Temperamental Correlates of Disruptive Behavior Disorders in Young Children: Preliminary Findings

Dina R. Hirshfeld-Becker, Joseph Biederman, Stephen V. Faraone, Heather Violette, Jessica Wrightsman, and Jerrold F. Rosenbaum
Background: Our objective was to test the hypothesis that temperamental behavioral disinhibition measured in early childhood would be associated with disruptive behavior disorders. Methods: We used variables from laboratory-based behavioral observations originally devised to assess behavioral inhibition to construct a theory-based a priori definition of behavioral disinhibition in 200 young children at-risk for panic disorder, depression, or both and 84 children of parents without anxiety or major depressive disorder. We then compared behaviorally disinhibited and nonbehaviorally disinhibited children on rates of DSM-III-R disorders and measures of academic and social dysfunction. Results: Behavioral disinhibition was significantly associated with higher rates of disruptive behavior disorders and mood disorders. Children with behavioral disinhibition were significantly more likely than nondisinhibited, noninhibited children to have attention-deficit/hyperactivity disorder (ADHD) and to have comorbid mood and disruptive behavior disorders. Moreover, disinhibited children had lower Global Assessment of Functioning Scale scores and were more likely to have been in special classes and to have problems with school behavior and leisure activities. Conclusions: These results suggest that behavioral disinhibition may represent a temperamental precursor to disruptive behavior problems, particularly ADHD. Longitudinal studies using behavioral assessments of behavioral disinhibition are needed to confirm these findings. Biol Psychiatry 2002;50:563574 2002 Society of Biological Psychiatry Key Words: Disruptive behavior disorders, behavioral disinhibition, attention-deficit/hyperactivity disorder, mood disorders, psychopathology

Introduction
dentifying precursors to emergent psychopathology in children of preschool age offers a critical opportunity to understand the pathways of the development of disorders and to design early preventive interventions. This issue is particularly critical for children at risk for psychopathology by virtue of having a parent with a psychiatric disorder, because not all such children develop psychopathology. Thus, the ability to identify those children at highest risk from among those already at-risk because of parental psychopathology has high clinical and public health importance. One promising approach to identifying precursors to emergent psychopathology in young children is to conduct studies that explore the implications of temperamental differences in early childhood. One of the best-studied temperamental measures is behavioral inhibition to the unfamiliar, characterized by a tendency to respond to novel situations with hesitancy, fear, reticence, or restraint (Kagan 1989; Kagan et al 1988). This is a well-characterized laboratory-based assessment of temperament suitable for the evaluation of very young children. Studies conducted over the past 15 years by our group and others have supported the idea that behavioral inhibition increases the risk for anxiety disorders, particularly social anxiety (Battaglia et al 1997; Biederman et al 1990, 1993, in press; Hayward et al 1998; Hirshfeld et al 1992; Manassis et al 1995; Rosenbaum et al 1988, 2000; Schwartz et al 1999). Our research, however, has also documented an inverse relationship between behavioral inhibition and disruptive behavioral disorders. We found that in young children at risk for panic disorder and depression, behavioral inhibition was negatively associated with lifetime history of DSM-III-R disruptive behavior disorders, including attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (Biederman et al, 2001). This
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From the Pediatric Psychopharmacology Unit (DRH-B, JB, SVF, HV, JW) and Clinical Psychopharmacology Unit (JB, JFR), Department of Psychiatry, Massachusetts General Hospital; Department of Psychiatry, Harvard Medical School (DRH-B, JB, SVF, JFR); and the Department of Psychiatry, Massachusetts Mental Health Center and Harvard Institute of Psychiatric Epidemiology and Genetics (SVF), Boston, Massachusetts. Address reprint requests to Dina R. Hirshfeld-Becker, Ph.D., Pediatric Psychopharmacology Research Program, Massachusetts General Hospital, Building 149, 13th Street, Suite 10018, Charlestown MA 02129. Received March 5, 2001; revised September 10, 2001; accepted September 18, 2001.

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observation is not entirely surprising because behavior disorders are marked by the absence of restraint, and one might hypothesize that children that are highly cautious and restrained might also be less likely to exhibit behavior disorders. Review of the literature provides findings consistent with this hypothesis. For example, Caspi and Silva (1995) found that children observed to be inhibited at age 3 scored low on self-report measures of aggression and impulsivity at age 18. Similarly, Schwartz et al (1996) found that children observed to be behaviorally inhibited as toddlers reported lower rates of externalizing behavior, delinquent behavior, and aggressive behavior on the Youth Self-Report form at age 13. Likewise, Kerr et al (1997) found that disruptive and nondisruptive boys rated by their peers as behaviorally inhibited at ages 10 to 12 were less likely to show delinquent behaviors at ages 13 to 15. Other groups have found similar inverse associations between social anxiety or anxiety disorders and aggressive or delinquent behavior. For example, Walker et al (1991) reported that the presence of comorbid anxiety disorders in boys with conduct disorder was inversely associated with predatory activity and aggression. Pliszka (1989) found that among children with ADHD, comorbid overanxious disorder was negatively related to observed disinhibition of responses on a cognitive task as well as to presence of conduct disorder. Using subjects from a large longitudinal sample, Pine (2000) found an inverse association between symptoms of social phobia and stability of symptoms of conduct disorder over time. This evidence raises the intriguing possibility that children who show the temperamental extreme of absence of restraint, boldness, and disinhibition may be positively predisposed to develop disruptive behavior disorders such as ADHD, oppositional-defiant disorder, and conduct disorder. This hypothesis is consistent with Grays theory in which disruptive behavior disorders are viewed as the result of deficient activity of a behavioral inhibition system that mediates anxiety as well as excessive activity of a behavioral activation system that mediates appetitive and aggressive behaviors (Gray 1982, Gray and McNaughton 1996). There is evidence that behavioral disinhibition may represent a moderately stable temperamental tendency (Kagan et al 1989; Reznick et al 1986). In longitudinal studies by Kagan and colleagues, 107 children from two cohorts selected in toddlerhood (at ages 21 or 31 months) as extremely inhibited or extremely uninhibited were found largely to retain these classifications through age 7.5 years. The correlation between the aggregate of measures used to rate observed inhibited/uninhibited behaviors in toddlerhood and at age 7.5 in the first cohort (n 41) was .67 (p .001) and in the second cohort was .39 (p .01; Kagan 1989).

