dimensional psychopathology in preschool offspring of parents with bipolar disorder

Dimensional psychopathology in preschool offspringof parents with bipolar disorder

Hagai Maoz,1 Tina Goldstein,1 David A. Axelson,1 Benjamin I. Goldstein,2 Jieyu Fan,1

Mary Beth Hickey,1 Kelly Monk,1 Dara Sakolsky,1 Rasim S. Diler,1 David Brent,1 SatishIyengar,1 David J. Kupfer,1 and Boris Birmaher1

1Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine,Pittsburgh, PA, USA; 2Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto,

ON, Canada

Background: The purpose of this study is to compare the dimensional psychopathology, as ascertained by parentalreport, in preschool offspring of parents with bipolar disorder (BP) and offspring of community control parents.Methods: 122 preschool offspring (mean age 3.3 years) of 84 parents with BP, with 102 offspring of 65 controlparents (36 healthy, 29 with non-BP psychopathology), were evaluated using the Child Behavior Checklist (CBCL),the CBCL-Dysregulation Profile (CBCL-DP), the Early Childhood Inventory (ECI-4), and the Emotionality ActivitySociability (EAS) survey. Teachers’ Report Forms (TRF) were available for 51 preschoolers. Results: After adjustingfor confounders, offspring of parents with BP showed higher scores in the CBCL total, externalizing, somatic, sleep,aggressive, and CBCL-DP subscales; the ECI-4 sleep problem scale; and the EAS total and emotionality scale. Theproportion of offspring with CBCL T-scores ≥2 SD above the norm was significantly higher on most CBCL subscalesand the CBCL-DP in offspring of parents with BP compared to offspring of controls even after excluding offspring withattention deficit hyperactivity disorder and/or oppositional defiant disorder. Compared to offspring of parents withBP-I, offspring of parents with BP-II showed significantly higher scores in total and most CBCL subscales, the ECI-4anxiety and sleep scales and the EAS emotionality scale. For both groups of parents, there were significantcorrelations between CBCL and TRF scores (r = .32–.38, p-values ≤.02). Conclusions: Independent of categoricalaxis-I psychopathology and other demographic or clinical factors in both biological parents, preschool offspring ofparents with BP have significantly greater aggression, mood dysregulation, sleep disturbances, and somaticcomplaints compared to offspring of control parents. Interventions to target these symptoms are warranted.Keywords: BP, offspring, dimensional psychopathology.

IntroductionOnset of bipolar disorder (BP) usually occurs duringthe adolescent years, but initial symptoms mayappear earlier (Birmaher & Axelson, 2006; Leibenluft& Rich, 2008; Merikangas et al., 2012). BP signifi-cantly disrupts the normative developmental trajec-tory and is associated with serious psychosocialdifficulties in youth that continue into adulthood.Therefore, there is a need to promptly identify andtreat and/or prevent the early manifestations of thisillness (Birmaher & Axelson, 2006).

As the single most significant risk factor fordeveloping BP is a positive family history (Luby &Navsaria, 2010; Pavuluri, Henry, Nadimpalli, O’con-nor, & Sweeney, 2006), research aiming to identifyearly BP phenotypes has focused on offspring ofindividuals with BP. School-aged offspring of parentswith BP are specifically at risk for developing BP, butthey also are at high risk for other psychiatricdisorders, especially anxiety and disruptive disor-ders (Birmaher et al., 2009; Delbello & Geller, 2001).Studies focusing on dimensional psychopathology(as opposed to categorical diagnoses) show thatrelative to offspring of healthy or non-BP parents,school-aged offspring of parents with BP exhibit

more internalizing problems, aggression, irritability,depressed mood, rapid mood fluctuations, affectivedysregulation, anxiety symptoms, and attention andsleep difficulties (Dienes, Chang, Blasey, Adleman, &Steiner, 2002; Diler et al., 2011; Duffy, Alda, Craw-ford, Milin, & Grof, 2007; Giles, Delbello, Stanford, &Strakowski, 2007).

The scanty literature regarding preschool-agedoffspring of parents with BP suggest that similar tothe school-aged offspring, preschool offspring alsohave significantly higher rates of attention deficitand hyperactive disorder (ADHD), disruptive behav-ior disorders (DBDs), and anxiety disorders relativeto offspring of control parents (Hirshfeld-Beckeret al., 2006; Radke-Yarrow, Nottelmann, Martinez,Fox, & Belmont, 1992). For example, in the largestpreschool age high-risk study published to date, wedemonstrated higher rates of ADHD among pre-school offspring of parents with BP as compared withpreschool offspring of parents with non-BP psycho-pathology and preschool offspring of healthy con-trols after adjusting for confounding factors (e.g.,demographic factors and both biological parents’non-BP comorbid disorders) (Birmaher et al., 2010).

The above preschool offspring studies mainlyfocused on the presence of DSM categorical psycho-pathology. However, preschool-aged children oftenpresent psychiatric symptomatology that does notConflict of interest statement: No conflicts declared.

© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA

Journal of Child Psychology and Psychiatry 55:2 (2014), pp 144–153 doi:10.1111/jcpp.12137

fulfill full criteria for categorical diagnoses. Further-more, only evaluating categorical diagnoses mayobscure the detection of subthreshold symptomsthat may predate the onset of syndromal disorders.In fact, in our prior study, not a single child metDSM-IV criteria for BP, but preschool offspring ofparents with BP had significantly higher rates ofsubthreshold manic and depressive symptoms com-pared to offspring of controls (Birmaher et al., 2010).The few available preschool studies using dimen-sional methods also show that compared to offspringof controls, preschool offspring of parents with BPhave higher rates of behavioral disinhibition, disrup-tive and depressive symptoms, fidgetiness, hyperac-tivity, aggression, and difficulty managing anger andhostile impulses (Hirshfeld-Becker et al., 2006; Rad-ke-Yarrow et al., 1992; Zahn-Waxler et al., 1988).Thus, even though these preschoolers have not yetdeveloped BP or other axis-I psychopathology, theyexhibit a variety of psychopathological symptomsthat may precede the onset of full threshold disor-ders. However, the existing preschool studies exam-ining dimensional psychopathology are limited bysmall sample sizes and by only using offspring ofhealthy parents as a comparison group. The latterlimitation is important, as we do not know whetherthe increased rates of dimensional psychopathologyin preschool offspring of parents with BP is specifi-cally related to parental diagnosis of BP, comorbidnon-BP psychopathology, or environmental factorsassociated with parental psychopathology.

