Rebecca Tillman

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

Controlled study of switching from attention-deficit/hyperactivity disorder to a prepubertal and early adolescent bipolar I disorder phenotype during 6-year prospective follow-up: rate, risk, and predictors.

Rate, risk, and predictors of switching from attention-deficit/hyperactivity disorder (ADHD) to a prepubertal and early adolescent bipolar I disorder phenotype (PEA-BP-I) were examined in a blindly rated, controlled, prospective 6-year follow-up that included assessments at 2-year intervals. Subjects were outpatients obtained by consecutive new case ascertainment. There were 81 subjects who were 9.7 +/- 2.0 years. Subjects had DSM-IV ADHD (hyperactive or combined subtypes); a Childrens Global Assessment Scale (CGAS) score of < or =60, consistent with moderate-severe impairment; and no BP or major depressive disorder (MDD) diagnoses. PEA-BP-I was defined as DSM-IV BP I (manic or mixed phase), with cardinal symptoms (elation and/or grandiosity), to avoid diagnosing mania by symptoms that overlapped with those of ADHD, and by a CGAS score of < or =60. Morbid risk of switching to PEA-BP-I was 28.5%. Significant predictors of switching in a multivariate Cox model were more severe baseline CGAS, paternal recurrent MDD, and less stimulant use. BP I in first-degree relatives, antidepressants, psychosocial measures, and life events were not predictive.

Temperament and Character Factors in a Prepubertal and Early Adolescent Bipolar Disorder Phenotype Compared to Attention Deficit Hyperactive and Normal Controls

OBJECTIVE To compare temperament and character (T/C) factors in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP), attention deficit hyperactivity disorder (ADHD), and normal community controls (NC). METHODS Subjects in PEA-BP (n = 101), ADHD (n = 68), and NC (n = 94) groups were diagnostically assessed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia given separately to mothers about their children and to children about themselves. Diagnosis of PEA-BP was defined as Diagnostic and Statistical Manual of Mental Disorders, fourth edition, bipolar disorder (manic or mixed phase) with at least one cardinal symptom of mania (i.e., elation and/or grandiosity) to avoid diagnosing mania by symptoms that overlapped with those for ADHD. The Junior Temperament and Character Inventory (JTCI) was used to measure T/C factors. Separate JTCI data were obtained from mothers about their children and from children about themselves. RESULTS Parent- and child-reported novelty seeking were significantly higher in PEA-BP than in NC subjects. Novelty seeking was significantly higher in the ADHD group than in the NC group only by parent report. Parent and/or child report showed PEA-BP and ADHD subjects to be significantly less reward-dependent, persistent, self-directed, and cooperative than NC subjects. Parent-reported cooperativeness was significantly lower in PEA-BP than in ADHD subjects. CONCLUSION These findings are consistent with studies of novelty seeking in adults who had either BP or ADHD and are discussed in relationship to genetic studies of dopamine receptors and novelty seeking.

Definitions of Rapid, Ultrarapid, and Ultradian Cycling and of Episode Duration in Pediatric and Adult Bipolar Disorders: A Proposal to Distinguish Episodes from Cycles

OBJECTIVE To propose terminology to distinguish cycles from episodes in children and adults with bipolar disorder (BP). METHODS To examine current definitions of rapid cycling and episodes in both child and adult BP, an Internet search of the MEDLINE database was conducted. RESULTS Investigations of rapid cycling in adults used the terms cycle and episode interchangeably to describe discrete periods of mood disorders. Two studies of children and one study of adults with BP, however, reported cycles occurring daily (ultradian cycling) or every few days (ultrarapid cycling). Without definitions to differentiate cycles from episodes, determining the overall duration of illness in subjects who experience ultrarapid or ultradian cycling is not possible. For example, a child cycled twice a day, every day, for 365 days (1 year). With the terminology currently in use, it is unclear whether this should be described as a single episode that had a duration of 365 days or as approximately 730 episodes (2 cycles per day x 365 days), each less than 24 hours in duration. Moreover, adults with BP may have more intermittent pathology than children (e.g., adults may cycle 4 days per week, versus children may cycle 7 days per week). CONCLUSION The following definitions are proposed. (1) Episodes will be defined by (a) the duration from onset to offset of a period of at least 2 weeks in length during which only one mood state persists or (b) the duration from onset to offset of a period of ultrarapid or ultradian cycling for at least 2 weeks. (2) Cycles will be defined by mood switches occurring daily or every few days during an episode. Further research will be needed to elucidate potential differences between child and adult cycling patterns.

Trajectories of Preschool Disorders to Full DSM Depression at School Age and Early Adolescence: Continuity of Preschool Depression

OBJECTIVE Preschool-onset depression, a developmentally adapted form of depression arising between ages 3 and 6, has demonstrated numerous validated features, including characteristic alterations in stress reactivity and brain function. This syndrome is characterized by subthreshold DSM criteria for major depressive disorder, raising questions about its clinical significance. To clarify the utility and public health significance of the preschool-onset depression construct, the authors investigated diagnostic outcomes of preschool children at school age and in adolescence. METHOD In a longitudinal prospective study of preschool children, the authors assessed the likelihood of meeting full criteria for major depressive disorder at age 6 or later as a function of preschool depression, other preschool axis I disorders, maternal history of depression, nonsupportive parenting, and traumatic life events. RESULTS Preschool-onset depression emerged as a robust predictor of major depressive disorder in later childhood even after accounting for the effect of maternal history of depression and other risk factors. Preschool-onset conduct disorder also predicted major depression in later childhood, but this association was partially mediated by nonsupportive parenting, reducing by 21% the effect of preschool conduct disorder in predicting major depression. CONCLUSIONS Study findings provide evidence that this preschool depressive syndrome is a robust risk factor for developing full criteria for major depression in later childhood, over and above other established risk factors. The results suggest that attention to preschool depression and conduct disorder in addition to maternal history of depression and exposure to trauma may be important in identifying young children at highest risk for later major depression and applying early interventions.