Seventy-two percent of the uninhibited toddlers retained their uninhibited status (i.e., remained below the median on the inhibition index) by age 7.5, and only 10% changed to become extremely inhibited. Moreover, Goldsmith and Lemery (2000) found that among 58 children assessed via laboratory observations during toddlerhood, those rated as stably bold by their mothers at age 4 and 7 were significantly more likely to have been uninhibited as toddlers. Similarly, Rothbart and colleagues found that children observed to display strong approach behavior during infancy continued to show approach behaviors according to parent report at age 7 (Derryberry and Reed 1994). These data suggest that behavioral disinhibition is a moderately stable temperamental tendency. Several longitudinal studies support the hypothesis of a connection between temperamental disinhibition and disruptive behavior disorders. For example, our group found that children studied by Kagan and colleagues who remained uninhibited in observations at ages 21 months, 4, 5, and 7.5 years were significantly more likely than all others in the sample to be diagnosed with oppositional disorder by age 8 (Hirshfeld et al 1992). Tremblay et al (1994) found that boys rated by their kindergarten teachers as high in impulsivity, low in anxiety, and low in reward dependence were at highest risk for early-onset stable delinquent behavior at ages 10 through 13. Dimensional measures of impulsivity and, to a lesser degree, anxiety and low reward dependence contributed to the risk for delinquency. Similarly, Raine et al (1998) studied a large sample of children from the island of Mauritius whom they observed for stimulation-seeking and fear behaviors at age 3 and then assessed via parent-completed Child Behavior Checklist at age 11. These authors found that stimulation seeking at age 3 (including maximal exploration and spontaneous verbalizations) predicted aggressive behavior at age 11. Additionally, in a small study, Rothbart et al (1994) found that children observed to show high approach behaviors in infancy had higher parentreported impulsivity at age 7 as well as lower scores on inhibitory control and attentional processing. Other studies by Caspi et al (1995, 1996) have documented associations between behavioral undercontrol (indexed through observed lability, restlessness, short attention span, and negativism) at ages 3 through 5 and externalizing behaviors at ages 13 through 15; aggression, danger seeking, and impulsivity at age 18; and antisocial personality at age 21. In our study, we used behavioral measures of temperament in children from a high-risk sample to derive a theoretically defined categorical measure of behavioral disinhibition. We operationalized behavioral disinhibition as a tendency to seek out novelty, approach unfamiliar stimuli, and display disinhibition of speech or action. We then examined correlates of behavioral disinhibition in child psychopathology and

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functioning. We hypothesized that behavioral disinhibition would be associated with disruptive behavior disorders including ADHD and oppositional defiant disorder and with associated measures of poorer academic and psychosocial functioning.

Methods and Materials

Subjects
As described in earlier reports (Rosenbaum et al 2000), we recruited three groups of parents who had at least one child in the age range to be assessed temperamentally using standardized age protocols (age 2 6 years): 1) 119 parents treated for panic disorder (PD) with or without comorbid major depression (MDD) and their 151 children; 2) 37 parents treated for MDD who had no history of either PD or agoraphobia and their 49 children; and 3) 60 control parents with neither major anxiety nor mood disorders and their 84 children. Because of high comorbid depression among parents in the PD group, we subdivided it into two groups: 22 children who had a parent with PD but not MDD, and 129 children who had a parent (or in 11 cases, 2 separate parents) with both PD and MDD. Parents with PD and MDD had been recruited from clinical referrals and advertising and were included if they met full DSM-III-R criteria for PD or MDD by structured psychiatric interview and had been treated for these disorders. Control parents free of major anxiety (PD, agoraphobia, social phobia, or obsessive compulsive disorder) or mood disorders (MDD, bipolar disorder, or dysthymia) had been recruited through advertisements to hospital personnel and in community newspapers and were included only if they did not meet DSM-III-R criteria for these disorders. This study was approved by the internal review board, and all participants (parents) signed written consent. Children assented to study procedures.

Diagnostic Assessments of Parents and Children

We conducted direct psychiatric assessments with each parent using the Structured Clinical Interview for DSM-III-R (SCID; Spitzer et al 1990). We conducted psychiatric assessments of all children who reached age 5 or older during the first (5-year) wave of data collection (n 216), using the Kiddie-SADS-E (Orvaschel and Puig-Antich 1987) completed with the mothers. We documented the degree of impairment associated with each diagnosis, the age of onset of each symptom, and the type of treatment obtained. We assessed socioeconomic status (SES) with the Hollingshead (1975) Four-Factor Index, which includes information about both parents educational level and occupation. Interviews were conducted by raters with bachelors degrees in psychology under the supervision of two senior psychiatrists (JB and JFR). The raters underwent a training program that required them 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, 5) rate several subjects under the supervision of the project coordinator, 6) undergo continued supervision of their assessments by senior project staff, and 7) audio tape all interviews for later random

