Kristine Bolhofner

DSM-IV mania symptoms in a prepubertal and early adolescent bipolar disorder phenotype compared to attention-deficit hyperactive and normal controls.

OBJECTIVE To compare the prevalence of Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) mania symptoms in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) to those with attention deficit hyperactivity disorder (ADHD) and normal community controls (CC). METHODS To optimize generalizeability, subjects with PEA-BP and ADHD were consecutively ascertained from outpatient pediatric and psychiatric sites, and CC subjects were obtained from a random survey. All 268 subjects (93 with PEA-BP, 81 with ADHD, and 94 CC) received comprehensive, blind, baseline research assessments of mothers about their children and of children about themselves. PEA-BP was defined by DSM-IV mania with elation and/or grandiosity as one criterion to ensure that subjects had one of the two cardinal symptoms of mania and to avoid diagnosing mania only by criteria that overlapped with those for ADHD. RESULTS Five symptoms (i.e., elation, grandiosity, flight of ideas/racing thoughts, decreased need for sleep, and hypersexuality) provided the best discrimination of PEA-BP subjects from ADHD and CC controls. These five symptoms are also mania-specific in DSM-IV (i.e., they do not overlap with DSM-IV symptoms for ADHD). Irritability, hyperactivity, accelerated speech, and distractibility were very frequent in both PEA-BP and ADHD groups and therefore were not useful for differential diagnosis. Concurrent elation and irritability occurred in 87.1% of subjects with PEA-BP. Data on suicidality, psychosis, mixed mania, and continuous rapid cycling were also provided. CONCLUSION Unlike late teenage/adult onset bipolar disorder, even subjects with PEA-BP selected for DSM-IV mania with cardinal symptoms have high rates of comorbid DSM-IV ADHD. High rates of concurrent elation and irritability were similar to those in adult mania.

Diagnostic Characteristics of 93 Cases of a Prepubertal and Early Adolescent Bipolar Disorder Phenotype by Gender, Puberty and Comorbid Attention Deficit Hyperactivity Disorder

OBJECTIVE Etiopathogenetic and treatment studies require homogeneous phenotypes. Therefore, effects of gender, puberty, and comorbid attention deficit hyperactivity disorder (ADHD) on DSM-IV mania criteria and other characteristics of a prepubertal and early adolescent bipolar disorder (PEA-BP) phenotype were investigated. METHOD Consecutively ascertained PEA-BP (with or without comorbid ADHD) outpatients (n = 93) were blindly assessed by research nurses with comprehensive instruments given to mothers and children separately, consensus conferences, and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one criterion and to be definite cases by severity ratings. RESULTS Subjects were aged 10.9 +/- 2.6 years, had current episode length of 3.6 +/- 2.5 years, and had early age of onset at 7.3 +/- 3.5 years. No significant differences were found by gender, puberty, or comorbid ADHD on rates of mania criteria (e.g., elation, grandiosity, racing thoughts), mixed mania, psychosis, rapid cycling, suicidality, or comorbid oppositional defiant disorder (ODD), with few exceptions. Subjects with comorbid ADHD were more likely to be younger and male. Pubertal subjects had higher rates of hypersexuality. CONCLUSIONS These findings support that the PEA-BP phenotype is homogeneous except for differences (hyperactivity, hypersexuality) that mirror normal development.

Psychosocial functioning in a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE To compare psychosocial functioning (PF) in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) sample to two comparison groups, i.e., attention-deficit/hyperactivity disorder (ADHD) and community controls (CC). METHOD There were 93 PEA-BP (with or without comorbid ADHD), 81 ADHD, and 94 CC subjects who were participants in an ongoing study, the Phenomenology and Course of Pediatric Bipolar Disorders. Cases in the PEA-BP and ADHD groups were outpatients obtained by consecutive new case ascertainment, and CC subjects were from a survey conducted by the Research Triangle Institute. To fit the study phenotype, PEA-BP subjects needed to have current DSM-IV mania or hypomania with elation and/or grandiosity as one criterion. Assessments for PF were by experienced research nurses who were blind to group status. Mothers and children were separately interviewed with the Psychosocial Schedule for School Age Children-Revised. RESULTS Compared with both ADHD and CC subjects, PEA-BP cases had significantly greater impairment on items that assessed maternal-child warmth, maternal-child and paternal-child tension, and peer relationships. CONCLUSIONS Clinicians need to consider PF deficits when planning interventions. In the PEA-BP group, there was a 43% rate of hypersexuality with a <1% rate of sexual abuse, supporting hypersexuality as a manifestation of child mania.

