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

Pharmacological and non-drug treatment of child bipolar I disorder during prospective eight-year follow-up.

OBJECTIVES: The Phenomenology and Course of Pediatric Bipolar Disorders study, a National Institute of Mental Health-funded study of child bipolar I disorder (BP-I) begun in 1995, is a prospective follow-up study that included collecting pharmacological and non-drug treatment data. METHODS: There were 115 first-episode subjects who fit full DSM-IV criteria for BP-I, mixed or manic phase, with severity scores in the clinically impaired range, ascertained by consecutive new case ascertainment. Subjects were assessed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS), given separately to parents about their children and to children about themselves. All treatment was provided by the subjects' own community practitioners, exactly as if they had not been in the research study. Thus, families were only seen for research assessments, and research staff were not at all involved in their treatment. Data on type, dose, and duration of pharmacological and non-drug treatment were collected. During follow-up, 93.9% (n = 108) were assessed at each of the nine assessment times. RESULTS: During the eight years, only 62.6% received any antimanic medication (antipsychotic, anticonvulsant, lithium) at any time. Percents who received non-antimanic medication included 77.4% medication for attention-deficit hyperactivity disorder and 64.3% antidepressants. A total of 67.8% of subjects were taking two or more concurrent medication classes. Subjects ascertained from psychiatric versus pediatric sites received antimanics significantly more frequently (p = 0.006). Earlier recovery during eight-year follow-up was predicted by greater percent of weeks on lithium (p = 0.017). CONCLUSIONS: Given these findings, and the poor prognosis from prospective follow-up of this sample reported elsewhere, there is a need for further research that informs the development of effective treatment strategies.

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.

Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome.

CONTEXT: Child bipolar I disorder (BP-I) is a contentious diagnosis. OBJECTIVE: To investigate continuity of child and adult BP-I and characteristics of later episodes. DESIGN: Inception cohort longitudinal study. Prospective, blinded, controlled, consecutive new case ascertainment. SETTING: University medical school research unit. Subjects There were 115 children, enrolled from 1995 through 1998, aged 11.1 (SD, 2.6) years with first episode DSM-IV BP-I, mixed or manic phase, with 1 or both cardinal symptoms (elation or grandiosity) and score of 60 or less on the Children's Global Assessment Scale (CGAS). All DSM-IV severity and duration criteria were fulfilled. Separate interviews were conducted of parents about their children and of children about themselves. MAIN OUTCOME MEASURES: Washington University in St Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS); Psychosocial Schedule for School Age Children-Revised; CGAS. RESULTS: Retention was 93.9% (n = 108) for completing assessments at every one of the 9 follow-up visits. Subjects spent 60.2% of weeks with any mood episodes and 39.6% of weeks with mania episodes, during 8-year follow-up. During follow-up, 87.8% recovered from mania, but 73.3% relapsed to mania. Even accounting for family psychopathology, low maternal warmth predicted relapse to mania, and more weeks ill with manic episodes was predicted by low maternal warmth and younger baseline age. Largely similar to first episodes, second and third episodes of mania were characterized by psychosis, daily (ultradian) cycling, and long duration (55.2 and 40.0 weeks, respectively), but significantly shorter than first episodes. At 8-year follow-up, 54 subjects were 18.0 years or older. Among subjects 18.0 years or older, 44.4% had manic episodes and 35.2% had substance use disorders. CONCLUSIONS: In grown-up subjects with child BP-I, the 44.4% frequency of manic episodes was 13 to 44 times higher than population prevalences, strongly supporting continuity. The rate of substance use disorders in grown-up child BP-I was similar to that in adult BP-I.

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 Children's 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.

Psychotic phenomena in 257 young children and adolescents with bipolar I disorder: delusions and hallucinations (benign and pathological).

OBJECTIVES: In contrast to studies of adult bipolar I disorder (BP-I), there is a paucity of data on psychotic phenomena in child BP-I. Therefore, the aim of this work was to describe delusions and hallucinations in pediatric BP-I. METHODS: Subjects were 257 participants, aged 6-16, in either of two large, ongoing, NIMH-funded studies, 'Phenomenology and Course of Pediatric Bipolar Disorders' or 'Treatment of Early Age Mania (TEAM)'. All subjects had current DSM-IV BP-I (manic or mixed phase) with a Children's Global Assessment Scale score

Proposed definitions of bipolar I disorder episodes and daily rapid cycling phenomena in preschoolers, school-aged children, adolescents, and adults.