checking. Kappa coefficients of agreement were computed between the interviewers and board-certified psychiatrists who listened to audiotaped interviews. Based on 173 interviews, the mean Kappa was 0.86. All subjects were diagnosed based on a consensus judgment by two senior psychiatrists (JB and JFR). Children were evaluated by interviewers blind to the temperamental data on the child and to the diagnostic status of the parents. Blindness was assured as follows: 1) interviewers about children were blind to all diagnostic information about parents, including their ascertainment status; 2) interviewers of or about parents or children were blind to all information about temperamental assessment; 3) the final diagnostic classifications of all subjects (parents and children) were done by clinicians blind to the original recruitment group, to all temperamental and nonpsychiatric data collected from the individual being diagnosed, and to all information about other family members. In addition, we collected dimensional measures of psychopathology in children aged 2 years and older using the Child Behavior Checklist (CBCL) for preschoolers (23 years old) and for school-age children (4 18 years old) completed by the mother (Achenbach 1991, 1992). For the purpose of this analysis, we combined data from corresponding scales in the two CBCL measures. We also assessed the following areas of functioning in children over 5 years: social functioning, school functioning, and treatment history. We assessed social functioning using the Global Assessment of Functioning Scale (GAF) of the DSMIII-R and the Social Adjustment Inventory for Children and Adolescents (SAICA; John et al 1987), a semistructured interview that assesses adaptive functioning in children and adolescents. The SAICA covers four major role areas: school, sparetime activities, peer relations, and home life. We measured school functioning using three indices: placement in special class, in-school resource-room tutoring, and repeated grades. Finally, we obtained treatment history information by inquiring on the Kiddie-SADS-E about the nature and duration of treatment the child had received.

Assessment of Temperament
Temperamental assessments measured the childs reaction to unfamiliar people, rooms, objects, and test procedures (Kagan 1994). Children were accompanied by mothers and evaluated in the Harvard Infant Study laboratory by research assistants under the direction of Jerome Kagan and Nancy Snidman. Evaluations consisted of a 90-min battery in which children interacted with an unfamiliar female examiner who led them through a series of cognitive and behavioral tasks. Each child was evaluated once, either at age 2, age 4, or age 6, using an age-specific protocol. As might be expected, maturational processes affecting the growing childs behavior make it necessary to have different protocols for younger and older children. Similarly, different variables differentiate inhibited from noninhibited children at different ages. Inhibited 2-year-olds are more likely to display fear, distress, and avoidance in the face of novel stimuli, whereas older children are more likely to display minimal vocalization and smiling. Table 1 presents the specific episodes in each assessment and descriptions of the variables coded for each age group.

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Table 1. Variables Used to Define Behavioral Disinhibition

A. Assessment protocols Laboratory situations observed (in order presented) Exposure to an unfamiliar room containing unfamiliar objects Requests by an unfamiliar female examiner to implement separate actions with the unfamiliar objects Acceptance of electrodes on the body (to measure heart rate) Sitting and standing heart rates Standing with eyes closed Standing in the dark Acceptance of a blood pressure cuff Procedure for evaluating spatial memory Acceptance of a drop of liquid on the tongue Reaction to criticism for failing to build a difficult construction with blocks Memory for a story A door opened, and a gloved hand appeared; put an object on the floor, and then closed the door A test of recall memory for digits Requests to implement unusual actions (e.g., spilling juice on the table, hitting the examiners hand) Exposure to a second unfamiliar room Encounter with a stranger who requested that the child approach and play with her toy Encounter with an adult dressed as a clown who requested that the child approach Encounter with a toy dinosaur that moved, made noise, and requested that the child approach Matching Familiar Figure Test A modified Stroop procedure Questions about a series of words read to the child Memory for a second story Sitting and standing heart rate Sitting and standing blood pressure B. Rationale for use of variables Age 2: Variables available (Reason for using or not using variable in italics) Avoidance fears (number of attempts to avoid stimuli); novelty-seeking: rated BD if child had no avoidance (11.5% of sample) Distress fears (number of displays of distress); not deemed specific to disinhibition (children may be distressed yet disinhibited) 3-point rating of resistance to electrodes and blood pressure (1 no resistance; 3 refusal); not deemed relevant 3-point rating of distractibility ( 1 minimal; 3 maximal); not deemed specific to childs disinhibition (was positively correlated with distress fears and may therefore have been confounded by anxiety) 3-point rating of childs frequency of vocalization (1 minimal; 3 maximal); verbal disinhibition: rated BD if child showed maximal vocalization (23% of sample) Age group 2 and 4 years 2 and 4 years

Table 1. (Continued)
3-point rating of childs frequency of smiling (1 minimal; 3 maximal); not deemed relevant 4-point rating of childs approach of clown (1 approach; 4 cry, no approach); novelty-seeking: rated BD if child approached clown (23% of sample) Age 4: Variables Available (Reason for using or not using variable in italics) 3-point rating of inhibition in first situation; minimal inhibition relevant but not a good discriminator (80% minimally inhibited) 3-point rating of inhibition in second situation;minimal inhibition relevant, but not a good discriminator (80% minimally inhibited) Number of smiles across rest of battery; not deemed relevant Number of spontaneous comments across rest of battery; verbal disinhibition: rated BD if child made more comments than 75% of children from control families 3-point rating of resistance to electrocardiogram (1 no resistance; 3 refusal); not deemed relevant 3-point rating of resistance to blood pressure cuff (1 no resistance; 3 refusal); not deemed relevant Number of delays (2 secs) in complying with unusual requests; behavioral disinhibition: rated BD if child showed no delays (9.7%) 4-point global rating of fear across entire battery (1 no signs of fear, 4 cried or exhibited fear multiple times); not deemed relevant (69% had no fear) 4-point rating of shyness across entire battery (1 not shy; 4 extremely shy); minimal shyness relevant, but 64% minimally shy 4-point global rating of resistance across entire battery (1 none; 4 maximal); not deemed relevant 4-point rating of voice quality (1 spontaneous and loud; 4 whispering); loudness and spontaneity relevant but 64% scored 1. 4-point global rating of inhibition (1 uninhibited; 4 extremely inhibited); minimal inhibition relevant, but not a good discriminator 42% were rated uninhibited. Age 6: Variables available (Reason for using or not using variable in italics) Number of smiles across battery; not deemed relevant Number of spontaneous comments across battery; verbal disinhibition: rated BD if child made more comments than 75% of children from control families Response style to Matching Familiar Figures Test (impulsive vs. reflective), impulsive style relevant to behavioral disinhibition (60% had impulsive style) 3-point rating of resistance to electrocardiogram (1 no resistance; 3 refusal); not deemed relevant 3-point rating of resistance to blood pressure cuff (1 no resistance; 3 refusal); not deemed relevant 4-point global rating of fear across entire battery (1 no signs of fear, 4 cried or exhibited fear multiple times); not deemed relevant (92% had no fear) 4-point rating of shyness across entire battery (1 not shy; 4 extremely shy); minimal shyness relevant, but 58% minimally shy; rating not coded with high reliability 4-point global rating of resistance across entire battery (1 none; 4 maximal); not deemed relevant 4-point global rating of inhibition (1 uninhibited; 4 extremely inhibited); minimal inhibition relevant (43.6% scored 1).
BD, behaviorally disinhibited.

