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Relationship Between Separation Anxiety Disorder, Parental Panic Disorder, and Atopic Disorders in Children: A Controlled High-Risk Study
Relationship Between Separation Anxiety Disorder, Parental Panic Disorder, and Atopic Disorders in Children: A Controlled High-Risk Study MARCIA J. SLATTERY, M.D., M.H.S., DONALD F. KLEIN, M.D., SALVATORE MANNUZZA, PH.D., JOHN L. MOULTON III, PH.D., DANIEL S. PINE, M.D., AND RACHEL G. KLEIN, PH.D.
ABSTRACT Objective: To test the hypotheses that rates of atopic disorders are elevated in offspring of parents with panic disorder (PD) and in children with separation anxiety disorder (SAD). Method: Rates of atopic disorders were assessed in 343 offspring (aged 6–17 years) of parents with PD, nonpanic psychiatric disorders, and no psychiatric disorder. Lifetime history of atopic disorders was determined by parental responses to a clinician-administered questionnaire assessing medical treatment for asthma and allergies. Logistic regression analyses assessed the association between atopic disorders and parental PD, and between atopic disorders and probable or definite childhood SAD. Analyses controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. Results: Increased rates of atopic disorders were found in offspring of parents with PD (odds ratio [OR] = 2.56, 95% confidence interval [CI] = 1.27–5.16, p = .009) and in children with SAD (OR = 2.71, 95% CI = 1.22–6.03, p = .015). Associations remained significant when both parental PD and SAD were included in the model, suggesting that each contributed independently to increased rates of atopy. The interaction of parental PD and child SAD was not significant. Conclusions: Atopic disorders in children are associated with parental PD and with childhood SAD. Results do not appear to support that having both childhood SAD and a parent with PD confers increased risk for atopic disorders above and beyond either condition alone. J. Am. Acad. Child Adolesc. Psychiatry, 2002, 41(8):947–954. Key Words: separation anxiety disorder, panic disorder, atopy, asthma, allergy.
A relationship between separation anxiety disorder (SAD) in children and panic disorder (PD) in adults has been suggested. Klein (1964) first proposed the “separation anxiety hypothesis” of panic disorder on the basis of clinical retrospective reports of increased rates of childhood separation anxiety symptoms in adults with agoraphobia and panic attacks, as compared with other psychiatric patients. Although not all studies have been consistent (Biederman et al., 2001; Lipsitz et al., 1994), several studies provide converging Accepted March 8, 2002. Dr. Slattery is with the Mayo Clinic, Rochester, MN, and the New York University Child Study Center, New York; Dr. D.F. Klein is with the New York State Psychiatric Institute, New York; Drs. Mannuzza, Moulton, Pine, and R.G. Klein are with the New York University Child Study Center. This research was supported by U.S. Public Health Service grants MH-37592 and MH-30906. The authors thank Mary Guardino, Director, Freedom From Fear, Staten Island, NY, for access to patients, and Maren K. Olsen, Ph.D., Bioinformation and Biostatistics Department, Duke University, for review of analyses. Reprint requests to Dr. Slattery, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. 0890-8567/02/4108–0947䉷2002 by the American Academy of Child and Adolescent Psychiatry.
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evidence of a relationship between SAD and PD. Retrospective studies describe increased rates of SAD in adults with PD (Ayuso et al., 1989; Balon et al., 1989; Zitrin and Ross, 1988). A prospective longitudinal study of children with SAD reports an elevated rate of PD among these children in adulthood (Klein, 1995). In addition, family studies report increased rates of SAD in offspring of parents with PD and agoraphobia (Berg, 1976; Capps et al., 1996; Weissman et al., 1984). A relationship between SAD and PD is also suggested by psychophysiological studies. In a study of carbon dioxide sensitivity, Pine and colleagues (2000) found patterns of respiratory abnormalities specifically in children with SAD, but not social anxiety disorder, that were similar to those found in adults with PD (Papp et al., 1997). Allergic disorders provide an additional framework in which to examine the association between SAD and PD. Specifically, a relationship has been suggested between PD in adults, anxiety disorders in children, and a familial cluster of IgE-mediated allergies often referred to as 947
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atopy (Schmidt-Traub and Bamler, 1997). The term more accurately describes an inherited predisposition to the development of these disorders, rather than the disorders themselves (Panhuysen et al., 1995). Atopic disorders include asthma, urticaria (hives), allergic rhinitis (hay fever), and atopic dermatitis (eczema) (Blumenthal, 1997). Several studies provide evidence of a relationship between asthma, allergies, and PD in adults. Clinical studies of adults with asthma report increased rates of PD as compared with the prevalence of PD in community studies (Perna et al.,1997; Shavitt et al., 1992; Yellowlees et al., 1988). Conversely, clinical studies of adults with PD describe increased rates of respiratory disease, including asthma, as compared with obsessive-compulsive disorder, eating disorders, and V-code diagnoses (Perna et al., 1994; Spinhoven et al., 1994; Zandbergen et al., 1991). Schmidt-Traub and Bamler (1997) examined the rate of PD in subjects with IgE-mediated allergies (n = 100) and the rate of allergies in subjects with PD (n = 79); each group was compared with a healthy control group (n = 66). The rate of PD (10%) and panic attacks (35%) in subjects with allergies was elevated compared with rates of PD (2%) and panic attacks (17%) in controls. Subjects with PD had an increased rate of allergies (70%) compared with controls (29%). There is a paucity of clinical and epidemiological studies examining the relationship between allergic disorders and specific childhood anxiety disorders. Several studies have suggested a relationship between asthma and anxiety symptoms in children but did not assess specific anxiety diagnoses (Butz and Alexander, 1993; Graham et al., 1967; McNichol et al., 1973; Norrish et al., 1977; Silverglade et al., 1994). Of the studies that used structured diagnostic interviews to examine specific anxiety disorders in asthmatic children, results differ as to whether SAD or general anxiety disorder (GAD) occurs most often. Vila and colleagues (2000) reported rates of anxiety disorders in 82 children with asthma (mean age = 11); 35% had any anxiety disorder, 29% had GAD, 16% had SAD, 10% had social anxiety disorder, and 1% had PD. In a similar study of 62 asthmatic children (mean age = 15), Wamboldt and colleagues (1996) described rates of anxiety disorders including any anxiety disorder (28%), overanxious disorder (24%), SAD (15%), agoraphobia (3%), simple phobia (6%), and PD (0%). Bussing and colleagues (1996) compared rates of anxiety in 37 asthmatic children (mean age = 11) compared with 31 healthy controls. All anxiety disorders were elevated in children with 948
asthma as compared with controls, including any anxiety disorder (43% versus 19%), SAD (32% versus 13%), overanxious disorder (8% versus 0%), PD (5% versus 0%), and phobia (16% versus 6%). The prevalence of specific anxiety disorders in children with atopic disorders other than asthma is unknown. Similarly, there are no published studies investigating the rate of atopic disorders in clinical samples of children with anxiety disorders. Indirect support for a relationship between atopy and anxiety disorders among children may be suggested by other data. Kagan (1994) reported increased rates of allergies in children with behavioral inhibition. This may suggest a relationship between atopy and anxiety disorders in children, since behavioral inhibition is a temperamental trait associated with increased rates of anxiety in children (Hirshfeld et al., 1992). Existing studies do not provide insight into potential mechanisms for the association between anxiety and atopic disorders. Wamboldt and colleagues (1998) suggested that atopic disorders may represent markers for a familial subtype of anxiety characterized by genetic factors shared with atopy. If this is correct, an anxiety disorder in the parent would predict the presence of asthma or allergies in the child, even in the absence of anxiety in the child. Preliminary evidence for this model is suggested in one study by Merikangas and colleagues (1999), who reported increased rates of allergies and eczema in children of parents with anxiety disorders compared with children of parents with substance abuse or no psychiatric disorder. The present study further examines these associations by investigating the relationship between atopy, parental PD, and SAD in children. We hypothesize that (1) offspring of parents with PD will have increased rates of atopic disorders as compared with offspring of parents without panic disorder, and (2) that children with SAD will have increased rates of atopic disorders as compared with children without SAD. METHOD Subjects Data were drawn from a larger study examining the risk for psychopathology conferred to children by parents with anxiety and mood disorders compared with non-ill parents. Nonpsychotic psychiatrically ill parents with anxiety and mood disorders with children aged 6 to 17 years were identified by random chart review from three outpatient treatment centers in the New York City area. Non-ill comparison parents were identified by chart review and the acquaintanceship procedure. Charts of a major New York medical center dental clinic were reviewed to identify children aged 6 to 17 years. Identified par-
