offspring of parents
with a range of distinct anxiety diagnoses, from examining effects of comorbid disorders within parents, and
from following offspring longitudinally
through adolescence or beyond.
Beyond documenting the increased
risk for anxiety among offspring of
parents with anxiety and mood disorders, the high-risk studies provide
evidence for an important early predictor of adulthood anxiety disorders:
childhood disorders. Since the offspring
in these studies are at moderately
increased genetic risk for the adulthood
disorders, which have heritabilities in
the 0.3–0.4 range [Smoller and Tsuang,
1998], the disorders they manifest may
represent prodromes of these disorders.
If disorders in offspring parallel those
reported retrospectively by affected
adults, the hypothesis that childhood
disorders are antecedents of the adulthood disorders gains further support.
The finding that in some cases, children
present specifically with their parents’
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
disorder suggests continuity of anxiety
disorders from childhood to adulthood,
and is consistent with retrospective reports indicating that a substantial proportion of adults with panic disorder
[Von Korff et al., 1985], social phobia
[Stein, 2006], and specific phobia [Öst,
1987] report childhood onset. On the
other hand, the finding that childhood
separation anxiety disorder, social phobia (or DSM-III-R avoidant disorder),
and GAD (or DSM-III-R overanxious
disorder) are found in offspring of
parents with different disorders suggests
that these childhood disorders may be
important developmental precursors to
different anxiety disorders. These findings
dovetail with retrospective accounts by
adults presenting clinically with panic
disorder and social phobia, of whom at
least half report having had one of these
three childhood disorders [Otto et al.,
1994, 2001].
EARLY SYMPTOMATIC
ANTECEDENTS
A total of 14 studies, summarized in
Table II, have prospectively examined
the course of childhood anxiety disorders (in 12 samples) from early to
middle childhood or from adolescence
to young adulthood. The converging
evidence suggests that early anxiety
symptoms or disorders, whether found
in clinical, community, epidemiologic,
or offspring-at-risk samples, significantly increase the risk of meeting
criteria for anxiety disorders later in life.
For example, two epidemiologic studies
found that children diagnosed with an
anxiety disorder in pre- or early adolescence were nearly three times as likely as
those without a prior anxiety disorder
to have an anxiety disorder in young
adulthood [Pine et al., 1998; KimCohen et al., 2003]. Follow-up of
clinical samples have also found that
childhood anxiety increases the risk for
later anxiety. Moreover, studies from
two large epidemiologic samples suggest
that childhood major depression may
also increase the risk for development of
subsequent anxiety disorders [Costello
et al., 2003; Kim-Cohen et al., 2003;
Gregory et al., 2007].
101
In the studies that examined individual disorders, evidence for both
homotypic (i.e., predicting to the same
disorder) and heterotypic (i.e., predicting to other anxiety disorders) continuity was found. For example, Pine et al.
[1998] found that social phobia, simple
phobia, and childhood overanxious
disorder/GAD in adolescence each predicted the corresponding disorder in
early adulthood; however, overanxious
disorder also predicted specific and
social phobia and depressive disorders.
Similarly, scales from a self-report questionnaire measuring separation anxiety
disorder, GAD, social phobia and panic
disorder at ages 10–12 each predicted
the corresponding scale 2 years later;
however each scale was also predicted in
roughly equal measure by the combination of all of the others (heterotypic
scales) [Ferdinand et al., 2007]. In the
Dunedin Study [Gregory et al., 2007],
adults age 32 with GAD, social phobia,
and agoraphobia had greater rates at ages
11–15 of all three childhood disorders
assessed (OAD, separation anxiety disorder and phobias), whereas adults with
specific phobia only had childhood
phobias (assessed using an instrument
that did not distinguish social and
specific phobias). In a high-risk sample
[Biederman et al., 2007], separation
anxiety disorder at mean age six significantly increased the risk of a range of
anxiety and mood disorders 5 years later.
Thus, having a childhood anxiety
disorder, particularly separation anxiety
disorder, overanxious disorder/GAD,
or social or specific phobia appears
significantly to heighten the risk for
a range of later anxiety disorders.
Thus, having a childhood
anxiety disorder, particularly
separation anxiety disorder,
overanxious disorder/GAD, or
social or specific phobia appears
significantly to heighten the
risk for a range of later anxiety
disorders.
(1) SADS-L
(2) K-SADS-E
(1) SADS-L
(2) K-SADS-E
N ¼ 214,
ages 6–23
N ¼ 145,
ages 6–24
(parent and direct
child interviews)
Warner et al.
[1995]
PD þ MDD
PD
PD þ MDD
PDAG þ
MDD
PDAG
(1) DIS
(2) DICA-P
Mufson et al.
[1992]a
Biederman et al.
[1991]
Sylvester et al.
[1988]
AG or
OCD
PD
(1) ADIS
(2) CAS
N ¼ 59,
ages 7–12
(direct child
interviews);
93% Caucasian,
7% African
American
N ¼ 125,
ages 7–17
(direct ch. ints)
N ¼ 121,
ages 4–22
(parent
interviews);
100% Caucasian
Turner et al.
[1987]
MDD þ PD
Diagnoses
of anxiety
probands
(1) DIS
(2) DICA
(1) SADS-L
(2) ‘‘screening
instrument’’
for diagnosis
of offspring
N ¼ 194,
ages 6–17
(community
sample; parent
interviews)
Weissman et al.
[1984]
References
Diagnostic
interview
Sample size,
age of children,
and ethnicity of
children (where
reported)
Early-onset
(<30) MDD
MDD
MDD
MDD
Dysthymic
Disorder
MDD without
anxiety
disorder
Diagnoses of
psychiatric
control
probands
Neverpsychiatrically-ill
controls
Neverpsychiatrically-ill
controls
Children
without known
psychiatric dxs
& siblings
Normal
controls
No DSM-III
diagnoses
Neverpsychiatrically-ill
controls
Description
of normal
control
probands
Anx:
SAD:
SOC:
Anx:
SAD:
PD:
PDAG:
Anx:
SAD:
OAD:
Phob:
Anx:
Anx:
SAD:
SOC:
OAD:
Anx:
SAD:
PD:
AG:
SOC:
n ¼ 60
28%
15%
12%
Anx:
SAD:
OAD:
Phob:
n ¼ 14,
21%
14%
14%
7%
Anx:
SAD:
SOC.:
Anx:
SAD:
PD:
PDAG:
Anx:
n ¼ 50
42%
n ¼ 79
46%
20%
4%
5%
n ¼ 17,
24%
12%
6%
Anx:
SAD:
SOC:
OAD:
Anx:
SAD:
PD:
AG:
SOC:
n ¼ 19
37%
37%
5%
5%
5%
n ¼ 16
37%
25%
0%
12%
n ¼ 25
48%
16%
24%
24%
In offspring of anxious probands
n ¼ 74
34%
18%
4%
5%
n ¼ 32
34%
12%
16%
n ¼ 12
8%
0%
8%
0%
n ¼ 27
44%
n ¼ 38
0%
0%
0%
0%
0%
n ¼ 14
22%
7%
7%
7%
In offspring
of psychiatric
control probands
Rates of anxiety and depressive disorders
TABLE I. Rates of Anxiety Disorders in the High-Risk Offspring of Parents With Anxiety Disorders
Anx:
SAD:
SOC:
Anx:
SAD:
PD:
PDAG:
Anx:
SAD:
OAD:
Phob:
Anx:
Anx:
SAD:
SOC:
OAD:
Anx:
SAD:
PD:
AG:
SOC:
n ¼ 20
20%
10%
0%
0%
n ¼ 36
20%
3%
11%
n ¼ 47
11%
4%
2%
2%
n ¼ 48
15%
n ¼ 87
2%
0%
0%
0%
1%
n ¼ 29
3%
0%
0%
3%
In offspring
of normal
controls
102
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
ARTICLE
(1) SCID
(2) K-SADS-E
N ¼ 312,
ages 5–25;
mean age 6.8
(parent interviews;
direct interviews
for children age
12 and older);
93% Caucasian,
3% AfricanAmerican,
2% Latino,
2% Asian
Biederman et al.