2, 4, and 6 years 4 and 6 years 4 and 6 years 4 and 6 years 2, 4, and 6 years 2 years 2 years 2 years 4 and 6 years 4 and 6 years

4 and 6 years 2 and 4 years

2 years 2 years

2 years 2 years

6 years 4 and 6 years 4 and 6 years 4 and 6 years 4 and 6 years 4 and 6 years

Table 1 also outlines the rationale for the variables used to define behavioral disinhibition, which can be characterized by novelty seeking (operationalized as approaching unfamiliar stim-

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uli) and impulsivity (operationalized as disinhibition of speech or action). Two-year-olds who showed minimal avoidance of the unfamiliar stimuli presented in the interactions with the examiner, maximal approach of a clown (approaching an unfamiliar stimulus that most children avoid), or maximal vocalization (disinhibition of speech) were considered behaviorally disinhibited. To be considered behaviorally disinhibited, 4-year-olds had to have made more spontaneous comments than 75% of children of nonclinical comparison parents (disinhibition of speech) or to have shown minimal delay in carrying out unusual or socially unacceptable requests such as spilling juice on the table, scribbling in a book, and throwing a ball at the examiners face (disinhibition of action). For 6-year-olds, the only variable that appeared to clearly identify disinhibited youngsters was the number of spontaneous comments. Although impulsive style on the Matching Familiar Figures test (Kagan 1964) and global rating as uninhibited also appeared relevant to disinhibition, they were not good discriminators; too many children were rated impulsive or uninhibited because the scales had been originally chosen to identify inhibited rather than uninhibited children. To avoid basing the rating in this age group on a single variable, however, the latter two variables were combined and added to the spontaneous comments variable as follows: 6-year-olds were considered behaviorally disinhibited if they made more spontaneous comments than 75% of children of nonclinical comparison parents (disinhibition of speech) and either received a rating of extremely uninhibited on the global rating of inhibition or showed impulsive style (disinhibition of action) as measured by the Matching Familiar Figures test. All variables were rated by a single rater (Jerome Kagan). Based on a random sample of 20 videotapes, the reliabilities were as follows: spontaneous comments, intraclass correlation (ICC) .89; number of delays in completing requests, ICC .91; global 4-point rating of inhibition, kappa .70. For the purpose of comparison, we contrasted children classified as behaviorally disinhibited with those who had been previously classified as inhibited (Biederman et al, 2001). In that analysis, three definitions of inhibition were used: 1) a dichotomous measure based (for 2-year-olds) on number of fears (four or more avoidant or distress fears) or on being rated as making minimal vocalizations or smiles during the battery, or (for 4- and 6-year-olds) on making fewer spontaneous comments and smiles than the lowest 20th percentile of non-at-risk comparison children in their age group; 2) the global rating of inhibition (rated for 4- and 6-year-olds only), for which a child had to receive at least a 3 to be rated as inhibited; and (3) a rating based on a summary inhibition score derived from a principle factors factor analysis of all behavioral variables in Table 1, performed separately by age group, where children were rated as inhibited if they scored in the upper 20th percentile of non-at-risk comparison children in their age range. To be classified as inhibited, 2-year-olds had to meet both definitions available to them, and 4and 6-year-olds had to meet two out of three definitions.

demographic variable as a potential confound if logistic or ordinal regression showed it to be significantly associated (at the conservative level of p .1) with both the predictor and outcome variables. We then used the potential confound as a covariate in the logistic and ordinal regression models used to assess the link between child temperament and child outcomes. We contrasted child outcomes in behaviorally disinhibited children with inhibited children, children who were neither inhibited nor disinhibited, and with both contrast groups combined. Multiple members of a single family (i.e., multiple siblings) cannot be considered independently sampled because they share genetic, cultural, and social risk factors. To deal with this problem, for all comparisons we used generalized estimating equation (GEE) method to estimate general linear models (Diggle et al 1994; Liang and Zeger 1986) controlling for one or more potentially confounding variables where necessary, as implemented in the STATA statistical software package (STATA 1997) Unlike standard linear or logistic regression models, GEE models produce consistent standard errors and p values in the presence of intrafamilial clustering. We chose specific models to conform to the distribution of the variable: the binomial family and a logit link for binary outcomes, the gaussian family and identity link for normally distributed outcomes, and the poisson family and log link for ordinal outcomes. We used Walds test to assess the statistical significance of individual regressors. We used Fishers Exact Test in place of GEE when there were one or more zero frequencies in the two-way table defined by the categorical predictor and dichotomous outcome. All tests were two-tailed with alpha set at .05.