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ents were screened by a social worker who administered a brief psychiatric questionnaire; those with negative screens were scheduled for a psychiatric interview (described below). In the acquaintanceship procedure, parents with anxiety and mood disorders (from the psychiatrically ill group) were asked to identify six acquaintances who were the same age, gender, and ethnicity and who had children aged 6 to 17. One acquaintance was randomly chosen and contacted. As with the chart review procedure, parents were screened and subsequently interviewed. Approximately half of the control group was recruited through each of the recruitment methods. There were three parental diagnostic groups. In the PD group (n = 95 families, 150 children), one or both parents had lifetime PD and neither parent had lifetime mood or psychotic disorder. In the nonpanic anxiety and/or mood disorder group (n = 69 families, 113 children), one or both parents had lifetime nonpanic anxiety disorder including social phobia (n = 12, 17%), obsessive-compulsive disorder (n = 4, 6%), and/or a mood disorder including major depressive disorder (n = 62, 90%), dysthymia (n = 12, 17%) or bipolar I disorder (n = 8, 12%), and neither parent had lifetime psychotic disorder. In the control group (n = 44 families, 80 children), neither parent had lifetime anxiety, mood, or psychotic disorder. Subjects were 343 offspring, aged 6 to 17 years (mean = 11.6, SD = 3.5). Offspring were grouped on the basis of parental and child psychiatric diagnoses. Written informed consent (and child assent) was obtained from all subjects, regardless of group or method of recruitment. Measures Overview. Interviewers were advanced-level clinical psychology doctoral students, a clinical psychologist, and a psychiatric social worker trained in differential diagnostic assessment. Interview training included required readings, discussion of differential diagnoses of symptoms and disorders, extensive review of diagnostic instruments and existing narrative summaries, and completion of 40 DSM-IV case vignettes. Ongoing supervision (to minimize “rater drift”) included regularly scheduled meetings to receive feedback on narrative summaries and to review diagnostically ambiguous cases. Interviewers were blind to group membership and study hypotheses. Parents and children were assessed by different interviewers, who wrote detailed narratives that were blindly reviewed by senior investigators. Narrative reviews served as a validity check to ensure that diagnostic criteria were carefully followed. Parent Diagnoses. Parents were administered the Structured Clinical Interview for DSM-IV (First et al., 1995; Spitzer et al., 1992), which assesses lifetime presence of all major psychiatric illnesses. When the second parent was not available for interview (49% of cases), the Family Informant Schedule and Criteria-Updated for DSM-IV (Schleyer and Mannuzza, 1995) was administered to the available parent. Child Diagnoses. An informant interview with the child’s mother was conducted; children aged 9 years and older were also interviewed directly. Children and mothers were administered the Parent as Respondent Informant Schedule (PARIS; Klein and Mannuzza, 1992; Kentgen et al., 1997). The PARIS assesses lifetime presence of all major child and adolescent DSM-IV disorders. Child lifetime diagnoses were considered present if DSM-IV criteria were met in the direct interview with the child and/or in the parent interview about the child. A definite disorder was diagnosed when DSM-IV criteria were met; a probable diagnosis was assigned when functional impairment was present despite fewer symptoms (Gittelman et al., 1985). A disorder was considered present on the basis of either a probable or definite diagnosis. This decision was considered consistent with clinical practice, since both levels of certainty required significant functional disruption.
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Atopy. Atopy was assessed with a medical questionnaire administered to the parents by clinicians. Questionnaire items included treatment for asthma, allergy, diabetes, seizures, or any other illness. The presence of an atopic disorder was defined as an affirmative response to at least one of two (yes/no) questions regarding whether the child had ever received medical treatment for asthma or allergies. Data Analysis Atopy was the dependent variable. Because children included siblings, variables could not be considered independent. Therefore, associations between atopy and parental PD and between atopy and SAD were assessed with generalized estimating equations (GEE) using the SAS statistical program (SAS, Version 8.1, SAS Institute Inc., Cary, NC). GEE, an extension of the general linear model, permits the analysis of clustered binary data that may be correlated. In this case, clusters were the 208 families in the study; the binary outcome was atopy (yes/no). Age and sex were included as covariates on the basis of increased rates of asthma in prepubertal children, particularly boys (Schachter et al., 1984; Sly, 1996). Because treatment seeking may be associated with parental and child psychological distress (Garralda and Bailey, 1986; Horwitz et al., 1985), as well as parental characteristics of higher education and income (Horwitz et al., 1985), we controlled for SES and for medical treatment reported by parents for all other illnesses. We calculated odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of the associations and examined robust standard errors to reduce the likelihood of type I errors. Alpha was set at p < .05 for a priori hypotheses and p < .01 for secondary analyses. All contrasts were two-tailed. The output of analyses using GEE and logistic regression (SPSS, Version 10.1.0; SPSS Inc., Chicago, IL) were compared. Because the significance of the contrasts were identical between the analyses (i.e., a significant cluster effect was not present), we report results from the logistic regression. RESULTS Demographic Characteristics
The 343 children ranged in age from 6 years 0 months to 17 years 11 months (mean = 11.6 years, SD = 3.5 years) (Table 1). There were slightly more girls (54%) than boys. The majority of children were white (76%), with the minority comprising African American (11%), Hispanic (8%), and other (5%) ethnic groups. Household socioeconomic status ranged from 1 to 5 (mean = 2.9, SD = 1.0), with 1 representing upper class and 5 representing lower class (Hollingshead and Redlich, 1958). There were 40 children with treated atopy (12%); 26 (9%) had asthma, 10 (4%) had allergies, and 4 (1%) had both asthma and allergies. Paired comparisons of offspring of parents with/without PD, children with/without SAD, and children with/without atopy (Table 1) indicated a significant contrast (p < .05) for age only in offspring of parents with PD versus no PD; all other contrasts were nonsignificant. The majority of parents were married (67%), with the minority comprising separated (9%), divorced (15%), widowed (1%), and single (8%) parents. Mothers’ mean age was 41.2 years; the mean age of fathers was 44.0 years. 949
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TABLE 1 Child Demographic Variables (N = 343 Children) Children With Separation Anxiety Disorder a All Children (N = 343) Gender, n (%) Female Male Ethnicity, n (%) White AfAm Hispanic Other Age, mean (SD) [Range] SES, mean (SD)
Yes (n = 49)
No (n = 294)
186 (54) 157 (46)
19 (39) 30 (61)
138 (47) 156 (53)
262 (76) 38 (11) 28 (8) 15 (4) 11.6 (3.5) [6.0–17.9] 2.9 (1.0)
33 (67) 229 (78) 9 (18) 29 (10) 4 (8) 24 (8) 3 (6) 12 (4) 11.4 (3.3) 11.5 (3.5) [6.0–17.6] [6.0–17.9] 3.1 (1.1) 2.9 (1.0)
Offspring of Parents With Panic Disorder * Yes (n = 150) 72 (48) 78 (52)
No (n = 193) 85 (44) 108 (56)
119 (79) 143 (74) 10 (7) 28 (15) 17 (11) 11 (6) 4 (3) 11 (6) 10.9 (3.3) 11.9 (3.5) [6.0–17.6] [6.0–17.9] 2.9 (1.0) 2.9 (1.1)
Children With Atopy a Yes (n = 40) 23 (58) 17 (43)
No (n = 303) 134 (44) 169 (56)
28 (70) 234 (77) 5 (13) 33 (11) 4 (10) 24 (8) 3 (8) 12 (4) 12.0 (3.8) 11.4 (3.4) [6.2–17.9] [6.0–17.9] 2.9 (1.0) 2.9 (1.1)
Note: AfAm = African American; SES = socioeconomic status. a No significant group differences. * Significant difference only for age, PD (yes) < PD (no), t341 = 2.61; p < .05.
