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.     

Relationship between self-reported childhood behavioral inhibition and lifetime anxiety disorders in a clinical sample

To examine the association between an early inhibited temperament and lifetime anxiety disorders, we studied a sample of patients with major depression who were not selected on the basis of comorbid axis I anxiety disorders. One-hundred eighty-nine adults (range = 17-68 years) referred to a tertiary depression unit underwent structured diagnostic interviews for depression and anxiety and completed two self-report measures of behavioral inhibition, the retrospective measure of behavioural inhibition (RMBI) [Gladstone and Parker, 2005] and the adult measure of behavioural inhibition (AMBI) [Gladstone and Parker, 2005]. Patients' scores were classified into "low," "moderate," or "high" inhibition. While groups did not differ in terms of depression severity, there were differences across groups in clinically diagnosed nonmelancholic status and age of onset of first episode. Those reporting a high degree of childhood inhibition were significantly more likely to qualify for a diagnosis of social phobia, and this association was independent of their scores on the AMBI. Findings are discussed in light of the existing risk-factor literature and support the hypothesis that an early inhibited temperament may be a significant precursor to later anxiety, especially social anxiety disorder.     

Behavioral inhibition and disinhibition as hypothesized precursors to psychopathology: implications for pediatric bipolar disorder.

Attention has been devoted over the past two decades to the identification of temperamental risk factors for child psychopathology. These qualities, evident in toddlerhood or earlier, have the advantage of being measurable in standardized laboratory observations well before children reach the age of onset or diagnosis of psychiatric disorders. Our group's programmatic research over the past 15 years, and that of others, has provided evidence linking "behavioral inhibition to the unfamiliar" in toddlerhood or early childhood with later social anxiety disorder. In addition, recent results by our group have suggested that "behavioral disinhibition" in early childhood, measured by the same laboratory methods, may be linked with later disruptive behavior and comorbid mood disorders. In this article, we discuss our approach to the study of temperamental precursors to disorders in high-risk children, summarize the literature linking behavioral inhibition and disinhibition to later psychopathology, and suggest directions to take in applying this methodology to the search for temperamental precursors to pediatric bipolar disorder.     

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.     

Temperament and character among Korean children and adolescents with anxiety disorders

The purpose of this study was to evaluate the temperament and character of children and adolescents with anxiety disorders in samples from Korean community. The study subjects were children and adolescents diagnosed with social phobia (n = 66), separation anxiety disorder (n = 47), specific phobia (n = 415), and obsessive–compulsive disorder (n = 42) with the diagnostic interview schedule for children, version IV (DISC-IV) in representative community samples. Among these, we excluded other psychiatric disorder comorbid samples, with the exception of externalizing disorders. We assessed the subjects of each anxiety group using the junior temperament and character inventory (JTCI). Social phobias were significantly associated with high harm avoidance and low self-directedness on the JTCI. The association of specific phobias with high harm avoidance, and obsessive–compulsive disorder with low self-directedness was also significant. Separation anxiety disorder was not associated with any temperament and character on the JTCI. Children and adolescents with anxiety disorders have different temperaments and character profiles in accordance with diagnostic groups, which implies the specific pathophysiological mechanism of each anxiety disorder.     

Impact of childhood life events and trauma on the course of depressive and anxiety disorders

Hovens JGFM, Giltay EJ, Wiersma JE, Spinhoven P, Penninx BWJH, Zitman FG. Impact of childhood life events and trauma on the course of depressive and anxiety disorders. Objective: Data on the impact of childhood life events and childhood trauma on the clinical course of depressive and anxiety disorders are limited. Method: Longitudinal data were collected from 1209 adult participants in the Netherlands Study of Depression and Anxiety (NESDA). Childhood life events and trauma at baseline were assessed with a semi‐structured interview and the clinical course after 2 years with a DSM‐IV‐based diagnostic interview and Life Chart Interview. Results: At baseline, 18.4% reported at least one childhood life event and 57.8% any childhood trauma. Childhood life events were not predictive of any measures of course trajectory. Emotional neglect, psychological and physical abuse, but not sexual abuse, were associated with persistence of both depressive and comorbid anxiety and depressive disorder at follow‐up. Emotional neglect and psychological abuse were associated with a higher occurrence of a chronic course. Poor course outcomes were mediated mainly through a higher baseline severity of depressive symptoms. Conclusion: Childhood trauma, but not childhood life events, was associated with an increased persistence of comorbidity and chronicity in adults with anxiety and/or depressive disorders. More unfavourable clinical characteristics at baseline mediate the relationship between childhood trauma and a poorer course of depressive and anxiety disorders.     