[2001a]
(1) SADS
(2) K-SADS-E
Anx (PD,
OCD,
SOC);
(1) SCID
(2) K-SADS
PD þ MDD
PD
Animal
Phobia
PD
Anx (PDAG,
SOC, GAD)
Anx/MDD
(PD, OCD,
GAD)
PDAG
(1) ADIS-R
(2) DISC-C/
DISC-P
(1) DIPS
N ¼ 87,
(2) Kinder-DIPS
age 5–15;
(parent and direct
child interviews)
N ¼ 32,
ages 8–14;
(parent and direct
child interviews)
13% Caucasian,
13% AfricanAmerican,
13% AsianAmerican,
6% Latino
N ¼ 129,
ages 7–12;
(parent and direct
child interviews);
83% Caucasian,
15% AfricanAmerican,
2% East Indian
N ¼ 192,
ages 7–18;
(parent and direct
child interviews)
Unnewehr et al.
[1998]
Merikangas
et al. [1998a]
Beidel and
Turner [1997]
Capps et al.
[1996]
MDD
N/A
Parents
without PDAG
and MDD
Neverpsychiatrically-ill
controls
Neverpsychiatrically-ill
controls
Neverpsychiatrically-ill
controls
MDD
Substance
Abuse or
Dependence
Neverpsychiatrically-ill
controls
N/A
n ¼ 23
17%
48%
n ¼ 141
26%
27%
4%
10%
19%
13%
4%
18%
3%
65%
32%
n ¼ 26,
27%
19%
8%
0%
14%
4%
5%
15%
8%
2Anx:
SAD:
PD:
SOC:
AG:
OAD:
GAD:
Phob:
OCD:
2Anx:
SAD:
PD:
SOC:
AG:
OAD:
GAD:
Phob:
OCD:
n ¼ 46
15%
20%
4%
11%
7%
11%
0%
11%
2%
2Anx:
SAD:
PD:
SOC:
AG:
OAD:
GAD:
Phob:
OCD:
n ¼ 99
4%
4%
0%
2%
3%
4%
1%
10%
0%
7%
13%
n ¼ 57
11%
7%
0%
0%
5%
4%
n ¼ 30
n ¼ 48
8%
0%
2%
2%
n ¼ 16
0%
0%
0%
0%
0%
(Continued)
SAD/
OAD/PD:
AG/Phob:
Anx:
SAD:
PD:
SOC:
OAD:
Phob:
SAD/
OAD/
PD:
AG/Phob:
Anx:
SAD:
PD:
SOC:
OAD:
Phob
N/A
n ¼ 77
10%
3%
0%
1%
8%
1%
n ¼ 58
22%
12%
2%
7%
12%
7%
n ¼ 34,
Anx:
SAD:
PD:
SOC:
OAD:
Phob:
n ¼ 24
21%
4%
13%
0%
Anx:
SAD:
SOC.:
OAD:
Anx:
SAD:
SOC.:
OAD:
n ¼ 29
33%
0%
7%
3%
n ¼ 28,
33%
4%
0%
21%
Anx:
SAD:
SOC.:
OAD:
Anx:
SAD:
Avoid:
OAD:
GAD:
N/A
n ¼ 16
68%
56%
13%
25%
13%
Anx:
SAD:
Avoid:
OAD:
GAD:
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
103
N ¼ 78,
ages 7-18
(parent and direct
child interviews);
98% Caucasian
2% AfricanAmerican
N ¼ 593,
ages 26–39
(parent and direct
offspring
interviews);
91% Caucasian
N ¼ 319,
ages 7–18,
mean age 10
(parent interviews
and direct child
interviews for
children age 12
and older);
95% Caucasian
PD þ MDD
PD
GAD
(1) SCID-IV
(2) DISC
(1) SCID
(2) K-SADS-E
OCD
Diagnoses
of anxiety
probands
(1) SCID-IV
(2) DICA
Diagnostic
interview
MDD
N/A
N/A
Diagnoses of
psychiatric
control
probands
Parents without
PDAG and MDD
No lifetime
history of GAD
(may have other
psychiatric
disorders)
No lifetime
history of OCD
Description
of normal
control
probands
2Anx:
SAD:
PD:
SOC:
AG:
GAD:
Phob:
OCD:
Anx:
Anx:
SAD:
OAD:
Phob:
OCD:
n ¼ 27,
37%
37%
15%
15%
26%
5%
15%
8%
n ¼ 136
42%
36%
10%
22%
24%
4%
18%
3%
2Anx:
SAD:
PD:
SOC:
AG:
GAD:
Phob:
OCD:
n ¼ 53
28%
30%
2%
15%
7%
0%
11%
2%
2Anx:
SAD:
PD:
SOC:
AG:
GAD:
Phob:
OCD:
Anx:
n ¼ 90
41%
N/A
Anx:
SAD:
OAD:
Phob:
OCD:
N/A
n ¼ 103
12%
12%
3%
6%
3%
1%
10%
0%
n ¼ 503
19%
n ¼ 35
26%
6%
9%
9%
3%
In offspring
of normal
controls
n ¼ 43
51%
17%
32%
21%
23%
In offspring of anxious probands
In offspring
of psychiatric
control Probands
Rates of anxiety and depressive disorders
Italicized percentages indicate those reported to differ significantly from rates in the non-affected control group.
SADS-L, schedule for affective disorders and schizophrenia, lifetime version; CAS, children’s assessment schedule; ADIS, anxiety disorders interview schedule, R, for DSM-III-R; DISC,
diagnostic interview schedule for children; DIS, diagnostic interview schedule; DICA-P, diagnostic interview for children and adolescents-parent version; KSADS, schedule for affective
disorders and schizophrenia, child version, E, epidemiological version; DIPS, German version of the ADIS-R; Kinder-DIPS, German version of the ADIS-C/P; SCID, structured clinical
interview for DSM-III-R, IV, for DSM-IV; DICA, diagnostic interview for children and adolescents; Anx, presence of any anxiety disorder; 2Anx, presence of two or more anxiety
disorders in a child; PD, panic disorder; PDAG, panic disorder with agoraphobia; AG, agoraphobia; MDD, major depressive disorder; OCD, obsessive compulsive disorder; GAD, generalized
anxiety disorder; SOC, social phobia; SAD, separation anxiety disorder; OAD, childhood overanxious disorder; Phob, specific phobia.
a
Follow-up of Weissman et al. [1984] study, with overlapped sample.
b
Follow-ups of Biederman et al. [2001a] study.