Prevalence of Atopy in Offspring of Parents With and Without PD
There was a significantly higher rate of treated atopy among the offspring of parents with PD as compared with offspring of parents without PD (OR = 2.56, 95% CI = 1.27–5.16, p = .009) (Table 2). Secondary analyses examined the diagnostic specificity of this association. Children were grouped on the presence or absence of parent diagnoses for the purpose of conducting two contrasts. There were too few offspring of parents with nonpanic anxiety disorders (n = 27) to permit comparison with offspring of parents with PD. Offspring of parents with PD were compared with offspring of parents with other disorders (i.e., any nonpanic anxiety or mood disorder) and offspring of control parents (i.e., parents without any mood, anxiety or psychotic disorders). Offspring of parents with PD had significantly higher rates of atopic disorders compared with offspring of parents with other psychiatric disorders (OR = 3.35, 95% CI = 1.37–8.15, p = .008). Although the odds of atopy among the offspring of parents with PD was nearly twice the odds among the offspring of control parents, the difference did not reach significance (OR = 1.92, 95% CI = 0.78–4.72, p = .15) (Table 2). Finally, rates of atopic disorders in children with one or both parents with PD were compared. Two of six (33%) children with PD in both parents had atopic disorders, compared with 23 of 144 (16%) children with PD in one parent. 950
Prevalence of Atopy in Children With and Without SAD
Children with probable or definite SAD had a significantly higher rate of atopic disorders than children without SAD (OR = 2.71, 95% CI = 1.22–6.03, p = .015) (Table 3). Secondary analyses examined whether this relationship had diagnostic specificity. Children with SAD were compared with children with non-SAD anxiety disorders and children with no history of psychiatric illness. Non-SAD anxiety disorders included GAD (n = 9, 8%), PD (n = 2, 2%), social phobia (n = 47, 40%), specific phobia (n = 77, 65%), obsessive-compulsive disorder (n = 3, 3%), posttraumatic stress disorder (n = 1, 1%), and anxiety disorder not otherwise specified (n = 5, 4%). Restricting analyses to definite (i.e., full criteria) diagnoses of SAD and non-SAD anxiety disorders did not alter any of the relationships reported. The rate of atopic disorders in children with SAD was significantly higher than that observed among children who had never been psychiatrically ill (OR = 5.85, 95% CI = 1.79–19.09, p = .003) (Table 3). Although the odds of atopic disorders among children with SAD were twice as high as those observed among children with non-SAD anxiety disorders, the difference did not reach significance (OR = 2.14, 95% CI = 0.86–5.37, p = .10). Further analyses examined the relationship between parental PD and childhood SAD as related to childhood atopy. The association between atopic disorders and parental PD, and between atopic disorders and child SAD, J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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TABLE 2 Relationship Between Parental Panic Disorder and Atopic Disorders in Offspring Contrasts of Ill-Parent Diagnostic Groups χ2 Adjusted OR (95% CI)
Parental Diagnoses A Parental Panic Disorder: Yes (n = 150 Offspring)
B Parental Panic Disorder: No (n = 193 Offspring)
A vs. B
15 (7.8) 178 (92.2)
χ 1 = 6.84; p = .01 OR = 2.56 (1.27–5.16) p = .009
a
2
Atopy, n (%) Yes No
25 (16.7) 125 (83.3)
A Panic Disorder (n = 150)
B Nonpanic Anxiety Disorder and/or Mood Disorderb (n = 113)
C Not Ill Controls (n = 80)
A vs. B
Yes No
25 (16.7) 125 (83.3)
8 (7.1) 105 (92.9)
A vs. C
B vs. C
χ21 = 5.40; p = .02 χ21 = 2.73; p = .10 χ21 = 0.18; p = .67 OR = 3.35 OR = 1.92 OR = 0.56 (1.37–8.15) (0.78–4.72) (0.17–1.80) p = .008 p = .15 p = .33
Atopy,a n (%) 7 (8.7) 73 (91.3)
Note: Logistic regression controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. OR = odds ratio; CI = confidence interval. a Atopy = lifetime history of allergy or asthma in the child. b DSM-IV nonpanic anxiety and/or mood disorders in parents include social phobia, obsessive-compulsive disorder, major depressive disorder, dysthymia, and bipolar I disorder. TABLE 3 Relationship Between Separation Anxiety Disorder (SAD) and Atopic Disorders in Offspring Contrasts of Ill-Child Diagnostic Groups χ2 Adjusted OR (95% CI)
Child Psychiatric Disorder A SAD: Yes (n = 49 Children)
B SAD: No (n = 294 Children)
A vs. B
29 (9.9) 265 (90.1)
χ21 = 6.46; p = .01 OR = 2.71 (1.22–6.03) p = .015
Atopy,a n (%) Yes No
11 (22.4) 38 (77.6)
A SAD (n = 49)
B Non-SAD Anxiety Disorderb (n = 118)
C Never Ill (n = 105)
a
Atopy, n (%) Yes No
A vs. B
11 (22.4) 38 (77.6)
14 (11.9) 104 (88.1)
5 (4.8) 100 (95.2)
A vs. C
B vs. C
χ 1 = 3.05; p = .08 χ 1 = 11.23; p = .001 χ 1 = 3.60; p = .06 OR = 2.14 OR = 5.85 OR = 2.23 (0.86–5.37) (1.79–19.09) (0.74–6.75) p = .10 p = .003 p = .155 2
2
2
Note: Logistic regression controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. OR = odds ratio; CI = confidence interval. a Atopy = lifetime history of allergy or asthma in the child. b DSM-IV non-SAD anxiety disorders include social phobia, obsessive-compulsive disorder, generalized anxiety disorder, specific phobia, posttraumatic stress disorder, and anxiety disorder-not otherwise specified. “B” comparison group did not include 71 children with psychiatric disorders other than anxiety disorders. J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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remained significant when both variables were included in the logistic regression model (OR = 2.32, 95% CI = 1.14–4.72, p = .02; OR = 2.31, 95% CI = 1.02–5.24, p < .05, respectively). However, the interaction of parental PD and child SAD was not significant (OR 0.37, 95% CI = 0.07–1.93, p = .24) in predicting atopy, indicating that the effects of parental PD and child SAD were not multiplicative. The proportion of children with atopic disorders with/without parents with PD and with/ without SAD were compared (Table 4). Offspring of parents with PD who also had SAD had the highest rate of atopic disorders (24%); offspring of parents without PD or SAD had the lowest rate (6%). Analyses of variance for proportions with arcsine transformation showed a significant main effect for parental PD and SAD, but the interaction was not significant. DISCUSSION
We report on the relationship of atopic disorders in children with parental PD and childhood SAD in a welldefined sample, using standardized measures. There was a specific association between atopic disorders and parental PD compared with other parental psychiatric disorders. The lack of statistical significance between rates of atopy in offspring of parents with PD compared with offspring of control parents may be related to the smaller number of offspring in the parent control group (n = 80) compared with the number of offspring in the parent nonPD anxiety and/or mood disorder group (n = 113). Rates of atopic disorders were also significantly higher in children with SAD relative to children without SAD, and more specifically, in contrast to never-ill children. Additional studies are necessary to assess the relationship between atopic disorders in children with SAD and other types of anxiety disorders. Finally, parental PD and child SAD each appear to contribute independently to increased rates of atopic disorders TABLE 4 Rate of Atopic Disorders Among Children With/Without SAD and With/Without Parental PD Parental PD Child SAD Yes No
Yes
No
7/29 (24%) 18/121 (15%)
4/20 (20%) 11/173 (6%)
Note: Numerators sum to 40 = total number of children with atopic disorders. SAD = separation anxiety disorder; PD = panic disorder.
