DEPRESSION AND ANXIETY 22:114–120 (2005)

Research Article

PARENTAL PREDICTORS OF PEDIATRIC PANICDISORDER/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 panicdisorder/agoraphobia (PD/AG) in offspring at high risk for PD/AG.Comparisons were made between parents with PD who had a child with PDor 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, andbipolar disorder in the parents with PD and their spouses accounted for the riskfor childhood onset PD/AG in the offspring. This risk was particularly high ifboth parents were affected with social phobia. These findings suggest thatpsychiatric comorbidity with other anxiety disorders and with bipolar disorderin parents with PD and their spouses confer a particularly high risk in theiroffspring 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

INTRODUCTIONA recent study of young children of parents withpanic disorder (PD) found that parental PD increasedthe risk for PD and agoraphobia (AG) in theiryoung offspring [Biederman et al., 2001]. However,because only a minority of high-risk childrendeveloped PD/AG in childhood, questions remain asto whether additional risk factors besides PD in theparent may account for early-onset PD in theoffspring.

The parents with PD had significantly elevated ratesof comorbidity with mood and other anxiety disorders,including separation anxiety disorder, simple phobia,obsessive–compulsive disorder, generalized anxietydisorder, and AG, raising the possibility that comor-bidity in the parents with PD may be a risk factor forearly-onset PD in their offspring [Biederman et al.,2004]. Similar findings have been documented in theextant literature, which has documented high comor-bidity between PD and bipolar disorder, obsessive–compulsive disorder, social phobia, and posttraumaticstress disorder [Goodwin and Hoven, 2002]. Also,because many adults with PD in our study had

early-onset PD, it is possible that early age of onsetof PD may breed true.

The main goal of this study was to evaluate riskfactors for early-onset PD/AG in children at risk forPD. To this end, we compared patterns of comorbidity

Published online 28 September 2005 in Wiley InterScience

(www.interscience.wiley.com).

DOI 10.1002/da.20122

Received for publication 24 June 2004; Revised 14 September

2004; Accepted 15 July 2005

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

1Pediatric Psychopharmacology Clinic, Massachusetts Gen-

eral Hospital, Boston, Massachusetts2Department of Psychiatry, SUNY Upstate Medical University,

Syracuse, New York3Department of Psychiatry, Harvard Medical School, Cam-

bridge, Massachusetts

rr 2005 Wiley-Liss, Inc.

and age of onset of PD in parents of children at risk,with and without PD/AG. We hypothesized that moodand other anxiety disorders, and early onset of PD inthe parent with PD, would be associated with earlyonset PD/AG in the offspring. To the best of ourknowledge, this issue has not been adequately ad-dressed previously in the literature.

METHODSSUBJECTS

Detailed study methodology has been reported inprevious publications [Rosenbaum et al., 2000]. Briefly,three groups of adult probands were recruited for astudy of behavioral inhibition in their offspring; theseindividuals were recruited from clinic referrals orin response to advertisements calling for adults intreatment 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 nohistory of either PD or AG and their 67 children; and(3) 61 comparison adults with neither major anxietynor mood disorders and their 119 children. Bothparents of all children were included in the study.Parents ranged in age from 24 to 53 years. Theirchildren’s ages ranged from 1 to 27 years, and allparents had at least one child age 2–6 years. Onlypatients who received a positive lifetime DSM-III-Rdiagnosis of PD or major depression by structuredpsychiatric interview, and who had been treated forthese disorders, were included in the PD and depres-sion groups. The comparison group of adults was freeof major anxiety disorders (PD, AG, social phobia,generalized anxiety disorder, or obsessive–compulsivedisorder) or mood disorders (major depression, bipolardisorder, or dysthymia) and were recruited throughadvertisements to hospital personnel and in communitynewspapers. This study was approved by the institutionalreview board, and all parents signed written informedconsent. Children assented to study procedures.

