Comorbidity of parental anxiety disorders as risk for childhood-onset anxiety in inhibited children.

OBJECTIVE: Previous work suggested that children of parents with panic disorder and agoraphobia were likely to be classified as behaviorally inhibited and that behaviorally inhibited children were likely to develop anxiety disorders. However, the factors determining which inhibited children were at risk for childhood onset of anxiety disorders remained unknown. The authors of this study hypothesized that greater anxiety loading in parents would increase the risk for anxiety disorders in children with behavioral inhibition. METHOD: Using DSM-III structured interviews, the authors examined patterns of aggregation of anxiety disorders in parents of two existing cohorts of children, one cross-sectional and clinically derived (31 children, 60 parents) and the other epidemiologically derived and longitudinal (40 children, 75 parents). Within each cohort, parents were stratified into three groups based on the presence (behavioral inhibition and anxiety) or absence (behavioral inhibition only, no behavioral inhibition and no anxiety) of behavioral inhibition and two or more anxiety disorders in their child. RESULTS: Parents of children with behavioral inhibition and anxiety, from both the clinical and nonclinical cohorts, had significantly higher rates of two or more anxiety disorders than did parents of children with behavioral inhibition only and parents of children with no behavioral inhibition and no anxiety. CONCLUSIONS: These results indicate that the presence of parental loading for anxiety disorders may help to identify the subgroup of inhibited children at very high risk for developing childhood-onset anxiety disorders.     

Further evidence of an association between behavioral inhibition and anxiety disorders: results from a family study of children from a non-clinical sample

Behavioral inhibition to the unfamiliar, identifiable in early childhood and reflecting the tendency to exhibit withdrawal and excessive autonomic arousal to challenge or novelty, has been found to be prevalent in young offspring of parents with panic disorder and agoraphobia and associated with risk for anxiety disorders in these children. Using family study methodology, we now examine psychopathology in first degree relatives of children from a non-clinical longitudinal cohort identified at 21 months of age as inhibited (N = 22) or uninhibited (N = 19) and followed through the age of seven years for a study of preservation of temperamental characteristics in normal children. These assessments were compared with evaluations of the first degree relatives of 20 normal comparison children. Psychiatric assessments of parents (N = 110) and siblings (N = 72) were based on structured interviews conducted blindly to the temperamental classification of the index child. Parents of inhibited children, compared with parents of uninhibited and normal controls, had significantly higher risks for multiple (greater than or equal to 2) anxiety disorders, continuing anxiety disorders (both a childhood and adulthood anxiety disorder in the same parent), social phobia, and childhood avoidant and overanxious disorders. These findings provide additional support for the hypothesis linking behavioral inhibition with risk for anxiety disorder.     

Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression

The objective of this study was to evaluate the longitudinal course of psychiatric disorders in children of parents with and without panic disorder and major depression as they transition through the period of risk from early to late childhood. Over a 5-year follow-up, we compared the course of psychiatric disorders in offspring of parents with panic disorder, major depression, or neither disorder. Subjects consisted of 233 offspring (from 151 families) with baseline and follow-up assessments. Subjects were comprehensively assessed with structured diagnostic interviews. Anxiety disorders at baseline were used to predict anxiety disorders and major depression at follow-up using stepwise logistic regression. Separation anxiety disorder significantly increased the risk for the subsequent development of specific phobia, agoraphobia, panic disorder, and major depression, even after parental panic and depression were covaried. Agoraphobia significantly increased the risk for subsequent generalized anxiety disorder. These findings suggest that separation anxiety disorder is a major antecedent disorder for the development of panic disorder and a wide range of other psychopathological outcomes, and that it increases the risk for subsequent psychopathology even among children already at high familial risk for anxiety or mood disorder.     

Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression

OBJECTIVE: The purpose of the study was to evaluate 1) whether an underlying familial predisposition is shared by all anxiety disorders or whether specific risks are associated with specific disorders, and 2) whether panic disorder and major depression have a familial link. METHOD: The study compared four groups of children: 1) offspring of parents with panic disorder and comorbid major depression (N=179), 2) offspring of parents with panic disorder without comorbid major depression (N=29), 3) offspring of parents with major depression without comorbid panic disorder (N=59), and 4) offspring of parents with neither panic disorder nor major depression (N=113). RESULTS: Parental panic disorder, regardless of comorbidity with major depression, was associated with an increased risk for panic disorder and agoraphobia in offspring. Parental major depression, regardless of comorbidity with panic disorder, was associated with increased risks for social phobia, major depression, disruptive behavior disorders, and poorer social functioning in offspring. Both parental panic disorder and parental major depression, individually or comorbidly, were associated with increased risk for separation anxiety disorder and multiple (two or more) anxiety disorders in offspring. CONCLUSIONS: These findings confirm and extend previous results documenting significant associations between the presence of panic disorder and major depression in parents and patterns of psychopathology and dysfunction in their offspring.     