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among children. The results of the present study do not suggest a multiplicative effect of parental PD and child SAD in predicting atopy among children. That is, the risk of atopic disorders in children who are offspring of parents with PD and who have SAD does not appear to be above and beyond that of either condition alone. The elevated rate of atopic disorders in children with PD in both parents (33%) compared with that of children with PD in one parent (16%) and no PD in either parent (8%) may reflect a genetic relationship between parental PD and atopy. However, due to small sample sizes, this finding must be viewed as suggestive only and requires further study. The present study adds to the scant data on the relationship between atopy and anxiety disorders in children. It is the first to report a relationship between parental PD and childhood atopic disorders in a high-risk sample. Merikangas et al. (1999) reported an increased rate of allergies in offspring of parents with anxiety disorders compared with offspring of parents with no psychiatric disorder or parents with a history of substance abuse and no anxiety disorder; whether this relationship is specific to parental PD is not reported. The present study supports earlier reports of a relationship between asthma and SAD and suggests that the association includes allergies as well. To our knowledge, no other clinical studies have examined atopy in children with specific anxiety disorders. The relationship between atopy and parental PD, and between atopy and SAD, may be due to several factors. Shared genetic and/or environmental variables may explain some or all of the observed association. Wamboldt and colleagues (1998) suggest that anxiety and atopic disorders may reflect an additive genetic effect. If so, preliminary findings from the present study are consistent with a genetic association between atopy and SAD, and atopy and PD. Alternatively, the association of atopic disorders with PD and SAD may reflect shared environmental determinants. For example, some studies suggest an association between family dysfunction and increased levels of anxiety in children with asthma (Bender et al., 2000; Bussing and Burket, 1993). Other studies suggest that chronic illnesses such as asthma may invoke increased levels of fear, worry, and overprotectiveness in parents, thus contributing to separation anxiety in the child (Bussing et al., 1996; Mrazek et al., 1998). In addition, the co-occurrence of atopic disorders and anxiety disorders may reflect similar mechanisms of neurobiological dysfunction. Respiratory studies of panic disorder and asthma in adults propose a model of cenJ . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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tral CO2 chemoreceptor hypersensitivity and activation of a suffocation alarm system (Klein, 1993; Papp et al., 1993). Similar respiratory mechanisms may explain the relationship between childhood asthma and SAD, as suggested by preliminary evidence of respiratory parallels between PD and SAD (Pine et al., 2000). Immune dysfunction may mediate physiological changes in children with atopic disorders and anxiety disorders, as suggested by abnormalities in cell-mediated and humoral immunity in adults with PD (Andreoli et al., 1992; Coplan et al., 1999; Ramesh et al., 1991; Rapaport, 1998). Finally, similarities in autonomic and central nervous system adrenergic and cholinergic dysfunction are suggested in studies of allergy (Lemanske et al., 1985; Marshall,1993), adult PD (Noyes et al., 1992; Weissman et al., 1990; Yeragani et al., 1991), SAD (Rogeness et al., 1990), and childhood asthma (Miller and Wood, 1997). Limitations
Although children were selected from a well-defined group of parents, results may not generalize to a community sample. For example, severity of parental psychopathology, method of recruitment, and procedure for diagnostic assessment may be relevant variables that may differ in a community sample. Also, low base rates of atopic disorders and small numbers of children in each anxiety group, especially GAD, prevented the comparison of rates of atopic disorders between “pure” disorders. Determination of atopy was based on rates of medically treated asthma or allergies. Medical testing (e.g., skin tests) combined with clinical history would provide more objective evidence of atopic status. Finally, offspring of parents with PD and children with SAD may have increased somatic concerns, increased health care use, and hence, increased opportunity for medical detection and treatment of atopic disorders compared with other psychiatric groups. We attempted to address these potential differences by controlling for other treated illnesses in the logistic regression. Clinical Implications
The association between childhood atopic disorders and anxiety disorders in children and their parents highlights the importance of a medical and psychiatric history in the clinical care of children. Co-occurring anxiety and atopic disorders may affect the diagnosis and management of one another, as suggested in studies of symptom severity and use of medications in children with asthma and anxiety (ten Thoren and Petermann, 2000). J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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Rogeness GA, Cepeda C, Macedo CA, Fischer C, Harris WR (1990), Differences in heart rate and blood pressure in children with conduct disorder, major depression and separation anxiety. Psychiatr Res 33:199–206 Schachter EN, Doyle CA, Beck GJ (1984), A prospective study of asthma in a rural community. Chest 85:623–630 Schleyer B, Mannuzza S (1995), Family Informant Schedule and Criteria-Revised for DSM-IV (FISC-IV). New York: New York State Psychiatric Institute (available from Salvatore Mannuzza, NYU Child Study Center, 550 First Avenue, New York, NY 10016) Schmidt-Traub S, Bamler KJ (1997), The psychoimmunological association of panic disorder and allergic reaction. Br J Clin Psychol 36:51–62 Shavitt RG, Gentil V, Mandetta R (1992), The association of panic/agoraphobia and asthma: contributing factors and clinical implications. Gen Hosp Psychiatry 14:420–423 Silverglade L, Tosi DJ, Wise PS, D’Costa A (1994), Irrational beliefs and emotionality in adolescents with and without bronchial asthma. J Gen Psychol 121:199–207 Sly MR (1996), Allergic disorders. In: Textbook of Pediatrics, Behrman RE, Kliegman RM, Arvin AM, eds. Philadelphia: Saunders, pp 610–656 Spinhoven P, Ros M, Westgeest A, Van der Does AJ (1994), The prevalence of respiratory disorders in panic disorder, major depressive disorder and V-code patients. Behav Res Ther 32:647–649 Spitzer RL, Williams JB, Gibbon M, First MB (1992), The Structured Clinical Interview for DSM-III-R (SCID). Arch Gen Psychiatry 49:624–629 ten Thoren C, Petermann F (2000), Reviewing asthma and anxiety. Respir Med 94:409–415 Vila G, Nollet-Clemencon C, de Blic J, Mouren-Simeoni MC, Scheinmann P (2000), Prevalence of DSM-IV anxiety and affective disorders in a pediatric population of asthmatic children and adolescents. J Affect Disord 58:223–231 Wamboldt MZ, Schmitz S, Mrazek D (1998), Genetic association between atopy and behavioral symptoms in middle