A novel early intervention for preschool depression: findings from a pilot randomized controlled trial.

BACKGROUND Validation for depression in preschool children has been established; however, to date no empirical investigations of interventions for the early onset disorder have been conducted. Based on this and the modest efficacy of available treatments for childhood depression, the need for novel early interventions has been emphasized. Large effect sizes (ES) for preschool psychotherapies for several Axis I disorders suggest that earlier intervention in depression may also be promising. Therefore, a novel form of treatment for preschool depression, Parent-Child Interaction Therapy Emotion Development (PCIT-ED) was developed and tested. METHODS A preliminary randomized controlled trial (RCT) was conducted comparing PCIT-ED to psycho-education in depressed 3- to 7-year-olds and their caregivers. A total of 54 patients met symptom criteria for DSM-IV major depressive disorder and were randomized, 19 patients completed the active treatment (n = 8 dropouts) and 10 completed psycho-education (n = 17 dropouts). RESULTS Both groups showed significant improvement in several domains, with PCIT-ED showing significance in a greater number of domains. An intent-to-treat analysis suggested that PCIT-ED was significantly more effective than psycho-education on executive functioning (p = .011, ES = 0.12) and emotion recognition skills (p = .002, ES = 0.83). CONCLUSIONS The RCT proved feasible and suggests an individual control condition should be used in future trials to minimize differential dropout. These pilot data, although limited by power, suggest that PCIT-ED may be a promising early intervention for depression. Larger scale randomized controlled trials of PCIT-ED for depressed preschoolers are now warranted.

Life Events in a Prepubertal and Early Adolescent Bipolar Disorder Phenotype Compared to Attention-Deficit Hyperactive and Normal Controls

OBJECTIVE To examine life events in subjects with a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) compared to those in subjects with attention-deficit hyperactivity disorder (ADHD) and normal controls (NC). METHODS To optimize generalizeability, subjects with PEA-BP (n = 93) and ADHD (n = 81) were consecutively ascertained from pediatric and psychiatric sites. Subjects in the NC group (n = 94) were obtained from a random survey. PEA-BP was defined by Diagnostic and Statistical Manual of Mental Disorders (fourth edition) mania with at least one of the cardinal symptoms of mania (i.e., elation and/or grandiosity) to avoid diagnosing mania only by criteria that overlapped with those for ADHD. All subjects received comprehensive, blind research assessments of mothers about their children and separately of children about themselves. Assessment instruments included the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) and the Life Events Checklist. Data from the Life Events Checklist were examined by total life events and by subcategories of dependent, independent, or uncertain relationships to the child. RESULTS Total, independent, dependent, and uncertain life events were all significantly more frequent in the PEA-BP subjects compared to both the ADHD and NC groups. CONCLUSIONS Because there was no a priori reason to expect significantly more independent life events in the PEA-BP compared to the ADHD and NC groups, these results warrant further research into the role of life events in the onset of PEA-BP.

Preschool is a sensitive period for the influence of maternal support on the trajectory of hippocampal development

Significance Data from a longitudinal neuroimaging study beginning in the preschool period and including three brain scans through school age and early adolescence were used to investigate the effects of maternal support on the development of the hippocampus. Consistent with animal findings showing that early support enhances hippocampal development and later adaptive coping, findings demonstrated that early childhood maternal support predicted a steeper hippocampal growth trajectory. The data also suggested that early childhood was a sensitive period when the effects of support had a more powerful effect on hippocampal growth. The hippocampal growth trajectory was associated with better emotion regulation in early adolescence. Findings suggest that enhancing early childhood maternal support fosters healthy childhood brain development and emotion functioning. Building on well-established animal data demonstrating the effects of early maternal support on hippocampal development and adaptive coping, a few longitudinal studies suggest that early caregiver support also impacts human hippocampal development. How caregiving contributes to human hippocampal developmental trajectories, whether there are sensitive periods for these effects, as well as whether related variation in hippocampal development predicts later childhood emotion functioning are of major public health importance. The current study investigated these questions in a longitudinal study of preschoolers assessed annually for behavioral and emotional development, including observed caregiver support. One hundred and twenty-seven children participated in three waves of magnetic resonance brain imaging through school age and early adolescence. Multilevel modeling of the effects of preschool and school-age maternal support on hippocampal volumes across the three waves was conducted. Hippocampal volume increased faster for those with higher levels of preschool maternal support. Subjects with support 1 SD above the mean had a 2.06 times greater increase in total hippocampus volume across the three scans than those with 1 SD below the mean (2.70% vs. 1.31%). No effect of school-age support was found. Individual slopes of hippocampus volume were significantly associated with emotion regulation at scan 3. The findings demonstrate a significant effect of early childhood maternal support on hippocampal volume growth across school age and early adolescence and suggest an early childhood sensitive period for these effects. They also show that this growth trajectory is associated with later emotion functioning.

Treatment Moderators and Predictors of Outcome in the Treatment of Early Age Mania (TEAM) Study

OBJECTIVE Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome. METHOD TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naïve patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome. RESULTS Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS. CONCLUSIONS Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information--Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681.