A controlled study of behavioral inhibition in children of parents with panic disorder and depression

OBJECTIVE: "Behavioral inhibition to the unfamiliar" has been proposed as a precursor to anxiety disorders. Children with behavioral inhibition are cautious, quiet, introverted, and shy in unfamiliar situations. Several lines of evidence suggest that behavioral inhibition is an index of anxiety proneness. The authors sought to replicate prior findings and examine the specificity of the association between behavioral inhibition and anxiety. METHOD: Laboratory-based behavioral observations were used to assess behavioral inhibition in 129 young children of parents with panic disorder and major depression, 22 children of parents with panic disorder without major depression, 49 children of parents with major depression without panic disorder, and 84 children of parents without anxiety disorders or major depression (comparison group). A standard definition of behavioral inhibition based on previous research ("dichotomous behavioral inhibition") was compared with two other definitions. RESULTS: Dichotomous behavioral inhibition was most frequent among the children of parents with panic disorder plus major depression (29% versus 12% in comparison subjects). For all definitions, the univariate effects of parental major depression were significant (conferring a twofold risk for behavioral inhibition), and for most definitions the effects of parental panic disorder conferred a twofold risk as well. CONCLUSIONS: These results suggest that the comorbidity of panic disorder and major depression accounts for much of the observed familial link between parental panic disorder and childhood behavioral inhibition. Further work is needed to elucidate the role of parental major depression in conferring risk for behavioral inhibition in children.     

Lack of association between behavioral inhibition and psychosocial adversity factors in children at risk for anxiety disorders

OBJECTIVE: In a previous controlled study of offspring at risk for anxiety disorders, the authors found that parental panic disorder with comorbid major depression was associated with child behavioral inhibition, the temperamental tendency to be quiet and restrained in unfamiliar situations. To explore whether this association was mediated by environmental factors, the authors examined associations between psychosocial adversity variables and behavioral inhibition in this group of children. METHOD: Subjects included 200 offspring of parents with panic disorder and/or major depression and 84 comparison children of parents without mood or anxiety disorders. Behavioral inhibition was assessed through laboratory observations. The associations between behavioral inhibition and the following psychosocial factors were examined: socioeconomic status; an index of adversity factors found in previous studies to be additively associated with child psychopathology; family intactness, conflict, expressiveness, and cohesiveness; exposure to parental psychopathology; sibship size; birth order; and gender. RESULTS: The results showed no associations between behavioral inhibition and any of the psychosocial factors in the study group as a whole, despite adequate power to detect medium effect sizes. Among low-risk comparison children only, some definitions of behavioral inhibition were associated with low socioeconomic status, low family cohesion, and female gender. CONCLUSIONS: The results suggest that the psychosocial adversity factors examined in this study do not explain the previous finding that offspring of parents with panic disorder are at high risk for behavioral inhibition.     

Further evidence of association between behavioral inhibition and social anxiety in children

OBJECTIVE: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. METHOD: Behavioral inhibition, determined by using standard laboratory observations, was assessed in four groups of children (age 2-6 years): 129 children of parents with both panic disorder and major depression, 22 children of parents with panic disorder alone, 49 children of parents with major depression alone, and 84 comparison children of parents with neither panic disorder nor major depression. Psychopathology in children > or =5 years was compared between children with behavioral inhibition (N=64) and without (N=152). RESULTS: Social anxiety disorder (social phobia or avoidant disorder) was significantly more likely to be found in the children with behavioral inhibition (17%) than in those without (5%). Noninhibited children were significantly more likely than inhibited children to have disruptive behavior disorders (20% versus 6%, respectively) and had higher scores on the attention problems scale of the Child Behavior Checklist (mean=52.1 versus 50.8). CONCLUSIONS: This study adds to the growing literature suggesting an association between behavioral inhibition and social anxiety disorder and an inverse relationship between inhibition and disruptive behavior disorders.     

