Joan L. Luby

Memory improvement following induced hyperinsulinemia in alzheimer's disease

Dementia of the Alzheimer type (DAT) is accompanied by disruption in glucose regulation and utilization that may contribute to its characteristic memory impairment. Increasing glucose availability by raising plasma glucose improves memory in patients with DAT. Such memory improvement is associated with a secondary elevation in plasma insulin levels, raising the question of whether improvement is due to changes in insulin levels, independent of hyperglycemia. Distributions of insulin receptors in the hippocampus and insulin-mediated increases in glucose utilization in entorhinal cortex provide potential mechanisms for such improvement. We show that raising plasma insulin through intravenous infusion while keeping plasma glucose at a fasting baseline level produces striking memory enhancement for patients with DAT. Previous findings of hyperglycemic memory enhancement were also replicated. Patients with DAT also showed abnormal plasma levels of glucoregulatory hormones and metabolites at baseline and during metabolic manipulations. Our findings suggest that neuroendocrine factors play an important role in the pathophysiology of DAT.

The Effects of Poverty on Childhood Brain Development: The Mediating Effect of Caregiving and Stressful Life Events

IMPORTANCE The study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This study was conducted at an academic research unit at the Washington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of a magnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to-needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of childrens white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained using magnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain development at school age further underscores the importance of attention to the well-established deleterious effects of poverty on child development. Findings that these effects on the hippocampus are mediated by caregiving and stressful life events suggest that attempts to enhance early caregiving should be a focused public health target for prevention and early intervention. Findings substantiate the behavioral literature on the negative effects of poverty on child development and provide new data confirming that effects extend to brain development. Mechanisms for these effects on the hippocampus are suggested to inform intervention.

Preschool Depression: Homotypic Continuity and Course Over 24 Months

CONTEXT Childhood depression is a serious and relapsing psychiatric disorder. However, to date studies have focused mostly on children aged 6 years and older. Validation for depression in preschool children has been provided by 2 independent study samples. While several studies have demonstrated stability and poor outcomes of internalizing symptoms in preschoolers, there has not yet been longitudinal data available to inform the course of preschool depression and whether it shows homotypic continuity into early childhood. OBJECTIVE To examine the 24-month course of preschool depression and whether it showed homotypic vs heterotypic continuity or was a developmentally transient phenomenon. DESIGN Blindly rated, prospective, 24-month, longitudinal follow-up study. SETTING Community sites. Patients Three hundred six preschoolers aged 3 to 6 years recruited from community sites and oversampled for symptoms of depression. Main Outcome Measure Recurrence/stability of depression and predictors of course. RESULTS Preschoolers with depression at baseline had the highest likelihood of subsequent depression 12 and/or 24 months later compared with preschoolers with no baseline disorder and with those who had other psychiatric disorders. Preschoolers with depression at baseline were more likely to have later depression rather than other psychiatric disorders. Findings from a logistic regression analysis indicated that when controlling for demographic variables, risk factors, and comorbid disorders, depression during the preschool period and family history of affective disorders were the most robust and significant predictors of later depression. CONCLUSIONS Preschool depression, similar to childhood depression, is not a developmentally transient syndrome but rather shows chronicity and/or recurrence. Homotypic continuity of preschool MDD during a 24-month period was found. These results underscore the clinical and public health importance of identification of depression as early as preschool. Further follow-up of preschoolers with depression is warranted to inform the longitudinal course throughout childhood.

Maternal support in early childhood predicts larger hippocampal volumes at school age

Early maternal support has been shown to promote specific gene expression, neurogenesis, adaptive stress responses, and larger hippocampal volumes in developing animals. In humans, a relationship between psychosocial factors in early childhood and later amygdala volumes based on prospective data has been demonstrated, providing a key link between early experience and brain development. Although much retrospective data suggests a link between early psychosocial factors and hippocampal volumes in humans, to date there has been no prospective data to inform this potentially important public health issue. In a longitudinal study of depressed and healthy preschool children who underwent neuroimaging at school age, we investigated whether early maternal support predicted later hippocampal volumes. Maternal support observed in early childhood was strongly predictive of hippocampal volume measured at school age. The positive effect of maternal support on hippocampal volumes was greater in nondepressed children. These findings provide prospective evidence in humans of the positive effect of early supportive parenting on healthy hippocampal development, a brain region key to memory and stress modulation.

A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.

CONTEXT There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. OBJECTIVE To investigate which medication to administer first to antimanic medication-naive subjects. DESIGN, SETTING, AND PARTICIPANTS The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments. INTERVENTIONS Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg). MAIN OUTCOME MEASURES Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents. RESULTS There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; χ(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001). CONCLUSIONS Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00057681

The clinical significance of preschool depression: Impairment in functioning and clinical markers of the disorder