Biederman et al.
[2006]b
Johnson et al.
[2006]
Black et al.
[2003]
References
Sample size,
age of children,
and ethnicity of
children (where
reported)
TABLE I. (Continued )
104
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
ARTICLE
Clinical
Clinical
Klein [1995]
Last et al. [1996]
Epidemiologic
Clinical
Epidemiologic (Christchurch
Health and Dev’t Study)
Epidemiologic
Pine et al. [1998]
Weissman et al. [1999]
Woodward and
Fergusson [2001]
Costello et al. [2003]
Epidemiologic
Clinical
High-Risk
Kim-Cohen et al. [2003]
Aschenbrand et al. [2003]
Bosquet and Egeland
[2006]
b
Epidemiologic
(Dunedin Study)
Newman et al. [1996]
b
Community
Sample type
Ferdinand and
Verlhurst[1995]
References
CBCL, K-SADS (at age 17)
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
(Continued)
Correlations between CBCL ‘‘anxiety/depression’’ scores and anxiety
symptoms at age 17.5:
. Childhood CBCL score, r ¼ 0.20 (P < 0.05)
. Preadolescent CBCL score, r ¼ 0.08 (NS)
. CBCL score at age 16, r ¼ 0.43 (P < 0.001)
Controlling for comorbidity, past anxiety disorders increased the
risk of having future anxiety
disorders (OR ¼ 2.0)
N ¼ 155, offspring of low-income mothers, assessed numerous
times from birth to age 17.5 years
Ethnicity: 70% Caucasian, 9% African American, 2% Native
American or Hispanic, 16% multi-racial
CAPA
N ¼ 1,420, North Carolina birth cohort,
ages 9–13; Ethnicity: predominantly Caucasian, 25% American
Indian, 8% African American,
<1% Hispanic, FU at age 16
Rates of anxiety disorder at FU:
. 76.9% in those with 3þ prior anxiety disorders
. 45.9% in those with 2 prior anxiety disorders
. 41.8% in those with 1 prior anxiety disorder
. 13.3% in those without a prior anxiety disorder
. No significant differences in rate of PDA at FU between those with
prior SAD, GAD, or SOC
. Those with prior SAD had greater risk of developing SPEC, OCD,
or PTSD/ASD (OR ¼ 4.8)
DISC, CIDI
N ¼ 964, New Zealand birth cohort, ages 15–16,
FU period ¼ 1 to 5 years
No significant difference between groups in risk of developing
subsequent anxiety disorders
N ¼ 85, children who received treatment for SOC, GAD, or SAD, ADIS-C/P, ADIS-IV-L
ages 9–13, Ethnicity: 87% Caucasian, 5% African American, 2%
Asian, 4% Other, FU period ¼ mean of 7 years
K-SADS,
SADS-LA
N ¼ 44, children with anxiety, ages 6–12; 83 with MDD and 91
NPI controls, Ethnicity: 33% Caucasian, 32%
African-American, 33%
Hispanic, FU period ¼ mean of 11.9 years
Anxiety at Times 1 and 2 predicted anxiety at Time 3:
. Simple phobia ! Simple phobia (OR ¼ 3.79)
. SOC and OAD ! SOC (OR ¼ 3.29 and 2.27)
. OAD and ‘‘PD features’’ ! GAD (OR ¼ 2.48/3.39)
Of those with anxiety disorders at age 21, 61.5% had a prior anxiety
disorder, 18.9% had a different prior disorder and 19.5% had no
prior disorder
. 81.9% of initial anxiety disorders remitted by FU, with an 8%
relapse rate of initial disorder
. 15.5% of anxiety group developed new anxiety disorder (vs.
10% and 2.4% of ADHD and NPI groups).
Compared to controls, those with prior SAD had greater rates of PD
(7% vs. 0%)
Controlling for sex, an anxiety disorder before age 15 predicted an
anxiety disorder at age 26 (OR ¼ 2.9)
DISC
N ¼ 776, children ages 9–18, assessed at mean ages 13.7, 16.4,
and 22.1, Ethnicity: 91% Caucasian,
FU period ¼ 9 years
Results
Clinically elevated ‘‘Anxious/Depressed’’ Score at
Time 1 significantly predicted clinically elevated ‘‘Anxious/
Depressed’’ Score at Time 2 (OR ¼ 3.0)
N ¼ 1,037, New Zealand birth cohort assessed multiple times from DISC, DIS
age 11 to 26, Ethnicity: 91% Caucasian, FU period ¼ 15 years
DISC, DIS
K-SADS
N ¼ 102, children ages 5–18 with anxiety disorders, 58 children
with ADHD, and 87 NPI controls, Ethnicity: 72% Caucasian,
FU period ¼ 3–4 years
N ¼ 961, New Zealand birth cohort assessed at ages 11, 13, 15,
18, and 21, Ethnicity: 91% Caucasian, FU period ¼ 10 years
Semi-structured clinical
interview
N ¼ 54, children treated with imipramine for SAD, and 60
community controls, FU period ¼ 15 years
Measures
CBCL young
adult self-report
N ¼ 459, Dutch adolescents, ages 13–16, FU period ¼ 8 years
Sample characteristicsa
TABLE II. Prospective Studies of the Association Between Childhood Anxiety and Later Anxiety Disorders
ARTICLE
105
Community
Ferdinand et al. [2007]
Results
RCADS (self-report
questionnaire)
Examined prediction of each symptom scale at Time 2 by the same
scale at Time 1 (homotypic) or by all other scales at Time 1
(heterotypic). Variances reflecting homotypic vs. heterotypic
continuity were:
. SAD: 2.3% vs. 2.0%
. GAD 3.6% vs. 4.2%
. SOC: 3.7% vs. 1.3%
. PD: 3.2% vs. 2.3%
Controlling for parental diagnosis:
. SAD at Time 1 increased risk at Time 2 for SPEC (OR 4.7),
AG (OR 9.1), and PD (OR 9.2)
. AG at Time 1 predicted GAD at Time 2 (OR 3.9)
N ¼ 2,067, children from the Dutch general population,
ages 10–12, FU period ¼ 2 years
Measures
. Adults with GAD, SOC, AG, PTSD, OCD or SPEC all had
elevated anxiety dxs at 11–15
. Those with GAD, SOC, and AG all had elevations in all three
childhood anxiety disorders, but those with SPEC only had
elevated phobias
. Adults with GAD, SOC, AG, PTSD, OCD all had an excess of
MDD at 11–15
. Those with SOC, AG, and especially PTSD had an excess of
disruptive behavior disorders at 11–15
K-SADS
N ¼ 963, New Zealand birth cohort assessed at ages 11–32.
DISC, DIS (Anxiety dxs
assessed at 11–15 were
Examined which disorders from ages 11 to 15 differed
between individuals with or without anxiety disorders at age 32
SAD, OAD, and phobias)
Ethnicity: 91% Caucasian, FU period ¼ 21 years
N ¼ 233, offspring of parents with PD and/or MDD,
ages 5–13; Ethnicity: 95% Caucasian, FU period ¼ 4.5 years
Sample characteristicsa
Information on ethnicity of sample included where available.