Results
Table 2 shows demographic variables for the behaviorally disinhibited and contrast children. (Three children who were classified as both inhibited and disinhibited were excluded from further analyses.) There was an association with gender, with boys more likely to be classified as disinhibited than inhibited. Therefore, we statistically controlled our analyses for gender as described in Methods and Materials. As had been previously reported, rates of behavioral inhibition differed significantly between parental diagnostic groups (Rosenbaum et al 2000); however, rates of behavioral disinhibition did not differ significantly between parental groups, with 41% of children of parents with PD MD, 36.4% of offspring of parents with PD but not MD, 38.8% of children of parents with MD but not PD, and 29% of children of non-PD/non-MD comparison parents classified as having behavioral disinhibition (Wald 2(3) 3.12, p .37, ns). As seen in Figure 1A, behavioral disinhibition was significantly associated with any disruptive behavior disorder. Behaviorally disinhibited children were more likely to have at least one such disorder compared inhibited children [2(3) 11.31, p .010; odds ratio (OR) 4.7 (1.514.4),

Data Analyses
To determine whether demographic variables confounded our tests of the effects of behavioral disinhibition on outcome, we followed the guidelines of Weinberg (1993) and classified a

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Table 2. Associations between Behavioral Disinhibition and Demographic Variables

Children with behavioral disinhibition (% or M SD) (n 101) 18.8 51.5 29.7 64.4a 84.2 94.1 4.0 2 0 5.9 1.0 2.1 1.0 1.9 .8 Children with neither disinhibition nor inhibition (% or M SD) (n 93) 14.0 58.1 28.0 53.8 85.0 89.3 1.1 3.2 6.5 6.1 1.0 1.9 1.0 2.1 .9 Children with behavioral inhibition (% or M SD) n 87)
2

Demographic variable Age distribution at Temperamental Assessment: % 2-year-olds % 4-year-olds % 6-year-olds Gender (% Male) Intactness of family Race Caucasian African American Hispanic Asian Mean age at diagnostic assessment Socioeconomic status Number of children in family

Significance (2) 1.10, ns

20.7 55.2 24.1 48.3 88.5 94.3 3.4 1.2 1.2 5.9 .9 2.2 .9 1.9 .8

2(2) 5.21, p .07 2(2) .59, ns 2(2) 2.25, ns

2(2) 3.20, ns 2(2) 4.05, ns 2(2) 1.62, ns

All associations were tested by generalized estimating equation models controlling for intrafamilial clustering. The association with race was tested using the two-tiered variable Caucasians versus non-Caucasians. a z 2.19, p .028 versus behaviorally inhibited children.

z 2.72, p .007]; noninhibited/nondisihibited children (OR 2.3 [0.96 5.5], z 1.87, p .06), or both groups combined (OR 3.0 [1.5 6.4], z 2.97, p .003). This association was accounted for by the higher rates of ADHD among behaviorally disinhibited children compared with both other groups [2(3) 10.90, p .012; OR versus inhibited children 3.4 (1.39.0), z 2.52, p .012; OR versus noninhibited/nondisinhibited children 2.8 (1.17.3) z 2.17, p .030; OR versus both groups combined 3.0 (1.4 6.6), z 2.81, p .005]. As revealed in Figure 1B, the rate of any mood disorder was significantly higher among children with behavioral disinhibition compared with all children without behavioral disinhibition [11% vs. 3%, 2(2) 6.56, p .038; OR 3.6 (1.112.2), z 2.08, p .037]. Despite the fact that inhibited and noninhibited nondisinhibited children had equally low rates of any mood disorder (3% each), the difference between these groups and the disinhibited group did not reach statistical significance. Although the behaviorally disinhibited children were 4 times more likely than all nonbehaviorally disinhibited children to exhibit MDD (9% vs. 2%), this association which was significant in the univariate comparison [2(1) 4.22, p .04] lost full significance when gender was covaried [2(2) 4.83, p .09, OR 3.7 (0.9 14.5), z 1.88, p .06], most likely because of limited statistical power. Similarly, the contrasts between the disinhibited children and the inhibited or noninhibited/nondisinhibited children did not reach significance. Although the association between behavioral disinhibition (vs. all others) and mood disorder lost significance

when the presence or absence of any disruptive behavior disorder was covaried [2(3) 11.56, p .009, OR 2.6 (.7 8.9), z 1.48, p .14], the association between disruptive behavior disorder (vs. all others) and behavioral disinhibition retained significance when the presence or absence of any mood disorder was covaried [2(3) 17.74, p .0005, OR 2.7 (1.25.7), z 2.53, p .011], as did the analysis that contrasted rates of disruptive behavior disorder in disinhibited versus inhibited children [2(4) 18.9, p .0008; OR 4.3 (1.4 13.1), z 2.52, p .012]. These findings suggest that the association with mood disorder may have been mediated by comorbidity between disruptive behavior disorders and mood disorders in these children. As seen in Figure 1C, children with behavioral disinhibition were more likely to have comorbid disruptive behavior disorder plus mood disorder than noninhibited/ nondisinhibited children (p .018 by Fishers Exact Test) and than both other groups combined [2(1) 4.08, p .04, OR 9.3 (1.1 81.0), z 2.02, p .043 with the test restricted to boys because no girls had both disorders]. In all six cases in which these disorders were comorbid in a child with behavioral disinhibition, the onset of the mood disorder either coincided with (n 3) or followed (n 3) the onset of the behavior disorder. There were no significant associations between behavioral disinhibition and childhood anxiety disorders. The CBCL scales for which significant differences were found are indicated in Figure 2. Children with behavioral disinhibition showed small but significant elevations in the T-scores on scales indicating anxious/depressed [2(2)