Parental predictors of pediatric panic disorder/agoraphobia: a controlled study in high-risk offspring

Our objective was to evaluate parental risk factors for pediatric-onset panic disorder/agoraphobia (PD/AG) in offspring at high risk for PD/AG. Comparisons were made between parents with PD who had a child with PD or AG (N = 27) and parents with PD without children with PD or AG (N = 79). Comparisons were also made between the spouses of these parents with PD. Separation anxiety disorder, social phobia, obsessive-compulsive disorder, and bipolar disorder in the parents with PD and their spouses accounted for the risk for childhood onset PD/AG in the offspring. This risk was particularly high if both parents were affected with social phobia. These findings suggest that psychiatric comorbidity with other anxiety disorders and with bipolar disorder in parents with PD and their spouses confer a particularly high risk in their offspring to develop PD/AG in childhood.     

Laboratory-observed behavioral disinhibition in the young offspring of parents with bipolar disorder: a high-risk pilot study

OBJECTIVE: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. METHOD: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2-6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. RESULTS: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. CONCLUSIONS: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.     

A high risk study of young children of parents with panic disorder and agoraphobia with and without comorbid major depression

Using family study methodology and psychiatric assessments by blind raters, this study tested hypotheses about patterns of familial association between anxiety and depressive disorders among high risk children of clinically referred parents. The study design contrasted five groups of children defined by the presence or absence in a parent of (1) panic disorder and agoraphobia (PDAG) without comorbid major depressive disorder (MDD) (n = 14); (2) comorbid PDAG plus MDD (PDAG + MDD) (n = 25); (3) MDD without comorbid PDAG (n = 12); (4) other psychiatric disorders (n = 23); and (5) normal comparisons (n = 47). While the PDAG and PDAG + MDD groups had similarly elevated rates of anxiety disorders and MDD, offspring of MDD parents had an elevated rate of MDD but not of anxiety disorders. Among children of parents with PDAG + MDD, the presence of an anxiety disorder did not significantly increase the risk for MDD in the same child. Thus, anxiety and MDD did not cosegregate among children of PDAG parents. These findings indicate that parental PDAG, either alone or comorbidly with MDD, increases the risk for both anxiety and depressive disorders in offspring. In the absence of PDAG, however, parental MDD does not appear to place children at risk for anxiety disorders. These findings are most consistent with the hypothesis that PDAG and PDAG + MDD share common familial etiologic factors while MDD alone is an independent disorder. More studies are needed to confirm these preliminary findings as well as to identify mediating factors that influence the transition from childhood to adult anxiety disorders.     

Depression and anxiety disorders in parents and children. Results from the Yale family study

The children (aged 6 to 17 years) of probands with primary major depression, with and without various anxiety disorders, were compared with the children of a matched normal control group. The results from the study of these young children parallel our previous findings among the adult first-degree relatives of these probands. Depression in the proband increased the risk of depression in the children. Depression plus panic disorder or agoraphobia in the proband conferred an additional risk of depression and of an anxiety disorder in the children. Panic disorder in the parents conferred more than a threefold increased risk of separation anxiety in the children. Other factors that increased the risk to children were degree of familial loading for psychiatric illness, parental assortative mating, and parental recurrent depression. The findings suggest a relationship between depression and some of the anxiety disorders, and between adult panic disorder and agoraphobia and transmission of anxiety disorders to children.     

Clinical outcomes of laboratory-observed preschool behavioral disinhibition at five-year follow-up.

BACKGROUND: Behavioral disinhibition refers to a temperamental tendency to exhibit boldness, approach, and spontaneity in unfamiliar situations. We previously found it to be associated with childhood disruptive behavior and mood disorders, as well as with parental bipolar disorder. In the present study, our objective was to examine the diagnostic outcome in middle childhood of behavioral disinhibition assessed at preschool age among offspring at risk for anxiety and mood disorders. METHODS: The sample consisted of 284 children, including offspring of parents with panic disorder or major depression and comparison offspring of parents without these disorders, who had been assessed with laboratory observations of temperament at ages 21 months to 6 years. We reassessed 215 of the children (77%) at 5-year follow-up (mean age 9.6 years) with structured diagnostic interviews. RESULTS: Compared with noninhibited, nondisinhibited control subjects, behaviorally disinhibited children had higher lifetime rates of comorbid mood plus disruptive behavior disorders and higher current rates of any disruptive behavior disorder and of oppositional defiant disorder. CONCLUSIONS: Behavioral disinhibition appears to be a temperamental antecedent of disruptive behavior disorders and their comorbidity with mood disorders in middle childhood, which may be targeted for preventive intervention.     

