DEPRESSION AND ANXIETY 22:114–120 (2005) Research Article PARENTAL PREDICTORS OF PEDIATRIC PANIC DISORDER/AGORAPHOBIA: A CONTROLLED STUDY IN HIGH-RISK OFFSPRING Joseph Biederman, M.D.,1 Carter Petty, M.A.,1 Stephen V. Faraone, Ph.D.,2 Dina R. Hirshfeld-Becker, Ph.D.,1 Aude Henin, Ph.D.,1 Meghan Dougherty, B.S.,1 Teresa J. LeBel, M.A.,1 Mark Pollack, M.D.,3 and Jerrold F. Rosenbaum, M.D.3 Our objective was to evaluate parental risk factors for pediatric-onset panic disorder/agoraphobia (PD/AG) in offspring at high risk for PD/AG. Comparisons were made between parents with PD who had a child with PD or AG (N 5 27) and parents with PD without children with PD or AG (N 5 79). Comparisons were also made between the spouses of these parents with PD. Separation anxiety disorder, social phobia, obsessive–compulsive disorder, and bipolar disorder in the parents with PD and their spouses accounted for the risk for childhood onset PD/AG in the offspring. This risk was particularly high if both parents were affected with social phobia. These findings suggest that psychiatric comorbidity with other anxiety disorders and with bipolar disorder in parents with PD and their spouses confer a particularly high risk in their offspring to develop PD/AG in childhood. Depression and Anxiety 22:114–120, 2005. & 2005 Wiley-Liss, Inc. Key words: children; youth; anxiety disorders; genetic; family A INTRODUCTION recent study of young children of parents with panic disorder (PD) found that parental PD increased the risk for PD and agoraphobia (AG) in their young offspring [Biederman et al., 2001]. However, because only a minority of high-risk children developed PD/AG in childhood, questions remain as to whether additional risk factors besides PD in the parent may account for early-onset PD in the offspring. The parents with PD had significantly elevated rates of comorbidity with mood and other anxiety disorders, including separation anxiety disorder, simple phobia, obsessive–compulsive disorder, generalized anxiety disorder, and AG, raising the possibility that comorbidity in the parents with PD may be a risk factor for early-onset PD in their offspring [Biederman et al., 2004]. Similar findings have been documented in the extant literature, which has documented high comorbidity between PD and bipolar disorder, obsessive– compulsive disorder, social phobia, and posttraumatic stress disorder [Goodwin and Hoven, 2002]. Also, because many adults with PD in our study had r 2005 Wiley-Liss, Inc. early-onset PD, it is possible that early age of onset of PD may breed true. The main goal of this study was to evaluate risk factors for early-onset PD/AG in children at risk for PD. To this end, we compared patterns of comorbidity 1 Pediatric Psychopharmacology Clinic, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York 3 Department of Psychiatry, Harvard Medical School, Cambridge, Massachusetts Contract grant sponsor: National Institutes of Health; Grant number: 2 R01 MH47077 Correspondence to: Joseph Biederman, M.D., Massachusetts General Hospital, Pediatric Psychopharmacology Research, Yawkey Center for Outpatient Care, YAW-6A-6900, 32 Fruit Street, Boston, MA 02114. E-mail: jbiederman@partners.org Received for publication 24 June 2004; Revised 14 September 2004; Accepted 15 July 2005 DOI 10.1002/da.20122 Published online 28 September 2005 in Wiley InterScience (www.interscience.wiley.com). Research Article: Pediatric Panic Disorder/Agoraphobia and age of onset of PD in parents of children at risk, with and without PD/AG. We hypothesized that mood and other anxiety disorders, and early onset of PD in the parent with PD, would be associated with early onset PD/AG in the offspring. To the best of our knowledge, this issue has not been adequately addressed previously in the literature. METHODS SUBJECTS Detailed study methodology has been reported in previous publications [Rosenbaum et al., 2000]. Briefly, three groups of adult probands were recruited for a study of behavioral inhibition in their offspring; these individuals were recruited from clinic referrals or in response to advertisements calling for adults in treatment for PD or major depression. These included (1) 131 adults treated for PD and their 227 children; (2) 39 adults treated for major depression, who had no history of either PD or AG and their 67 children; and (3) 61 comparison adults with neither major anxiety nor mood disorders and their 119 children. Both parents of all children were included in the