childhood. J Child Psychol Psychiatry 39:1007–1016 Wamboldt MZ, Weintraub P, Krafchick D, Wamboldt FS (1996), Psychiatric family history in adolescents with severe asthma. J Am Acad Child Psychiatry 35:1042–1049 Weissman MM, Leckman JF, Merikangas KR, Gammon GD, Prusoff BA (1984), Depression and anxiety disorders in parents and children: results from the Yale Family Study. Arch Gen Psychiatry 41:845–852 Weissman MM, Markowitz JS, Ouellette R, Greenwald S, Kahn JP (1990), Panic disorder and cardiovascular/cerebrovascular problems: results from a community study. Am J Psychiatry 147:1504–1508 Yellowlees PM, Haynes S, Potts N, Ruffin RE (1988), Psychiatric morbidity in patients with life-threatening asthma: initial report of a controlled study. Med J Aust 149:246–249 Yeragani VK, Pohl R, Balon R, Jung I, Kareus R (1991), Heart rate in panic disorder. Acta Psychiatr Scand 83:79 Zandbergen J, Bright M, Pols H, Fernandez I, de Loof C, Griez EJ (1991), Higher lifetime prevalence of respiratory diseases in panic disorder? Am J Psychiatry 148:1583–1585 Zitrin CM, Ross DC (1988), Early separation anxiety and adult agoraphobia. J Nerv Ment Dis 176:621–625
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ABSTRACT Objective: To test the hypotheses that rates of atopic disorders are elevated in offspring of parents with panic disorder (PD) and in children with separation anxiety disorder (SAD). Method: Rates of atopic disorders were assessed in 343 offspring (aged 6–17 years) of parents with PD, nonpanic psychiatric disorders, and no psychiatric disorder. Lifetime history of atopic disorders was determined by parental responses to a clinician-administered questionnaire assessing medical treatment for asthma and allergies. Logistic regression analyses assessed the association between atopic disorders and parental PD, and between atopic disorders and probable or definite childhood SAD. Analyses controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. Results: Increased rates of atopic disorders were found in offspring of parents with PD (odds ratio [OR] = 2.56, 95% confidence interval [CI] = 1.27–5.16, p = .009) and in children with SAD (OR = 2.71, 95% CI = 1.22–6.03, p = .015). Associations remained significant when both parental PD and SAD were included in the model, suggesting that each contributed independently to increased rates of atopy. The interaction of parental PD and child SAD was not significant. Conclusions: Atopic disorders in children are associated with parental PD and with childhood SAD. Results do not appear to support that having both childhood SAD and a parent with PD confers increased risk for atopic disorders above and beyond either condition alone. J. Am. Acad. Child Adolesc. Psychiatry, 2002, 41(8):947–954. Key Words: separation anxiety disorder, panic disorder, atopy, asthma, allergy.
A relationship between separation anxiety disorder (SAD) in children and panic disorder (PD) in adults has been suggested. Klein (1964) first proposed the “separation anxiety hypothesis” of panic disorder on the basis of clinical retrospective reports of increased rates of childhood separation anxiety symptoms in adults with agoraphobia and panic attacks, as compared with other psychiatric patients. Although not all studies have been consistent (Biederman et al., 2001; Lipsitz et al., 1994), several studies provide converging Accepted March 8, 2002. Dr. Slattery is with the Mayo Clinic, Rochester, MN, and the New York University Child Study Center, New York; Dr. D.F. Klein is with the New York State Psychiatric Institute, New York; Drs. Mannuzza, Moulton, Pine, and R.G. Klein are with the New York University Child Study Center. This research was supported by U.S. Public Health Service grants MH-37592 and MH-30906. The authors thank Mary Guardino, Director, Freedom From Fear, Staten Island, NY, for access to patients, and Maren K. Olsen, Ph.D., Bioinformation and Biostatistics Department, Duke University, for review of analyses. Reprint requests to Dr. Slattery, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. 0890-8567/02/4108–0947䉷2002 by the American Academy of Child and Adolescent Psychiatry.
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evidence of a relationship between SAD and PD. Retrospective studies describe increased rates of SAD in adults with PD (Ayuso et al., 1989; Balon et al., 1989; Zitrin and Ross, 1988). A prospective longitudinal study of children with SAD reports an elevated rate of PD among these children in adulthood (Klein, 1995). In addition, family studies report increased rates of SAD in offspring of parents with PD and agoraphobia (Berg, 1976; Capps et al., 1996; Weissman et al., 1984). A relationship between SAD and PD is also suggested by psychophysiological studies. In a study of carbon dioxide sensitivity, Pine and colleagues (2000) found patterns of respiratory abnormalities specifically in children with SAD, but not social anxiety disorder, that were similar to those found in adults with PD (Papp et al., 1997). Allergic disorders provide an additional framework in which to examine the association between SAD and PD. Specifically, a relationship has been suggested between PD in adults, anxiety disorders in children, and a familial cluster of IgE-mediated allergies often referred to as 947
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atopy (Schmidt-Traub and Bamler, 1997). The term more accurately describes an inherited predisposition to the development of these disorders, rather than the disorders themselves (Panhuysen et al., 1995). Atopic disorders include asthma, urticaria (hives), allergic rhinitis (hay fever), and atopic dermatitis (eczema) (Blumenthal, 1997). Several studies provide evidence of a relationship between asthma, allergies, and PD in adults. Clinical studies of adults with asthma report increased rates of PD as compared with the prevalence of PD in community studies (Perna et al.,1997; Shavitt et al., 1992; Yellowlees et al., 1988). Conversely, clinical studies of adults with PD describe increased rates of respiratory disease, including asthma, as compared with obsessive-compulsive disorder, eating disorders, and V-code diagnoses (Perna et al., 1994; Spinhoven et al., 1994; Zandbergen et al., 1991). Schmidt-Traub and Bamler (1997) examined the rate of PD in subjects with IgE-mediated allergies (n = 100) and the rate of allergies in subjects with PD (n = 79); each group was compared with a healthy control group (n = 66). The rate of PD (10%) and panic attacks (35%) in subjects with allergies was elevated compared with rates of PD (2%) and panic attacks (17%) in controls. Subjects with PD had an increased rate of allergies (70%) compared with controls (29%). There is a paucity of clinical and epidemiological studies examining the relationship between allergic disorders and specific childhood anxiety disorders. Several studies have suggested a relationship between asthma and anxiety symptoms in children but did not assess specific anxiety diagnoses (Butz and Alexander, 1993; Graham et al., 1967; McNichol et al., 1973; Norrish et al., 1977; Silverglade et al., 1994). Of the studies that used structured diagnostic interviews to examine specific anxiety disorders in asthmatic children, results differ as to whether SAD or general anxiety disorder (GAD) occurs most often. Vila and colleagues (2000) reported rates of anxiety disorders in 82 children with asthma (mean age = 11); 35% had any anxiety disorder, 29% had GAD, 16% had SAD, 10% had social anxiety disorder, and 1% had PD. In a similar study of 62 asthmatic children (mean age = 15), Wamboldt and colleagues (1996) described rates of anxiety disorders including any anxiety disorder (28%), overanxious disorder (24%), SAD (15%), agoraphobia (3%), simple phobia (6%), and PD (0%). Bussing and colleagues (1996) compared rates of anxiety in 37 asthmatic children (mean age = 11) compared with 31 healthy controls. All anxiety disorders were elevated in children with 948