Psychopathology in the young offspring of parents with bipolar disorder: a controlled pilot study

Studies have suggested that the offspring of parents with bipolar disorder are at risk for a spectrum of psychopathology, but few have focused on children in the youngest age ranges or examined the impact of comorbid parental disorders. We utilized a pre-existing sample of young (mean age: 6.8 years) offspring of parents with bipolar disorder (n=34), of parents with panic or major depression (n=179), and of parents with neither mood or anxiety disorder (n=95). Children were assessed blindly to parental diagnoses using the Schedule for Affective Disorders and Schizophrenia-Epidemiologic version (K-SADS-E). Offspring of bipolar parents had significantly higher rates of disruptive behavior and anxiety disorders than offspring from both of the comparison groups, accounted for by elevated rates of ADHD and overanxious disorder. These comparisons were significant even when lifetime histories of the corresponding categories of comorbid disorders in the parents (disruptive behavior disorders and anxiety disorders) were covaried. In addition, offspring of bipolar parents had increased rates of bipolar I disorder, compared with psychiatric controls. Results support the hypotheses of elevated behavior, anxiety, and mood disorders among offspring at risk for bipolar disorder, and suggest that this psychopathology is already evident in early childhood.     

Childhood and family characteristics in panic and generalized anxiety disorders

The author compared 32 patients who had generalized anxiety disorders with 29 patients who had panic disorder and agoraphobia with panic attacks. He observed that patients with generalized anxiety disorder more often had lost their fathers and/or mothers before the age of 16 years, whereas patients with panic disorder and agoraphobia with panic attacks had more often experienced chronic anxiety in childhood. More parents and siblings of patients with panic disorder had affective disorders and alcohol abuse than did parents and siblings of patients with anxiety disorders.     

Stable behavioral inhibition and its association with anxiety disorder.

"Behavioral inhibition to the unfamiliar" is a temperamental construct reflecting the tendency to be shy, timid, and constrained in novel situations. Previous work has suggested that it may be associated with anxiety disorders in children. Psychopathology was assessed in children from a nonclinical sample originally identified as behaviorally inhibited or uninhibited at 21 months and followed through 7 1/2 years. Children who remained inhibited at 4, 5 1/2 and 7 1/2 years (Stable Inhibited) had higher rates of anxiety disorders than children who were not consistently inhibited. Their parents had higher rates of multiple childhood anxiety disorders and of continuing anxiety disorder. These results suggest that the association between behavioral inhibition and anxiety disorder is accounted for by children who have stable behavioral inhibition.     

Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study

This naturalistic European multicenter study aimed to elucidate the association between major depressive disorder (MDD) and comorbid anxiety disorders. Demographic and clinical information of 1346 MDD patients were compared between those with and without concurrent anxiety disorders. The association between explanatory variables and the presence of comorbid anxiety disorders was examined using binary logistic regression analyses. 286 (21.2%) of the participants exhibited comorbid anxiety disorders, 10.8% generalized anxiety disorder (GAD), 8.3% panic disorder, 8.1% agoraphobia, and 3.3% social phobia. MDD patients with comorbid anxiety disorders were characterized by younger age (social phobia), outpatient status (agoraphobia), suicide risk (any anxiety disorder, panic disorder, agoraphobia, social phobia), higher depressive symptom severity (GAD), polypsychopharmacy (panic disorder, agoraphobia), and a higher proportion receiving augmentation treatment with benzodiazepines (any anxiety disorder, GAD, panic disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder). The results in terms of treatment response were conflicting (better response for panic disorder and poorer for GAD). The logistic regression analyses revealed younger age (any anxiety disorder, social phobia), outpatient status (agoraphobia), suicide risk (agoraphobia), severe depressive symptoms (any anxiety disorder, GAD, social phobia), poorer treatment response (GAD), and increased administration of benzodiazepines (any anxiety disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder) to be associated with comorbid anxiety disorders. Our findings suggest that the various anxiety disorders subtypes display divergent clinical characteristics and are associated with different variables. Especially comorbid GAD appears to be characterized by high symptom severity and poor treatment response.     

The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder.

