Marcia J. Slattery

Regarding “Antibiotic Prophylaxis with Azithromycin or Penicillin for Childhood-Onset Neuropsychiatric Disorders”

BACKGROUND The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) describes a subgroup of children with obsessive-compulsive disorder and/or tic disorder that experience symptom exacerbations following streptococcal infections. We hypothesized that the prevention of streptococcal infections among children in the PANDAS subgroup would decrease neuropsychiatric symptom exacerbations. METHODS Twenty-three subjects with PANDAS were enrolled in a double blind, randomized controlled trial. Antibiotic prophylaxis with penicillin or azithromycin was administered for 12 months. Rates of streptococcal infections and neuropsychiatric symptom exacerbations were compared between the study year and the baseline year prior to entry. RESULTS Significant decreases in streptococcal infections during the study year were found with a mean of .1 (.3 SD) per subject, compared to the baseline year with 1.9 (1.2 SD) in the penicillin group and 2.4 (1.1 SD) in the azithromycin group [p<.01]. Significant decreases in neuropsychiatric exacerbations during the study year were also found with a mean of .5 (.5 SD) per subject in the penicillin group and .8 (.6 SD) in the azithromycin group, compared to the baseline year with 2.0 (.9 SD) in the penicillin group and 1.8 (.6 SD) in the azithromycin group [p<.01]. CONCLUSIONS Penicillin and azithromycin prophylaxis were found to be effective in decreasing streptococcal infections and neuropsychiatric symptom exacerbations among children in the PANDAS subgroup.

Early Risk Factors and Developmental Pathways to Chronic High Inhibition and Social Anxiety Disorder in Adolescence

OBJECTIVE Evidence suggests that chronic high levels of behavioral inhibition are a precursor of social anxiety disorder. The authors sought to identify early risk factors for, and developmental pathways to, chronic high inhibition among school-age children and the association of chronic high inhibition with social anxiety disorder by adolescence. METHOD A community sample of 238 children was followed from birth to grade 9. Mothers, teachers, and children reported on the childrens behavioral inhibition from grades 1 to 9. Lifetime history of psychiatric disorders was available for the subset of 60 (25%) children who participated in an intensive laboratory assessment at grade 9. Four early risk factors were assessed: female gender; exposure to maternal stress during infancy and the preschool period; and at age 4.5 years, early manifestation of behavioral inhibition and elevated afternoon salivary cortisol levels. RESULTS All four risk factors predicted greater and more chronic inhibition from grades 1 to 9, and together they defined two developmental pathways. The first pathway, in girls, was partially mediated by early evidence of behavioral inhibition and elevated cortisol levels at age 4.5 years. The second pathway began with exposure to early maternal stress and was also partially mediated by childhood cortisol levels. By grade 9, chronic high inhibition was associated with a lifetime history of social anxiety disorder. CONCLUSIONS Chronic high levels of behavioral inhibition are associated with social anxiety disorder by adolescence. The identification of two developmental pathways suggests the potential importance of considering both sets of risk factors in developing preventive interventions for social anxiety disorder.

Longitudinal stability and developmental properties of salivary cortisol levels and circadian rhythms from childhood to adolescence.

This study aimed to (1) identify a stable, trait-like component to cortisol and its circadian rhythm, and (2) investigate individual differences in developmental trajectories of HPA-axis maturation. Multiple salivary cortisol samples were collected longitudinally across four assessments from age 9 (3rd grade) through age 15 (9th grade) in a community sample of children (N = 357). Sophisticated statistical models examined cortisol levels and its rhythm over time; effects of age, puberty and gender were primarily considered. In addition to situation-specific and stable short-term or epoch-specific cortisol components, there is a stable, trait-like component of cortisol levels and circadian rhythm across multiple years covering the transition from childhood into adolescence. Youth had higher cortisol and flatter circadian rhythms as they got older and more physically developed. Girls had higher cortisol, stronger circadian rhythms, and greater developmental influences across adolescence. Distinguishing a stable, trait-like component of cortisol level and its circadian rhythm provides the empirical foundation for investigating putative mechanisms underlying individual differences in HPA functioning. The findings also provide important descriptive information about maturational processes influencing HPA-axis development.

Influence of early life stress on later hypothalamic–pituitary–adrenal axis functioning and its covariation with mental health symptoms: A study of the allostatic process from childhood into adolescence

The hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism in the allostatic process through which early life stress (ELS) contributes to disease. Studies of the influence of ELS on childrens HPA axis functioning have yielded inconsistent findings. To address this issue, the present study considers multiple types of ELS (maternal depression, paternal depression, and family expressed anger), mental health symptoms, and two components of HPA functioning (traitlike and epoch-specific activity) in a long-term prospective community study of 357 children. ELS was assessed during the infancy and preschool periods; mental health symptoms and cortisol were assessed at child ages 9, 11, 13, and 15 years. A three-level hierarchical linear model addressed questions regarding the influences of ELS on HPA functioning and its covariation with mental health symptoms. ELS influenced traitlike cortisol level and slope, with both hyper- and hypoarousal evident depending on type of ELS. Further, type(s) of ELS influenced covariation of epoch-specific HPA functioning and mental health symptoms, with a tighter coupling of HPA alterations with symptom severity among children exposed previously to ELS. Results highlight the importance of examining multiple types of ELS and dynamic HPA functioning in order to capture the allostatic process unfolding across the transition into adolescence.

