Parental predictors of pediatric panic disorder/agoraphobia: a controlled study in high-risk offspring
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DEPRESSION AND ANXIETY 22:114120 (2005)
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 (N5 27) and parents with PD without children with PD or AG (N5 79).Comparisons were also made between the spouses of these parents with PD.Separation anxiety disorder, social phobia, obsessivecompulsive 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 22:114120,2005. & 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 rates
of comorbidity with mood and other anxiety disorders,including separation anxiety disorder, simple phobia,obsessivecompulsive 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, obsessivecompulsive 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 risk
factors 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
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., MassachusettsGeneral Hospital, Pediatric Psychopharmacology Research,
Yawkey Center for Outpatient Care, YAW-6A-6900, 32 Fruit
Street, Boston, MA 02114. E-mail: email@example.com
1Pediatric Psychopharmacology Clinic, Massachusetts Gen-
eral Hospital, Boston, Massachusetts2Department of Psychiatry, SUNY Upstate Medical University,
Syracuse, New York3Department of Psychiatry, Harvard Medical School, Cam-
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.
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. Theirchildrens ages ranged from 1 to 27 years, and allparents had at least one child age 26 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 obsessivecompulsivedisorder) 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.
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 SchizophreniaEpidemiolo-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 childs 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.  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 and
supervised raters with a bachelors 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.
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,N5 27) and parent probands without children withPD/AG (Proband Parents without PD/AG offspring,N5 79). Comparisons were also made between thespouses of these parent probands (Spouses with PD/AG offspring, N5 27; Spouses without PD/AG off-spring, N5 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 who
had PD or AG. Seventy-one percent of children with
TABLE 1. Demographics
Parent Probands withPD/AG offspring
(N5 27)Parent Probands withoutPD/AG offspring (N5 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
Spouses withoutPD/AG offspring
(N5 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
Parent probands withoutPD/AG offspring
(N5 79) Test statistic P value
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 .17
N (%) 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 1.2Obsessivecompulsive 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 (SD5 1.7, median5 4.5) and rangedfrom 4 to 9 years of age. The mean age of AG onsetwas 4.6 (SD5 1.6, median5 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/AG5 6.873.0, without PD/AG5 6.772.6, P5.83).Findings in Probands With PD. Proband Parents
with PD/AG offspring had higher rates [OR 4 2] ofobsessivecompulsive disorder (OR5 2.9; P5.02),social phobia (OR5 2.1), simple phobia (OR5 2.1),separation anxiety disorder (OR5 2.1), and bipolardisorder (OR5 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(OR5 4.5, P5.04), avoidant disorder (OR5 6.8),obsessivecompulsive disorder (OR5 3.1), social pho-bia (OR5 2.9), psychoactive substance use disorders(OR5 2.6), separation anxiety disorder (OR5 2.2),and major depression (OR5 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 to
have an OR greater than 2 in both the parent probandsand spouses (separation anxiety disorder, social phobia,obsessivecompulsive 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 (OR5 10.2,P5.03) 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,P5.02; 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, obsessivecompulsive 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 of
bipolar disorder and PD with evidence that childrenare at greater risk for early-onset PD/AG if they haveparents with PD and bipo...