BACKGROUND: Behavioral inhibition to the unfamiliar (BI) is a heritable temperamental phenotype involving the tendency to display fearful, avoidant, or shy behavior in novel situations. BI is a familial and developmental risk factor for panic and phobic anxiety disorders. We previously observed an association between BI and a microsatellite marker linked to the corticotropin releasing hormone (CRH) gene in children at risk for panic disorder. To evaluate this further, we genotyped additional families for this marker and a panel of markers encompassing the CRH locus. METHODS: Sixty-two families that included parents with panic disorder and children who underwent laboratory-based behavioral observations were studied. Family-based association tests and haplotype analysis were used to evaluate the association between BI and polymorphisms spanning the CRH locus. RESULTS: We examined a set of markers which we found to reside in a block of strong linkage disequilibrium encompassing the CRH locus. The BI phenotype was associated with the microsatellite marker (p=.0016) and three single nucleotide polymorphisms (SNPs), including a SNP in the coding sequence of the gene (p=.023). Haplotype-specific tests revealed association with a haplotype comprising all of the markers (p=.015). CONCLUSIONS: These results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders. Genetic studies of anxiety-related temperament represent an important strategy for identifying the genetic basis of anxiety disorders.     

Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects

BACKGROUND: Carbon dioxide (CO(2)) sensitivity is postulated to be a familial risk marker of panic disorder (PD). Exaggerated responses to CO(2) inhalation have been reported in adults with PD and their unaffected adult relatives, as well as in clinic-referred children with anxiety disorders. OBJECTIVE: To test in a family-based design whether CO(2) hypersensitivity is a familial risk marker for PD and associated with current anxiety disorders in children and adolescents. SETTING AND PARTICIPANTS: One hundred forty-two offspring (aged 9-19 years) of parents with PD, major depressive disorder, or no disorder. Forty-five (32%) had a current anxiety disorder, excluding specific phobia. DESIGN AND MAIN OUTCOME MEASURES: Parents and offspring received diagnostic assessments. Offspring underwent 5% CO(2) inhalation at home. Panic symptoms and panic attacks were rated with the Acute Panic Inventory at baseline, while anticipating CO(2) delivery ("threat"), and during CO(2) inhalation. Respiratory rate and volume were measured with spirometry. RESULTS: No group differences were found in Acute Panic Inventory ratings at baseline or in respiratory measures during threat. Risk for PD was not associated with CO(2) sensitivity (panic symptoms and respiratory physiologic response). During CO(2) inhalation, offspring with anxiety disorders, relative to offspring without anxiety disorders, experienced significantly more panic symptoms and panic attacks, as well as elevated respiratory rates. During threat, panic symptoms were significantly and independently associated with both parental PD and offspring anxiety disorders. CONCLUSIONS: No support was obtained for CO(2) hypersensitivity as a familial risk marker for PD in children and adolescents. Links between childhood anxiety disorders and CO(2) sensitivity were replicated. Familial risk for PD in children and adolescents may be associated with vulnerability to anticipatory anxiety.     

Behavioral inhibition in childhood predicts smaller hippocampal volume in adolescent offspring of parents with panic disorder

Behavioral inhibition (BI) is a genetically influenced behavioral profile seen in 15–20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI− based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation.     

Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study

To investigate the role of "behavioral inhibition to the unfamiliar" as an early temperamental characteristic of children at risk for adult panic disorder and agoraphobia (PDAG), we compared children of parents with PDAG with those from psychiatric comparison groups. Fifty-six children aged 2 to 7 years, matched for age, socioeconomic status, ethnic background, and ordinal position, were blindly evaluated at the Harvard Infant Study laboratory, Cambridge, Mass. The rates of behavioral inhibition in children of probands with PDAG, with or without comorbid major depressive disorder (MDD), were significantly higher than for our comparison group without PDAG. Further, the data suggest a progression of increasing rates of inhibition from the comparison group without MDD (15.4%), to MDD (50.0%), and to comorbid PDAG and MDD (70%) and PDAG (84.6%). In contrast, the rate of behavioral inhibition in children of probands with MDD did not meaningfully differ from the comparison group without MDD. Behavioral inhibition to the unfamiliar, as defined and measured in the previous work of the Harvard Infant Study program, is highly prevalent in the offspring of adults in treatment for PDAG. These children appear to be at risk for distress and disability in childhood and also perhaps for development of psychiatric disorder in later childhood and aulthood.