Clinical course of children and adolescents with bipolar spectrum disorders

CONTEXT: Despite the high morbidity associated with bipolar disorder (BP), few studies have prospectively studied the course of this illness in youth. OBJECTIVE: To assess the longitudinal course of BP spectrum disorders (BP-I, BP-II, and not otherwise specified [BP-NOS]) in children and adolescents. DESIGN: Subjects were interviewed, on average, every 9 months for an average of 2 years using the Longitudinal Interval Follow-up Evaluation. SETTING: Outpatient and inpatient units at 3 university centers. PARTICIPANTS: Two hundred sixty-three children and adolescents (mean age, 13 years) with BP-I (n = 152), BP-II (n = 19), and BP-NOS (n = 92). MAIN OUTCOME MEASURES: Rates of recovery and recurrence, weeks with syndromal or subsyndromal mood symptoms, changes in symptoms and polarity, and predictors of outcome. RESULTS: Approximately 70% of subjects with BP recovered from their index episode, and 50% had at least 1 syndromal recurrence, particularly depressive episodes. Analyses of weekly mood symptoms showed that 60% of the follow-up time, subjects had syndromal or subsyndromal symptoms with numerous changes in symptoms and shifts of polarity, and 3% of the time, psychosis. Twenty percent of BP-II subjects converted to BP-I, and 25% of BP-NOS subjects converted to BP-I or BP-II. Early-onset BP, BP-NOS, long duration of mood symptoms, low socioeconomic status, and psychosis were associated with poorer outcomes and rapid mood changes. Secondary analyses comparing BP-I youths with BP-I adults showed that youths significantly more time symptomatic and had more mixed/cycling episodes, mood symptom changes, and polarity switches. CONCLUSIONS: Youths with BP spectrum disorders showed a continuum of BP symptom severity from subsyndromal to full syndromal with frequent mood fluctuations. Results of this study provide preliminary validation for BP-NOS.     

Substance use disorders among adolescents with bipolar spectrum disorders

Objective: We set out to examine the prevalence and correlates of substance use disorders (SUD) in a large sample of adolescents with bipolar disorder (BP). Methods: Subjects were 249 adolescents ages 12 to 17 years old who fulfilled DSM‐IV criteria for bipolar I disorder [(BPI), n = 154], or bipolar II disorder [(BPII), n = 25], or operationalized criteria for BP not otherwise specified [(BP NOS), n = 70], via the Schedule for Affective Disorders and Schizophrenia for School‐Aged Children (K‐SADS). As part of the multi‐site Course and Outcome of Bipolar Youth study, demographic, clinical, and family history variables were measured via intake clinical interview with the subject and a parent/guardian. Results: The lifetime prevalence of SUD among adolescents with BP was 16% (40/249). Results from univariate analyses indicated that subjects with, as compared to without, SUD were significantly less likely to be living with both biological parents, and that there was significantly greater lifetime prevalence of physical abuse, sexual abuse, suicide attempts, conduct disorder, and posttraumatic stress disorder among subjects with SUD. Subjects with SUD reported significantly greater 12‐month prevalence of trouble with police, and females with SUD reported significantly greater 12‐month prevalence of pregnancy and abortion. Significant predictors of SUD in a logistic regression model included living with both biological parents (lower prevalence), conduct disorder and suicide attempts (increased prevalence). In logistic regression analyses controlling for demographic differences and conduct disorder, SUD remained significantly associated with trouble with police, whereas the association of SUD with pregnancy and abortion was reduced to a statistical trend. The prevalence of SUD was not significantly different among child‐ versus adolescent‐onset BP subjects. Conclusions: SUD among adolescents with BP is associated with profound hazards including suicide attempts, trouble with police, and teenage pregnancy and abortion.     