OBJECTIVE While much is now known about depression during school age and adolescence, whether clinical depression can onset even earlier in development during the preschool period remains under explored. The earliest possible identification of depression may be important for the design of prevention and early developmental intervention programs. This study investigated functional impairment associated with depression, symptoms that served as the best markers of depression vs. other disorders, as well as depression severity between two depressed sub-groups and other diagnostic comparison groups. METHOD Three hundred and five preschoolers between the ages of 3.0 and 6.0 and their primary caregivers were recruited using a depression screening checklist distributed at community sites. The Preschool Age Psychiatric Assessment (PAPA) was used to derive psychiatric diagnoses in the study sample. Multivariate analyses of covariance were used to investigate the effects of depression on independent measures of functional impairment while controlling for the effects of co-morbidities. RESULTS Functional impairment specifically associated with depression was found in multiple domains and contexts, however depressed preschoolers were not developmentally delayed. The symptoms of guilt and extreme fatigue were found to be highly specific for preschool depression. A statistically significant hierarchy of depression severity was found between diagnostic comparison groups, in the expected direction with the highest in a melancholic subgroup. CONCLUSIONS Validation for preschool depression with associated functional impairment across contexts was found in preschool children. These findings replicate and extend earlier evidence for validity of MDD diagnosed in the preschool period and highlight the need for clinical attention. The finding that these depressed and impaired preschoolers were not yet developmentally delayed may have important public health significant significance as it suggests a possible window of opportunity for early intervention. Study findings were limited by reliance on parent and teacher informants and a cross-sectional view.

Practice Parameters for the Psychiatric Assessment of Infants and Toddlers (0–36 Months)

These practice parameters describe the psychiatric assessment of infants and toddlers (0-36 months) and support the growth of infant and toddler psychiatry, a rapidly developing field. Infants and toddlers are brought to clinical attention because of concerns about emotional, behavioral, relational, or developmental difficulties. It is axiomatic that the infant or toddler must be understood, evaluated, and treated within the context of the family. A perspective that is developmental, relational, and multidimensional and that borrows from the knowledge of multiple disciplines is essential. Collaborative efforts support the urgent need and incomparable opportunity to understand and to intervene early and preventively with young children and their families.

Quantitative assessment of autistic symptomatology in preschoolers

Given a growing emphasis on early intervention for children with autism, valid quantitative tools for measuring treatment response are needed. The Social Responsiveness Scale (SRS) is a brief (15–20 minute) quantitative measure of autistic traits in 4-to 18-year-olds, for which a version for 3-year-olds was recently developed. We obtained serial SRS measurements on 73 preschool children with (n = 51) and without (n = 22) autism spectrum conditions. Inter-rater reliability (mothers and teachers) and test–retest reliability were of the order of 0.75 (Pearsons r). There was substantial agreement between SRS scores and (1) the Vineland Adaptive Behavior Composite (Pearsons r = –0.86) and (2) scores for social impairment on the Autism Diagnostic Interview–Revised (r = 0.63). Overall, quantitative autistic trait scores tended to improve over time in preschoolers, irrespective of treatment conditions. We conclude that it is possible to obtain reliable quantitative measurements of autistic social impairment in preschoolers, suitable for assessing treatment response.

Parent-child interaction therapy emotion development: a novel treatment for depression in preschool children.

Background: Psychotherapies with known efficacy in adolescent depression have been adapted for prepubertal children; however, none have been empirically validated for use with depressed very young children. Due to the centrality of the parent–child relationship to the emotional well being of the young child, with caregiver support shown to mediate the risk for depression severity, we created an Emotional Development (ED) module to address emotion development impairments identified in preschool onset depression. The new module was integrated with an established intervention for preschool disruptive disorders, Parent Child Interaction Therapy (PCIT). Preliminary findings of an open trial of this novel intervention, PCIT‐ED, with depressed preschool children are reported. Methods: PCIT was adapted for the treatment of preschool depression by incorporating a novel emotional development module, focused on teaching the parent to facilitate the childs emotional development and enhance emotion regulation. Eight parent–child dyads with depressed preschoolers participated in 14 sessions of the treatment. Depression severity, internalizing and externalizing symptoms, functional impairment, and emotion recognition/discrimination were measured pre‐ and posttreatment. Results: Depression severity scores significantly decreased with a large effect size (1.28). Internalizing and externalizing symptoms as well as functional impairment were also significantly decreased pre‐ to posttreatment. Conclusions: PCIT‐ED seems to be a promising treatment for preschoolers with depression, and the large effect sizes observed in this open trial suggest early intervention may provide a window of opportunity for more effective treatment. A randomized controlled trial of PCIT‐ED in preschool depression is currently underway. Depression and Anxiety, 2011.

Preschool Depression The Importance of Identification of Depression Early in Development

The empirical finding that school-aged children could suffer clinical depression refuted the widely held assumption that this age group would be too developmentally immature to experience depressive symptoms. Currently childhood depression is a well-recognized and widely treated clinical disorder. Following more recent developmental findings emphasizing the emotional sophistication of very young children, scientific studies have demonstrated that depression can arise early in life, during the preschool period of development. Preschool depression is characterized by typical symptoms of depression such as anhedonia; changes in sleep, appetite, and activity level; and excessive guilt. Further, longitudinal continuity of preschool depression into school age has been established, suggesting that preschool depression is an early manifestation of the later childhood disorder. Based on the known efficacy of early developmental intervention in a number of domains and disorders related to the greater neuroplasticity of the brain earlier rather than later in childhood, it is important to identify depression at the earliest possible point. Early intervention strategies for preschool depression that focus on enhancing emotional development are currently being tested.