The main purpose of this study is to examine thepresence of dimensional psychopathology in pre-school offspring of parents with BP as compared withoffspring of control parents with and without non-BPpsychopathology. To our knowledge, this is the firstcomprehensive study to examine dimensional psy-chopathology in a large sample of preschoolers athigh risk to develop BP. On the basis of existingliterature, we hypothesized that after adjusting forany between-group significant demographic andclinical difference, offspring of parents with BPwould show higher levels of dimensional psychopa-thology, particularly aggressive behavior, attentionproblems, and emotional reactivity.

MethodsParticipants

Subjects included in this study were recruitedthrough the Pittsburgh Bipolar Offspring Study(BIOS). The methods employed in BIOS aredescribed in detail in prior publications (Birmaheret al., 2010). Briefly, 122 preschool offspring of 84parents (82.1% females) with BP-I (n = 51) or BP-II(n = 33) and 102 offspring of 65 control parents (36healthy and 29 with non-BP psychopathology,75.3% females) were recruited. The parents with BPwere recruited through advertisement (53%), adult

BP studies (31%), and outpatient clinics (16%).There were no differences between recruitmentsources in BP subtype, age at onset of BP, or ratesof comorbidity. Exclusion criteria for parents werecurrent or lifetime diagnoses of schizophrenia, men-tal retardation, and mood disorders secondary tosubstance abuse, medical conditions, or medica-tions. Control parents were group matched by age,sex, and neighborhood and recruited from the com-munity via telephone using random dialing by theUniversity Center for Social and Urban Research ofthe University of Pittsburgh (Birmaher et al., 2010).The exclusion criteria for the control parents werethe same, with the additional requirements thatneither biological parent had BP, nor a first-degreerelative with BP. However, control parents couldhave other psychiatric disorders. Except for childrenwith a condition that impeded their participation inthe study (e.g., mental retardation), all offspring aged2–5 from each family were included.

Procedures

The study was approved by the University of Pitts-burgh Institutional Review Board. Informed consentwas obtained from all parents. As described in detailelsewhere (Birmaher et al., 2010), parents wereevaluated using the Structured Clinical Interviewfor DSM-IV (SCID). The psychiatric history of thechild’s first- and second-degree relatives was ascer-tained using the Family History–Research DiagnosticCriteria method (FH-RDC) (Andreasen, Endicott,Spitzer, & Winokur, 1977) plus ADHD, separationanxiety disorder (SAD), and DBD items from theschedule for affective disorders and schizophreniafor School-Age Children–Present and Lifetime ver-sion [K-SADS-PL] (Kaufman et al., 1997). The kap-pas for all disorders were ≥0.8. Forty-six percent ofthe biological coparents were evaluated directlyusing the SCID; the rest were evaluated indirectlyusing the FH-RDC. There was no difference in ratesof direct assessments used to obtain the biologicalcoparent’s psychiatric disorders between BP parentsand controls. Socioeconomic status (SES) was ascer-tained using the Hollingshead scale (Hollingshead,1975). Parents were interviewed about their off-spring’s axis-I disorders using a modified version ofthe KSADS-PL. Details regarding the use and thepsychometrics of KSADS-PL for preschoolers aredescribed in detail elsewhere (Birmaher et al., 2010).

To comprehensively assess dimensional symptomsof psychopathology in preschool offspring, we uti-lized three parent-report questionnaires: the ChildBehavior Checklist for ages 1½–5 (CBCL 1½–5)(Achenbach, 2001), The Early Child Inventory-4(ECI-4) (Sprafkin, Volpe, Gadow, Nolan, & Kelly,2002) and the Emotionality Activity Sociability sur-vey (EAS) (Buss, 1984).

The CBCL 1½–5 contains 99 items and has sevensyndrome subscales, including emotionally reactive,

© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

doi:10.1111/jcpp.12137 Dimensional psychopathology in preschool offspring of bipolar parents 145

anxious/depressed, somatic complaints, withdrawn,sleep problems, attention problems, and aggressivebehavior. In addition, it yields scores for two broadgroupings of syndromes: the internalizing, consistingof the first four subscales mentioned above, and theexternalizing, consisting of the last two. T-scores ≥2standard deviations (SD) above normal have beenrecommended as a clinically meaningful thresholdfor deviation from age- and sex-matched healthychildren (Achenbach, 2001). We also calculated theCBCL-Dysregulation Profile (CBCL-DP) that includesthe sum of T-scores of anxious/depressed, attentionproblems, and aggressive behavior subscales (Kimet al., 2012; Mick, Biederman, Pandina, & Faraone,2003). The CBCL-DP has been shown to run infamilies and to be associated with severe psychopa-thology (Althoff, Verhulst, Rettew, Hudziak, & vander Ende, 2010; Diler et al., 2011). Collateral infor-mation was obtained using the Caregiver-TeacherReport Form (TRF) (Achenbach, 2001) for a sub-sample of preschoolers who attended preschoolprograms. The TRF contains six subscales that, withthe exception of the sleep problems subscale, areidentical to the CBCL.

The ECI-4 includes 108 symptoms scored 0(‘never’) to 3 (‘very often’) for the following DSM-IVpreschool psychiatric disorders: ADHD, ODD, con-duct disorder, SAD, MDD, dysthymia, pervasivedevelopmental disorder, posttraumatic stress disor-der, sleep problems, feeding problems, reactiveattachment disorder, and elimination disorders(Gadow, Sprafkin, & Nolan, 2001; Sprafkin et al.,2002). In addition, it contains individual screeningitems for other disorders (e.g., selective mutism,simple phobia). The ECI-4 has adequate psycho-metrics in community and clinical preschoolsamples.

The Emotionality Activity Sociability survey (EAS)evaluates four temperamental dimensions (emo-tionality, activity, sociability and shyness) thatappear early in life and are stable throughoutdevelopment (Buss, 1984). The EAS contains 20items, each rated from 1 (‘not characteristic ortypical for the child’) to 5 (‘very characteristic ortypical’).

Statistical analyses

We analyzed the CBCL raw and T-scores as per themanual instructions. Cutoff scores for each CBCLsubscale and the CBCL-DP were set at T-score ≥70and ≥210, respectively. The sum of the total scoreswas used for the ECI and the EAS.

