Dina R. Hirshfeld-Becker

The developmental psychopathology of social anxiety disorder

The role of developmental theory and developmental psychopathology in understanding the development, maintenance, and course of social anxiety disorder (SAD) is explored in this article. Following a brief examination of the phenomenology of SAD in youth, we provide an overview of the tenets of developmental psychology and developmental psychopathology, including the principles of equifinality (i.e., the same outcome can result from diverse developmental pathways) and multifinality (i.e., the same risk factor can lead to or result in different outcomes). We review various pathways for the acquisition and maintenance of SAD (e.g., genetic and temperamental influences, parental factors, conditioning or learning experiences, peer influences, and cognitive styles) and conclude, consistent with a developmental psychopathology perspective, that multiple pathways to SAD exist and that the various precursors to SAD do not invariably lead to SAD. We suggest that specificity in outcome is afforded by the combination, timing, and circumstances surrounding these various risk factors. Finally, we propose studies to test the viability of the developmental psychopathology model in understanding SAD.

Behavioral Inhibition in Preschool Children At Risk Is a Specific Predictor of Middle Childhood Social Anxiety: A Five-year Follow-up

Objective: Behavioral inhibition (BI) to the unfamiliar represents the temperamental tendency to exhibit fearfulness, reticence, or restraint when faced with unfamiliar people or situations. It has been hypothesized to be a risk factor for anxiety disorders. In this prospective longitudinal study, we compared the psychiatric outcomes in middle childhood of children evaluated at preschool age for BI. Method: The baseline sample consisted of 284 children ages 21 months to 6 years, including offspring at risk for anxiety (children of parents with panic disorder and/or major depression) and comparison offspring of parents without mood or major anxiety disorders. They had been assessed for BI using age-specific laboratory protocols. We reassessed 215 of the children (76.5%) at 5-year follow-up at a mean age of 9.6 years using structured diagnostic interviews. Results: BI specifically predicted onset of social anxiety. The rate of lifetime social anxiety (DSM-IV social phobia or DSM-III-R avoidant disorder) was 28% versus 14% (odds ratio [OR] = 2.37; 95% confidence interval [CI]: 1.10–5.10) in inhibited versus noninhibited children. BI significantly predicted new onset of social phobia among children unaffected at baseline (22.2% vs 8.0% in inhibited versus noninhibited children (OR = 3.15, 95% CI: 1.16–8.57). No other anxiety disorders were associated with BI. Conclusion: BI appears to be a temperamental antecedent to subsequent social anxiety in middle childhood. Children presenting with BI should be monitored for symptoms of social anxiety and may be good candidates for preventive cognitive behavioral strategies.

Psychopathology in the Offspring of Parents with Bipolar Disorder: A Controlled Study

BACKGROUND To examine the risk for psychopathology in offspring at risk for bipolar disorder and the course of psychiatric disorders in these youth. METHODS Using structured diagnostic interviews (Structured Clinical Interview for DSM-IV [SCID] and Kiddie Schedule for Affective Disorders and Schizophrenia [K-SADS]), psychiatric diagnoses of 117 nonreferred offspring of parents with diagnosed bipolar disorder were compared with those of 171 age- and gender-matched offspring of parents without bipolar disorder or major depression. RESULTS Compared with offspring of parents without mood disorders, high-risk youth had elevated rates of major depression and bipolar disorder, anxiety, and disruptive behavior disorders. High-risk offspring also had significantly more impaired Global Assessment of Functioning (GAF) scores, higher rates of psychiatric treatment, and higher rates of placement in special education classes. Disruptive behavior disorders, separation anxiety disorder, generalized anxiety disorder (GAD), social phobia, and depression tended to have their onset in early or middle childhood, whereas bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, and substance use disorder had onset most frequently in adolescence. CONCLUSIONS These findings support the hypothesis that offspring of parents with bipolar disorder are at significantly increased risk for developing a wide range of severe psychiatric disorders and accompanying dysfunction. Early disruptive behavior and anxiety disorders, as well as early-onset depression, may be useful markers of risk for subsequent bipolar disorder in high-risk samples.

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.

Cognitive Behavioral Therapy for 4- to 7-Year-Old Children with Anxiety Disorders: A Randomized Clinical Trial.

OBJECTIVE To examine the efficacy of a developmentally appropriate parent-child cognitive behavioral therapy (CBT) protocol for anxiety disorders in children ages 4-7 years. METHOD DESIGN Randomized wait-list controlled trial. Conduct: Sixty-four children (53% female, mean age 5.4 years, 80% European American) with anxiety disorders were randomized to a parent-child CBT intervention (n = 34) or a 6-month wait-list condition (n = 30). Children were assessed by interviewers blind to treatment assignment, using structured diagnostic interviews with parents, laboratory assessments of behavioral inhibition, and parent questionnaires. ANALYSIS Chi-square analyses of outcome rates and linear and ordinal regression of repeated measures, examining time by intervention interactions. RESULTS The response rate (much or very much improved on the Clinical Global Impression Scale for Anxiety) among 57 completers was 69% versus 32% (CBT vs. controls), p < .01; intent-to-treat: 59% vs. 30%, p = .016. Treated children showed a significantly greater decrease in anxiety disorders (effect size [ES] = .55) and increase in parent-rated coping (ES = .69) than controls, as well as significantly better CGI improvement on social phobia/avoidant disorder (ES = .95), separation anxiety disorder (ES = .82), and specific phobia (ES = .78), but not on generalized anxiety disorder. Results on the Child Behavior Checklist Internalizing scale were not significant and were limited by low return rates. Treatment response was unrelated to age or parental anxiety but was negatively predicted by behavioral inhibition. Gains were maintained at 1-year follow-up. CONCLUSIONS Results suggest that developmentally modified parent-child CBT may show promise in 4- to 7-year-old children.