CBCL, child behavior checklist; semi-structured clinical interview, schedule for the assessment of conduct, hyperactivity, anxiety, mood, and psychoactive substances; KSADS, schedule for
affective disorders and schizophrenia, child version; DISC, diagnostic interview schedule for children; DIS, diagnostic interview schedule; SADS-LA, schedule for affective disorders and
schizophrenia, lifetime version; CIDI, composite international diagnostic interview; CAPA, child and adolescent psychiatric assessment; ADIS-IV, anxiety disorder interview schedule for
DSM-IV, C/P, child/parent version, L, lifetime; RCADS, revised child anxiety and depression scale; FU, follow-up; OR, odds ratio; PD, panic disorder; SAD, separation anxiety disorder;
SOC, social phobia; OAD, childhood overanxious disorder; GAD, generalized anxiety disorder; SPEC, specific phobia; OCD, obsessive compulsive disorder; AG, agoraphobia; PTSD,
post-traumatic stress disorder; ASD, acute stress disorder; ADHD, attention deficit-hyperactivity disorder; NPI, not psychiatrically ill.
a
Includes ethnicity where available.
b
Multiple follow-ups of the same sample.
Epidemiologic
High-Risk
Sample type
Gregory et al. [2007]
b
Biederman et al. [2007]
References
TABLE II. (Continued )
106
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ARTICLE
ARTICLE
This conclusion should be viewed in
light of the methodological limitations
of the studies reviewed. For example,
not all assessed the full spectrum of
childhood anxiety disorders, and some
of the longer prospective studies were
affected by changes to the classification
of childhood anxiety disorders between
DSM-III and DSM-IV. In addition,
some of the studies had gaps between
assessments during which psychopathology was not assessed, so that some
anxiety disorders may have been missed.
Also, with a few exceptions, the majority
of studies included mainly Caucasian
participants, limiting the generalizability
of findings. In addition, because participants in all but one of the studies
reviewed were still well within the age
range for the onset of anxiety disorders,
studies following these samples further
into adulthood are needed to elucidate
the full spectrum of risk signaled or
conferred by childhood anxiety. Moreover, since anxiety disorders can onset as
early as preschool-age [Egger and
Angold, 2006], studies are needed
which assess anxiety disorders in young
children and follow them through
adulthood.
TEMPERAMENTAL
ANTECEDENTS
Beyond considering syndromatic or
symptomatic antecedents, a growing
number of studies have focused on
temperamental characteristics that predate onset of anxiety disorders yet appear
to increase their likelihood. It is beneficial
to examine temperament very early in
life, to avoid its being confounded
by other factors (including onset of
psychopathology).
Behavioral Inhibition
The temperamental construct most
widely studied through prospective
standardized observational methods as
a potential antecedent to diagnosable
anxiety disorders is behavioral inhibition
to the unfamiliar (BI). BI refers to the
persistent tendency to exhibit restraint,
withdrawal, and reticence when faced
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
with novel or unfamiliar situations
and people [Kagan et al., 1988].
The temperamental construct
most widely studied through
prospective standardized
observational methods as a
potential antecedent to
diagnosable anxiety disorders is
behavioral inhibition to the
unfamiliar (BI). BI refers to the
persistent tendency to exhibit
restraint, withdrawal, and
reticence when faced with novel
or unfamiliar situations
and people.
It is found in 10–15% of children and is
moderately stable from toddlerhood
through the early elementary school
years, with higher stability among children more extreme in BI. Antecedents
to BI have been observed as early as age
3 months, including the tendency to
respond to novel stimuli with increased
distress and motor reactivity [Kagan
et al., 1999]. This ‘‘high reactive’’
behavior observed in infancy has been
shown in its own right to predict childhood anxiety symptoms.
BI is hypothesized to be rooted in
a lower threshold to limbic arousal,
specifically to higher reactivity of the
amygdalae and their projections to
the striatum, hypothalamus, sympathetic
chain, and cardiovascular system. Evidence for amygdalar reactivity derives
from two recent fMRI studies of adolescents or young adults who had
been classified as inhibited in toddlerhood [Schwartz et al., 2003; PerezEdgar et al., 2007], and multiple studies
have documented markers of sympathetic arousal in inhibited children,
including high and more stable heart
rate, elevated salivary cortisol, increased
startle response and increased right
frontal EEG activation in inhibited
youngsters (see Fox 2004; Hirshfeld-
107
Becker et al., 2004b for reviews). BI has
been shown to have moderate heritability (0.41–0.64) which is even higher
among children rated as extreme in
BI [Smoller and Tsuang, 1998]. It has
shown association with a genetic marker
at the corticotropin releasing hormone
(CRH) locus [Smoller et al., 2005].
Another study found a gene-environment interaction, in which children who
had both the short 5-HTTallele and low
social support had increased risk for BI
[Fox et al., 2005].
A growing number of studies have
suggested that BI is linked to risk for
social phobia in childhood and adolescence, and possibly to more broad risk
for anxiety or mood disorders later on.
Four high-risk studies have found laboratory observed preschool-age BI to be
elevated among offspring of parents with
panic disorder [Rosenbaum et al.,
1988, 2000; Manassis et al., 1995;
Battaglia et al., 1997], although one
study examining reactive temperament
and BI in infancy found no association
with maternal panic disorder [Warren
et al., 2003]. A ‘‘bottom-up’’ study
found elevated rates of anxiety disorders,
particularly social phobia, in parents of
children selected as BI based on laboratory observations compared with nonBI children [Rosenbaum et al., 1991].
Prospective longitudinal studies of children with laboratory-observed BI from
high-risk and community samples have
examined the outcome of childhood BI.
Although small pilot studies that
included only offspring of psychiatric,
but not of non-clinical, controls suggested that BI predicted anxiety disorders in general [Biederman et al.,
1990, 1993], larger, better controlled
studies have clarified that BI appears
prospectively associated with social anxiety in particular [Hayward et al., 1998;
Schwartz et al., 1999; Biederman et al.,
2001b]. For example, BI observed at
preschool-age among children at risk for
panic and depression predicted new
onset social phobia (but no other
disorders) by mean age 10 (22% vs. 8%,
P < 0.05), after covarying parental
dia gnosis [Hirshfeld-Becker et al.,
2007]. Similarly, among 13-year olds
who had been selected as inhibited or
108
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
uninhibited in toddlerhood, those with
BI had higher rates of generalized social
anxiety with impairment (34% vs. 9%,
P < 0.05), with the effect greatest for
girls (44% vs. 6%, P < 0.05) [Schwartz
et al., 1999]. No differences for specific
fears, separation anxiety, or performance
anxiety were found. Studies suggest
that BI is most predictive of anxiety
disorders when it is found among offspring of parents with anxiety disorders
[Rosenbaum et al., 1992; Biederman
et al., 2001b] and when it remains stable
across early childhood [Hirshfeld et al.,
1992].