We conducted analyses in several stages. First, weemployed univariate analyses using t-tests, chi-s-quare tests, and Fisher exact tests as appropriate tocompare between-group demographic and clinicalvariables for both parents and offspring. As it isimportant to evaluate whether dimensional psycho-pathology is present in offspring over and above the

effects of categorical diagnoses, we also comparedthe rates of categorical psychiatric disorders betweenthe two offspring groups. Second, we conductedmultivariate analysis using generalized linearmodeling in which we entered parental variableswith p-values <.2 in the univariate comparisons (i.e.,parental race, general functioning, comorbid anxietydisorders, ADHD, disruptive behavior disorders andSUD, coparents any axis-I disorder). Also, as somefamilies included more than one child, within-familycorrelations were adjusted using family unit as arandom effect in the mixed model. Third, we repeatedthe multivariate analysis above, controlling forbetween-group differences in rates of offspringDSM-IV categorical disorders. As expected, giventhe age of the sample, few preschoolers had TRFs.Thus, the TRF data were used to compare parentreport (i.e., CBCL) with teacher report using Pear-son’s correlations. All tests were two-sided with asignificance level set at 0.05.

ResultsParents

As shown in Table 1, there were no between-groupdemographic differences except that parents with BPwere significantly more likely to be Caucasian. Also,parents with BP had significantly greater rates ofnearly all psychiatric disorders than the controlparents (all p-values ≤.04) except for history ofseparation anxiety disorder, dysthymia, andbinge-eating disorders. Parents with BP had signif-icantly lower ratings of past and current overallfunctioning as assessed by the Global Assessment ofFunctioning (GAF). There were no statistical differ-ences in demographic and clinical factors betweenparents with BP-I and BP-II. The biological coparentsof offspring of parents with BP had significantlyhigher rates of any axis-I disorder than the coparentsof the controls (40.5% vs. 24.1%, v2 = 4.02, p = .05).In only two families, both parents had BP. Therewere no other significant differences between thecoparents.

Offspring

On average, 1.5 offspring per family were included inthe study. As shown in Table 2, there were nodemographic differences between offspring of par-ents with BP and offspring of controls. Thirty-two(26.2%) offspring of parents with BP had an axis-Idisorder compared to 10 (9.8%) offspring of thecontrols (p = .002). The most common disorderswere ADHD, oppositional defiant disorder (ODD),and anxiety disorders (mainly SAD), but only the rateof ADHD was significantly different between the twogroups of offspring. There were no differences inrates of psychiatric disorders between offspring ofparents with BP-I and BP-II.


146 Hagai Maoz et al. J Child Psychol Psychiatr 2014; 55(2): 144–53

Child Behavior Checklist (CBCL)

CBCLs were available for 218 offspring (97.3%). Asdepicted in Table 3, univariate analysis showed thatthe CBCL total and all subscales scores weresignificantly higher in the offspring of parents withBP than in the offspring of control parents (allp-values <.001). Adjusting for within-family correla-tions and between-group differences in parentaldemographic and clinical variables (i.e., parentalrace, general functioning, comorbid anxiety disor-ders, ADHD, disruptive behavior disorders andSUD, coparents’ any axis-I disorder), in comparisonwith offspring of the controls, offspring of parentswith BP had significantly higher scores in the CBCLtotal, externalizing, somatic complaints, sleep prob-lems, aggressive behavior and CBCL-DP. To evalu-ate whether the CBCL findings were accounted forby the higher prevalence of ADHD and a trend formore ODD in offspring of parents with BP, the

multivariate analysis was repeated also adjustingfor these disorders. This analysis yielded similarresults.

Significantly more offspring of parents with BP hadT-scores above the cutoff point (≥70) for all subscalesof CBCL except the somatic complaints subscale.The total, externalizing, sleep problems, and aggres-sive subscales remained significantly different evenafter excluding subjects with ADHD and ODD fromboth groups (23 offspring of BP parents and 6offspring of controls, Figure 1). Nineteen offspringof parents with BP (15.8%) compared to only 1 (1.0%)offspring of control parents had CBCL-DP ≥210(p < .001).

Both offspring of parents with BP-I and BP-IIshowed significantly higher raw and T-scores in allCBCL subscales compared to offspring of the con-trols. However, offspring of parents with BP-II hadhigher scores in total and almost all CBCL scores(e.g., externalizing and emotionally reactive) and the

Table 1 Demographic and clinical characteristics of parents with bipolar disorder (BP) and control parents

Parents with BP (n = 84) Control parents (n = 65) Statistics Overall p-value

(Age, years), mean (SD) 32.3 (5.6) 33.8 (7.56) T = 1.25 .22Sex (female), N (%) 69 (82.1) 49 (75.3) v2 = 0.22 .64Race (Caucasian), N (%) 75 (89.3) 48 (73.8) v2 = 6.8 .01SES, mean (SD) 35.6 (14.6) 38.8 (15.2) T = 1.27 .21Number of offspring, mean (SD) 2.4 (1.1) 2.3 (1.0) T = 0.17 .86GAF Current, mean (SD) 63.94 (12.9) 82.12 (12.0) T = 10.68 <.001

Highest in past 72.16 (10.6) 84.62 (10.1) T = 8.80 <.001Most severe in past 36.94 (15.4) 70.60 (16.2) T = 15.67 <.001

Any axis-I disorder, N (%) 84 (100.0) 29 (44.6) v2 = 61.3 <.001Bipolar I disorder 51 (60.7) 0 (0.0) FET <.001Bipolar II disorder 33 (39.3) 0 (0.0) FET <.001Depressive disordersa 0 (0.0) 16 (24.6) FET <.001Anxiety Disordersb 58 (69.0) 13 (20.0) v2 = 35.6 <.001ADHD 19 (22.6) 3 (4.6) v2 = 9.46 .003DBD 26 (31.0) 7 (10.8) v2 = 11.7 <.001SUD 50 (59.5) 19 (29.2) v2 = 13.9 <.001

Values are bolded in order to denote statistical significance.SES, socioeconomic status; ADHD, attention deficit hyperactivity disorder; DBDs, disruptive behavior disorder; SUDs, substanceuse disorders; GAF, Global Assessment of Functioning; FET, Fisher’s exact test.aMajor depression and dysthymic disorder.bGeneralized anxiety, separation anxiety, panic disorder, obsessive–compulsive disorder and posttraumatic stress disorder.