OBJECTIVE: Recent data from several large studies of pediatric bipolar I disorder reported baseline (current) episode duration ranging from less than a month to >or=1 year. These data may reflect actual sample differences, but the absence of uniformly applied definitions of episode duration, number of lifetime episodes and daily rapid cycling patterns during episodes may also account for these differences. METHOD: Proposals for definitions of episode and cycling phenomena were based upon data from the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS). RESULT: Episode would be used for the interval between onset and offset of full DSM-IV criteria for bipolar I disorder. Cycling would be used only to describe daily (ultradian) switching of mood states that occurs during an episode. CONCLUSION: Historically, in the adult bipolar literature the words "episode" and "cycle" were used interchangeably. "Rapid cycling," in this earlier literature, actually referred to multiple episodes per year. To avoid confusing episodes with daily cycling, the proposal is to use "episode" for the duration of DSM-IV criteria, to use "cycling" for daily switching phenomena during an episode, and to replace the historical term "rapid cycling" with "multiple episodes per year." These clarifications will be especially important for phenomenological research on preschool populations.

Controlled, blindly rated, direct-interview family study of a prepubertal and early-adolescent bipolar I disorder phenotype: morbid risk, age at onset, and comorbidity.

CONTEXT: A key question is whether a prepubertal and early-adolescent bipolar I disorder phenotype (PEA-BP-I) is the same illness as adult BP-I. This question arises because of the greater severity, longer current episode duration, preponderance of mania, and high rates of ultradian rapid cycling and comorbid attention-deficit/hyperactivity disorder (ADHD) in PEA-BP-I. OBJECTIVES: To examine morbid risk (MR) of BP-I in first-degree relatives of PEA-BP-I, ADHD, and healthy control probands, as well as imprinting, sibling recurrence risk, and anticipation. DESIGN: Controlled, blind direct interview. There were no family psychopathology exclusions for any proband group. SETTING: University medical school research unit. PARTICIPANTS: First-degree relatives 6 years and older (n = 690) of 219 probands (95 with PEA-BP-I, 47 with ADHD, and 77 healthy controls). The PEA-BP-I and ADHD probands were obtained by consecutive new case ascertainment, and healthy controls were from a random survey; proband diagnoses were validated via 4-year prospective follow-up. The PEA-BP-I probands had a mean +/- SD age of 10.8 +/- 2.6 years. Main Outcome Measure Morbid risk. RESULTS: The MR of BP-I was higher in relatives of PEA-BP-I probands compared with ADHD or healthy controls (P<.001 for both); the MR in relatives of ADHD and healthy controls was similar. The MR of BP-I in relatives with ADHD was higher (P<.001) and age at onset of BP-I was younger in parents with ADHD than in those without (P<.001). The MR of BP-I in relatives with oppositional, conduct, or antisocial disorders was higher than in those without (P<.001). Anticipation was evidenced by a younger age at onset of BP-I in probands than in their parents (P<.001). No imprinting was found. CONCLUSIONS: Findings support that PEA-BP-I and adult BP-I are the same diathesis, 7 to 8x greater familiality in child vs adult BP-I, and family study validation of PEA-BP-I, including its differentiation from ADHD.

Controlled study of encopresis and enuresis in children with a prepubertal and early adolescent bipolar-I disorder phenotype.

OBJECTIVE: To examine the prevalence of encopresis/enuresis, relationship between maternal hostility and encopresis, parent-child concordance of reporting encopresis/enuresis, and familial aggregation of enuresis in subjects with a prepubertal and early adolescent bipolar-I disorder phenotype (PEA-BP), attention-deficit/hyperactivity disorder (ADHD), and healthy controls (HC). METHOD: There were 268 consecutively ascertained subjects (93 PEA-BP, 81 ADHD, and 94 HC). PEA-BP was defined as DSM-IV BP-I (manic or mixed phase) with elation and/or grandiosity. The WASH-U-KSADS and Psychosocial Schedule for School-Age Children-Revised were administered to parents about their children and separately to children about themselves. RESULTS: Encopresis was more prevalent in PEA-BP versus HC subjects (15.1% versus 3.2%, chi2 = 6.4, p = .012). Enuresis was more common in PEA-BP versus HC (21.5% versus 6.4%, chi2 = 7.8, p = .005) and ADHD versus HC (22.2% versus 6.4%, chi2 = 6.1, p = .014) subjects. All enuresis onset in subjects not receiving lithium. Most encopresis (81.8%) and enuresis (75.0%) onset before mania. Familial aggregation of enuresis was more frequent in enuretics than nonenuretics (47.7% versus 5.4%, chi2 = 41.2, p < .0001). Maternal hostility was more prevalent in encopretic versus nonencopretic subjects (91.7% versus 55.6%, chi2 = 8.3, p = .004). Parent-child concordance on reporting encopresis and enuresis was poor to fair. CONCLUSIONS: Children with PEA-BP need to be evaluated for encopresis, enuresis, and mother-child relationships.