PROCEDURES

Parents received direct psychiatric assessments usingthe Structured Clinical Interview for DSM-III-R[SCID; Spitzer et al., 1990] for lifetime adult diag-noses, and supplements from the Kiddie Schedule forAffective Disorders and Schizophrenia—Epidemiolo-gical Version (KSADS-E) modules for childhooddisruptive behavior and anxiety disorders [Orvaschel,1994]. We conducted psychiatric assessments ofchildren age 5 and older by completing the KSADS-Ewith the mothers. Children under age 5 were notassessed for psychiatric disorders. Children age 12 andolder were interviewed directly by a separate inter-viewer. Children under 12 did not have direct inter-views, because they are limited in their expressive andreceptive language abilities, lack the ability to mapevents in time, and have limited powers of abstraction.

Given these limitations, there is a real question aboutwhether the young child’s self-perceptions, memories,feelings, and reported behavior can be reliably assessedthrough self-report. Although limited, studies on theuse of interview techniques among young childrenshow that their replies are unreliable [Achenbach et al.,1987; Breton et al., 1995; Edelbrock et al., 1985; Fallonand Schwab-Stone, 1994; Schwab-Stone et al., 1994].In contrast, Faraone et al. [1995] and others [Fallonand Schwab-Stone, 1994] have shown maternal reportsof psychopathology to reach high levels of reliability,even over a 1-year period.

We combined data from direct and indirect inter-views, and considered a diagnostic criterion positive ifit was endorsed in either interview. We assessedsocioeconomic status (SES) with the HollingsheadFour-Factor Index [Hollingshead, 1975], whichincludes information about subjects’ educational levelsand occupations.

Interviews were conducted by highly trained andsupervised raters with a bachelor’s degree in psychol-ogy under the supervision of the two senior investiga-tors (J. F. Rosenbaum and J. Biederman). Ratersunderwent a comprehensive training program in whichthey were required to (1) master the diagnosticinstruments, (2) learn about DSM-III-R criteria,(3) watch training tapes, (4) participate in interviewsperformed by experienced raters, and (5) rate severalsubjects under the supervision of the experiencedraters. Raters received ongoing supervision of theirassessments from senior project staff, and all interviewswere audiotaped for quality control. Diagnoses for allsubjects were made on the basis of a consensusjudgment by the same two senior investigators. Blindedevaluation was assured as follows: (1) Psychiatricinterviewers of parents were blind to the ascertainmentstatus of the parent (e.g., patient with PD, patient withmajor depression, comparison subject), and (2) the finaldiagnoses for all subjects were made by clinicians whowere blind to the subjects’ original recruitment group,to all nonpsychiatric data collected from the individualbeing diagnosed, and to all information about otherfamily members.

STATISTICAL ANALYSES

To determine the parental characteristics that putchildren at risk for early-onset PD/AG, we dividedfamilies into two groups: those with at least one childwith PD/AG and those with no children with PD/AG.Parents of these two groups were compared ondemographic variables, and all further analyses werecontrolled for demographic variables that differedbetween the groups. We then conducted three sets ofcomparisons between the two groups of families:psychiatric disorders in the parent probands of thetwo groups, disorders in the spouses of the parentprobands, and disorders present in both the parentproband and spouse. Therefore, differences between

115Research Article: Pediatric Panic Disorder/Agoraphobia

the two groups could be considered familial risk factorsfor pediatric PD/AG. Outcomes were assessed usinglogistic regression for binary variables, linear regres-sion for continuous variables, ordinal logistic regres-sion for ordinal variables, and negative binomialregression for count variables. All tests were two-tailedwith a set at a .05 level. Due to potential type II errorsgiven limited statistical power, odds ratios (ORs)greater than 2 were considered as meaningful trendsin these analyses.

RESULTSTo present a prudent analysis that was free of

ascertainment bias, our analysis was limited to families

in the panic disorder ascertainment group that includedprobands with PD and their spouses. Thus, each familyhad at least one parent with PD. Comparisons weremade between parent probands who had a child withPD/AG (Proband Parents with PD/AG offspring,N 5 27) and parent probands without children withPD/AG (Proband Parents without PD/AG offspring,N 5 79). Comparisons were also made between thespouses of these parent probands (Spouses with PD/AG offspring, N 5 27; Spouses without PD/AG off-spring, N 5 79). Neither proband parents nor theirspouses differed significantly on any of the demo-graphic variables assessed (Table 1).