Psychometric properties of the Retrospective Self Report of Inhibition (RSRI) in a representative German sample

The present study examined the internal consistency, factorial structure, and construct validity of the German version of the Retrospective Self Report of Inhibition (RSRI), a questionnaire measure of behavioral inhibition. The research was based on data from a German prospective-longitudinal community study of 3021 adolescents and young adults (aged 14-24 years at baseline). Diagnostic assessment was based on the DSM-IV/M-CIDI and general psychopathological distress was assessed with SCL-90-R. Results of confirmatory factor analysis indicated adequate fit of the two-factor model, suggested by the authors of the original version. Indices of internal consistency of the RSRI and its subscales 'social/school' and 'fear/illness' were shown to be sufficient for the total sample and even higher in subgroups of subjects with certain DSM-IV diagnoses. Associations with variables such as mental distress, parental psychopathology, and DSM-IV disorders were in line with theoretical assumptions and confirm different aspects of the validity (convergent, concurrent, predictive) of the instrument. The psychometric properties of the German RSRI were found to be comparable to those of the English version. The applicability of this questionnaire in German-speaking countries is therefore recommended for adolescents and young adults.     

Structural and functional bases of inhibited temperament

Children born with an inhibited temperament are at heightened risk for developing anxiety, depression and substance use. Inhibited temperament is believed to have a biological basis; however, little is known about the structural brain basis of this vulnerability trait. Structural MRI scans were obtained from 84 (44 inhibited, 40 uninhibited) young adults. Given previous findings of amygdala hyperactivity in inhibited individuals, groups were compared on three measures of amygdala structure. To identify novel substrates of inhibited temperament, a whole brain analysis was performed. Functional activation and connectivity were examined across both groups. Inhibited adults had larger amygdala and caudate volume and larger volume predicted greater activation to neutral faces. In addition, larger amygdala volume predicted greater connectivity with subcortical and higher order visual structures. Larger caudate volume predicted greater connectivity with the basal ganglia, and less connectivity with primary visual and auditory cortex. We propose that larger volume in these salience detection regions may result in increased activation and enhanced connectivity in response to social stimuli. Given the strong link between inhibited temperament and risk for psychiatric illness, novel therapeutics that target these brain regions and related neural circuits have the potential to reduce rates of illness in vulnerable individuals.     

Behavioral inhibition and obsessive-compulsive disorder

Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.     

The development and modification of temperamental risk for anxiety disorders: prevention of a lifetime of anxiety?

This review poses the question, is it possible to prevent the development of anxiety disorders through selective interventions? The article begins with a review of the major psychosocial risk factors for anxiety disorders. Evidence is reviewed to support the role of inhibited temperament, parent anxiety, environmental support of avoidant coping, and vicarious and instructional learning of avoidance as risks for anxiety. It is argued that the central focus of these risks is an inhibited temperament and that the other risk factors are likely to be both moderated and mediated by this temperamental style. Thus, a clear option for prevention would be to modify early inhibition. Some preliminary data are presented from the Macquarie University Preschool Intervention Project, a longitudinal study of a brief parent education program for the reduction of inhibited temperament in preschool children. Although there remains considerable room for stronger effects, preliminary results show clear promise that it may be possible to modify early risk for anxiety disorders.     

Performance monitoring and response inhibition in anxiety disorders with and without comorbid ADHD

Anxiety disorder (ANX) is characterized by heightened arousal, psychosocial and academic difficulties, and comorbidity with other disorders, in particular, attention-deficit/hyperactivity disorder (ADHD). The heightened arousal contributes to cognitive impairment by adversely affecting executive control of cognition. The nature of the effect on executive control is poorly understood. Research in this area could inform intervention, diagnostic, and etiological research. Our objective was to characterize children with ANX on measures of executive functioning, while controlling for comorbid ADHD. We compared children ages 6-14 with ANX (N=21), ADHD (N=78), ANX+ADHD (N=38), and normal controls (NC; N=40) on the stop task, a measure of performance monitoring and response inhibition. No difference was observed between NC and ANX groups in performance monitoring. Compared to the NC group, the three clinical groups showed inhibition deficits, and both ADHD and ANX+ADHD groups monitored less after responses. ANX was not associated with performance monitoring or inhibition deficits once comorbid ADHD was considered. This emphasizes the importance of controlling for comorbid ADHD in studies of cognition and anxiety.