A comparison of bipolar disorders in children in Italy and the United States.

BACKGROUND: The clinical presentation of bipolar disorders, though clearly recognized in adolescents, remains controversial in younger children and across cultures. The aim of this study was to compare the clinical presentation of bipolar disorders in Italian and American children between ages 5 and 12 years. METHODS: Sixty-seven children from six outpatient programs were enrolled (Italian sample: n=40; American sample: n=28) between January 2010 and June 2011. Children and their parents were interviewed by experienced clinicians using the Washington University in St. Louis Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present, Lifetime Version (WASH-U K-SADS). RESULTS: Italian children scored significantly higher on ratings of "elevated mood" (p=0.002), whereas American children scored significantly higher on ratings of "flight of ideas" (p=0.001) and "productivity" (p=0.001). Rates of comorbidity were different between groups. LIMITATIONS: Data were acquired from several sites in Italy as compared to from a single American site. Medication and educational information were not systematically collected. Furthermore, the sample collected may only reflect characteristics of a less severely ill group of bipolar children. CONCLUSIONS: Our comparison of Italian and American children with early onset bipolar disorders found that the phenotype of bipolar spectrum disorders is largely shared across cultures, although psychiatric comorbidities differed.

Characteristics of the child behavior checklist in adolescents with depression associated with bipolar disorder.

BACKGROUND: The child behavior checklist-Juvenile bipolar disorder phenotype (CBCL-JBD) has been proposed as a distinct profile specific to children and adolescents who have been diagnosed with bipolar disorder. The objective of this study was to examine whether bipolar disorder youth with depression exhibit the "CBCL-Juvenile bipolar disorder phenotype." METHODS: Thirty-two adolescents, ages 12-18 years, with a depressive episode associated with bipolar I disorder were recruited, and their primary caregivers completed the CBCL. RESULTS: Only the internalizing subscale (mean=70.2, SD=9.7) and total score (mean=71.5, SD=8.9) reached clinical significance (>70). Moreover, the CBCL-JBD profile scores of our subjects (204.6, SD=27.5) did not reach clinical significance (>210). LIMITATIONS: Our subjects differed demographically from those in studies that have confirmed the CBCL-Juvenile bipolar disorder phenotype with regards to sex, age and ADHD comorbidity, thus limiting the interpretability of our comparisons with other studies. Furthermore, our investigation involved a small sample size and did not include a control group, which should be addressed in future studies. CONCLUSIONS: The results of our study suggest that the CBCL-JBD profile is not characteristic of depressed youth with bipolar disorder. Better assessment tools for making an accurate and efficient diagnosis of bipolar disorder are needed so that appropriate treatment can be implemented and significant morbidity and mortality are minimized.

Functional MRI of sustained attention in bipolar mania.

We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.

Differential patterns of brain activation over time in adolescents with and without attention deficit hyperactivity disorder (ADHD) during performance of a sustained attention task.

OBJECTIVE: Recent morphometric studies suggest that children with ADHD may demonstrate differential or delayed brain development compared with children without ADHD. This study examines the developmental course of brain activation patterns during the performance of an attention task. METHOD: Ten adolescents with ADHD and 14 healthy comparison adolescents performed a continuous performance task in an fMRI twice, one year apart. RESULTS: In the absence of performance differences, children with ADHD and healthy comparison subjects activated frontal-parietal regions while performing an attention task at initial testing. Children with ADHD appeared to require continued use of the right middle frontal gyrus during administration of testing one year apart while healthy comparison subjects did not activate this region at the time of the second testing. CONCLUSIONS: There appear to be developmental differences in brain activation patterns on an attentional task between ADHD and healthy controls. More research is needed for examining the longitudinal course of functional brain activation in children with ADHD.

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings.

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.

Comparative efficacy and tolerability of drug treatments for bipolar disorder.