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Figure 1. Associations between behavioral disinhibition and DSM-III-R disruptive behavior disorders (A), mood disorders (B), and comorbid disruptive behavior and mood disorders (C). Associations were tested using a generalized estimation equation (GEE) model controlling for intrafamilial clustering, with gender covaried where associated with disorder. ADHD, attentiondeficit/hyperactivity disorder. MDD, major depressive disorder. Any disruptive behavior disorder includes ADHD, oppositional disorder and conduct disorder. Any mood disorder includes MDD, bipolar I disorder, bipolar II disorder, and dysthymia. a versus behaviorally inhibited; bversus neither inhibited nor disinhibited; cversus all others combined. *p.05; **p.01. 4

14.63, p .0007; versus noninhibited/nondisinhibited, z 3.23, p .001]; thought problems [2(2) 6.34, p .042; versus noninhibited/nondisinhibited: z 2.28, p .023; versus inhibited: z 2.41, p .016; versus all others: 2(1) 6.07, p .014, z 2.46, p .014], and sleep disturbance [2(2) 8.09, p .0175; versus noninhibited/nondisinhibited: z 2.82, p .005; versus inhibited: z 2.07, p .038; versus all others: 2(1) 6.02, p .014, z 2.45, p .014]. Children with behavioral disinhibition had lower levels of current and past (worst in lifetime) functioning compared with children without behavioral disinhibition. The mean (SD) current GAF score for children with behavioral disinhibition was 65.8 7.3 compared with 68.5 5.3 for children with behavioral inhibition [2(2) 9.77, p .0075; z 2.44, p .015]; 69.0 4.2 for children with neither inhibition nor disinhibition (z 3.11, p .002); and 68.7 4.7 for all children without behavioral disinhibition [2(1) 9.04, p .0026; z 3.01, p .003]. The mean (SD) past GAF score for children with behavioral disinhibition was 64.2 7.9 compared with 67.2 6.7 for children with behavioral inhibition [2(2) 11.80, p .0027; z 2.35, p .019]; 68.1 4.5 for children with neither inhibition nor disinhibition (z 3.43, p .001); and 67.7 5.6 for all nonbehaviorally disinhibited children [2(1) 9.71, p .0018; z 3.12, p .002]. Results from the SAICA indicated that behavioral disinhibition was significantly associated with higher ratings of school behavior problems (Mean SD on a 4-point scale, where higher scores indicate worse functioning), for behaviorally disinhibited versus inhibited children: 2.0 .9 versus 1.6 .7; 2(2) 7.78, p .02; z 2.39, p .017), versus noninhibited nondisinhibited children (1.5 .7; z 2.48, p .013), and versus both of these groups combined: 1.6 .7; 2(1) 7.22, p .0072; z 2.69, p .007. Disinhibited children also had lower involvement in free-time activities than inhibited children [1.9 .6 vs. 1.6 .5; 2(2) 7.94, p .019; z 2.77, p .006] and all nondisinhibited children [1.7 .6; 2(1) 5.86, p .016; z 2.42, p .016]. In addition,

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Figure 2. Associations between behavioral disinhibition and CBCL T-scores (Mean SD) for scales showing significant differences. Data from 2- to 3-year-old and 4- to 18-year-old Child Behavior Checklist (CBCL) scales were combined for the purpose of this analysis. (1) denotes 2- to 3-year-old CBCL scale (n 34 for behaviorally disinhibited, n 29 for neither inhibited nor disinhibited, and n 27 for behaviorally inhibited); (2) denotes 4- to 18-year-old CBCL scale (n 49 for behaviorally disinhibited, n 50 for neither inhibited nor disinhibited, and n 47 for behaviorally inhibited); (1,2) indicates that both age groups were combined (n 83 for behaviorally disinhibited, n 79 for neither inhibited nor disinhibited, and n 74 for behaviorally inhibited). Associations were tested using a generalized estimating equation model controlling for intrafamilial clustering. a versus behaviorally inhibited; b versus neither inhibited nor disinhibited; c versus all others combined. *p .05; **p .01.

Figure 3. Associations between behavioral disinhibition and school problems. Associations were tested using a generalized estimating equation model controlling for intrafamilial clustering, with gender covaried where associated with disorder or with Fishers Exact Test when there were one or more zero frequencies in the two-way table defined by the categorical predictor and outcome variables (indicated by Fishers Exact Test). a versus behaviorally inhibited; b versus neither inhibited nor disinhibited; c versus all others combined. *p .05; **p .01.

they were rated as having more problems with free time than were inhibited children [1.6 .7 vs. 1.3 .5; 2(2) 11.48, p .0032; z 3.30, p .001], noninhibited nondisinhibited children (1.4 .6; z 2.25, p .025), and both groups combined [1.3 .5; 2(1) 9.46, p .0021, z 3.08, p .002]. In addition, as seen in Figure 3, behavioral disinhibition was significantly associated with academic dysfunction as indicated by the fact that significantly more behaviorally disinhibited children were placed in special classes compared with all nonbehaviorally disinhibited children (5% vs. 0%, Fishers Exact Test, p .018). Although few children in the study had been treated with medication or hospitalized (1% each), significantly more children with behavioral disinhibition had received psychotherapy than had children with neither inhibition nor disinhibition [27.7% (18/65) vs. 10.0% (6/60), 2(3) 9.98, p .019, OR 3.18 (1.2 8.7), z 2.25, p .024] or than both groups combined [12% (14/116), 2(2) 10.0, p .0067, OR 2.4 (1.15.4), z 2.18, p .029]. Although the rates of behavioral disinhibition did not differ by parental diagnostic group, as reported above, we repeated all analyses covarying presence or absence of parental major depression and presence or absence of parental panic disorder to control for the possibility that

parental diagnoses were influencing the associations between behavioral disinhibition and child outcome measures. Only associations with comorbid disruptive behavior disorder plus any mood disorder and placement in a special class could not be tested because of the presence of cells in which the rates of these problems were zero. The great majority of associations retained full significance, and no comparison dropped below trend significance (p .1). The associations that dropped to trend level (p .1) significance were as follows: the comparison between ADHD in children with disinhibition and those with neither inhibition nor disinhibition (OR 2.4, z 1.85, p .06); the comparison between any mood disorder in children with disinhibition versus all others (OR 3.3, z 1.85, p .06); the associations between behavioral disinhibition and lower involvement in free-time activities (as rated on the SAICA; overall significance of equation dropped to p .1 even though the individual comparisons remained .05); and the associations between behavioral disinhibition and psychotherapy (OR vs. all others 2.3, z 1.93, p .05; OR vs. noninhibited/nondisinhibited 2.8, z 1.85, p .06).