Studies using retrospective or concurrent self-report measures of BI in
older children, adolescents, and adults
from community and clinical samples
have been mixed, with some finding
links to anxiety in general [e.g., van
Ameringen et al., 1998; Muris et al.,
2003] and others finding stronger or
more specific links to social anxiety
disorder [e.g., Mick and Telch, 1998;
Gladstone and Parker, 2006]. However,
whereas such studies may benefit from
the informant being able to report on
longer intervals of behavior than a brief
lab observation, they are also subject to
potential recall bias and social desirability; other limitations include differences in the informants’ knowledge of
normative development, the possibility
that concurrent BI may be confounded
by inhibition secondary to symptom
onset, and the absence (in most) of data
on parental psychopathology. If BI is
more common among offspring of
parents with anxiety, individuals endorsing BI in community or clinical samples
may have a greater probability of having
anxious parents, which may confound
associations between BI and anxiety in
general.
Questions remain as to the degree
to which BI is associated with depression
as well as social anxiety, since some
family [Kochanska, 1991; Rosenbaum
et al., 2000], prospective [Caspi et al.,
1996], cross-sectional [Muris et al.,
2003], and retrospective studies have
observed this association, but one found
that the link was accounted for by
comorbid social phobia [Gladstone and
Parker, 2006]. Other questions concern
the degree to which BI confers risk in
the absence of parental psychopathology
and the degree to which inhibition to
non-social (as opposed to social) stimuli,
usually assessed in only a brief segment of
the BI assessment, confers risk for
anxiety disorders. In addition, studies
of BI are limited by the lack of
observational assessments which are
standardized across laboratories, the
low to moderate correlations between
BI observed in the laboratory and
reported by parents, the absence of
information about the degree to which
BI observed in early childhood correlated with BI as reported retrospectively on questionnaires, and the paucity
of studies which have followed children
assessed as preschoolers through the
full period of risk for anxiety (i.e.,
through early adulthood). Despite these
questions and limitations, it seems clear
that BI measured in the preschool years is
a marker of risk for social anxiety
disorder in early and middle childhood
and early adolescence, especially in
children whose parents have anxiety
disorders. Although not all inhibited
preschoolers develop social anxiety by
early adolescence, a substantial proportion (34–44%) do. Longitudinal
follow-up of samples assessed via laboratory observation in early childhood
will clarify the full spectrum of risk
conferred by BI. Assessment and followup of epidemiologic or community
samples in which data about parental
diagnostic histories is also assessed would
help answer questions about the risk
conferred by BI in the absence of
parental psychopathology.
Other Temperamental and
Cognitive Risk Factors
At least three other temperamental
constructs and one cognitive risk factor,
AS, have received support from family
and/or prospective studies as potential
risk factors for anxiety disorders. Descriptions of the constructs and summaries of the pertinent evidence are
presented in Table III. The construct
with the most empirical support as a
precursor to panic disorder and possibly
other anxiety disorders is AS. Numerous
ARTICLE
cross-sectional studies have documented
an association between AS and panic
symptoms [McNally, 2002] which persists after controlling for other measures
of anxiety proneness such as trait anxiety.
The construct with the most
empirical support as a precursor
to panic disorder and possibly
other anxiety disorders is AS.
Numerous cross- sectional
studies have documented an
association between AS and
panic symptoms which persists
after controlling for other
measures of anxiety proneness
such as trait anxiety.
As detailed in Table III, multiple prospective studies have shown that AS
predicts onset of panic symptoms and
panic disorder in adults and adolescents.
Therefore it holds promise as a vulnerability marker; however, studies examining it among offspring at risk for
anxiety have shown mixed results. In
addition, in most studies, the variance in
panic or anxiety symptoms accounted
for by AS is typically small (ranging from
4% to 12%).
Few studies have examined the
overlap of these four similar constructs,
and the literature is limited by the
tendency in many studies to examine
internalizing symptoms as an outcome rather than anxiety disorders in
particular. In addition, the constructs
tend to show poor specificity for anxiety.
Neuroticism, in particular, is associated
with a wide range of disorders [Mineka
et al., 1998], and harm avoidance, shyness, and AS have also been associated
cross-sectionally with other disorders
(e.g., mood disorders). Efforts to refine
the prediction of anxiety from neuroticism/negative affectivity (NA) have had
some success. For example, (1) high NA
in the absence of low positive affectivity
differentiates anxiety from depression in
a wide number of cross-sectional studies
(Continued)
Shyness: Initial reticence, awkwardness, or anxiety with new people or in social settings. Generally measured by self-, parent-, or teacher-report
Prospective studies:
. In a community sample, shyness at multiple points in childhood was linked to high trait anxiety at age 10 [Fordham et al., 1999]
. In a representative sample, shyness throughout childhood was linked to higher anxiety/withdrawal at ages 13–14, with the most persistently shy children having 42% rate of anxiety
problems compared to 12% in those rarely or never rated shy [Prior et al., 2000]
Family studies:
. Shy preschoolers had mothers with significantly higher rates of social phobia than children with other behavior problems [Cooper et al., 1999]
Neuroticism/negative affectivity (N/NA): A sensitivity to negative stimuli, a predisposition to experience negative emotions or distress [Eysenck et al., 1967; Clark et al., 1994]. Measured with
questionnaires in adults and children, and in a few studies with observational measures in children
Prospective studies:
. Three studies found that high emotionality in infancy or childhood predicted anxious (or anxious/depressed) symptoms 1.5–6 years later, but in some it predicted externalizing scales
as well [Rende et al., 1993; Gjone et al., 1997; Rydell et al., 2003]. The latter of these found that fear (and fear regulation) at age 5 predicted internalizing symptoms at 1.5 years FU
whereas anger (and regulation of anger) predicted externalizing symptoms
. Among males in an unselected sample (the Dunedin Study), examiner-rated emotionality at age 3 predicted onset of panic and agoraphobia at ages 18–21, but not other anxiety
disorders [Craske et al., 2001]
. In a prospective study of 3,062 male conscripts in Zurich (followed from ages 19 to 36) questionnaire-rated neuroticism and autonomic lability were found to predict generalized
anxiety disorder or panic disorder [Angst et al., 1991]
. N/NA in children and adolescents predicted anxiety symptoms at 7-month follow-up, but only via the association with concurrent N/NA at FU [Lonigan et al., 2003]
Family and genetic studies:
. Emotionality (the tendency to get upset easily) was more common in the siblings and parents of children with anxiety plus comorbid depression [Masi et al., 2003]
. Multiple large twin studies have estimated the heritability of neuroticism in the 0.30–0.60 range [e.g., Mackinnon et al., 1990] with some of the association between neuroticism and
anxiety disorders accounted for by shared genetic variance [Hettema et al., 2006]
Harm avoidance (HA): The tendency to respond intensely to aversive stimuli and to avoid punishment, novelty, and non-reward (conceptualized as a combination of neuroticism and introversion)
[Cloninger, 1986]. Measured with self-report (or parent-report) questionnaires
Prospective studies:
. None known, however several studies suggest that HA changes with pharmacological or cognitive-behavioral treatment for anxiety disorders [e.g., Allgulander et al., 1998; Mortberg,
2007], and that HA pretreatment predicts higher anxiety post-treatment [e.g. Mortberg, 2007]
Family and genetic studies:
. HA was elevated among first degree relatives of adults with social phobia [Stein et al., 2001]