asthma as compared with controls, including any anxiety disorder (43% versus 19%), SAD (32% versus 13%), overanxious disorder (8% versus 0%), PD (5% versus 0%), and phobia (16% versus 6%). The prevalence of specific anxiety disorders in children with atopic disorders other than asthma is unknown. Similarly, there are no published studies investigating the rate of atopic disorders in clinical samples of children with anxiety disorders. Indirect support for a relationship between atopy and anxiety disorders among children may be suggested by other data. Kagan (1994) reported increased rates of allergies in children with behavioral inhibition. This may suggest a relationship between atopy and anxiety disorders in children, since behavioral inhibition is a temperamental trait associated with increased rates of anxiety in children (Hirshfeld et al., 1992). Existing studies do not provide insight into potential mechanisms for the association between anxiety and atopic disorders. Wamboldt and colleagues (1998) suggested that atopic disorders may represent markers for a familial subtype of anxiety characterized by genetic factors shared with atopy. If this is correct, an anxiety disorder in the parent would predict the presence of asthma or allergies in the child, even in the absence of anxiety in the child. Preliminary evidence for this model is suggested in one study by Merikangas and colleagues (1999), who reported increased rates of allergies and eczema in children of parents with anxiety disorders compared with children of parents with substance abuse or no psychiatric disorder. The present study further examines these associations by investigating the relationship between atopy, parental PD, and SAD in children. We hypothesize that (1) offspring of parents with PD will have increased rates of atopic disorders as compared with offspring of parents without panic disorder, and (2) that children with SAD will have increased rates of atopic disorders as compared with children without SAD. METHOD Subjects Data were drawn from a larger study examining the risk for psychopathology conferred to children by parents with anxiety and mood disorders compared with non-ill parents. Nonpsychotic psychiatrically ill parents with anxiety and mood disorders with children aged 6 to 17 years were identified by random chart review from three outpatient treatment centers in the New York City area. Non-ill comparison parents were identified by chart review and the acquaintanceship procedure. Charts of a major New York medical center dental clinic were reviewed to identify children aged 6 to 17 years. Identified par-
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ents were screened by a social worker who administered a brief psychiatric questionnaire; those with negative screens were scheduled for a psychiatric interview (described below). In the acquaintanceship procedure, parents with anxiety and mood disorders (from the psychiatrically ill group) were asked to identify six acquaintances who were the same age, gender, and ethnicity and who had children aged 6 to 17. One acquaintance was randomly chosen and contacted. As with the chart review procedure, parents were screened and subsequently interviewed. Approximately half of the control group was recruited through each of the recruitment methods. There were three parental diagnostic groups. In the PD group (n = 95 families, 150 children), one or both parents had lifetime PD and neither parent had lifetime mood or psychotic disorder. In the nonpanic anxiety and/or mood disorder group (n = 69 families, 113 children), one or both parents had lifetime nonpanic anxiety disorder including social phobia (n = 12, 17%), obsessive-compulsive disorder (n = 4, 6%), and/or a mood disorder including major depressive disorder (n = 62, 90%), dysthymia (n = 12, 17%) or bipolar I disorder (n = 8, 12%), and neither parent had lifetime psychotic disorder. In the control group (n = 44 families, 80 children), neither parent had lifetime anxiety, mood, or psychotic disorder. Subjects were 343 offspring, aged 6 to 17 years (mean = 11.6, SD = 3.5). Offspring were grouped on the basis of parental and child psychiatric diagnoses. Written informed consent (and child assent) was obtained from all subjects, regardless of group or method of recruitment. Measures Overview. Interviewers were advanced-level clinical psychology doctoral students, a clinical psychologist, and a psychiatric social worker trained in differential diagnostic assessment. Interview training included required readings, discussion of differential diagnoses of symptoms and disorders, extensive review of diagnostic instruments and existing narrative summaries, and completion of 40 DSM-IV case vignettes. Ongoing supervision (to minimize “rater drift”) included regularly scheduled meetings to receive feedback on narrative summaries and to review diagnostically ambiguous cases. Interviewers were blind to group membership and study hypotheses. Parents and children were assessed by different interviewers, who wrote detailed narratives that were blindly reviewed by senior investigators. Narrative reviews served as a validity check to ensure that diagnostic criteria were carefully followed. Parent Diagnoses. Parents were administered the Structured Clinical Interview for DSM-IV (First et al., 1995; Spitzer et al., 1992), which assesses lifetime presence of all major psychiatric illnesses. When the second parent was not available for interview (49% of cases), the Family Informant Schedule and Criteria-Updated for DSM-IV (Schleyer and Mannuzza, 1995) was administered to the available parent. Child Diagnoses. An informant interview with the child’s mother was conducted; children aged 9 years and older were also interviewed directly. Children and mothers were administered the Parent as Respondent Informant Schedule (PARIS; Klein and Mannuzza, 1992; Kentgen et al., 1997). The PARIS assesses lifetime presence of all major child and adolescent DSM-IV disorders. Child lifetime diagnoses were considered present if DSM-IV criteria were met in the direct interview with the child and/or in the parent interview about the child. A definite disorder was diagnosed when DSM-IV criteria were met; a probable diagnosis was assigned when functional impairment was present despite fewer symptoms (Gittelman et al., 1985). A disorder was considered present on the basis of either a probable or definite diagnosis. This decision was considered consistent with clinical practice, since both levels of certainty required significant functional disruption.