Children with a prepubertal and early adolescent bipolar disorder phenotype from pediatric versus psychiatric facilities.

OBJECTIVE: To examine characteristics between subjects with a prepubertal and early adolescent bipolar disorder phenotype from pediatric versus psychiatric venues. METHOD: Subjects (N = 93) with a prepubertal and early adolescent bipolar disorder phenotype were obtained through consecutive new case ascertainment from designated pediatric and psychiatric sites from 1995 to 1998. Children needed DSM-IV bipolar I disorder (manic or mixed phase) with elation and/or grandiosity as one criterion to avoid diagnosing mania only by symptoms that overlapped with those of attention-deficit/hyperactivity disorder. Comprehensive assessment included the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, given separately to parents about their children and to children about themselves by experienced research nurses blinded to subjects' diagnostic status. RESULTS: Rates of mixed mania (chi = 7.1, p = .008) and suicidality (chi = 7.2, p = .007) were significantly higher at psychiatric versus pediatric venues. Subjects from pediatric sites were significantly more likely to be living with their intact biological family (chi = 5.3, p = .022). Significantly more subjects with a prepubertal and early adolescent bipolar disorder phenotype ascertained at psychiatric sites versus pediatric sites were taking an antimanic medication (chi = 9.5, p = .002), while stimulant medication was significantly more common among subjects ascertained at pediatric sites (chi = 19.0, p < .0001). CONCLUSIONS: These pediatric versus psychiatric site differences suggest that pediatricians may under-recognize mania and thus do not prescribe antimanic mood-stabilizing medications. Moreover, pediatricians may be more likely to refer children to psychiatrists when depression or suicidality is evident.

Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: Transmission of the brain-derived neurotrophic factor (BDNF) Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was examined. METHOD: The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one cardinal mania criterion (i.e., euphoria and/or grandiosity) to ensure differentiation from attention deficit hyperactivity disorder. Probands (mean age=10.7 years, SD=2.7) were obtained by consecutive new case ascertainment from designated pediatric and psychiatric venues. Parents and probands were interviewed separately by research nurses who were blind to the probands' diagnoses. Genotyping was done with TaqMan Assay-on-Demand. Analysis was done with the Family Based Association Test program. RESULTS: There were 53 complete, independent trios. The BDNF Val66 allele was preferentially transmitted (Family Based Association Test: chi(2)=6.0, df=1, p=0.014). CONCLUSIONS: This finding in child bipolar disorder is consistent with data for adults with bipolar disorder that show preferential transmission of the Val66 allele.

Relationship of parent and child informants to prevalence of mania symptoms in children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: A controversy regarding pediatric bipolar disorder is whether to use child in addition to parent informants. To investigate this issue, the authors conducted a study comparing separate child and parent interview data for child bipolar disorder. METHOD: Responses on the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia from 93 child and 93 parent informants were compared by using kappa statistics. Research nurses, blind to subject information, separately interviewed parents about their children and children about themselves. Different nurses were used for the parent and child in each family to avoid bias from the same research nurse interviewing a child after interviewing that child's parent. Mania was defined by DSM-IV criteria, with at least one of the two cardinal symptoms of mania (elated mood and/or grandiosity), to avoid diagnosing mania by symptoms that overlapped with those for attention deficit hyperactivity disorder (ADHD). RESULTS: Parent-child concordance was poor to fair for all cardinal and noncardinal mania symptoms. Kappas were not significantly different by age within the 7-14-year-old age range. CONCLUSIONS: Symptoms endorsed by just the child included substantial proportions of bipolar symptoms that have been shown to best differentiate mania from ADHD (i.e., elation, grandiosity, flight of ideas, racing thoughts, decreased need for sleep). These findings support the need for child informants in research on prepubertal and early adolescent bipolar disorder in children ages 7-14. Differences in mania symptom profiles between investigative groups may be, in part, due to whether child informants were assessed.

Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype.