There were 28 children coming from 27 families whohad PD or AG. Seventy-one percent of children with

TABLE 1. Demographics

Parent Probands withPD/AG offspring

(N 5 27)Parent Probands without

PD/AG offspring (N 5 79) P value

Age (Mean7SD) 38.276.4 38.575.4 F(1,104) 5 0.06 .81Males N (%) 4 (15) 9 (11) w2

(1) 5 0.22 .64Family socioeconomic status 2.271.1 2.370.9 w2

(1) 5 0.65 .42Family intact N (%) 64 (81) 22 (81) w2

(1) 5 0.00 .96

Spouses withPD/AG offspring

(N 5 27)

Spouses withoutPD/AG offspring

(N 5 79) P value

Age (Mean7SD) 39.776.1 39.575.6 F(1,104) 5 0.02 .88Males N (%) 23 (85) 70 (89) w2

(1) 5 0.22 .64

TABLE 2. Disorders in parent probands, all of whom have panic disorder

Parent probands withPD/AG offspring

(N 5 27)

Parent probands withoutPD/AG offspring

(N 5 79) Test statistic P value

Mean7SD Mean7SD

Age of onset of panic disorder 24.677.2 26.577.9 F(1,104) 5 1.17 .28Total no. of anxiety disorders 4.072.0 3.471.6 w2

(1) 5 1.89 .17N (%) N (%) w2

(1) OR

Avoidant disorder 1 (4) 5 (6) 0.28 .59 0.6Separation anxiety disorder 8 (30) 13 (16) 2.06 .15 2.1Overanxious disorder 14 (52) 30 (38) 1.58 .21 1.8Simple phobia 9 (33) 15 (19) 2.23 .14 2.1Social phobia 13 (48) 24 (30) 2.72 .10 2.1Generalized anxiety disorder 13 (48) 35 (44) 0.12 .73 1.2Obsessive–compulsive disorder 8 (30) 10 (13) 3.75 .05 2.9Agoraphobia 14 (52) 56 (71) 3.15 .08 0.4Major depressive disorder 21 (78) 60 (76) 0.04 .85 1.1Bipolar disorder 4 (15) 6 (8) 1.13 .29 2.1Psychoactive substance use disorders 12 (44) 42 (53) 0.61 .43 0.7Disruptive behavior disorders 5 (19) 19 (24) 0.36 .55 0.7Antisocial personality disorder 1 (4) 6 (8) 0.58 .45 0.5

�Boldfaced odds ratios considered as meaningful trends.

116 Biederman et al.

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 ofPD onset was 5.1 (SD 5 1.7, median 5 4.5) and rangedfrom 4 to 9 years of age. The mean age of AG onsetwas 4.6 (SD 5 1.6, median 5 4) and ranged from 4 to11 years of age. The age of children with PD/AG didnot differ significantly from the age of children withoutPD/AG (with PD/AG 5 6.873.0, without PD/AG 5 6.772.6, P 5.83).

Findings in Probands With PD. Proband Parentswith PD/AG offspring had higher rates [OR 4 2] ofobsessive–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 bipolardisorder (OR 5 2.1) compared with Proband Parentswithout PD/AG offspring. Neither mean number ofanxiety disorders nor age of onset of PD differedbetween the two groups of parents (Table 2).

Findings in Spouses. Spouses with PD/AG off-spring 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 pho-bia (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 withSpouses without PD/AG offspring. The mean numberof anxiety disorders did not differ between the twogroups of spouses (Table 3).

Findings in Both Parents. For disorders found tohave an OR greater than 2 in both the parent probandsand spouses (separation anxiety disorder, social phobia,obsessive–compulsive disorder, and bipolar disorder),we also examined the contribution of having twoparents afflicted with a given disorder. This analysis

showed that the rate of social phobia (OR 5 10.2,P 5.03) in both parents was higher in parents ofoffspring with PD/AG than in parents of offspringwithout PD/AG. In addition, we found that the totalnumber of anxiety disorders in both parents ofoffspring with PD/AG was higher compared to thetotal number of anxiety disorders in both parents ofoffspring without PD/AG (Ms: 5.072.3 vs. 3.872.0,P 5.02; Table 4).