Comparison of manic and depressive symptoms between children and adolescents with bipolar spectrum disorders

Objective: To compare the most severe lifetime (current or past) mood symptoms, duration of illness, and rates of lifetime comorbid disorders among youth with bipolar spectrum disorders [BP (bipolar‐I, bipolar‐II and bipolar–not otherwise specified)]. Methods: A total of 173 children (<12 years) with BP, 101 adolescents with childhood‐onset BP, and 90 adolescents with adolescent‐onset BP were evaluated with standardized instruments. Results: Depression was the most common initial and frequent episode for both adolescent groups, followed by mania/hypomania. Adolescents with childhood‐onset BP had the longest illness, followed by children and then adolescents with adolescent‐onset BP. Adjusting for sex, socioeconomic status, and duration of illness, while manic, both adolescent groups showed more ‘typical’ and severe manic symptoms. Mood lability was more frequent in childhood‐onset and adolescents with early‐onset BP. While depressed, both adolescent groups showed more severe depressive symptoms, higher rates of melancholic and atypical symptoms, and suicide attempts than children. Depressed children had more severe irritability than depressed adolescents. Early BP onset was associated with attention‐deficit hyperactivity disorder, whereas later BP onset was associated with panic, conduct, and substance use disorders. Above‐noted results were similar when each BP subtype was analyzed separately. Conclusions: Older age was associated with more severe and typical mood symptomatology. However, there were differences and similarities in type, intensity, and frequency of BP symptoms and comorbid disorders related to age of onset and duration of BP and level of psychosocial development. These factors and the normal difficulties youth have expressing and modulating their emotions may explain existing complexities in diagnosing and treating BP in youth, particular in young children, and suggest the need for developmentally sensitive treatments.     

Phenomenology of anxiety and depressive disorders in children and adolescents

In recent years, clinicians and researchers have demonstrated renewed interest in the study of anxiety and depression in children and adolescents. There is difficulty in determining the constituents' characteristics of, and distinguishing between, anxiety and depression. Further understanding of the phenomenology of these disorders may result from observation, by attending to the subjective experiences of the child and adolescent, and by studying the biologic factors associated with anxiety and depressive disorders. Despite the fact that much remains unknown concerning the disorders of anxiety and depression in children and adolescents, considerable progress has been made toward a better understanding of the phenomenology of depressive disorders in children and adolescents.     

Adjunctive topiramate in hospitalized children and adolescents with bipolar disorders

OBJECTIVE: The aim of this study was to assess topiramate as adjunctive treatment in children and adolescents hospitalized with bipolar disorders. METHODS: Medical records of all children and adolescents with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) (APA, 2000) diagnosis of bipolar disorder, type I, hospitalized for an acute manic, mixed, or depressive episode, were reviewed. The primary outcome measure was the Clinical Global Impression-Severity (CGI-S) score. RESULTS: Twenty-five (25) children and adolescents received topiramate, with a mean final dose of 126 mg/day (range, 25-350 mg). Overall CGI-S scores significantly improved from 5.3+/-1.0 to 3.5+/-0.7, and mania CGI-S scores decreased from 5.4+/-1.0 to 3.3+/-0.9. Sixteen (16) of 25 (64%) bipolar patients were classified as responders (defined by an endpoint overall CGI-I score of less than or equal to 2). No serious adverse events occurred during treatment. Of 25 patients evaluated, 1 (4%) experienced mild sedation while treated with topiramate. CONCLUSIONS: Preliminary results of this retrospective chart review suggest that adjunctive topiramate may be associated with improvements in children and adolescents hospitalized for an acute manic, mixed, or depressive episode. Randomized and controlled trials with adjunctive topiramate in this population are needed to further explore this observation.     