. A twin study of 2,680 adult Australian twin pairs, estimated that the heritability of HA (44%) was comparable to that of Eysenck’s neuroticism (35–45%), but that the two constructs
appeared to capture somewhat different dimensions of personality [Heath et al., 1994]
. Two independent studies have reported that HA shows linkage to a locus on chomosome 8p21 [Cloninger et al., 1998; Zohar et al., 2003]
Anxiety sensitivity (AS): The tendency to interpret sensations of physiological arousal as having harmful physical, psychological or social consequences [Reiss et al., 1985; McNally et al., 1994]. This
misinterpretation of benign sensations of arousal is hypothesized to contribute to a ‘‘fear of fear’’ cycle, in which anxiety about the sensations further increases arousal, and further fuels the anxiety. AS is
hypothesized to predispose to panic disorder, and other anxiety disorders. Measured via self-report questionnaires
TABLE III. Prospective and Family Study Evidence for Other Precursors to Anxiety Disorder
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
109
Prospective studies:
. Among 151 college students, baseline AS predicted the number, frequency, and intensity of panic attacks as well as the likelihood of developing an anxiety disorder at 3-year FU
[Maller et al., 1992]
. Among 1,401 young adults experiencing a stressful situation (i.e., military training), high AS predicted the onset of spontaneous panic attacks after controlling for history of panic
attacks and trait anxiety [Schmidt et al., 1997, 1999]
. In a community sample of 404 adults, baseline AS predicted panic attacks, anxiety, and other diagnoses over 2-year FU [Schmidt et al., 2006]
. Over a 1-year period, AS predicted (a) maintenance and relapse of panic disorder among affected adults and (b) the emergence of panic attacks among adults without panic disorder
[Ehlers et al., 2003]
. In a 4-year prospective study of more than 2,000 high school students, AS predicted the onset of panic attacks, after controlling for negative affectivity and history of major depression
[Hayward et al., 2000]
. In a community sample of 107 African-American adolescents, high AS predicted symptoms of panic at 6 months, though not once initial levels of panic were controlled [Ginsburg and
Drake, 2002]
. Multiple physiologic challenge studies in adults and children find that high AS predicts anxious response to physiologic challenges [e.g., Leen-Feldner et al., 2007]
Family and genetic studies:
. In two separate studies, offspring at risk for anxiety or mood disorders did not have higher levels of AS than offspring of healthy control parents ; van Beek et al., 2005]
. In a sample of adolescents, an association between AS and anxiety symptoms and disorders was evident only among those with a familial risk for anxiety disorders [Pollock et al., 2002]
. AS was found to mediate the relationship between parental psychopathology and child anxiety in one study [Drake et al., 2007]
. Heritability of AS estimated at 45% [Stein et al., 1999]
. Adults with the S/S 5-HTTLPR genotype with higher levels of reported childhood maltreatment had significantly higher levels of AS than subjects in other groups. No relationship
was found for neuroticism, suggesting that the effect was specific to AS [Stein et al., 2007]
TABLE III. (Continued )
110
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
ARTICLE
(see [Lonigan et al., 2004] and [PerezEdgar and Fox, 2005]); (2) high NA in
the presence of low effortful control
(EC)—the capacity for active voluntary
regulation of attention or behavior
[Posner and Rothbart, 1998]—shows
links to anxiety and attentional bias for
threat in some studies (see [Lonigan
et al., 2004]); and (3) subcomponents of
NA such as fear and anger have shown
differential association with anxiety and
disruptive behaviors in some studies, but
not others. However, more work
needs to be done to define under what
circumstances NA (even with normal
positive affectivity, high EC, or fearful as
opposed to angry affect) leads to anxiety
rather than to other outcomes.
Finally, the studies of all of these
constructs could benefit from the application of observational methods to
enable their measurement early in childhood before the onset of other symptomatic antecedents to anxiety. Now
that observational laboratory batteries
have been developed to assess NA and its
subcomponents (e.g., the LAB TAB)
and EC [Kochanska and Knaack, 2003]
in toddlerhood and early childhood, a
fruitful avenue of research might be
to examine these temperamental constructs early in life and to assess the
degree to which they prospectively
predict onset of anxiety. Similarly,
research on AS has been limited by its
reliance upon self-report questionnaires,
which caps the age at which it can be
reliably assessed in children. However,
novel paradigms have been developed
that use signal detection methodology to
examine children’s auditory perceptual
bias for heartbeat sounds [Eley et al.,
2004; Pollock et al., 2006]. Such protocols may offer a means to operationalize
hypervigilance to internal sensations
characteristic of high AS individuals
without reliance on language-ability
and insight, possibly making them
suitable for use with young children.
PHYSIOLOGIC MARKERS
OF RISK FOR
ANXIETY DISORDER
Although the literature on physiologic
markers is scant, studies have suggested
ARTICLE
that infants and young offspring at
risk for anxiety disorders show markers
of higher physiologic arousal, including
elevated heart rates under stress
[Battaglia et al., 1997], salivary cortisol
[Warren et al., 2003], increased startle
responsivity [Grillon et al., 1997], and
disturbed sleep [Merikangas et al., 1999;
Warren et al., 2003]. Other physiologic
factors point to risk for panic disorder.
For example, in healthy adults with no
history of panic attacks, family history of
panic disorder was associated with
increased likelihood of panic symptoms
after exposure to 35% CO2, and
ventilatory abnormalities during inhalation of 5% CO2 [Coryell, 1997; Coryell
et al., 2006b], suggesting that these may
be markers of risk for panic disorder. In
the same sample, adults who had displayed abnormal ventilatory response
were more likely to develop panic
attacks over 4-year follow-up [Coryell
et al., 2006a]. Similarly, in a large
study of unselected youths, a history of
respiratory problems at age 15 predicted
panic onset by 18–21 in females, as
did having a parent with a respiratory
disorder [Craske et al., 2001]. In males,
having had asthma by age 18 or having
had frequent colds and infections at age 3
was also associated with panic disorder.
Despite these promising studies, far
more work on physiologic precursors
to anxiety among children at risk and in
other samples is needed.
HYPOTHESIZED
ENVIRONMENTAL
RISK FACTORS
Twin studies in children and adults
estimate much larger contributions to
anxiety from unique or unshared environmental factors than from shared
environmental factors (e.g., [Hettema
et al., 2005; Spatola et al., 2007]). True to
these estimates, few sociodemographic
or family environment factors have
been found to predict anxiety disorders
in longitudinal studies, although a
few studies found low SES to be a
predictor (e.g., [Moffitt et al., 2007]).
Several different shared (e.g., parenting
behaviors) and unshared environmental
factors, including life events, peer rela-
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
tionships, and perinatal factors, have
been examined for their influence on
anxiety. We discuss them briefly below,
and direct the reader to more thorough
reviews (see for example our prior
reviews of environmental factors in
Fredman et al. [2003] and Ollendick
and Hirshfeld-Becker [2002]).
Parenting Behaviors
Experimental studies in animals have
suggested that parenting behaviors can
influence anxious behaviors in offspring.
For example, in rhesus monkeys and
rats, infants bred to be ‘‘high-reactive’’
showed decreased anxiety behaviors
after being fostered by highly nurturant
rhesus or rat mothers [Suomi, 1997;
Caldji et al., 1998]. Such findings
Experimental studies in
animals have suggested that
parenting behaviors can
influence anxious behaviors in
offspring. For example, in
rhesus monkeys and rats,
infants bred to be
‘‘high-reactive’’ showed
decreased anxiety behaviors
after being fostered by highly
nurturant rhesus or rat mothers.
raise the hypothesis that parenting
behaviors in humans might similarly
influence the development of anxiety.