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

Six-Month Stability and Outcome of a Prepubertal and Early Adolescent Bipolar Disorder Phenotype

OBJECTIVE Six-month follow-up data are provided on a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP). Stabilities were defined as continuous presence of PEA-BP and of individual mania criteria between baseline and 6 months. METHOD Baseline and 6-month assessments of consecutively ascertained PEA-BP outpatients (n = 91) included comprehensive instruments given to mothers and children, separately, by research nurses; consensus conferences; and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one mania criterion and to be definite cases by severity ratings. RESULTS Of the 93 baseline subjects, 91 completed the 6-month assessment, for a retention rate of 97.8%. Baseline age was 10.9 +/- 2.7 years, and age of onset of current episode was 7.3 +/- 3.5 years. At 6 months, 85.7% still had full criteria and severity for mania or hypomania, and only 14.3% had recovered. Six-month stabilities of elated mood and grandiosity were high. Cox modeling and logistic regression did not show any significant effect of multiple covariates (e.g., gender, puberty, psychosis, mixed mania, rapid cycling, or naturalistic treatment). CONCLUSIONS These longitudinal stability findings provide validation of a PEA-BP phenotype. Poor outcome was consistent with similarity of PEA-BP baseline characteristics to those of treatment-resistant adult-onset mania.

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.

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.

Effects of age, sex, and independent life events on amygdala and nucleus accumbens volumes in child bipolar I disorder.

BACKGROUND Relationships between environment and cortical-limbic-striatal pathways are not well-researched in child bipolar I disorder (BP-I). METHODS This was a controlled, blindly rated magnetic resonance imaging study of children with DSM-IV BP-I, manic or mixed type, compared with matched typically developing children (TC). RESULTS There were 47 subjects (21 BP-I, 26 TC) aged 14.0+/-3.1 (BP-I onset age 8.8+/-4.2). Total intracranial volume was greater in male subjects (n=28) versus female subjects (n=19) [F(1,44)=24.3, p< .001], controlling for age. Volumes were not significantly different in BP-I and TC groups, after accounting for multiple comparisons, in the medial orbital frontal cortex, rostral anterior cingulate cortex, hippocampus, amygdala (AMG), or nucleus accumbens (NAcc). Across subjects (n=47), a greater number of independent life events (ILE) was associated with smaller AMG [F(1,36)=7.8, p= .009] and NAcc [F(1,36) = 9.4, p= .004] volumes, controlling for total intracranial volume (TICV), group, age, sex, and family psychopathology. Use of stimulant medication at the time of the scan was associated with larger AMG volume [F(1,41)=9.0, p= .005], controlling for TICV, group, age, and sex. In male subjects, the age x group interaction was a significant predictor in general linear models of AMG (p= .028) and NAcc (p= .030) volumes. Effects of low maternal warmth were not significant. CONCLUSIONS Findings suggest that ILE affect AMG and NAcc volume, but further research is needed to examine specificity to child BP-I. Furthermore, differential age x group (child BP-I vs. TC) effects only in male subjects are consistent with differential brain development by sex.

GAD1 single nucleotide polymorphism is in linkage disequilibrium with a child bipolar I disorder phenotype.

BACKGROUND Pediatric bipolar I disorder (BP-I) and childhood schizophrenia (SZ) share certain symptoms (e.g., psychosis, aggression/irritability [A/I]), and the psychotic and A/I features are treated with neuroleptics in both disorders. Thus, it is of interest to examine the association of GAD1 to child BP-I because of its recently reported association to childhood SZ. METHODS Child BP-I probands were obtained by consecutive new case ascertainment, and the phenotype was defined as current DSM-IV BP-I (manic or mixed phase) with at least one of the cardinal symptoms of mania (i.e., elation and/or grandiosity) and a Childrens Global Assessment Scale score < or =60 (clinical impairment). These child BP-I probands are part of a large, ongoing, longitudinal study in which the phenotype has been validated by unique symptoms, longitudinal stability, and 7-8 times greater family loading than adult BP-I probands. Genotyping was performed using a TaqMan Validated SNP Genotyping Assay, and FBAT was used for analysis. RESULTS There were 48 families. The rs2241165 A allele was preferentially transmitted (FBAT chi(2) = 5.2, df = 1, p = 0.022). No interaction between this GAD1 SNP and the Val66 BDNF allele was found. CONCLUSIONS These data are consistent with some shared genetic vulnerability between child BP-I and SZ, which may be related to similar treatments.