Screening for Childhood Mental Health Problems: Outcomes and Early Identification.

BACKGROUND Many childhood psychiatric problems are transient. Consequently, screening procedures to accurately identify children with problems unlikely to remit and thus, in need of intervention, are of major public health concern. This study aimed to develop a universal school-based screening procedure based on the answers to three questions: (1) What are the broad patterns of mental health problems from kindergarten to grade 5? (2) What are the grade 5 outcomes of these patterns? (3) How early in school can children likely to develop the most impairing patterns be identified accurately? METHODS Mothers and teachers reported on a community sample (N = 328) of childrens internalizing and externalizing symptoms in kindergarten and grades 1, 3, and 5. In grade 5, teachers reported on childrens school-based functional impairments, physical health problems, and service use; mothers reported on childrens specialty mental health care. RESULTS Four patterns distinguished children who (1) never evidenced symptoms; (2) evidenced only isolated symptoms; or evidenced recurrent symptoms, either (3) without or (4) with comorbid internalizing and externalizing. By grade 5, children with recurrent comorbid symptoms had the greatest impairments, physical health problems, and service use. These children can be identified quite accurately by grade 1. CONCLUSIONS Universal screening at school entry can effectively identify children likely to develop recurrent comorbid symptoms, and would provide a basis for developing optimal targeted intervention programs.

Depression, anxiety, and dermatologic quality of life in adolescents with atopic dermatitis

The negative psychosocial impact of atopic dermatitis (AD) on quality of life is well established,1–3 with itching, scratching, sleep loss, and social embarrassment among the most commonly reported difficulties contributing to school, work, financial, and social struggles. Increasing evidence suggests that depression and anxiety are also more common in adults with AD, and that the association of AD with these psychiatric symptoms may be influenced by factors such as AD disease severity, subjective vs. objective assessment of AD severity, and quality of life. No studies have objectively assessed the prevalence of depression and anxiety in youth with AD, or the association of these symptoms with AD severity or quality of life. With the world-wide growing prevalence of AD, and mounting evidence of the psychosocial and economic burden of this disease, identifying specific patterns and potential mechanisms of psychiatric symptom co-morbidity in age-defined populations is increasingly important for the development of targeted assessments and treatment interventions.

Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety

Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates’ capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.

Structure and Measurement of Depression in Youths: Applying Item Response Theory to Clinical Data

Our goals in this article were to use item response theory (IRT) to assess the relation of depressive symptoms to the underlying dimension of depression and to demonstrate how IRT-based measurement strategies can yield more reliable data about depression severity than conventional symptom counts. Participants were 3,403 children and adolescents from 12 contributing clinical and nonclinical samples; all participants had received the Kiddie Schedule of Affective Disorders and Schizophrenia for School-Aged Children. Results revealed that some symptoms reflected higher levels of depression and were more discriminating than others. Furthermore, use of IRT-based information about symptom severity and discriminability in the measurement of depression severity was shown to reduce measurement error and increase measurement fidelity.

Relational and Overt Aggression in Disruptive Adolescents: Prediction from Early Social Representations and Links with Concurrent Problems

Childrens representations of conflict and distress situations at 7 years were examined as developmental precursors to relational aggression, overt aggression, and psychiatric symptoms in early adolescence. Children were identified in early adolescence. Children were identified in preschool as normally developing or with behavior problems. Overt, but not relational, aggression, was correlated with concurrent disruptive symptoms in adolescence. Childhood predictors of adolescent aggression were found only for girls: Early hostile themes predicted more relational and overt aggression, while prosocial themes predicted less relational aggression. Also for girls only, early emotions foretold later functioning: Sadness predicted a higher ratio of relational to overt aggression, while inexpressiveness predicted disruptive, anxiety, and depressive symptoms. Relational and overt aggression are discussed with regard to sex differences in symptom changes over time.

Neurocognitive function and state cognitive stress appraisal predict cortisol reactivity to an acute psychosocial stressor in adolescents.

Stress and associated alterations in hypothalamic-pituitary-adrenal (HPA) function have deleterious influence on the development of multiple mental and physical health problems. Prior research has aimed to identify individuals most at risk for the development of these stress-related maladies by examining factors that may contribute to inter-individual differences in HPA responses to acute stress. The objectives of this study were to investigate, in adolescents, (1) whether differences in neurocognitive abilities influenced cortisol reactivity to an acute stressor, (2) whether internalizing psychiatric disorders influenced this relationship, and (3) whether acute cognitive stress-appraisal mechanisms mediated an association between neurocognitive function and cortisol reactivity. Subjects were 70 adolescents from a community sample who underwent standardized neurocognitive assessments of IQ, achievement, and declarative memory measures at mean age 14 and whose physiological and behavioral responses to a standardized psychosocial stress paradigm (Trier Social Stress Test, TSST) were assessed at mean age 18. Results showed that, among all adolescents, lower nonverbal memory performance predicted lower cortisol reactivity. In addition, internalizing disorders interacted with verbal memory such that the association with cortisol reactivity was strongest for adolescents with internalizing disorders. Finally, lower secondary cognitive appraisal of coping in anticipation of the TSST independently predicted lower cortisol reactivity but did not mediate the neurocognitive-cortisol relationship. Findings suggest that declarative memory may contribute to inter-individual differences in acute cortisol reactivity in adolescents, internalizing disorders may influence this relationship, and cognitive stress appraisal also predicts cortisol reactivity. Developmental, research, and clinical implications are discussed.