Lithium has been the backbone of treatment for bipolar disorder for several decades, although recent advances have identified a number of other medications that have efficacy in treating various phases of the illness. These include the antiepileptic drugs valproate semisodium (divalproex sodium) and carbamazepine and some new antiepileptic drugs (e.g. lamotrigine and topiramate), and the atypical antipsychotics (e.g. olanzapine, clozapine and risperidone). Conventional antipsychotics continue to be used frequently in bipolar disorder, although they may be somewhat less effective than other treatments. Otherwise, to date, none of these treatments have been shown to be consistently more effective than any other, so that drug adverse effects and tolerability often dictate which agents are used in an individual patient. Drugs commonly used for the treatment of bipolar disorder are generally tolerated by most patients in large samples. However, the unique adverse effect signature of a drug will often suggest that it will be less tolerable in some patients than in others. Identifying a specific treatment for a specific patient requires a careful individualised assessment of the risk of adverse effects for that patient's unique circumstances.

Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance.

Previously, we reported progressively greater behavioral responses to repeated d-amphetamine in human subjects that represented a potential model of behavioral sensitization. To extend this work, 59 healthy volunteers were randomly assigned to one of three protocols: (1) placebo administered on days 1, 3, and 5 (PPP); (2) placebo administered on days 1 and 3, and d-amphetamine (0.25 mg/kg) on day 5 (PPA); and (3) d-amphetamine administered on days 1, 3, and 5 (AAA). Comparisons were made among the three groups to determine whether repeated d-amphetamine produced an increased behavioral response. Subjective ratings of vigor and euphoria exhibited the greatest response following the third dose of the AAA group, as hypothesized. In contrast, drug liking was greatest following a single or first d-amphetamine dose. These effects were greater in women. Progressive changes in subjective responses following repeated d-amphetamine administration may occur in healthy human subjects, although this effect may be greater for women.

Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset.

OBJECTIVES: To compare demographic and clinical characteristics between bipolar adolescents with and without a history of stimulant treatment, we hypothesized that adolescents treated with stimulants would have an earlier age at onset of bipolar disorder, independent of co-occurring attention-deficit-hyperactivity disorder (ADHD). METHOD: Thirty-four adolescents hospitalized with mania were assessed using the Washington University at St Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS). We systematically evaluated age at onset of bipolar disorder and pharmacological treatment history. RESULTS: Bipolar adolescents with a history of stimulant exposure prior to the onset of bipolar disorder had an earlier age at onset of bipolar disorder than those without prior stimulant exposure. Additionally, bipolar adolescents treated with at least two stimulant medications had a younger age at onset compared with those who were treated with one stimulant. There was no difference in age at onset of bipolar disorder between bipolar adolescents with and without ADHD. CONCLUSIONS: Our results suggest that stimulant treatment, independent of ADHD, is associated with younger age at onset of bipolar disorder. A behavioral sensitization model is proposed to explain our findings. There are several limitations to our study including the small sample size, the retrospective assessment of stimulant exposure and age at onset of bipolar disorder, and the inclusion of only hospitalized patients, who may be more likely to present with a severe illness. Nonetheless, future prospective longitudinal investigations that systematically assess the effects of stimulant medications in children with or at genetic risk for bipolar disorder are warranted.

Effects of race on psychiatric diagnosis of hospitalized adolescents: a retrospective chart review.

BACKGROUND: Several studies have reported that patient ethnicity influences psychiatric diagnosis, although this has only been examined in adolescents in two prior studies. One study was based on an outpatient sample and the other was a retrospective study involving a relatively small sample of inpatients. We hypothesized that, as reported in adults, African American adolescents would be diagnosed with schizophrenic spectrum disorders more frequently than Caucasians, and Caucasians correspondingly would receive more affective disorders diagnoses. METHODS: We retrospectively examined the charts of all adolescents (ages 12-18 years) admitted to the Adolescent Psychiatry Unit at Cincinnati Children's Hospital Medical Center (n = 1,001) between July 1995 and June 1998 for demographic information and discharge diagnoses. We used insurance status as a proxy for socioeconomic status. RESULTS: African American males were more commonly diagnosed with schizophrenic spectrum disorders than were African American women, Caucasian women, and Caucasian men. There were significantly more African Americans diagnosed with conduct disorder than Caucasians. In contrast, Caucasians were diagnosed with alcohol use disorders and major depression more often. CONCLUSIONS: Patient race and sex may influence clinical psychiatric diagnoses of hospitalized adolescents. Further investigations using structured interviews are necessary to determine whether the disparity in clinical diagnosis is secondary to actual gender and racial differences in the rates of illnesses in hospitalized adolescents or due to other factors that may contribute to diagnostic practices.

Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections.