study. Parents ranged in age from 24 to 53 years. Their children’s ages ranged from 1 to 27 years, and all parents had at least one child age 2–6 years. Only patients who received a positive lifetime DSM-III-R diagnosis of PD or major depression by structured psychiatric interview, and who had been treated for these disorders, were included in the PD and depression groups. The comparison group of adults was free of major anxiety disorders (PD, AG, social phobia, generalized anxiety disorder, or obsessive–compulsive disorder) or mood disorders (major depression, bipolar disorder, or dysthymia) and were recruited through advertisements to hospital personnel and in community newspapers. This study was approved by the institutional review board, and all parents signed written informed consent. Children assented to study procedures. PROCEDURES Parents received direct psychiatric assessments using the Structured Clinical Interview for DSM-III-R [SCID; Spitzer et al., 1990] for lifetime adult diagnoses, and supplements from the Kiddie Schedule for Affective Disorders and Schizophrenia—Epidemiological Version (KSADS-E) modules for childhood disruptive behavior and anxiety disorders [Orvaschel, 1994]. We conducted psychiatric assessments of children age 5 and older by completing the KSADS-E with the mothers. Children under age 5 were not assessed for psychiatric disorders. Children age 12 and older were interviewed directly by a separate interviewer. Children under 12 did not have direct interviews, because they are limited in their expressive and receptive language abilities, lack the ability to map events in time, and have limited powers of abstraction. 115 Given these limitations, there is a real question about whether the young child’s self-perceptions, memories, feelings, and reported behavior can be reliably assessed through self-report. Although limited, studies on the use of interview techniques among young children show that their replies are unreliable [Achenbach et al., 1987; Breton et al., 1995; Edelbrock et al., 1985; Fallon and Schwab-Stone, 1994; Schwab-Stone et al., 1994]. In contrast, Faraone et al. [1995] and others [Fallon and Schwab-Stone, 1994] have shown maternal reports of psychopathology to reach high levels of reliability, even over a 1-year period. We combined data from direct and indirect interviews, and considered a diagnostic criterion positive if it was endorsed in either interview. We assessed socioeconomic status (SES) with the Hollingshead Four-Factor Index [Hollingshead, 1975], which includes information about subjects’ educational levels and occupations. Interviews were conducted by highly trained and supervised raters with a bachelor’s degree in psychology under the supervision of the two senior investigators (J. F. Rosenbaum and J. Biederman). Raters underwent a comprehensive training program in which they were required to (1) master the diagnostic instruments, (2) learn about DSM-III-R criteria, (3) watch training tapes, (4) participate in interviews performed by experienced raters, and (5) rate several subjects under the supervision of the experienced raters. Raters received ongoing supervision of their assessments from senior project staff, and all interviews were audiotaped for quality control. Diagnoses for all subjects were made on the basis of a consensus judgment by the same two senior investigators. Blinded evaluation was assured as follows: (1) Psychiatric interviewers of parents were blind to the ascertainment status of the parent (e.g., patient with PD, patient with major depression, comparison subject), and (2) the final diagnoses for all subjects were made by clinicians who were blind to the subjects’ original recruitment group, to all nonpsychiatric data collected from the individual being diagnosed, and to all information about other family members. STATISTICAL ANALYSES To determine the parental characteristics that put children at risk for early-onset PD/AG, we divided families into two groups: those with at least one child with PD/AG and those with no children with PD/AG. Parents of these two groups were compared on demographic variables, and all further analyses were controlled for demographic variables that differed between the groups. We then conducted three sets of comparisons between the two groups of families: psychiatric disorders in the parent probands of the two groups, disorders in the spouses of the parent probands, and disorders present in both the parent proband and spouse. Therefore, differences