Discussion
In this study, we operationalized a laboratory observationbased behavioral construct, termed behavioral disinhibition, characterized by a tendency to explore novelty, to

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readily approach unfamiliar stimuli, and to display disinhibition of speech or action. We hypothesized that behavioral disinhibition was a temperamental trait in children at risk for disruptive behavior disorders. We found that children with behavioral disinhibition not only had higher rates of disruptive behavior disorders, most particularly ADHD, as measured in diagnostic interviews, but also had higher rates of mood disorder and the combination of both. Despite the young age (mean age 6) of participating children, those with behavioral disinhibition already had higher rates of placement in special classes, higher ratings of school behavior problems, more problems involving free-time activities, lower overall functioning, and higher rates of psychosocial treatment. Contrasts with children with behavioral inhibition, as well as children with neither inhibition nor disinhibition, suggested that our results were accounted for by elevations in these problems among disinhibited children and not simply by reduced rates in inhibited children. These results support the hypothesis that behavioral disinhibition represents a temperamental precursor to disruptive behavior disorders. Our findings are consistent with other studies reporting similar associations between behavioral disinhibition and ADHD (Quay 1997), impulsivity and attentional problems (Rothbart et al 1994), aggressive behavior (Raine et al 1998), and delinquency (Tremblay et al 1994). Although the mechanism of association between behavioral disinhibition and disruptive behavior disorders remains unknown, several explanations have been offered. Disruptive behavior disorders may entail deficient activity of Grays behavioral inhibition system, which inhibits ongoing behaviors in response to signals of novelty, and excessive activity of the behavioral activation system, which mediates approach behaviors in response to signals of reward (Gray 1982; Gray and McNaughton 1996). For example, Quay argued, based on laboratory evidence, that underactivity of the behavioral inhibition system represents an underlying feature of ADHD (Quay 1997). Barkley, using a different conceptualization, also argued for deficits in inhibitory control as central in ADHD (Barkley 1997). Kagan conceptualized behavioral inhibition as reflecting a low threshold to limbic and sympathetic arousal (Kagan et al 1987); in contrast, behavioral disinhibition may represent a higher threshold to arousal, for which children may compensate by seeking novel stimuli. Some investigators have theorized that ADHD children suffer from a state of underarousal, behaving as though normal levels of environmental stimulation were insufficient (Zentall and Zentall 1983). To compensate, these children increase contact with novel stimuli, by moving, looking around, and speaking (Brimer and Levine 1983; Zentall and Meyer 1987). In addition, sensation seeking has also been hypothesized to underlie some

forms of aggressive behavior (Raine 1993; Raine et al 1990). Another construct that may be related to behavioral disinhibition is that of novelty-seeking, conceptualized as a heritable tendency to experience excitement in response to novel stimuli that leads individuals to initiate exploratory activity, make impulsive decisions, approach cues of reward, and easily become frustrated (Cloninger 1987; Cloninger et al 1993). Authors have suggested that children with ADHD may be especially sensitive to immediate rewards and especially prone to frustration when rewards are denied or withdrawn (Campbell and Werry 1986). This may underlie their tendency to be easily distracted by potential external rewards or novel events and their particular difficulty delaying gratification. It is likely that children with BD would be classifiable in Cloningers system as high novelty seeking/low harm avoidant (impatient, talkative, overactive, extraverted, aggressive, and danger seeking; Cloninger 1987). Children with behavioral disinhibition, despite the young age of the sample, had significantly higher rates of mood disorders compared with non-behaviorally disinhibited children. This association was accounted for by children who also had disruptive behavior disorders, and indeed the rate of comorbid behavior and mood disorders was significantly elevated in the behaviorally disinhibited children compared with non-behaviorally disinhibited children. In all cases, the mood disorder either followed or co-occurred with the onset of the behavior disorder. These findings are consistent with the literature documenting significant comorbidity between ADHD and mood disorders. The rate of co-occurrence of these disorders has been estimated at 15% to 75% in children and adolescents from epidemiologic, pediatric, and psychiatric clinical samples (Angold and Costello 1993; Biederman et al 1991; Jensen et al 1993; Spencer et al 1999). Evidence from a longitudinal study at our center of children with ADHD suggested that comorbid major depression at baseline was associated with poorer prognostic course of ADHD at 4-year follow-up, including lower psychosocial functioning, higher rates of hospitalization, and poorer interpersonal and familial functioning (Biederman et al 1998). Studies from other centers support the worse prognosis associated with comorbidity of ADHD and mood disorders (Kovacs et al 1984, 1988). If confirmed, our results suggest that some children may follow a developmental trajectory into mood disorder marked by temperamental disinhibition, ADHD, and ultimately depression. The ability to target early those children most at risk for ADHD with comorbid depression would enable preventive intervention that might mitigate this disabling course. The results of our study should be interpreted in light of