OBJECTIVE: To investigate the reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections. METHOD: The 1986 version of the KSADS was modified and expanded to include onset and offset of each symptom for both current and lifetime episodes, expanded prepubertal mania and rapid cycling sections, and categories for attention-deficit/hyperactivity disorder and other DSM-IV diagnoses. To optimize diagnostic research, skip-outs were minimized. Subjects participated in the ongoing "Phenomenology and Course of Pediatric Bipolar Disorder" study. Mothers and children were interviewed separately by research nurses who were blind to diagnostic group status. In addition, ratings of off-site child psychiatrists, made from the narrative documentation given for each WASH-U-KSADS item, were compared with research nurse ratings. This work was performed between 1995 and 2000. RESULTS: There was 100% interrater reliability, five consecutive times, as both interviewer and observer after 10 to 15 trials. The kappa values of comparisons between research nurse and off-site blind best-estimate ratings of mania and rapid cycling sections were excellent (0.74-1.00). High 6-month stability for mania diagnoses (85.7%) and for individual mania items and validity against parental and teacher reports were previously reported. CONCLUSIONS: The WASH-U-KSADS mania and rapid cycling sections have acceptable reliability.

One-year recovery and relapse rates of children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: The study examined 1-year recovery and relapse rates for mania in subjects who met criteria for a prepubertal and early adolescent bipolar disorder phenotype. METHOD: Outpatients identified by consecutive new-case ascertainment were assessed by means of separate child and parent interviews, consensus conferences, and blind best estimates. The definition of the prepubertal and early adolescent bipolar disorder phenotype was DSM-IV mania with elation and/or grandiosity as one criterion. RESULTS: Of 93 subjects seen at baseline, 89 were seen at 1 year (95.7% retention). The rate of recovery from mania was 37.1%, and the rate of relapse after recovery was 38.3%. No covariates were significantly associated with recovery or relapse. CONCLUSIONS: The low recovery and high relapse rates supported the study hypothesis of poor outcomes, which was made on the basis of similarity between the characteristics of the prepubertal and early adolescent bipolar disorder phenotype (long episode duration and high prevalence of mixed mania, psychosis, and rapid cycling) and those of severe bipolar disorder in adults.

Review of studies of child and adolescent offspring of bipolar parents.

OBJECTIVE: The authors reviewed studies of child and adolescent offspring of bipolar (BP) parents. Findings from these studies are critically discussed with respect to methodological issues that can inform future designs. METHODS: A Medline search was performed to identify studies that examined child and adolescent offspring of BP parents. Publications were excluded if they did not separate offspring of BP parents from offspring of major depressive disorder or schizoaffective parents ("affective offspring") or did not separately analyze data from child- and adolescent-age versus adult offspring. RESULTS: Seventeen studies fit these review criteria. Rates of mood disorders in child and adolescent offspring of BP parents ranged from 5 to 67% compared with rates in offspring of healthy volunteers of 0-38%. Rates of non-mood disordered psychopathology ranged from 5 to 52% in offspring of BP parents and from 0 to 25% in offspring of healthy volunteers. Rates of mood disorders and of other psychopathology were increased in offspring of BP parents compared with offspring of healthy volunteers in all of the eight studies that included a comparison group of offspring of healthy volunteers. CONCLUSIONS: Studies suggest that children (< or =21 years) of BP parents are at increased risk for developing mood and other disorders (e.g., disruptive, anxiety). Therefore, additional investigations are clearly warranted. In the context of current research on diagnosis, assessment, longitudinal course and comorbidity of childhood mania, the following suggestions for the design of future studies should be considered: 1) Phenotypic specification of bipolar manifestations (e.g., BP-I, BP-II, BP-NOS) in child/adolescent offspring and in bipolar parents themselves. 2) Control groups that are pediatric-age relevant and thus include attention-deficit hyperactivity disorder. 3) Assessments that include items for prepubertal mania and for onsets and offsets of all occurrences of symptoms and of environmental factors (e.g., life events) in offspring and in parents so that trajectories of overlap and sequence between child and parental mania can be investigated. 4) These detailed onsets and offsets of symptoms are also necessary to investigate prodromal manifestations of mania in the offspring. 5) Unaffected offspring present a unique opportunity to study pre- and postmorbid cognitive and physiological endophenotypes and structural and functional brain abnormalities. Findings from offspring studies will be crucial to inform research on the development of early intervention and prevention strategies.