Table 2 Demographic and clinical characteristics of offspring of parents with bipolar disorder (BP) and offspring of control parents

Offspring of parentswith BP (n = 122)

Offspring of controlparents (n = 102) Statistics Overall p-value

Age, years, mean (SD) 3.28 (1.23) 3.24 (1.18) F = 0.03 .85Sex (female), N (%) 63 (51.6) 45 (44.1) v2 = 1.61 .21Race (Caucasian), N (%) 97 (79.5) 79 (77.5) v2 = 0.35 .55Living with both biological parents, N (%) 81 (66.4) 77 (75.5) v2 = 2.16 .14Any axis-I disorder, N (%) 32 (26.2) 10 (9.8) v2 = 9.97 .002

Any mood disordera 3 (2.5) 0 (0.0) FET .25Any anxiety disorderb 13 (10.7) 5 (4.9) v2 = 2.47 .1ADHD 19 (15.6) 2 (2.0) v2 = 12.21 <.001ODD 14 (11.5) 5 (4.9) v2 = 3.70 .07≥2 axis-I disorders 21 (17.2) 7 (6.9) v2 = 5.42 .02

Values are bolded in order to denote statistical significance.ADHD, attention deficit hyperactivity disorder; ODD, oppositional defiant disorder; FET, Fisher’s exact test.aBipolar disorder not otherwise specified (2 offspring) and depressive disorder (1 offspring).bGeneralized anxiety, separation anxiety, panic disorder, obsessive–compulsive disorder and posttraumatic stress disorder.



CBCL-DP than the offspring of parents with BP-I(p-values ≤.03). These results were adjusted formultiple comparisons, yielding similar results.

Caregiver–Teacher Reports (TRF)

TRFs were available for 53.3% of the preschoolers(56/105). Five reports were incomplete, leaving atotal of 51 TRFs (23 offspring of parents with BP and

28 offspring of control parents). There were nodemographic or clinical differences between childrenwhose caregivers did or did not complete the TRFs.Pearson’s correlations for total, internalizing, andexternalizing scores of the parent’s CBCL and theTRF ranged from 0.32 to 0.38 (all p-values ≤.02).There were no significant differences in the CBCLcorrelations with the TRF between parents with BPand control parents.

Table 3 Mean raw scores of Child Behavior Checklist (CBCL), Dysregulation Profile (CBCL-DP), Early Child Inventory (ECI) andEmotionality Activity Sociability (EAS) scale in offspring of parents with BP and offspring of control parents

Offspring of parentswith BP (n = 120)

Offspring of controlparents (n = 98) F stat

Unadjustedp-value

Adjustedp-valuesa

Adjustedp-valuesb

CBCL, mean (SD)Total 46.97 (30.2) 23.64 (18.7) 44.59 <.001 .05 .02Internalizing 11.78 (9.6) 5.38 (5.8) 33.60 <.001 .13 .31Externalizing 18.53 (12.5) 9.73 (7.9) 36.67 <.001 <.01 .03Emotionally reactive 3.72 (3.5) 1.63 (2.1) 26.79 <.001 .07 .36Anxious/depressed 3.76 (3.3) 1.89 (2.2) 23.30 <.001 .50 .84Somatic complaints 2.05 (2.1) 0.82 (1.5) 24.02 <.001 <.01 .03Withdrawn 2.25 (2.5) 1.04 (1.6) 17.74 <.001 .14 .29Sleep problems 4.37 (3.2) 2.31 (2.4) 27.60 <.001 <.01 <.01Attention problems 3.39 (2.7) 1.83 (1.8) 24.98 <.001 .13 .38Aggressive behavior 15.13 (10.4) 7.91 (6.7) 35.30 <.001 <.01 .03CBCL-DP 22.18 (14.7) 11.62 (9.3) 16.53 <.001 .02 .03

ECI, mean (SD)c

ADHD 20.79 (12.0) 13.29 (9.2) 26.03 <.001 .24 .56ODD 9.15 (6.3) 5.11 (4.4) 27.54 <.001 .03 .14Conduct disorder 3.11 (4.4) 1.23 (2.2) 14.49 <.001 .15 .17MDD 5.69 (3.5) 4.13 (2.4) 13.56 <.001 .24 .52Dysthymia 4.23 (2.9) 2.95 (2.0) 13.36 <.001 .22 .55SAD 4.14 (4.3) 1.98 (2.3) 19.41 <.001 .10 .15Generalized Anxiety 7.66 (4.6) 4.55 (3.6) 28.78 <.001 .03 .15Sleep disorder 3.83 (2.6) 2.45 (2.0) 17.79 <.001 <.01 <.01

EAS, mean (SD)d

Total 65.27 (7.3) 61.36 (6.8) 16.32 <.001 .01 .05Emotionality 14.90 (5.1) 11.38 (4.4) 28.74 <.001 <.01 <.01Shyness 12.71 (4.6) 12.56 (4.2) 0.06 .81 .60 .54Activity 20.57 (3.4) 20.43 (3.1) 0.18 .76 .39 .48Sociability 17.00 (3.3) 16.67 (3.1) 0.62 .43 .25 .25

Values are bolded in order to denote statistical significance.aOverall p-values are adjusted for proband’s race, current GAF, ADHD, DBD, anxiety disorders and SUD, co-parent’s any axis-Idisorder.bAdjusting for parental factors as mentioned plus offspring’s ADHD and ODD.cn = 209 (113 offspring of parents with BP, 96 offspring of controls).dn = 217 (119 offspring of parents with BP, 98 offspring of controls).

0

5

10

15

20

25

offspring of parents with BP

Offspring of parents with BP excluding offspring with ADHD and/or ODDOffspring of control parents

Offspring of control parents excluding offspring with ADHD and/or ODD

Figure 1 Percentage of preschool offspring with T-score >2SD above norm. *p ≤ .01 (after excluding offspring with ADHD and/or ODD)



Early Childhood Inventory – 4 (ECI-4)

The ECI-4 was available for 209 offspring (93.3% ofthe total sample). There was no difference in rate ofECI-4 completion between offspring of parents withBP and offspring of control parents. Also, there wereno significant demographic and clinical differencesbetween offspring with and without ECI-4. The meanECI-4 unadjusted scores in all ECI-4 categories weresignificantly higher in offspring of parents with BPcompared to offspring of control parents. Afteradjusting for between-group parental differences,offspring of parents with BP had significantly higherscores in ODD, generalized anxiety disorder, andsleep problems. However, after adjusting for thepresence of offspring categorical ADHD and/or ODDdiagnoses, the only between-group significant differ-ence that remained significant was the sleep prob-lems category (Table 3). Offspring of parents withBP-II had higher anxiety and sleep problems cate-gory scores compared to offspring of parents withBP-I (p-values = .04).

Emotionality Activity sociability (EAS) survey

The EAS was available for 96% of the sample.Offspring of parents with BP had significantly higherscores in total EAS and the emotionality scalecompared to offspring of the controls (Table 3).These differences remained significant after adjust-ing for between-group parental demographic andclinical variables and offspring ADHD and/or ODD.