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several limitations. First, we relied on cross-sectional data. Thus, although we hypothesize that behavioral disinhibition represents a trait observable in early childhood that may represent a precursor to ADHD or to other disruptive behavior disorders, the possibility remains that the behavioral disinhibition we observed at later ages (e.g., age 6) was a symptom of concurrent ADHD. Nevertheless, because the majority of temperamental assessments took place at ages 2 and 4 years and all of the diagnostic assessments took place at age 5 or later, a good proportion of children did not have concurrent assessments of behavioral disinhibition and ADHD. All 2- and 4-year-olds who were evaluated diagnostically and 29.7% of the 6-yearolds had their evaluations at least a year after the temperamental assessment, meaning that only 24% of the total diagnostic evaluations were concurrent with the temperamental assessments. Although the separate (concurrent and prospective) groups were too small for meaningful analyses, comparison of rates of outcome variables between the two groups revealed the same patterns of association within both groups, suggesting that our results were not simply accounted for by overlap of signs of behavioral disinhibition and concurrent symptoms of ADHD. A second limitation is the fact that behavioral disinhibition was assessed only at a single point for each child. Although evidence from prior longitudinal studies suggests that extreme uninhibition is moderately stable from toddlerhood through early childhood (Kagan et al 1989; Goldsmith and Lemery 2000; Reznick et al 1986), we do not know whether the children we classified as disinhibited retained these classifications over time. Prospective longitudinal studies with repeated temperamental assessments are needed to enhance our understanding of the stability of disinhibition, as well as to assess associations between stability of disinhibition and risk for psychopathology. It might be argued that because a high rate of vocalization is part of the definition of behavioral disinhibition at all ages, and talkativeness is a symptom of ADHD, our results might be due to the overlap of talkativeness in the definitions of both of these constructs; however, prodromes of clinical disorders often share overlapping symptoms with the disorder itself. This is to be expected because the prodrome evolves into the disorder. For example, prodromal indicators of schizophrenia in individuals at high risk include negative symptoms and social withdrawal, which are also criteria for its diagnosis. The behavioral disinhibition assessment differs from the assessment of ADHD in two important ways. First, it uses laboratory observations under standard conditions to quantify and contrast vocalizations with those of normal comparison children instead of relying only on reports by

parents or teachers or clinical impressions of talkativeness. Second, the assessments can be conducted at a point very early in childhood when ADHD cannot be diagnosed confidently. That the laboratory assessments of vocalization are significantly associated with ADHD bodes well for our ultimate aim of using developmentally sensitive means for identifying early in toddlerhood or preschool children more likely to develop ADHD. That the constructs are not tautological is supported by the finding that the majority of disinhibited children did not meet criteria for ADHD and that a minority of children with ADHD were not behaviorally disinhibited. Another limitation is that in defining behavioral disinhibition, we were constrained to the use of variables originally used for coding behavioral inhibition. This created several difficulties. First, in an effort to cast a broad net to maximize our sensitivity to behavioral disinhibition, we classified a third of our sample as behaviorally disinhibited. Second, we were constrained to define behavioral disinhibition to a great degree as the inverse of behavioral inhibition. This is problematic because many theorists argue that inhibition and disinhibition are separate categories or strains, with empirical evidence mitigating against the idea that they simply represent two opposite ends of a spectrum (Kagan 1989). To address these problems, future studies are needed with batteries designed more specifically to capture behavioral disinhibition. For example, it would be useful to expand the rating system for the childs approach of unfamiliar toys to capture more variability toward the disinhibited extreme, following the approach of Raine et al (1998). In addition, it would be useful to use tasks specifically designed to capture disinhibition of action and failure to inhibit behaviors. For example, one might give each child an independent task to perform in a testing room containing appealing toys, and code the degree to which the child engages in off-task behavior (Barkley 1987; Pliszka 1989). One might also use inhibitory control batteries developed by Kochanska et al (1996, 1997) for children aged 2 through 6 years, which measure ability to delay approach of desirable objects, to slow down motor behavior, to suppress activity to a signal, and to speak softly. Another limitation was the fact that our diagnostic and psychosocial data relied heavily on maternal reports. Psychiatric patients may exaggerate symptoms in their children, or alternatively, mothers without psychopathology may underreport problem behaviors (Mick et al 2000). The children in our sample were too young to be interviewed directly, particularly when emphasizing lifetime diagnoses and queries requiring sophisticated understanding of emotional and behavioral regulation. In addition, because children were from a sample primarily at-risk for PD with depression, it is not known whether our results are

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generalizable to other children with behavioral disinhibition. A final limitation was the finding that several of the associations noted dropped just below significance when parental diagnostic status was covaried. This change was likely due to decreased power resulting from inclusion of additional variables in the equations, because parental diagnosis was not significantly associated with disinhibition. Examination of rates of ADHD and any mood disorder within the offspring of parents with MD or PD revealed that they maintained the pattern of higher rates of these disorders in those offspring with behavioral disinhibition. Further high-risk studies with larger numbers of children within differing parental diagnostic groups and including other parental diagnostic groups more germane to behavioral disinhibition (e.g., parental ADHD) are needed to examine interactions between parental diagnostic status and child temperament in predicting child psychopathology. Despite these limitations, we obtained promising results suggesting that behavioral disinhibition is related to disruptive behavior disorders and mood disorders and their combination as well as to interpersonal and school dysfunction. These results are consistent with the hypothesis that behavioral disinhibition represents an early temperamental precursor to disruptive behavior disorders in general and ADHD in particular. If confirmed, this research could be of great importance, because it could lead to the ability to recognize toddlers or preschoolers at later risk for attentional, behavioral, and academic problems who could benefit from preventive intervention.
National Institute of Mental Health Grant Nos. MH-47077 05 (Drs. Rosenbaum and Biederman) and MH-01538 02 (Dr. Hirshfeld-Becker) supported this research. The authors gratefully acknowledge Dr. Jerome Kagan and Dr. Nancy Snidman at the Department of Psychology at Harvard University for their contributions to this project. We acknowledge Dr. David Rettew for his contribution to reliability assessments.

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