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Atopy. Atopy was assessed with a medical questionnaire administered to the parents by clinicians. Questionnaire items included treatment for asthma, allergy, diabetes, seizures, or any other illness. The presence of an atopic disorder was defined as an affirmative response to at least one of two (yes/no) questions regarding whether the child had ever received medical treatment for asthma or allergies. Data Analysis Atopy was the dependent variable. Because children included siblings, variables could not be considered independent. Therefore, associations between atopy and parental PD and between atopy and SAD were assessed with generalized estimating equations (GEE) using the SAS statistical program (SAS, Version 8.1, SAS Institute Inc., Cary, NC). GEE, an extension of the general linear model, permits the analysis of clustered binary data that may be correlated. In this case, clusters were the 208 families in the study; the binary outcome was atopy (yes/no). Age and sex were included as covariates on the basis of increased rates of asthma in prepubertal children, particularly boys (Schachter et al., 1984; Sly, 1996). Because treatment seeking may be associated with parental and child psychological distress (Garralda and Bailey, 1986; Horwitz et al., 1985), as well as parental characteristics of higher education and income (Horwitz et al., 1985), we controlled for SES and for medical treatment reported by parents for all other illnesses. We calculated odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of the associations and examined robust standard errors to reduce the likelihood of type I errors. Alpha was set at p < .05 for a priori hypotheses and p < .01 for secondary analyses. All contrasts were two-tailed. The output of analyses using GEE and logistic regression (SPSS, Version 10.1.0; SPSS Inc., Chicago, IL) were compared. Because the significance of the contrasts were identical between the analyses (i.e., a significant cluster effect was not present), we report results from the logistic regression. RESULTS Demographic Characteristics
The 343 children ranged in age from 6 years 0 months to 17 years 11 months (mean = 11.6 years, SD = 3.5 years) (Table 1). There were slightly more girls (54%) than boys. The majority of children were white (76%), with the minority comprising African American (11%), Hispanic (8%), and other (5%) ethnic groups. Household socioeconomic status ranged from 1 to 5 (mean = 2.9, SD = 1.0), with 1 representing upper class and 5 representing lower class (Hollingshead and Redlich, 1958). There were 40 children with treated atopy (12%); 26 (9%) had asthma, 10 (4%) had allergies, and 4 (1%) had both asthma and allergies. Paired comparisons of offspring of parents with/without PD, children with/without SAD, and children with/without atopy (Table 1) indicated a significant contrast (p < .05) for age only in offspring of parents with PD versus no PD; all other contrasts were nonsignificant. The majority of parents were married (67%), with the minority comprising separated (9%), divorced (15%), widowed (1%), and single (8%) parents. Mothers’ mean age was 41.2 years; the mean age of fathers was 44.0 years. 949
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TABLE 1 Child Demographic Variables (N = 343 Children) Children With Separation Anxiety Disorder a All Children (N = 343) Gender, n (%) Female Male Ethnicity, n (%) White AfAm Hispanic Other Age, mean (SD) [Range] SES, mean (SD)
Yes (n = 49)
No (n = 294)
186 (54) 157 (46)
19 (39) 30 (61)
138 (47) 156 (53)
262 (76) 38 (11) 28 (8) 15 (4) 11.6 (3.5) [6.0–17.9] 2.9 (1.0)
33 (67) 229 (78) 9 (18) 29 (10) 4 (8) 24 (8) 3 (6) 12 (4) 11.4 (3.3) 11.5 (3.5) [6.0–17.6] [6.0–17.9] 3.1 (1.1) 2.9 (1.0)
Offspring of Parents With Panic Disorder * Yes (n = 150) 72 (48) 78 (52)
No (n = 193) 85 (44) 108 (56)
119 (79) 143 (74) 10 (7) 28 (15) 17 (11) 11 (6) 4 (3) 11 (6) 10.9 (3.3) 11.9 (3.5) [6.0–17.6] [6.0–17.9] 2.9 (1.0) 2.9 (1.1)
Children With Atopy a Yes (n = 40) 23 (58) 17 (43)
No (n = 303) 134 (44) 169 (56)
28 (70) 234 (77) 5 (13) 33 (11) 4 (10) 24 (8) 3 (8) 12 (4) 12.0 (3.8) 11.4 (3.4) [6.2–17.9] [6.0–17.9] 2.9 (1.0) 2.9 (1.1)
Note: AfAm = African American; SES = socioeconomic status. a No significant group differences. * Significant difference only for age, PD (yes) < PD (no), t341 = 2.61; p < .05.
Prevalence of Atopy in Offspring of Parents With and Without PD
There was a significantly higher rate of treated atopy among the offspring of parents with PD as compared with offspring of parents without PD (OR = 2.56, 95% CI = 1.27–5.16, p = .009) (Table 2). Secondary analyses examined the diagnostic specificity of this association. Children were grouped on the presence or absence of parent diagnoses for the purpose of conducting two contrasts. There were too few offspring of parents with nonpanic anxiety disorders (n = 27) to permit comparison with offspring of parents with PD. Offspring of parents with PD were compared with offspring of parents with other disorders (i.e., any nonpanic anxiety or mood disorder) and offspring of control parents (i.e., parents without any mood, anxiety or psychotic disorders). Offspring of parents with PD had significantly higher rates of atopic disorders compared with offspring of parents with other psychiatric disorders (OR = 3.35, 95% CI = 1.37–8.15, p = .008). Although the odds of atopy among the offspring of parents with PD was nearly twice the odds among the offspring of control parents, the difference did not reach significance (OR = 1.92, 95% CI = 0.78–4.72, p = .15) (Table 2). Finally, rates of atopic disorders in children with one or both parents with PD were compared. Two of six (33%) children with PD in both parents had atopic disorders, compared with 23 of 144 (16%) children with PD in one parent. 950
Prevalence of Atopy in Children With and Without SAD
Children with probable or definite SAD had a significantly higher rate of atopic disorders than children without SAD (OR = 2.71, 95% CI = 1.22–6.03, p = .015) (Table 3). Secondary analyses examined whether this relationship had diagnostic specificity. Children with SAD were compared with children with non-SAD anxiety disorders and children with no history of psychiatric illness. Non-SAD anxiety disorders included GAD (n = 9, 8%), PD (n = 2, 2%), social phobia (n = 47, 40%), specific phobia (n = 77, 65%), obsessive-compulsive disorder (n = 3, 3%), posttraumatic stress disorder (n = 1, 1%), and anxiety disorder not otherwise specified (n = 5, 4%). Restricting analyses to definite (i.e., full criteria) diagnoses of SAD and non-SAD anxiety disorders did not alter any of the relationships reported. The rate of atopic disorders in children with SAD was significantly higher than that observed among children who had never been psychiatrically ill (OR = 5.85, 95% CI = 1.79–19.09, p = .003) (Table 3). Although the odds of atopic disorders among children with SAD were twice as high as those observed among children with non-SAD anxiety disorders, the difference did not reach significance (OR = 2.14, 95% CI = 0.86–5.37, p = .10). Further analyses examined the relationship between parental PD and childhood SAD as related to childhood atopy. The association between atopic disorders and parental PD, and between atopic disorders and child SAD, J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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TABLE 2 Relationship Between Parental Panic Disorder and Atopic Disorders in Offspring Contrasts of Ill-Parent Diagnostic Groups χ2 Adjusted OR (95% CI)
Parental Diagnoses A Parental Panic Disorder: Yes (n = 150 Offspring)
B Parental Panic Disorder: No (n = 193 Offspring)
A vs. B
15 (7.8) 178 (92.2)
χ 1 = 6.84; p = .01 OR = 2.56 (1.27–5.16) p = .009
a
2
Atopy, n (%) Yes No
25 (16.7) 125 (83.3)
A Panic Disorder (n = 150)
B Nonpanic Anxiety Disorder and/or Mood Disorderb (n = 113)
C Not Ill Controls (n = 80)
A vs. B
Yes No
25 (16.7) 125 (83.3)
8 (7.1) 105 (92.9)
A vs. C
B vs. C
χ21 = 5.40; p = .02 χ21 = 2.73; p = .10 χ21 = 0.18; p = .67 OR = 3.35 OR = 1.92 OR = 0.56 (1.37–8.15) (0.78–4.72) (0.17–1.80) p = .008 p = .15 p = .33
Atopy,a n (%) 7 (8.7) 73 (91.3)
Note: Logistic regression controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. OR = odds ratio; CI = confidence interval. a Atopy = lifetime history of allergy or asthma in the child. b DSM-IV nonpanic anxiety and/or mood disorders in parents include social phobia, obsessive-compulsive disorder, major depressive disorder, dysthymia, and bipolar I disorder. TABLE 3 Relationship Between Separation Anxiety Disorder (SAD) and Atopic Disorders in Offspring Contrasts of Ill-Child Diagnostic Groups χ2 Adjusted OR (95% CI)