Offspring of parents with BP-II had higher scoresin the emotionality scale compared to offspring ofparents with BP-I (p-value = .05).

There was a significant positive correlationbetween the emotionality scale and total EAS andthe CBCL-DP score (R = .67 and 0.59 respectively,p-values ≤.01).

DiscussionIn a previous paper, we showed that preschooloffspring of parents with BP were more likely to haveADHD and to have two or more psychiatric disor-ders, compared to offspring of control parents(Birmaher et al., 2010). However, only analyzingthe prevalence of categorical disorders in preschooloffspring does not give a complete picture of theirpsychopathology. In this study, preschool offspringof parents with BP showed significantly higher levelsof dimensional psychopathology compared to pre-school offspring of community controls, independentof between-group differences in parental demo-graphic and clinical factors, as well as differentialrates of categorical disorders in offspring. Specifi-cally, they showed higher scores in the CBCL total,externalizing, somatic, sleep, aggressive, andCBCL-DP subscales, the ECI-4 sleep problems scaleand the EAS total and emotionality scales. Further

analysis showed that the proportion of offspring withCBCL T-scores ≥2 SD above the norm was signifi-cantly higher in most CBCL subscales in offspring ofparents with BP compared to offspring of the con-trols after adjusting for confounding factors and evenafter excluding offspring with ADHD and/or ODD(Figure 1).

Unexpectedly, most of the CBCL scores, the ECI-4anxiety and sleep scales, and EAS emotionalityscores were significantly higher in offspring of par-ents with BP-II when compared with offspring ofparents with BP-I.

Similar to our results, the limited available litera-ture has reported more dimensional psychopathol-ogy in preschool offspring of parents with BP whencompared to offspring of controls (Hirshfeld-Beckeret al., 2006; Radke-Yarrow et al., 1992; Zahn-Waxler et al., 1988). These findings could have beenattributed to higher prevalence of categorical psy-chopathology in the offspring (e.g., ADHD) and theparents, as well as to poor individual and familyfunctioning found in parents with BP when com-pared with control parents (Fagiolini et al., 2005;Moreno et al., 2012).

High rates of psychopathology have also beenreported in school-aged offspring of parents withother axis-I disorders, raising the possibility that theabove-noted findings may not be specific for off-spring of parents with BP (Goodman et al., 2011).However, in our study, even after adjusting for othernon-BP parental axis-I disorders, the offspring ofparents with BP continued to show more dimen-sional psychopathology than the offspring of thecontrols, suggesting that these symptoms indeed arespecific for preschool offspring of parents with BP.

Using different instruments, higher rates ofexternalizing problems have been found in severalhigh-risk studies of school-age and preschoolchildren of parents with BP compared to offspring ofcontrols (Duffy et al., 2007; Farchione et al., 2007;Giles et al., 2007; Radke-Yarrow et al., 1992; Shaw,Egeland, Endicott, Allen, & Hostetter, 2005;Zahn-Waxler et al., 1988). The externalizing subscaleof the CBCL includes the aggressive behavior (e.g.,behavioral problems, defiance, hostility, and temperoutbursts) and the attention subscales. In our study,in the univariate analyses, both the attention andaggression subscales were significantly higher in thepreschoolers of parents with BP. However, only theaggression subscale remained significant in the mul-tivariate analysis. The presence of aggression inoffspring at high risk for BP is a consistent finding inthe literature (Conus et al., 2008; Diler et al., 2011;Farchione et al., 2007;Giles et al., 2007;Henin et al.,2005; Shaw et al., 2005). Studies in school-agechildren show that aggressive and other externalizingbehaviors are associated with the development ofdisruptive, anxiety, depression, and substance usedisorders during adolescence and adulthood in com-munity samples (Reef, Diamantopoulou, van Meurs,



Verhulst, & van der Ende, 2011; Stringaris &Goodman, 2009). However, in the context of familyhistory for BP, aggression may be associated withincreased risk for BP. In contrast to aggressivesymptoms, perhaps due to methodological differ-ences, studies evaluating the association betweenattention problems among youth and the risk for BPyield inconsistent results (Diler et al., 2011; Duffy,2012; Farchione et al., 2007; Giles et al., 2007; Shawet al., 2005).

The CBCL-DP, which is composed of the aggres-sion, attention, and the anxious/depressed sub-scales of the CBCL, was also significantly higher inoffspring of parents with BP when compared withoffspring of the controls. This phenotype has beenassociated with emotional and behavioral dysregu-lation in preschoolers (Kim et al., 2012). Across ages,children with the CBCL-DP tend to exhibit mooddysregulation, poor overall functioning, marked psy-chosocial impairment and high risk for ADHD,anxiety, BP, and cluster B personality disorders(Althoff et al., 2010; Meyer et al., 2009). As with theexternalizing findings noted above, aggression wasthe only subscale that remained significant afteradjusting for several confounding factors, suggestingagain that aggression may be specifically related tofamilial loading for BP.

The EAS emotionality scores, which were signif-icantly correlated with the CBCL-DP, were alsosignificantly higher in offspring of parents with BP.The emotionality scale represents a global patternof distress and a temperamental tendency tobecome easily and intensely aroused (Buss,1984). Despite methodological differences in theliterature, high emotional reactivity is one of themost consistent findings in preschool- andschool-aged offspring of parents with BP (Conuset al., 2008; Luby & Navsaria, 2010; Shaw et al.,2005). These offspring have higher levels of irrita-bility, are easily excited, and exhibit problems inemotional regulation compared to offspring ofcontrols (Farchione et al., 2007; Shaw et al.,2005). High emotional reactivity has also beenassociated with future depression, disruptive, andanxiety disorders (Reef et al., 2011; Roza, Hofstra,van der Ende, & Verhulst, 2003; Stringaris,Maughan, & Goodman, 2010) and increased riskfor BP in the context of family history of BP (Conuset al., 2008; Luby & Navsaria, 2010).

Some, but not all, studies report that offspring ofparents with BP have high rates of anxiety anddepressive symptoms (Duffy et al., 2007; Egelandet al., 2012; Shaw et al., 2005). In the univariateanalyses of the CBCL and the ECI-4, we also foundthat anxiety and depressive symptoms were higherin offspring of parents with BP. However, thesedifferences were no longer significant after adjustingfor confounding factors, suggesting that these symp-toms might be associated with general parentalpsychopathology and not specifically with BP.