DISCUSSIONIn an evaluation of parental risk factors for pediatric-

onset PD/AG in offspring at high risk for PD/AG,we found that separation anxiety disorder, socialphobia, obsessive–compulsive disorder, and bipolardisorder in parents with PD and their spousesaccounted for the risk for childhood-onset PD/AG inthe offspring. Further analysis of these four disordersshowed that this risk was particularly high if bothparents were affected with social phobia. In addition,the number of anxiety disorders in both parents waspredictive of pediatric-onset PD/AG in the children. Incontrast, age of onset of PD in the parent was not a riskfactor. These findings suggest that psychiatric comor-bidity with other anxiety disorders and with bipolardisorder in parents with PD and their spouses confer aparticularly high risk in their offspring to developPD/AG in childhood.

Our findings expand on the familial relationship ofbipolar disorder and PD with evidence that childrenare at greater risk for early-onset PD/AG if they haveparents with PD and bipolar disorder compared to onlya parent with PD. For example, MacKinnon et al.

TABLE 3. Disorders in spouses of parent probands

Spouses with PD/AGoffspring (N 5 27)

Spouses without PD/AGoffspring (N 5 79) w2

(1) P value

Mean7SD Mean7SD

Total no. of anxiety disorders 0.971.3 0.571.0 2.32 .13N (%) N (%) OR�

Avoidant disorder 2 (8) 1 (1) 2.52 .11 6.8Separation anxiety disorder 3 (12) 4 (5) 1.08 .30 2.3Overanxious disorder 3 (12) 6 (8) 0.37 .55 1.6Simple phobia 2 (8) 4 (5) 0.24 .63 1.6Social phobia 5 (19) 6 (8) 2.52 .11 2.9Generalized anxiety disorder 4 (16) 9 (11) 0.35 .55 1.5Obsessive–compulsive disorder 1 (4) 1 (1) 0.60 .44 3.1Agoraphobia 2 (8) 4 (5) 0.24 .63 1.6Panic disorder 2 (8) 4 (5) 0.21 .65Major depressive disorder 12 (46) 23 (29) 2.48 .12 2.1Bipolar disorder 5 (19) 4 (5) 4.31 .04 4.5Psychoactive substance use disorders 20 (77) 44 (56) 3.65 .06 2.6Disruptive behavior disorders 6 (25) 20 (26) 0.00 .95 1.0Antisocial personality disorder 4 (15) 9 (11) 0.28 .60 1.4

�Boldfaced odds ratios considered as meaningful trends.

117Research Article: Pediatric Panic Disorder/Agoraphobia

[1997, 2002] have shown that first-degree relatives ofprobands with PD and bipolar disorder have signifi-cantly greater risk for PD than first-degree relatives ofprobands with only bipolar disorder. Interestingly,rates of bipolar disorder reached statistical significanceonly in the spouses. This suggests that risk for pediatricPD/AG may be due to a combination of bipolar/panicgenes whose transmission may come from the one orboth parents. More work is needed to further evaluatethese findings.

The finding that parents with PD and comorbidobsessive–compulsive disorder (OCD) were morelikely to have PD/AG offspring compared to parentswith only PD is consistent with the finding by Nestadtet al. [2001]. These investigators reported that first-degree relatives of OCD probands had significantlyhigher rates of PD and AG compared with first-degreerelatives of controls. Findings from a latent classanalysis by Nestadt et al. [2003] suggested that OCDassociated with comorbid PD may constitute a distinctsubtype of OCD (or PD). Our results suggest thatchildren who have parents with this hypothesizedsubtype are at greater risk for pediatric-onset PD/AG.

Our results showing that parental loading of anxietydisorders in general, and particularly social phobia, areassociated with early-onset PD/AG in their childrenare also consistent with the literature. For example,Venturello [2002] found that early-onset PD patientshad higher familial loading for psychiatric disorders ingeneral and for PD in particular compared to patientswith adult-onset PD.

Although not reaching statistical significance, par-ents with PD/AG children had twice the rate ofseparation anxiety compared to parents without PD/AG children. Because previous studies have shown arelationship between early separation anxiety disorderand subsequent development of early-onset PD in thesame individual [Biederman et al., in press; Goodwinet al., 2001], more work is needed to evaluate whether

separation anxiety in the parent is also a risk for early-onset PD in the offspring.