between 116 Biederman et al. the two groups could be considered familial risk factors for pediatric PD/AG. Outcomes were assessed using logistic regression for binary variables, linear regression for continuous variables, ordinal logistic regression for ordinal variables, and negative binomial regression for count variables. All tests were two-tailed with a set at a .05 level. Due to potential type II errors given limited statistical power, odds ratios (ORs) greater than 2 were considered as meaningful trends in these analyses. RESULTS To present a prudent analysis that was free of ascertainment bias, our analysis was limited to families in the panic disorder ascertainment group that included probands with PD and their spouses. Thus, each family had at least one parent with PD. Comparisons were made between parent probands who had a child with PD/AG (Proband Parents with PD/AG offspring, N 5 27) and parent probands without children with PD/AG (Proband Parents without PD/AG offspring, N 5 79). Comparisons were also made between the spouses of these parent probands (Spouses with PD/ AG offspring, N 5 27; Spouses without PD/AG offspring, N 5 79). Neither proband parents nor their spouses differed significantly on any of the demographic variables assessed (Table 1). There were 28 children coming from 27 families who had PD or AG. Seventy-one percent of children with TABLE 1. Demographics Parent Probands with PD/AG offspring (N 5 27) Age (Mean7SD) Males N (%) Family socioeconomic status Family intact N (%) 38.276.4 4 (15) 2.271.1 64 (81) Parent Probands without PD/AG offspring (N 5 79) 38.575.4 9 (11) 2.370.9 22 (81) Spouses with PD/AG offspring (N 5 27) Age (Mean7SD) Males N (%) 39.776.1 23 (85) P value F(1,104) 5 0.06 w2(1) 5 0.22 w2(1) 5 0.65 w2(1) 5 0.00 Spouses without PD/AG offspring (N 5 79) 39.575.6 70 (89) .81 .64 .42 .96 P value F(1,104) 5 0.02 w2(1) 5 0.22 .88 .64 TABLE 2. Disorders in parent probands, all of whom have panic disorder Age of onset of panic disorder Total no. of anxiety disorders Avoidant disorder Separation anxiety disorder Overanxious disorder Simple phobia Social phobia Generalized anxiety disorder Obsessive–compulsive disorder Agoraphobia Major depressive disorder Bipolar disorder Psychoactive substance use disorders Disruptive behavior disorders Antisocial personality disorder Parent probands with PD/AG offspring (N 5 27) Parent probands without PD/AG offspring (N 5 79) Mean7SD Mean7SD 24.677.2 4.072.0 N (%) 1 (4) 8 (30) 14 (52) 9 (33) 13 (48) 13 (48) 8 (30) 14 (52) 21 (78) 4 (15) 12 (44) 5 (19) 1 (4) Boldfaced odds ratios considered as meaningful trends. Test statistic P value 26.577.9 3.471.6 N (%) F(1,104) 5 1.17 w2(1) 5 1.89 w2(1) .28 .17 5 (6) 13 (16) 30 (38) 15 (19) 24 (30) 35 (44) 10 (13) 56 (71) 60 (76) 6 (8) 42 (53) 19 (24) 6 (8) 0.28 2.06 1.58 2.23 2.72 0.12 3.75 3.15 0.04 1.13 0.61 0.36 0.58 .59 .15 .21 .14 .10 .73 .05 .08 .85 .29 .43 .55 .45 OR 0.6 2.1 1.8 2.1 2.1 1.2 2.9 0.4 1.1 2.1 0.7 0.7 0.5 Research Article: Pediatric Panic Disorder/Agoraphobia PD/AG (20/28) had only AG, 11% (3/28) had only PD, and 18% (5/28) had both AG and PD. The mean age of PD onset was 5.1 (SD 5 1.7, median 5 4.5) and ranged from 4 to 9 years of age. The mean age of AG onset was 4.6 (SD 5 1.6, median 5 4) and ranged from 4 to 11 years of age. The age of children with PD/AG did not differ significantly from the age of children without PD/AG (with PD/AG 5 6.873.0, without PD/ AG 5 6.772.6, P 5.83). Findings in Probands With PD. Proband Parents with PD/AG offspring had higher rates [OR 4 2] of obsessive–compulsive disorder (OR 5 2.9; P 5.02), social phobia (OR 5 2.1), simple phobia (OR 5 2.1), separation anxiety disorder (OR 5 2.1), and bipolar disorder (OR 5 2.1) compared with Proband Parents without PD/AG offspring. Neither mean number of anxiety disorders nor age of onset of PD differed between the two groups of parents (Table 2). Findings in Spouses. Spouses with PD/AG offspring had higher rates (OR 4 2) of bipolar disorder (OR 5 4.5, P 5.04), avoidant disorder (OR 5 6.8), obsessive–compulsive disorder (OR 5 3.1), social phobia (OR 5 2.9), psychoactive substance use disorders (OR 5 2.6), separation anxiety disorder (OR 5 2.2), and major depression (OR 5 2.1) compared with Spouses without PD/AG offspring. The mean number of anxiety disorders did not differ between the two groups of spouses (Table 3). Findings in Both Parents. For disorders found to have an OR greater than 2 in both the parent probands and spouses (separation anxiety disorder, social phobia, obsessive–compulsive disorder, and bipolar disorder), we also examined the contribution of having two parents afflicted with a given disorder. This analysis 117 showed that the rate of social phobia (OR 5 10.2, P 5.03) in both parents was higher in parents of offspring with PD/AG than in parents of offspring without PD/AG. In addition, we found that the total number of anxiety disorders in both parents of offspring with PD/AG was higher compared to the total number of anxiety disorders in both parents of offspring without PD/AG (Ms: 5.072.3 vs. 3.872.0, P 5.02; Table 4). DISCUSSION In an evaluation of parental risk factors for pediatriconset PD/AG in offspring at high risk for PD/AG, we found that separation anxiety disorder, social phobia, obsessive–compulsive disorder, and bipolar disorder in parents with PD and their spouses accounted for the risk for childhood-onset PD/AG in the offspring. Further analysis of these four disorders showed that this risk was particularly high if both parents were affected with social phobia. In addition, the number of anxiety disorders in both parents was predictive of pediatric-onset PD/AG in the children. In contrast, age of onset of PD in the parent was not a risk factor. These findings suggest that psychiatric comorbidity with other anxiety disorders and with bipolar disorder in parents with PD and their spouses confer a particularly high risk in their offspring to develop PD/AG in childhood. Our findings expand on the familial relationship of bipolar disorder and PD with evidence that children are at greater risk for early-onset PD/AG if they have parents with PD and bipolar disorder compared to only a parent with PD. For example, MacKinnon et al. TABLE 3. Disorders in spouses of parent probands Total no. of anxiety disorders Avoidant disorder Separation anxiety disorder Overanxious disorder Simple phobia Social phobia Generalized anxiety disorder Obsessive–compulsive disorder Agoraphobia Panic disorder Major depressive disorder Bipolar disorder Psychoactive substance use disorders Disruptive behavior disorders Antisocial personality disorder Spouses with PD/AG offspring (N 5 27) Spouses without PD/AG offspring (N 5 79) Mean7SD Mean7SD 0.971.3 N (%) 2 3 3 2 5 4 1 2 2 12 5 20 6 4 (8) (12) (12) (8) (19) (16) (4) (8) (8) (46) (19) (77) (25) (15) Boldfaced odds ratios considered as meaningful trends. w2(1) P value 0.571.0 N (%) 2.32 .13 1 4 6 4 6 9 1 4 4 23 4 44 20 9 2.52 1.08 0.37 0.24 2.52 0.35 0.60 0.24 0.21 2.48 4.31 3.65 0.00 0.28 (1) (5) (8) (5) (8) (11) (1) (5) (5) (29) (5) (56) (26) (11) OR .11 .30 .55 .63 .11 .55 .44 .63 .65 .12 .04 .06 .95 .60 6.8 2.3 1.6 1.6 2.9 1.5 3.1 1.6 2.1 4.5 2.6 1.0 1.4 118 Biederman et al. TABLE 4. Disorders in both parent probands and spouses (positive if both parents have the disorder, negative otherwise) Total no. of anxiety disorders in both parents Both parents have disorder Separation anxiety disorder Social phobia Obsessive–compulsive disorder Bipolar disorder Parents with PD/AG offspring (N 5 27) Parents without PD/AG offspring (N 5 79) Mean7SD Mean7SD 5.072.3 3.872.0 N (%) N (%) 1 3 0 1 (4) (12) (0) (4) 2 1 0 0 (3) (1) (0) (0) w2(1) P value 5.35 .02 OR 0.09 4.66 NA Exact test .76 .03 NA .25 1.5 10.2 NA NA NA, not applicable. Boldfaced odds ratios considered as meaningful trends. [1997, 2002] have shown that first-degree relatives of probands with PD and bipolar disorder have significantly greater risk for PD than first-degree relatives of probands with only bipolar disorder. Interestingly, rates of bipolar disorder reached statistical significance only in the spouses. This suggests that risk for pediatric PD/AG may be due to a combination of bipolar/panic genes whose transmission may come from the one or both parents. More work is needed to further evaluate these findings. The finding that parents with PD and comorbid obsessive–compulsive disorder (OCD) were more likely to have PD/AG offspring compared to parents with only PD is consistent with the finding by Nestadt et al. [2001]. These investigators reported that firstdegree relatives of OCD probands had significantly higher rates of PD and AG compared with first-degree relatives of controls. Findings from a latent class analysis by Nestadt et al. [2003] suggested that OCD associated with comorbid PD may constitute a distinct subtype of OCD (or PD). Our results suggest that children who have parents with this hypothesized subtype are at greater risk for pediatric-onset