One of the most significant findings in our studywas the presence of sleep disturbances in offspringof parents with BP. The CBCL and ECI-4 sleepdisturbances were not accounted for by parentalpsychopathology and presence of ADHD and ODD inthe preschoolers. Moreover, it was the only findingthat survived the multiple regressions in the ECI-4.Similar findings have been reported in school-agestudies. These studies suggest that sleep distur-bances may precede the onset of BP (Dienes et al.,2002; Duffy et al., 2007; Luby & Navsaria, 2010;Shaw et al., 2005). However, sleep problems are alsoassociated with the development of other behavioraland emotional problems including aggression, anx-iety, and depression (Gregory & Sadeh, 2012); Asthese are also more prevalent in offspring of parentswith BP (Birmaher et al., 2009), there is a need forlongitudinal studies to verify whether early-onsetsleep disturbances are indeed a prodromal symptomfor BP in offspring of parents with this disorder.

Interestingly, after adjusting for confounding fac-tors, the scores in the somatic complaints subscaleof the CBCL, which includes items like headachesand gastrointestinal symptoms, were significantlyhigher in the offspring of parents with BP. A recentstudy in the Amish community also reported thatsomatic complaints in preschool offspring of parentswith BP-I might represent a prodromal symptom forBP-I (Egeland et al., 2012). Moreover, the presence ofsomatic symptoms was found to be correlated withfuture depressive disorders in adolescents, while thenumber of somatic symptoms was associated withfuture development of mania in adolescents withdepression (Bohman et al., 2012). It is yet to beestablished by longitudinal data whether increasedsomatic symptoms in preschool offspring of parentswith BP predict future psychopathology, especiallyBP.

Unexpectedly, after adjusting for confounding fac-tors and multiple comparisons, offspring of parentswith BP-II had significantly higher dimensional psy-chopathology compared to offspring of parents withBP-I. To our knowledge, there is only one other studythat showed that school-aged offspring of parentswith BP-II have more ADHD, anxiety, and mooddisorders compared to offspring of parents with BP-I(Garcia-Amador et al., 2013). The reasons for thesefindings are unclear as there were no demographic,clinical, and treatment differences between parentswith BP-I and II. However, these analyses werecross-sectional; longitudinal studies of adults withBP show that individuals with BP-II exhibit a morechronic course with more frequent depressive epi-sodes and more unstable interpersonal relationshipsand social maladjustment compared to patients withBP-I (Baek et al., 2011; Judd et al., 2003).

Similar to the literature (Achenbach, 2001;Berg-Nielsen, Solheim, Belsky, & Wichstrom,2012), there were significant moderate correlationsbetween the CBCLs and the TRFs and all parents.



Moreover, there were no differences in the correla-tions between the parents and teachers for bothgroups of parents, suggesting that parents with BPwere not over reporting symptoms in their offspring.

The results of this study need to be considered inthe light of the following limitations. First,psychopathology was assessed using only parentalreports, and we did not perform direct evaluationsand observations of the preschoolers. Second, theparents with BP who agreed to participate in BIOScould have had more psychopathology than thosewho refused to participate. However, the rates ofpsychiatric comorbidity and level of functioning inparents with BP in our study are similar to thosereported in the adult BP literature (Kessler, Meri-kangas, & Wang, 2007). Third, as expected, very fewpreschoolers had teachers’ reports. Finally, as this isa cross-sectional study, we do not know whether thefindings are stable over time. However, studiesanalyzing the continuity of psychopathology frompreschool age through adolescence show high sta-bility, especially for externalizing problems (Bufferd,Dougherty, Carlson, Rose, & Klein, 2012; Janson &Mathiesen, 2008).

In conclusion, the results of this study suggestthat independent of categorical axis-I psychopathol-ogy and other demographic or clinical factors in bothbiological parents, preschool offspring of parentswith BP, particularly offspring of parents with BP-II,have more dimensional psychopathology comparedto offspring of control parents. Specifically, they

showed more aggression, emotional dysregulation,sleep disturbances, and somatic complains. Giventhe distress and impairment associated with thispsychopathology and the risk to develop future moodand disruptive disorders, treating children withthese problems and their families is clearly indicated(Furlong et al., 2012; Luby, Lenze, & Tillman, 2012).Furthermore, considering that more than 75% ofthese offspring have not manifested any categoricalpsychiatric illness at intake, there is an importantopportunity for preventive interventions in thishigh-risk population (Garber et al., 2009; Miklowitzet al., 2011). In addition to targeting child’s psycho-pathology, addressing the parental own psychopa-thology is important as several studies have shownthat improvement of parental symptoms is associ-ated with prevention and/or amelioration of psycho-pathology in their offspring (Wickramaratne et al.,2011).

AcknowledgementsThis work is supported by NIMH Grant MH060952 (PI:Birmaher). The authors have declared that they have nocompeting or potential conflicts of interest.

CorrespondenceHagai Maoz, Western Psychiatric Institute and Clinic,3811 O’Hara Street, Bellefield Towers, Pittsburgh, PA,USA; Email: [email protected]; [email protected]

Key points

• School-aged offspring of parents with BP show more internalizing and externalizing psychopathology whencompared to offspring of healthy parents or parents with non-BP psychopathology.

• However, studies regarding preschool offspring of parents with BP are scant and limited.

• This study shows that independent of categorical axis-I psychopathology (e.g., ADHD), and other demographicor clinical factors in both biological parents, preschool offspring of parents with BP have more aggression,emotional dysregulation, sleep disturbances, and somatic complains compared to offspring of control parents(with and without other axis-I psychopathology).

• Longitudinal studies are warranted to assess whether the above-noted dimensional psychopathology inpreschool age is associated with future BP or other axis-I psychopathology.

ReferencesAchenbach, T. M. (2001). Manual for the Achenbach System of

Empirically Based Assessment Preschool Forms and Profiles.Burlington, VT: University of Vermont.

Althoff, R.R., Verhulst, F.C., Rettew, D.C., Hudziak, J.J., & vander Ende, J. (2010). Adult outcomes of childhooddysregulation: A 14-year follow-up study. Journal of theAmerican Academy of Child and Adolescent Psychiatry, 49,1105–1116.

Andreasen, N.C., Endicott, J., Spitzer, R.L., & Winokur, G.(1977). The family history method using diagnostic criteria.Reliability and validity. Archives of General Psychiatry, 34,1229–1235.

Baek, J.H., Park, D.Y., Choi, J., Kim, J.S., Choi, J.S., Ha, K.,…& Hong, K.S. (2011). Differences between bipolar I andbipolar II disorders in clinical features, comorbidity, andfamily history. Journal of Affective Disorders, 131, 59–67.