Mood symptoms in children and adolescents with autism spectrum disorders

Asperger Syndrome (AS) and High Functioning Autism (HFA) are psychiatric conditions belonging to the Autistic Spectrum Disorders (ASDs), characterized by social dysfunction and focused interest, in the absence of mental retardation. Previous reports suggest that AS/HFA may be associated with important psychiatric comorbidities. Among the psychiatric internalizing disorders, depression and anxiety are probably the most common disorders. The aim of this study is to evaluate the prevalence of mood disorders and identifying peculiar clinical features in subjects suffering from AS and HFA. 30 male patients with AS/HFA, 30 male patients affected by Major Depression (MD) and 35 male Typically Developing (TD) comparison were assessed with the CDI and the CDRS-R. Participants’ parents were invited to complete the CBCL and the P-YMRS. Moreover, the CGAS was rated by the clinicians. The evaluation of depressive symptoms showed that AS/HFA group reported higher depressive symptoms, as showed by CDI total, CBCL internalizing and CDRS-R total, compared to the TD group. No significant difference of depressive symptoms was found between the AS/HFA and the MD group, with the exception of CDRS-R total score. Moreover, linear regression analysis in the AS/HFA group between CGAS and depressive symptoms revealed that a higher level of depressive symptoms increased the risk of poorer global functioning. These results suggest that the depressive symptoms in AS/HFA patients may be associated with poorer global functioning, with a consequent impairment in their psychological profile and social adjustment, and should alert clinicians to the importance of assessing mood disorders in order to choose the appropriate treatment.     

Autism spectrum disorders in children and adolescents with Moebius sequence

Moebius sequence is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. A strong association of Moebius sequence with autism spectrum disorders (ASDs) has been suggested in earlier studies with heterogenous age groups. The primary caregivers of all children and adolescents with Moebius sequence aged 6–17 years known to the German Moebius foundation were anonymously asked to complete two screening measures of ASD [Behavior and Communication Questionnaire (VSK); Marburger Asperger’s Syndrome Rating Scale (MBAS)]. For those who reached the cut-off for ASD, well standardized diagnostic instruments (Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, WISC-III, and Kinder-DIPS) should be administered. Minimal diagnostic criteria for Moebius sequence were congenital facial weakness (uni- or bilateral) and impairment of ocular abduction (uni- or bilateral). Familiar cases should be excluded. The primary caregivers of 35/46 children and adolescents (18 males, 17 females, mean age 11.5 years) sent back completed questionnaires, but only 27 subjects met inclusion criteria. According to the primary caregivers, none of these subjects showed mental retardation. Two probands (both males 9 and 16 years old) reached the cut-off of the MBAS whereas the results of the VSK did not indicate ASDs in any of the patients. The 9 year old boy could be examined personally and did not meet diagnostic criteria of ASD. ASDs might be not as frequent as reported in previous studies on patients with Moebius sequence, at least not in patients without mental retardation.     

Physical aggression in children and adolescents with autism spectrum disorders

Aggression is a clinically significant problem for many children and adolescents with autism spectrum disorders (ASD). However, there have been few large-scale studies addressing this issue. The current study examined the prevalence and correlates of physical aggression in a sample of 1584 children and adolescents with ASD enrolled in the Autism Treatment Network. The prevalence of aggression was 53%, with highest prevalence among young children. Aggression was significantly associated with a number of clinical features, including self-injury, sleep problems, sensory problems, GI problems, communication and social functioning. In multivariate models, self-injury, sleep problems, and sensory problems were most strongly associated with aggression. The results indicate that aggression is markedly prevalent, and clinical implications and directions for future research are discussed.     

Externalizing disorders in consecutively referred children and adolescents with bipolar disorder

We describe a consecutive clinical sample of children and adolescents with bipolar disorder (BD), in order to define the pattern of comorbid externalizing disorders and to explore the possible influence of such a comorbidity on their cross-sectional and longitudinal clinical characteristics. The sample consisted of 59 bipolar patients: 35 males and 24 females, with a mean age 14.6 +/- 3 years (range, 7 to 18 years), diagnosed as either type I or II according to DSM-IV. All patients were screened for psychiatric disorders using historical information and a clinical interview, the Diagnostic Interview for Children and Adolescents-Revised (DICA-R). Severity and subsequent outcome of the symptomatology were recorded with the Clinical Global Impression (CGI), Severity and Improvement Scales, at the baseline and thereafter monthly for a period up to 48 months. BD disorder type I was present in 37 (62.7%) of the patients; 14 (23.7%) were affected by attention deficit-hyperactivity disorder (ADHD) and 10 (16.9%) by conduct disorder (CD). Comorbid ADHD was associated with an earlier onset of BD, while CD was highly associated with BD type I. Anxiety disorders appeared more represented in patients without CD. At the end of the observation, a lower clinical improvement was recorded in patients with CD. In our children and adolescents with BD, comorbidity with externalizing disorders such as ADHD and CD is common. The clinical implications of comorbid ADHD and CD are rather different. ADHD can be viewed as a precursor of a child-onset subtype of BD, while CD might represent a prodromal or a concomitant behavioral complication that identifies a more malignant and refractory form of BD.     