At least 47 cross-sectional studies of
parenting and child anxiety, using
mainly self-report and observational
methodology, have examined two
general parenting dimensions—warmth
versus criticism/rejection, and overcontrol versus autonomy granting [see,
Rapee, 1997; Wood et al., 2003;
Ginsburg et al., 2004; McLeod et al.,
2007 for reviews]. In general, these
studies suggest that parents of anxious
children tend to be more overprotective
and less granting of autonomy [e.g.,
Siqueland et al., 1996; Gruner et al.,
111
1999; Whaley et al., 1999; Bogels et al.,
2001; Hudson and Rapee, 2001] or less
warm and accepting [Whaley et al.,
1999; Hudson and Rapee, 2001]
than parents of non-anxious children.
Lower warmth and responsiveness are
theorized to foster poorer emotional
regulation, whereas overprotection and
high parental control are hypothesized to
lead to lower self-efficacy [Chorpita
and Barlow, 1998]. Other studies have
suggested that parents of anxious children tend to model anxiety, particularly
in the case of specific phobias [Gruner
et al., 1999; Whaley et al., 1999;
Muris et al., 2000], and that they tend
to encourage or reinforce anxious
avoidance [Barrett et al., 1996; Chorpita
et al., 1996; Dadds et al., 1996].
Some of the anxiety-related behaviors
observed in parents of anxious children
have also been found to be more common
in anxious parents [Hirshfeld et al., 1997;
Whaley et al., 1999; Lieb et al., 2000;
Woodruff-Borden et al., 2002; Turner
et al., 2003]. In particular, anxious parents
of school-age children appear to display
lower warmth and greater disengagement
than non-anxious parents; but do not tend
to restrict autonomy [Woodruff-Borden
et al., 2002; Turner et al., 2003; Dibartolo
and Helt, 2007].
A recent meta-analysis subsuming
47 cross-sectional studies with 12,879
participants examined the degree to
which parental rejection and control
were associated with childhood anxiety
disorders or trait anxiety [McLeod et al.,
2007]. Most relied on self- or parentreport, with 16 using direct observation of parent–child interactions. The
authors found an overall effect size of
0.21, with parenting behaviors accounting for only 4% of the total variance in
measures of child anxiety symptoms or
disorders. The effect size was 0.35 for
diagnosed anxiety disorders. Parental
rejection and control accounted for
4% and 6% of the variance in child
anxiety, respectively. Parental autonomy
granting (examined in only seven of
the studies) accounted for the greatest
proportion of variance in childhood
anxiety (ES ¼ 0.42, 18%), whereas
parental warmth accounted for the least
(ES ¼ 0.06, <1%).
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Because this literature is crosssectional, it remains unknown whether
parental control gives rise to anxiety in
children, arises in response to the child’s
anxiety, or interacts reciprocally with
child anxiety. Only a few empirical
studies have explored these effects. One
found that mothers reported greater
overprotection of their anxious than
non-anxious children, suggesting that
parenting behavior is shaped by child
anxiety [Hudson and Rapee, 2005].
However, these investigators found no
differences in mothers’ observed overprotection toward anxious versus nonanxious children during interactive
tasks; mothers of anxious children were
more intrusive and involved toward all
their children [Hudson and Rapee,
2001, 2002]. On the other hand, Moore
et al. [2004] found that mothers of
anxious children demonstrated lower
autonomy granting and lower warmth
during a conversation task, regardless
of maternal anxiety status, consistent
with the hypothesis that children
with anxiety may shape their mothers’
behavior.
Clearly, prospective studies are
needed to help eludicate the directionality of effect between child anxiety
and parental behaviors. One prospective
study, of mainly African American low
income families, found that greater
criticism and lower autonomy-granting
by parents when children were 6 years
old were significantly associated with
more symptoms of anxiety at 6-year
follow-up, but only in children of
anxious mothers [Ginsburg et al.,
2004]. This suggests that family-genetic
high-risk status and parental behaviors
interact to contribute to child anxiety.
Other prospective studies have shown
support for observed maternal control
and criticism (derisiveness) predicting
greater stability in inhibition from ages 2
to 4 [Rubin et al., 2002] and for observed
anxious-resistant attachment style at
12 months predicting a twofold increase
in anxiety disorders at age 17.5 [Warren
et al., 1997]. A third prospective study
supported a learning hypothesis: it found
that increased time in day-care in infancy
predicted reduced BI in toddlerhood
[Fox, 2004], suggesting that greater
naturalistic exposure to new people and
settings may reduce inhibition.
Beyond its highly cross-sectional
nature and the clear need for further
prospective studies, there are several
other limitations to the literature on
the relationship between parenting
behaviors and the development and
maintenance of child anxiety disorders.
First, other than the Ginsburg et al.
[2004] study, most studies of parenting
behavior and child anxiety have
included predominantly Caucasian
families, limiting the generalizability of
the findings. Second, studies have
relied mainly on self-report and observational measures. Self-report measures
are subject to biases in participants’
perceptions of parenting behaviors,
whereas for observational measures,
different types of autonomy-granting
situations observed and observational
coding schemes are used across research
labs. Studies suggest that variations in
the observational situations used (e.g.,
structured versus unstructured tasks)
can influence the parenting behaviors
observed [Ginsburg et al., 2006]. Third,
not all studies took into account parental
psychopathology; this variable is important to consider and control for, since it is
common among parents of clinically
anxious children and since behaviors
such as low warmth or high criticism
(found more commonly among anxious
parents) may serve as proxies for parental
anxiety.
Despite these limitations, experimental
modifications of parental behaviors (i.e.,
interventions teaching parents to model and
reinforce non-anxious coping instead of
avoidance) have shown efficacy in reducing
children’s anxiety symptoms [Rapee et al.,
2005], particularly when parents themselves
are anxious [Cobham et al., 1998]. Therefore, parents can learn to respond to a child’s
anxious behaviors in ways that can make a
positive difference in the child’s outcome.
[For a more detailed treatment of these
issues, see Hirshfeld-Becker and Biederman,
2002; Rapee, 2002].
Life Events
Retrospective studies of adults and
children have implicated past (e.g.,
ARTICLE
parental separations) and recent life
events (e.g., stressors, threats) in the
development of anxiety disorders.
Recent prospective studies have confirmed these results, finding links
between health problems, divorce,
abuse, and loss at ages 6–7 and increased
odds of anxiety disorder 1.5 years later
[Kroes et al., 2002]; between parental
separation, conduct disorder in a father
or stepfather, and poverty before age 5
and anxiety disorders at age 15 (controlling for maternal depression and anxiety)
[Phillips et al., 2005]; and between poor
academic performance in first grade and
anxiety in 7th grade [Grover et al.,
2005]. Another study found no relationship between parental divorce and
anxiety disorders 10 years later [Nomura
et al., 2002].
Peer Factors
Cross-sectional studies have found associations between peer rejection and
social anxiety. A recent prospective
study followed 144 ninth-graders over
a year and found that being left out or
rejected by peers accounted for significant variance in later social phobia
symptoms, whereas being teased or
bullied did not [Storch et al., 2005].