BACKGROUND: Diagnosis of child mania has been contentious. OBJECTIVE: To investigate natural history and prospective validation of the existence and long-episode duration of mania in children. DESIGN: Four-year prospective longitudinal study of 86 subjects with intake episode mania who were all assessed at 6, 12, 18, 24, 36, and 48 months. The phenotype was defined as DSM-IV bipolar I disorder (manic or mixed) with at least 1 cardinal symptom (elation and/or grandiosity) to ensure differentiation from attention-deficit/hyperactivity disorder. Parent and child informants were separately interviewed, by highly experienced research nurses, using the Washington University in St Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS). A Children's Global Assessment Scale score of 60 or less was needed to establish definite impairment. Treatment was by subjects' community practitioners. SETTING: Research unit in a university medical school. PARTICIPANTS: Subjects were obtained from psychiatric and pediatric sites by consecutive new case ascertainment, and their baseline age was 10.8 +/- 2.7 years. Onset of the baseline episode was 7.4 +/- 3.5 years. (Data are given as mean +/- SD.) MAIN OUTCOME MEASURES: Episode duration, weeks ill, recovery/relapse rates, and outcome predictors. RESULTS: Prospective episode duration of manic diagnoses, using onset of mania as baseline date, was 79.2 +/- 66.7 consecutive weeks. Any bipolar disorder diagnosis occurred during 67.1% +/- 28.5% of total weeks, during the 209.4 +/- 3.3 weeks of follow-up. Subjects spent 56.9% +/- 28.8% of total weeks with mania or hypomania (unipolar or mixed), and 38.7% +/- 28.8% of these were with mania. Major or minor depression and dysthymia (unipolar or mixed) occurred during 47.1% +/- 30.4% of total weeks. Polarity switches occurred 1.1 +/- 0.7 times per year. Low maternal warmth predicted faster relapse after recovery from mania (chi(2) = 13.6, P =.0002), and psychosis predicted more weeks ill with mania or hypomania (F(1,80) = 12.2, P =.0008). Pubertal status and sex were not predictive. (Data are given as mean +/- SD.) CONCLUSIONS: These findings validate the existence, long-episode duration, and chronicity of child mania. Differences from the natural history of adult bipolar disorder are discussed.

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.

Ages of onset and rates of syndromal and subsyndromal comorbid DSM-IV diagnoses in a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: To study rates and ages of onset of DSM-IV syndromal and subsyndromal comorbidity in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) (N = 93) compared to attention-deficit/hyperactivity disorder (ADHD) (N = 81). METHOD: The WASH-U-KSADS was given by raters blinded to subject group separately to mothers about their children and to children about themselves. PEA-BP was defined as DSM-IV mania with at least one cardinal symptom of mania (elation or grandiosity) to avoid diagnosing using only symptoms that overlapped with those for ADHD. Syndromal diagnoses required a CGAS score of 60 or less to ensure severity at a level of definite "caseness." RESULTS: PEA-BP subjects were aged 10.9 (SD = 2.6) at baseline and 6.8 (SD = 3.4) at onset of first mania episode. Rates of oppositional defiant disorder and total number of comorbidities were significantly higher in the PEA-BP group than the ADHD group. In PEA-BP subjects, mean ages of onset of ADHD occurred before the first manic episode, and obsessive compulsive, oppositional defiant, social phobia, generalized anxiety, separation anxiety, and conduct disorders occurred after. CONCLUSIONS: Onsets of ADHD before mania and of oppositional defiant disorder/conduct disorder after mania have clinical and research implications. These include the need to examine for mania symptoms in children with ADHD and/or oppositional defiant disorder/conduct disorder and to develop scales to differentiate preschool mania from ADHD. Comparison with other studies demonstrated the importance of DSM system and severity scales in reporting comorbidity rates.

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.

Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: Longitudinal outcomes of bipolar disorder with onset in the late teenage years or in adulthood have been reported, but little is known about the natural history of childhood-onset mania. This study sought to provide rates and predictors of recovery and relapse in children with a prepubertal and early adolescent bipolar disorder phenotype. METHOD: Eighty-nine consecutively ascertained outpatient subjects (mean age=10.9 years [SD=2.7]) received comprehensive research assessments, including separate interviews of mothers about their children and of children about themselves, at baseline and at 6, 12, 18, and 24 months after baseline. The study phenotype required DSM-IV mania with elation and/or grandiosity as one criterion to distinguish the study phenotype from a diagnosis of mania based on criteria overlapping with those for attention deficit hyperactivity disorder and to ensure that subjects had at least one of the two cardinal features of mania (i.e., elation and/or grandiosity). Subjects were treated by their own community practitioners. RESULTS: The proportions of subjects who recovered from mania and who relapsed after recovery were 65.2% and 55.2%, respectively. The mean time to recovery was 36.0 weeks (SD=25.0). Relapse occurred after a mean of 28.6 weeks (SD=13.2). Living with an intact biological family significantly predicted rate of recovery, and a low level of maternal warmth significantly predicted rate of relapse. CONCLUSIONS: The relatively poor outcomes of these subjects may be related to their phenotypic resemblance to severely ill adults with bipolar disorder who have mixed mania, continuous rapid cycling, psychosis, and treatment-resistant psychopathology. A lower level of effectiveness of mood stabilizers in children cannot be ruled out. Although the significance of maternal warmth as a predictor is consistent with reports in adult mania, the significance of intact family as a predictor may be unique to childhood mania.

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.