Child Psychiatric Disorder A SAD: Yes (n = 49 Children)
B SAD: No (n = 294 Children)
A vs. B
29 (9.9) 265 (90.1)
χ21 = 6.46; p = .01 OR = 2.71 (1.22–6.03) p = .015
Atopy,a n (%) Yes No
11 (22.4) 38 (77.6)
A SAD (n = 49)
B Non-SAD Anxiety Disorderb (n = 118)
C Never Ill (n = 105)
a
Atopy, n (%) Yes No
A vs. B
11 (22.4) 38 (77.6)
14 (11.9) 104 (88.1)
5 (4.8) 100 (95.2)
A vs. C
B vs. C
χ 1 = 3.05; p = .08 χ 1 = 11.23; p = .001 χ 1 = 3.60; p = .06 OR = 2.14 OR = 5.85 OR = 2.23 (0.86–5.37) (1.79–19.09) (0.74–6.75) p = .10 p = .003 p = .155 2
2
2
Note: Logistic regression controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. OR = odds ratio; CI = confidence interval. a Atopy = lifetime history of allergy or asthma in the child. b DSM-IV non-SAD anxiety disorders include social phobia, obsessive-compulsive disorder, generalized anxiety disorder, specific phobia, posttraumatic stress disorder, and anxiety disorder-not otherwise specified. “B” comparison group did not include 71 children with psychiatric disorders other than anxiety disorders. J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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remained significant when both variables were included in the logistic regression model (OR = 2.32, 95% CI = 1.14–4.72, p = .02; OR = 2.31, 95% CI = 1.02–5.24, p < .05, respectively). However, the interaction of parental PD and child SAD was not significant (OR 0.37, 95% CI = 0.07–1.93, p = .24) in predicting atopy, indicating that the effects of parental PD and child SAD were not multiplicative. The proportion of children with atopic disorders with/without parents with PD and with/ without SAD were compared (Table 4). Offspring of parents with PD who also had SAD had the highest rate of atopic disorders (24%); offspring of parents without PD or SAD had the lowest rate (6%). Analyses of variance for proportions with arcsine transformation showed a significant main effect for parental PD and SAD, but the interaction was not significant. DISCUSSION
We report on the relationship of atopic disorders in children with parental PD and childhood SAD in a welldefined sample, using standardized measures. There was a specific association between atopic disorders and parental PD compared with other parental psychiatric disorders. The lack of statistical significance between rates of atopy in offspring of parents with PD compared with offspring of control parents may be related to the smaller number of offspring in the parent control group (n = 80) compared with the number of offspring in the parent nonPD anxiety and/or mood disorder group (n = 113). Rates of atopic disorders were also significantly higher in children with SAD relative to children without SAD, and more specifically, in contrast to never-ill children. Additional studies are necessary to assess the relationship between atopic disorders in children with SAD and other types of anxiety disorders. Finally, parental PD and child SAD each appear to contribute independently to increased rates of atopic disorders TABLE 4 Rate of Atopic Disorders Among Children With/Without SAD and With/Without Parental PD Parental PD Child SAD Yes No
Yes
No
7/29 (24%) 18/121 (15%)
4/20 (20%) 11/173 (6%)
Note: Numerators sum to 40 = total number of children with atopic disorders. SAD = separation anxiety disorder; PD = panic disorder.
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among children. The results of the present study do not suggest a multiplicative effect of parental PD and child SAD in predicting atopy among children. That is, the risk of atopic disorders in children who are offspring of parents with PD and who have SAD does not appear to be above and beyond that of either condition alone. The elevated rate of atopic disorders in children with PD in both parents (33%) compared with that of children with PD in one parent (16%) and no PD in either parent (8%) may reflect a genetic relationship between parental PD and atopy. However, due to small sample sizes, this finding must be viewed as suggestive only and requires further study. The present study adds to the scant data on the relationship between atopy and anxiety disorders in children. It is the first to report a relationship between parental PD and childhood atopic disorders in a high-risk sample. Merikangas et al. (1999) reported an increased rate of allergies in offspring of parents with anxiety disorders compared with offspring of parents with no psychiatric disorder or parents with a history of substance abuse and no anxiety disorder; whether this relationship is specific to parental PD is not reported. The present study supports earlier reports of a relationship between asthma and SAD and suggests that the association includes allergies as well. To our knowledge, no other clinical studies have examined atopy in children with specific anxiety disorders. The relationship between atopy and parental PD, and between atopy and SAD, may be due to several factors. Shared genetic and/or environmental variables may explain some or all of the observed association. Wamboldt and colleagues (1998) suggest that anxiety and atopic disorders may reflect an additive genetic effect. If so, preliminary findings from the present study are consistent with a genetic association between atopy and SAD, and atopy and PD. Alternatively, the association of atopic disorders with PD and SAD may reflect shared environmental determinants. For example, some studies suggest an association between family dysfunction and increased levels of anxiety in children with asthma (Bender et al., 2000; Bussing and Burket, 1993). Other studies suggest that chronic illnesses such as asthma may invoke increased levels of fear, worry, and overprotectiveness in parents, thus contributing to separation anxiety in the child (Bussing et al., 1996; Mrazek et al., 1998). In addition, the co-occurrence of atopic disorders and anxiety disorders may reflect similar mechanisms of neurobiological dysfunction. Respiratory studies of panic disorder and asthma in adults propose a model of cenJ . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
SEPARATION ANXIETY, PARENTAL PANIC, ATOPY
tral CO2 chemoreceptor hypersensitivity and activation of a suffocation alarm system (Klein, 1993; Papp et al., 1993). Similar respiratory mechanisms may explain the relationship between childhood asthma and SAD, as suggested by preliminary evidence of respiratory parallels between PD and SAD (Pine et al., 2000). Immune dysfunction may mediate physiological changes in children with atopic disorders and anxiety disorders, as suggested by abnormalities in cell-mediated and humoral immunity in adults with PD (Andreoli et al., 1992; Coplan et al., 1999; Ramesh et al., 1991; Rapaport, 1998). Finally, similarities in autonomic and central nervous system adrenergic and cholinergic dysfunction are suggested in studies of allergy (Lemanske et al., 1985; Marshall,1993), adult PD (Noyes et al., 1992; Weissman et al., 1990; Yeragani et al., 1991), SAD (Rogeness et al., 1990), and childhood asthma (Miller and Wood, 1997). Limitations
Although children were selected from a well-defined group of parents, results may not generalize to a community sample. For example, severity of parental psychopathology, method of recruitment, and procedure for diagnostic assessment may be relevant variables that may differ in a community sample. Also, low base rates of atopic disorders and small numbers of children in each anxiety group, especially GAD, prevented the comparison of rates of atopic disorders between “pure” disorders. Determination of atopy was based on rates of medically treated asthma or allergies. Medical testing (e.g., skin tests) combined with clinical history would provide more objective evidence of atopic status. Finally, offspring of parents with PD and children with SAD may have increased somatic concerns, increased health care use, and hence, increased opportunity for medical detection and treatment of atopic disorders compared with other psychiatric groups. We attempted to address these potential differences by controlling for other treated illnesses in the logistic regression. Clinical Implications
The association between childhood atopic disorders and anxiety disorders in children and their parents highlights the importance of a medical and psychiatric history in the clinical care of children. Co-occurring anxiety and atopic disorders may affect the diagnosis and management of one another, as suggested in studies of symptom severity and use of medications in children with asthma and anxiety (ten Thoren and Petermann, 2000). J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 8 , AU G U S T 2 0 0 2
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