Rationale and Principles for Early Intervention with Young Children at Risk for Anxiety Disorders

Anxiety disorders are one of the most prevalent categories of disorder among adults and children. Children of parents with anxiety disorders are known to be at higher risk for anxiety disorders themselves, with manifestations of this risk often appearing in toddlerhood or early childhood. Yet because affected parents are often unskilled in anxiety management, they often have difficulty in helping their young children learn to manage anxiety. Literature on the course of anxiety disorders through childhood and on effective cognitive-behavioral interventions suggests that preventive interventions even with very young children could potentially be of benefit in mitigating the course of these often debilitating disorders. This paper outlines the rationale for offering early or preventive interventions to preschool-age children at risk and their parents and discusses means of identifying children to target for intervention and the importance of parental involvement. Drawing upon the literature on parental factors in childhood anxiety disorders as well as on effective intervention strategies with preschool-age children, it delineates principles for intervention with parents and effective components of intervention with youngsters in this age range.

Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition

BACKGROUND Behavioral inhibition to the unfamiliar (BI), a heritable temperamental profile involving an avoidant response to novel situations, may be an intermediate phenotype in the development of anxiety disorders. Corticotropin-releasing hormone (CRH) is a key mediator of the stress response through its effects on the hypothalamic-pituitary-adrenal axis and limbic brain systems. Transgenic mice overexpressing CRH exhibit BI-like behaviors, implicating this gene in the development of the phenotype. METHODS We genotyped a marker tightly linked to the CRH locus in 85 families of children who underwent laboratory-based behavioral assessments of BI and performed family-based association analyses. RESULTS We observed an association between an allele of the CRH-linked locus and BI (p =.015). Among offspring of parents with panic disorder, this association was particularly marked (p =.0009). We further demonstrate linkage disequilibrium between this marker and single nucleotide polymorphisms encompassing the CRH gene. CONCLUSIONS These results are consistent with the possibility that variants in the CRH gene are associated with anxiety proneness.

Influence of RGS2 on Anxiety-Related Temperament, Personality, and Brain Function

CONTEXT Although anxiety disorders are heritable, their genetic and phenotypic complexity has made the identification of susceptibility genes difficult. Well-validated animal models and intermediate phenotypes provide crucial tools for genetic dissection of anxiety. The gene encoding regulator of G protein signaling 2 (Rgs2) is a quantitative trait gene that influences mouse anxiety behavior, making its human ortholog (RGS2) a compelling candidate gene for human anxiety phenotypes. OBJECTIVE To examine whether variation in RGS2 is associated with intermediate phenotypes for human anxiety disorders. DESIGN Family-based and case-control association analysis of single-nucleotide polymorphisms at the RGS2 locus in 3 independent samples. SETTING Massachusetts General Hospital, University of California, San Diego, and San Diego State University. PARTICIPANTS Study participants included a family-based sample (n = 119 families) of children who underwent laboratory-based assessments of temperament (behavioral inhibition), a sample of 744 unrelated adults who completed assessments of extraversion and introversion, and 55 unrelated adults who underwent functional magnetic resonance imaging measures of response to emotional faces. MAIN OUTCOME MEASURES Laboratory-based behavioral measures of childhood temperament, self-report measure of personality, and functional magnetic resonance imaging response to emotion processing. RESULTS Markers spanning RGS2 were associated with childhood behavioral inhibition, a temperamental precursor of social anxiety disorder (haplotype P = 3 x 10(-5); odds ratio, 2.99 in complete trios). In independent samples, RGS2 markers, including rs4606, which has previously been associated with RGS2 expression, were also associated with introversion (a core personality trait in social anxiety disorder) and with increased limbic activation (insular cortex and amygdala) during emotion processing (brain phenotypes correlated with social anxiety). The genotype at rs4606 explained 10% to 15% of the variance in amygdala and insular cortex activation to emotional faces. CONCLUSIONS These results provide the first evidence that a gene that influences anxiety in mice is associated with intermediate phenotypes for human anxiety disorders across multiple levels of assessment, including childhood temperament, adult personality, and brain function. This translational research suggests that some genetic influences on anxiety are evolutionarily conserved and that pharmacologic modulation of RGS2 function may provide a novel therapeutic approach for anxiety disorders.

High risk studies and developmental antecedents of anxiety disorders

The past two decades have witnessed significant growth in our understanding of the developmental antecedents of anxiety disorders. In this article, we review studies of offspring at risk for anxiety disorders, longitudinal studies of the course of anxiety disorders in clinical, epidemiologic, and at‐risk samples, studies of hypothesized temperamental risk factors for anxiety, and give a brief overview of the literature on environmental risk factors. Clear developmental antecedents to anxiety disorders identified include (1) childhood anxiety disorders [in particular, separation anxiety and overanxious disorder/general anxiety disorder (GAD)], (2) behavioral inhibition which predicts later social phobia, (3) anxiety sensitivity which predicts later panic disorder, and (4) negative affectivity, which predicts a spectrum of psychopathology including anxiety disorders. Further prospective studies are needed to examine the roles of environmental factors such as parenting practices, peer influences, stressful life events, and perinatal stressors. Future studies could benefit from (1) beginning earlier in development and following individuals into adulthood, (2) assessing the overlap between multiple temperamental constructs, (3) greater use of observational measures of temperament and of parent–child and peer interactions, (4) greater attention to parental psychopathology which may confound associations noted, (5) exploration of other features of anxiety disorders (neurofunctional correlates, cognitive features, other aspects of emotional regulation) as potential precursors, and (6) intervention studies exploring whether modifying developmental antecedents can alter the course of anxiety disorders.

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.