PD/AG. Our results showing that parental loading of anxiety disorders in general, and particularly social phobia, are associated with early-onset PD/AG in their children are also consistent with the literature. For example, Venturello [2002] found that early-onset PD patients had higher familial loading for psychiatric disorders in general and for PD in particular compared to patients with adult-onset PD. Although not reaching statistical significance, parents with PD/AG children had twice the rate of separation anxiety compared to parents without PD/ AG children. Because previous studies have shown a relationship between early separation anxiety disorder and subsequent development of early-onset PD in the same individual [Biederman et al., in press; Goodwin et al., 2001], more work is needed to evaluate whether separation anxiety in the parent is also a risk for earlyonset PD in the offspring. Contrary to our expectations, we did not find a relationship between the age of onset of PD in the parent and PD/AG in the children. This stands in contrast to some studies that found rates of PD in relatives to be higher if the proband had early-onset PD compared to adult-onset PD [Goldstein et al., 1997; Segui et al., 2000]. This inconsistency may be due to methodological differences between studies. In our study, we used onset of PD as a continuous outcome, and only 15% of our parent probands had onsets of PD before age 18. Our findings should be viewed in the context of some methodological limitations. It might be argued that it is unusual to diagnose AG during childhood. However, several research groups have identified high rates of AG among children presenting clinically with PD (range 12–80%) [Goodwin and Gotlib, 2004; Kearney et al., 1997; Masi et al., 2000] or among community children exposed to major stressors [14.8%; Hoven et al., 2005]. In all of these studies, AG was found even among children in younger age groups. Similar arguments about the rarity of PD in youngsters were advanced in the past, yet the field has progressed to recognize that, indeed, PD does present in youngsters, albeit with slightly different phenomenological manifestations at different points in development [Kearney et al., 1997; Ollendick, 1998]. In similar fashion, the diagnosis of AG in children requires consideration of developmental issues. Some of the specific situations usually associated with AG in adults do not apply to children. For example, young children do not go out to malls or stores alone, drive alone, or ride alone on trains. On the other hand, they are expected to go out in the yard alone, to go to other parts of the house (e.g., other floors) alone, and to crowded places, and it is these sorts of situations that are queried on the KSADS AG module we used and Research Article: Pediatric Panic Disorder/Agoraphobia reported in studies of the phenomenology of child AG [Biederman et al., 1997; Kearney et al., 1997]. Agoraphobic fears in children can be differentiated from separation anxiety. The children we diagnose with AG do not necessarily suffer from separation anxiety disorder (i.e., they do not present with worries about harm befalling their parents, difficulty separating to attend school or other activities, or a need constantly to be with their parents). Although they have fears about venturing to certain settings alone, they are able to do so when accompanied by anyone (e.g., a friend, a sibling, a baby-sitter), not just by a parent. The number of children with PD/AG was small, limiting our statistical power to detect statistically significant differences. Thus, our findings should be viewed as preliminary until confirmed in larger studies. Moreover, because the children were on average 7 years old, they were still well within the age of risk for onset of pediatric PD/AG. Further waves of follow-up of this sample will be necessary to confirm the results observed. Our psychiatric assessments were made using DSM-III-R criteria; therefore, results may vary slightly from those that would have been obtained using DSMIV criteria. Because proband parents were clinically referred, findings may not generalize to other populations of families with parents and children with PD/ AG. Since findings are retrospective, they could have been influenced by recall bias. Because our analysis was correlational, we cannot conclude that our findings in the parents are the cause of early-onset PD/AG in the children. 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