Berg-Nielsen, T.S., Solheim, E., Belsky, J., & Wichstrom, L.(2012). Preschoolers’ psychosocial problems: In the eyesof the beholder? Adding teacher characteristics asdeterminants of discrepant parent-teacher reports. ChildPsychiatry and Human Development, 43, 393–413.

Birmaher, B., & Axelson, D. (2006). Course and outcome ofbipolar spectrum disorder in children and adolescents: Areview of the existing literature. Development andPsychopathology, 18, 1023–1035.



Birmaher, B., Axelson, D., Goldstein, B., Monk, K., Kalas, C.,Obreja, M., … & Kupfer, D. (2010). Psychiatric disorders inpreschool offspring of parents with bipolar disorder: ThePittsburgh Bipolar Offspring Study (BIOS). American Journalof Psychiatry, 167, 321–330.

Birmaher, B., Axelson, D., Monk, K., Kalas, C., Goldstein, B.,Hickey, M.B., … & Brent, D. (2009). Lifetime psychiatricdisorders in school-aged offspring of parents with bipolardisorder: The Pittsburgh Bipolar Offspring study. Archives ofGeneral Psychiatry, 66, 287–296.

Bohman, H., Jonsson, U., Paaren, A., von Knorring, L., Olsson,G., & von Knorring, A.L. (2012). Prognostic significance offunctional somatic symptoms in adolescence: A 15-yearcommunity-based follow-up study of adolescents withdepression compared with healthy peers. BMC Psychiatry,12, 90.

Bufferd, S.J., Dougherty, L.R., Carlson, G.A., Rose, S., & Klein,D.N. (2012). Psychiatric disorders in preschoolers:Continuity from ages 3 to 6. American Journal ofPsychiatry, 169, 1157–1164.

Buss, A.H. (1984). Temperament: Early developing personalitytraits. Hillsdale, NJ: Lawrence Erlbaum.

Conus, P., Ward, J., Hallam, K.T., Lucas, N., Macneil, C.,McGorry, P.D., & Berk, M. (2008). The proximal prodrome tofirst episode mania–a new target for early intervention.Bipolar Disorders, 10, 555–565.

Delbello, M.P., & Geller, B. (2001). Review of studies of childand adolescent offspring of bipolar parents. BipolarDisorders, 3, 325–334.

Dienes, K.A., Chang, K.D., Blasey, C.M., Adleman, N.E., &Steiner, H. (2002). Characterization of children of bipolarparents by parent report CBCL. Journal of PsychiatricResearch, 36, 337–345.

Diler, R.S., Birmaher, B., Axelson, D., Obreja, M., Monk, K.,Hickey, M.B., … & Kupfer, D. (2011). Dimensionalpsychopathology in offspring of parents with bipolardisorder. Bipolar Disorders, 13, 670–678.

Duffy, A. (2012). The nature of the association betweenchildhood ADHD and the development of bipolar disorder:A review of prospective high-risk studies. American Journalof Psychiatry, 169, 1247–1255.

Duffy, A., Alda, M., Crawford, L., Milin, R., & Grof, P. (2007).The early manifestations of bipolar disorder: A longitudinalprospective study of the offspring of bipolar parents. BipolarDisorders, 9, 828–838.

Egeland, J.A., Endicott, J., Hostetter, A.M., Allen, C.R., Pauls,D.L., & Shaw, J.A. (2012). A 16-year prospective study ofprodromal features prior to BPI onset in well Amish children.Journal of Affective Disorders, 142, 186–192.

Fagiolini, A., Kupfer, D.J., Masalehdan, A., Scott, J.A., Houck,P.R., & Frank, E. (2005). Functional impairment in theremission phase of bipolar disorder. Bipolar Disorders, 7,281–285.

Farchione, T.R., Birmaher, B., Axelson, D., Kalas, C., Monk,K., Ehmann, M., … & Brent, D. (2007). Aggression, hostility,and irritability in children at risk for bipolar disorder.Bipolar Disorders, 9, 496–503.

Furlong, M., Mcgilloway, S., Bywater, T., Hutchings, J., Smith,S. M., & Donnelly, M. (2012). Behavioural andcognitive-behavioural group-based parenting programmesfor early-onset conduct problems in children aged 3 to12 years. Cochrane Database Systematic Review, 2,CD008225.

Gadow, K.D., Sprafkin, J., & Nolan, E.E. (2001).DSM-IVSymptoms in community and clinic preschoolchildren. Journal of the American Academy of Child andAdolescent Psychiatry, 40, 1383–1392.

Garber, J., Clarke, G.N., Weersing, V.R., Beardslee, W.R.,Brent, D.A., Gladstone, T.R., … & Iyengar, S. (2009).Prevention of depression in at-risk adolescents: Arandomized controlled trial. JAMA, 301, 2215–2224.

Garcia-Amador, M., de la Serna, E., Vila, M., Romero, S.,Valenti, M., Sanchez-Gistau, V., … & Castro-Fornieles, J.(2013). Parents with bipolar disorder: Are diseasecharacteristics good predictors of psychopathology inoffspring? Eur Psychiatry, 28, 240–246.

Giles, L.L., Delbello, M.P., Stanford, K.E., & Strakowski, S.M.(2007). Child behavior checklist profiles of children andadolescents with and at high risk for developing bipolardisorder. Child Psychiatry and Human Development, 38,47–55.

Goodman, S.H., Rouse, M.H., Connell, A.M., Broth, M.R., Hall,C.M., & Heyward, D. (2011). Maternal depression and childpsychopathology: A meta-analytic review. Clinical Child andFamily Psychology Review, 14, 1–27.

Gregory, A.M., & Sadeh, A. (2012). Sleep, emotional andbehavioral difficulties in children and adolescents. SleepMedicine Reviews, 16, 129–136.

Henin, A., Biederman, J., Mick, E., Sachs, G.S.,Hirshfeld-Becker, D.R., Siegel, R.S., … & Nierenberg, A.A.(2005). Psychopathology in the offspring of parents withbipolar disorder: A controlled study. Biological Psychiatry,58, 554–561.

Hirshfeld-Becker, D.R., Biederman, J., Henin, A., Faraone,S.V., Cayton, G.A., & Rosenbaum, J.F. (2006).Laboratory-observed behavioral disinhibition in the youngoffspring of parents with bipolar disorder: A high-risk pilotstudy. American Journal of Psychiatry, 163, 265–271.