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.

Is impaired outcome following a first manic episode due to mood-incongruent psychosis?

BACKGROUND: Mood-incongruent psychosis during the course of bipolar disorder has been associated with poor outcome. However, it remains unknown whether this is secondary to persistent affective or psychotic symptoms or both. METHOD: Fifty patients with bipolar disorder between the ages of 16 and 45 years were recruited during their first psychiatric hospitalization for mania. These patients were evaluated using structured and semi-structured clinical instruments then followed longitudinally. Outcomes during the first eight months of follow-up were compared between patients with mood-incongruent psychosis and those without (i.e., patients with mood-congruent psychosis or no psychosis) during the index manic episode. Specifically, ratings of the percent of weeks during follow-up with psychosis and affective syndromes and symptoms, as well as ratings of global outcome (GAF), were compared. RESULTS: Patients with mood-incongruent psychosis at the index hospitalization exhibited significantly more weeks during follow-up with both mood-incongruent and mood-congruent psychotic symptoms than patients without mood-incongruent psychosis. Mood-incongruent psychosis was also associated with poorer overall functioning during the outcome interval. The groups did not differ in the percent of weeks with affective syndromes or symptoms. Treatment during follow-up did not differ between groups and was not associated with outcome variables in general. CONCLUSION: Mood-incongruent psychosis that occurs during the first manic episode appears to predict an increased likelihood of persistent psychotic symptoms during the subsequent eight months. This persistence of psychosis is associated with a worse overall course of illness as compared to patients without mood-incongruent psychosis. LIMITATIONS: These results apply to a relatively short outcome period and are from a single center.

The impact of substance abuse on the course of bipolar disorder.

BACKGROUND: Substance abuse occurs at high rates in bipolar disorder. The reasons for this co-occurrence are unknown. Alcohol use disorders have been associated with both earlier and later age of onset of bipolar disorder, in part based on the temporal associations of the two conditions. Both drug and alcohol use disorders are associated with impaired outcome of bipolar illness. This influence may involve both direct effects of alcohol or drugs on the initiation of affective symptoms and indirect effects on treatment compliance. To extend these previous findings we examined the temporal associations of substance abuse and affective symptoms in patients with new onset bipolar disorder. METHODS: Associations between affective symptoms and alcohol and cannabis use disorder symptoms were evaluated using regression and time-series correlative methods in 50 new-onset bipolar patients. RESULTS: The duration of alcohol abuse during follow-up was associated with the time patients experienced depression. The duration of cannabis abuse was associated with the duration of mania. Several subgroups could be identified with different temporal relationships among these disorders. CONCLUSIONS: Although the relationships among substance use and bipolar disorders are complex, systematic study of the courses of the disorders might clarify how these conditions interact longitudinally. As the numbers of subjects in specific subgroups are relatively small in this study, these results should be considered preliminary.

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.

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.

Eight-month functional outcome from mania following a first psychiatric hospitalization.

The aim of this study was to identify how different areas of function (role performance, interpersonal relationships, sexual activity and recreational enjoyment) differentially recover from a manic episode during the 8 months following a first psychiatric hospitalization. Fifty patients with bipolar disorder, 16-45 years of age, who met the criteria for a current manic episode were recruited during their first psychiatric hospitalization. Forty-two (84%) of these participated in follow-up. Patients were evaluated using structured and semi-structured clinical instruments and the four areas of functional outcome were assessed with the LIFE interview. Recovery of the four areas of function were compared using survival and correlational analyses. Logistic regression identified factors associated with functional outcome. The four aspects of function were not significantly intercorrelated at baseline or during follow-up. Moreover, the survival curves for the different areas of function significantly differed. Specifically, patients demonstrated better recovery of sexual activity and worse recovery of recreational enjoyment than the other areas of function. Different clinical and demographic variables predicted recovery of the different areas of function. In conclusion, following a first manic episode, recovery of psychosocial function can be divided into separate components, i.e., role function, interpersonal relationships, sexual activity and recreational enjoyment, that appear to be relatively independent. Further clarification of recovery of these different areas of function may lead to better integrated treatments that maximize functional improvement early in the course of bipolar disorder.