Cross-sectional studies have
found associations between peer
rejection and social anxiety. A
recent prospective study
followed 144 ninth-graders over
a year and found that being left
out or rejected by peers
accounted for significant
variance in later social phobia
symptoms, whereas being
teased or bullied did not.
The association between social anxiety
and peer relationships is likely reciprocal
[Morris, 2001]. [For further discussion
of the impact of peer factors on social
anxiety and psychosocial adjustment, see
Storch and Ledley, 2005].
ARTICLE
Perinatal Factors
Animal studies have suggested that
experimentally-induced stress during
pregnancy may influence the offspring’s
stress responses and fearful behavior
[e.g., Clarke and Schneider, 1993].
Indeed, in a prospective study of a large
community cohort (N ¼ 6,996), rates of
mother-rated emotional problems in
boys at age 6.75 years was predicted by
the mothers’ rating of their own anxiety
at 32 weeks gestation (odds ratio 1.64
[1.06–2.52]), even when maternal anxiety at two post-natal assessments was
covaried [O’Connor et al., 2003].
Although the study did not assess
maternal anxiety disorders (which could
have a genetic association with childhood emotional problems), the control
for post-natal anxiety can be considered
to partially control for maternal anxiety
disorder. Retrospective studies of
children found associations between
pregnancy or birth complications and
childhood anxiety disorders [Velez et al.,
1989; Rapee and Szollos, 2002] even
after controlling for parental anxiety
disorders [Hirshfeld-Becker et al.,
2004a]. However, a retrospective study
of adults found no associations for most
anxiety disorders, and a lower rate
of pregnancy complications for social
phobia [Foley et al., 2001].
CONCLUSION
A review of the literature on developmental antecedents to anxiety disorders
points to several clear risk factors and
many more that remain to be explored.
The evidence that offspring of parents
with anxiety disorder are at elevated risk
for a spectrum of anxiety disorders (with
a risk ratio compared with the offspring
of unaffected parents on the order of 2.5)
is clear, as is the finding that anxiety
disorders in childhood and adolescence
(particularly separation anxiety disorder,
overanxious disorder/GAD, and possibly social or specific phobias) predict
those in early adulthood (with odds
ratios in the 2.0–3.0 range; see
Table II). In addition, the evidence
suggesting that preschool-age behavioral
inhibition (BI) predicts social anxiety
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
disorder in childhood and early adolescence is strong (with odds ratios
corrected for parental psychopathology
on the order of 3.0 [Hirshfeld-Becker
et al., 2007]; and risk ratios not corrected
for parental psychopathology in the
order of 3.77 for adolescents in general
and 7.33 for girls only [Schwartz et al.,
1999]), as is the evidence that AS
increases vulnerability for the onset of
panic disorder and likely other anxiety
diagnoses (accounting for about 4–12%
of the variance in panic or anxiety
symptoms). Although not specific to
anxiety, NA also appears to predict later
anxiety symptoms. Promising evidence
is accruing in support of hypotheses
about parenting factors in anxiety disorders (with effect sizes in the 0.2–0.4
range), peer factors in social phobia, and
stressful life events, including perinatal
stressors (with odds ratios in the 1.0–
2.0 range), for anxiety disorders in
general.
As can be seen from the risk and
odds ratios and effect sizes reported in
the literature, parental psychopathology,
early anxiety disorders, and behavioral
inhibition appear to have moderate
associations with subsequent anxiety
disorders, whereas parenting factors
show small to moderate associations,
and perinatal factors may show relatively
small associations. However, because
most studies of one factor do not control
for others, these associations cannot be
assumed to be additive. More studies
are needed that examine multiple risk
factors in the same individuals and
examine their combined contributions
over time to the prospective risk for
anxiety disorders.
We can identify several additional
fruitful areas for future study: (1) Prospective longitudinal studies: First, although
several important long-term longitudinal
studies have been conducted, many more
are needed. Ideally, such studies would
begin in early childhood or during
gestation. Staggered longitudinal designs
(simultaneously following several different cohorts beginning perinatally, in
toddlerhood, in early and middle childhood, and in adolescence) could speed up
the time needed to understand the course
of hypothesized risk factors. In particular,
113
prospective studies examining the role of
harm avoidance, EC, parenting factors,
peer factors, and life events are needed.
In addition, given the potential overlap
in constructs, it would be useful to
measure multiple constructs in the
same samples and study their overlap
systematically. Twin studies could be
useful in determining the degree to
which different constructs share common
genetic and environmental variance.
Prospective studies of offspring at risk, in
whom the expected base rate of onset
of anxiety is higher, can complement
studies of representative community samples
to examine these issues.
(2) Greater use of observational measures: Although informative, questionnaires are subject to biases which can be
mitigated by complementary assessment
with observational measures. As discussed above, because anxiety disorders
can onset very early, the study of
temperamental precursors could benefit
from the development of creative ways
to observe temperamental characteristics
through standardized laboratory tasks
early in life. In addition, more ecologically valid observational methods are
needed for assessing parent and peer
interactions. For BI, better standardization of laboratory measures across
studies, and prospective comparisons
of retrospective questionnaires with
early laboratory measures would be
beneficial.
(3) Greater attention to parental psychopathology: Because of the clear risk
conferred by parental anxiety and possibly mood disorders, and because associations with parental psychopathology
could potentially confound other associations with anxiety (e.g., parenting
behaviors, perinatal anxiety, stressful
events, temperament) it is important
for investigators to assess and covary
lifetime history of anxiety disorders in
parents in order to understand whether
other factors mediate, moderate, or are
independent of the effects of parental
anxiety disorder.
(4) Examination of other potential
precursors: Our review did not exhaust
all of the features found to be crosssectionally associated with anxiety disorders. In particular, neurophysiologic
114
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
(e.g., right frontal EEG asymmetry) and
neurofunctional differences (e.g., amygdalar activation) associated with anxiety
could be fruitfully explored as potential
vulnerability factors for anxiety among
at-risk populations. Similarly, cognitive
(e.g., bias for threat, catastrophic interpretations, underappraisal of coping
resources) and emotional features of
anxiety (e.g., discomfort intolerance
[Schmidt et al., 2007]) should be
explored to determine whether they
predate onset of anxiety disorders.
Other factors may also be explored; for
example, a recent study found that
language impairment assessed at age 5
predicted social phobia at age 19 [Voci
et al., 2006]. More studies examining
interactions between known genotypes
and particular vulnerability factors in
predicting anxiety outcomes would be
particularly exciting.
(5) Greater inclusion of diverse populations among the individuals studied: As
reflected in our review, the majority of
prospective studies of developmental
antecedents to anxiety disorders have
included mainly Caucasian participants.
Greater efforts to focus on more diverse
populations are necessary in order to
improve our understanding of the role of
these risk factors among other groups.
(6) Intervention studies: Finally, since
a major impetus for the study of
developmental antecedents is the
informing of preventive interventions,
another important approach is to conduct intervention studies which modify
hypothesized risk factors and examine
whether onset of anxiety disorders can
be averted. Studies intervening to reduce
BI [Rapee et al., 2005] and AS (e.g.,
[McNally, 2002]) have been initiated,
and others are underway. The next
20 years promise to be as exciting as the
previous in the evolution of our understanding of the etiology of the anxiety
disorders.
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