Contrary to our expectations, we did not find arelationship between the age of onset of PD in theparent and PD/AG in the children. This stands incontrast to some studies that found rates of PD inrelatives to be higher if the proband had early-onsetPD compared to adult-onset PD [Goldstein et al.,1997; Segui et al., 2000]. This inconsistency may bedue to methodological differences between studies.In our study, we used onset of PD as a continuousoutcome, and only 15% of our parent probands hadonsets of PD before age 18.

Our findings should be viewed in the context of somemethodological limitations. It might be argued that it isunusual to diagnose AG during childhood. However,several research groups have identified high rates ofAG among children presenting clinically with PD(range 12–80%) [Goodwin and Gotlib, 2004; Kearneyet al., 1997; Masi et al., 2000] or among communitychildren exposed to major stressors [14.8%; Hovenet al., 2005]. In all of these studies, AG was found evenamong children in younger age groups. Similararguments about the rarity of PD in youngsters wereadvanced in the past, yet the field has progressed torecognize that, indeed, PD does present in youngsters,albeit with slightly different phenomenological mani-festations at different points in development [Kearneyet al., 1997; Ollendick, 1998].

In similar fashion, the diagnosis of AG in childrenrequires consideration of developmental issues. Someof the specific situations usually associated with AG inadults do not apply to children. For example, youngchildren do not go out to malls or stores alone, drivealone, or ride alone on trains. On the other hand, theyare expected to go out in the yard alone, to go to otherparts of the house (e.g., other floors) alone, and tocrowded places, and it is these sorts of situations thatare queried on the KSADS AG module we used and

TABLE 4. Disorders in both parent probands and spouses (positive if both parents have the disorder,negative otherwise)

Parents with PD/AGoffspring (N 5 27)

Parents without PD/AGoffspring (N 5 79) w2

(1) P value

Mean7SD Mean7SD

Total no. of anxiety disorders inboth parents

5.072.3 3.872.0 5.35 .02

Both parents have disorder N (%) N (%) OR

Separation anxiety disorder 1 (4) 2 (3) 0.09 .76 1.5Social phobia 3 (12) 1 (1) 4.66 .03 10.2Obsessive–compulsive disorder 0 (0) 0 (0) NA NA NABipolar disorder 1 (4) 0 (0) Exact test .25 NA

NA, not applicable.�Boldfaced odds ratios considered as meaningful trends.

118 Biederman et al.

reported in studies of the phenomenology of child AG[Biederman et al., 1997; Kearney et al., 1997].Agoraphobic fears in children can be differentiatedfrom separation anxiety. The children we diagnose withAG do not necessarily suffer from separation anxietydisorder (i.e., they do not present with worries aboutharm befalling their parents, difficulty separating toattend school or other activities, or a need constantly tobe with their parents). Although they have fears aboutventuring to certain settings alone, they are able to doso when accompanied by anyone (e.g., a friend, asibling, a baby-sitter), not just by a parent.

The number of children with PD/AG was small,limiting our statistical power to detect statisticallysignificant differences. Thus, our findings should beviewed as preliminary until confirmed in larger studies.Moreover, because the children were on average 7 yearsold, they were still well within the age of risk for onsetof pediatric PD/AG. Further waves of follow-up of thissample will be necessary to confirm the resultsobserved. Our psychiatric assessments were made usingDSM-III-R criteria; therefore, results may vary slightlyfrom those that would have been obtained using DSM-IV criteria. Because proband parents were clinicallyreferred, findings may not generalize to other popula-tions of families with parents and children with PD/AG. Since findings are retrospective, they could havebeen influenced by recall bias. Because our analysis wascorrelational, we cannot conclude that our findings inthe parents are the cause of early-onset PD/AG in thechildren.

Despite these limitations, this study documentsimportant parental risk factors associated with pedia-tric-onset PD/AG. Specifically, parents having socialanxiety and OCD and bipolar disorder in conjunctionwith PD confer a significant risk for their children todevelop pediatric-onset PD/AG. Although more re-search is needed to further clarify and confirm the risksfor pediatric PD/AG, awareness of these findings mayhelp parents with PD and their clinicians recognizethose children at very high risk to develop PD/AG inearly childhood.

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