Hollingshead, A. D. B. (1975). Four factor index of social status.New Haven, Conn: Yale University, Dept. of Sociology.

Janson, H., & Mathiesen, K.S. (2008). Temperament profilesfrom infancy to middle childhood: Development andassociations with behavior problems. DevelopmentalPsychology, 44, 1314–1328.

Judd, L.L., Schettler, P.J., Akiskal, H.S., Maser, J., Coryell, W.,Solomon, D., … & Keller, M. (2003). Long-term symptomaticstatus of bipolar I vs. bipolar II disorders. InternationalJournal of Neuropsychopharmacology, 6, 127–137.

Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C.,Moreci, P., … & Ryan, N. (1997). Schedule for affectivedisorders and Schizophrenia for School-AgeChildren-Present and Lifetime Version (K-SADS-PL): Initialreliability and validity data. Journal of the AmericanAcademy of Child and Adolescent Psychiatry, 36, 980–988.

Kessler, R.C., Merikangas, K.R., & Wang, P.S. (2007).Prevalence, comorbidity, and service utilization for mooddisorders in the United States at the beginning of thetwenty-first century. Annual Review of Clinical Psychology,3, 137–158.

Kim, J., Carlson, G.A., Meyer, S.E., Bufferd, S.J., Dougherty,L.R., Dyson, M.W., … & Klein, D.N. (2012). Correlates of theCBCL-dysregulation profile in preschool-aged children.Journal of Child Psychology and Psychiatry, 53, 918–926.

Leibenluft, E., & Rich, B.A. (2008). Pediatric bipolar disorder.Annual Review of Clinical Psychology, 4, 163–187.

Luby, J., Lenze, S., & Tillman, R. (2012). A novel earlyintervention for preschool depression: Findings from a pilotrandomized controlled trial. Journal of Child Psychology andPsychiatry, 53, 313–322.

Luby, J.L., & Navsaria, N. (2010). Pediatric bipolar disorder:Evidence for prodromal states and early markers. Journal ofChild Psychology and Psychiatry, 51, 459–471.

Merikangas, K.R., Cui, L., Kattan, G., Carlson, G.A.,Youngstrom, E.A., & Angst, J. (2012). Mania with andwithout depression in a community sample of USadolescents. Archives of General Psychiatry, 69, 943–951.

Meyer, S.E., Carlson, G.A., Youngstrom, E., Ronsaville, D.S.,Martinez, P.E., Gold, P.W., … & Radke-Yarrow, M. (2009).Long-term outcomes of youth who manifested theCBCL-pediatric bipolar disorder phenotype duringchildhood and/or adolescence. Journal of AffectiveDisorders, 113, 227–235.



Mick, E., Biederman, J., Pandina, G., & Faraone, S.V. (2003). Apreliminary meta-analysis of the child behavior checklistin pediatric bipolar disorder. Biological Psychiatry, 53,1021–1027.

Miklowitz, D.J., Chang, K.D., Taylor, D.O., George, E.L., Singh,M.K., Schneck, C.D., … & Garber, J. (2011). Earlypsychosocial intervention for youth at risk for bipolar I orII disorder: A one-year treatment development trial. BipolarDisorders, 13, 67–75.

Moreno, D.H., Bio, D.S., Petresco, S., Petresco, D., Gutt, E.K.,Soeiro-De-souza, M.G., & Moreno, R.A. (2012). Burden ofmaternal bipolar disorder on at-risk offspring: A controlledstudy on family planning and maternal care. Journal ofAffective Disorders, 143, 172–178.

Pavuluri, M.N., Henry, D.B., Nadimpalli, S.S., O’connor, M.M.,& Sweeney, J.A. (2006). Biological risk factors in pediatricbipolar disorder. Biological Psychiatry, 60, 936–941.

Radke-Yarrow, M., Nottelmann, E., Martinez, P., Fox, M.B., &Belmont, B. (1992). Young children of affectively ill parents:A longitudinal study of psychosocial development. Journal ofthe American Academy of Child and Adolescent Psychiatry,31, 68–77.

Reef, J., Diamantopoulou, S., van Meurs, I., Verhulst, F.C., &van der Ende, J. (2011). Developmental trajectories of childto adolescent externalizing behavior and adult DSM-IVdisorder: Results of a 24-year longitudinal study. SocialPsychiatry and Psychiatric Epidemiology, 46, 1233–1241.

Roza, S.J., Hofstra, M.B., van der Ende, J., & Verhulst, F.C.(2003). Stablepredictionofmoodandanxietydisordersbasedonbehavioralandemotionalproblems inchildhood:A14-yearfollow-up during childhood, adolescence, and youngadulthood. American Journal of Psychiatry, 160, 2116–2121.

Shaw, J.A., Egeland, J.A., Endicott, J., Allen, C.R., &Hostetter, A.M. (2005). A 10-year prospective study ofprodromal patterns for bipolar disorder among Amishyouth. Journal of the American Academy of Child andAdolescent Psychiatry, 44, 1104–1111.

Sprafkin, J., Volpe, R.J., Gadow, K.D., Nolan, E.E., & Kelly, K.(2002). A DSM-IV-referenced screening instrument forpreschool children: The Early Childhood Inventory-4.Journal of the American Academy of Child and AdolescentPsychiatry, 41, 604–612.

Stringaris, A., & Goodman, R. (2009). Longitudinal outcome ofyouth oppositionality: Irritable, headstrong, and hurtfulbehaviors have distinctive predictions. Journal of theAmerican Academy of Child and Adolescent Psychiatry, 48,404–412.

Stringaris, A., Maughan, B., & Goodman, R. (2010). What’s in adisruptive disorder? Temperamental antecedents ofoppositional defiant disorder: Findings from the Avonlongitudinal study. Journal of the American Academy ofChild and Adolescent Psychiatry, 49, 474–483.

Wickramaratne, P., Gameroff, M.J., Pilowsky, D.J., Hughes,C.W., Garber, J., Malloy, E., … & Weissman, M.M. (2011).Children of depressed mothers 1 year after remission ofmaternal depression: Findings from the STAR*D-Childstudy. American Journal of Psychiatry, 168, 593–602.

Zahn-Waxler, C., Mayfield, A., Radke-Yarrow, M., McKnew,D.H., Cytryn, L., & Davenport, Y.B. (1988). A follow-upinvestigation of offspring of parents with bipolar disorder.American Journal of Psychiatry, 145, 506–509.

Accepted for publication: 16 July 2013Published online: 30 December 2013



dimensional psychopathology in preschool offspring of parents with bipolar disorder

Documents