Assessment of anxiety in children and adolescents with autism spectrum disorders

Anxiety disorders are among the most common comorbid conditions in children and adolescents with autism spectrum disorders (ASDs), although assessment presents unique challenges. Many symptoms of anxiety appear to overlap with common presentations of autism. Furthermore, deficits in language and cognitive functioning make it difficult for such children to convey their emotional states accurately. A comprehensive review of the recent literature was conducted to assay the types and rates of use of tools for evaluating anxiety symptoms in children and adolescents with ASDs. We identified strengths and weaknesses in existing scales, identified instruments that (although imperfect) seem to have a good coverage for youngsters with ASDs, recommended strategies for studying anxiety in these youth, and offered suggestions for future scale development.     

The bipolar spectrum in children and adolescents: developmental issues

Bipolar disorders are common, chronic illnesses that can develop in children and adolescents at early ages. However, diagnosing bipolar disorders in youths can be difficult because currently defined gradations of the disorder, including bipolar I and bipolar II disorders and bipolar disorder not otherwise specified, were not created with the developmental differences of children in mind. Children with major depression or attention-deficit/hyperactivity disorder plus a family history of bipolar disorder may be presenting with prodromal signs and symptoms of a bipolar disorder, although longitudinal studies are needed to clarify risk factors for developing bipolar disorders. Neuropsychological and biological markers may eventually aid clinicians in distinguishing bipolar spectrum disorders and offering early intervention for at-risk children and adolescents.     

Obsessive-compulsive and spectrum disorders in children and adolescents.

The available literature indicates that OCD affecting children and adolescents is highly prevalent. Pediatric-onset OCD seems to share important similarities with the adult disorder but also shows important differences.For example, the clinical phenotype of OCD is remarkably consistent at all ages with some allowances for developmental expression. Pediatric patients frequently demonstrate poor insight into the nature of their obsessions, which in association with their limited verbal expression may make the diagnosis more difficult. Obsessions involving fear of harm and separation, compulsions without obsessions, and rituals involving family members are more common in younger patients. Treatment response,including serotonergic specificity and the need for robust dosing, is another feature shared by early- and adult-onset OCD. Imporfant differences across the life span can also be identified. Perhaps the clearest difference pertains to age of onset. Age-at-onset data have shown a bimodal distribution of age of onset of OCD, with one peak in preadolescent childhood and another peak in adulthood. Another distinction between child and adult OCD is gender representation. Whereas adult studies report equal gender representation or a slight female preponderance, pediatric clinical samples are clearly male predominant. Patterns of psychiatric comorbidity in pediatric OCD show high rates of tic and mood and anxiety disorders, similar to the patterns in adults, but also show a distinct association with disruptive behavior disorders (ADHD and oppositional defiant disorder) and other specific and pervasive developmental disorders. Family studies indicate that the disorder is highly familial and that a childhood onset of the disorder seems to be associated with a markedly increased risk for familial transmission of OCD, tic disorders, and ADHD.Both scientifically and clinically, the recognition of developmentally specific OCD phenotypes may be valuable. For example, research efforts aimed at identifying OCD-associated genes are likely to be more successful if developmentally homogeneous samples are studied instead of combining data from children, adolescents, and adults, as has been common in OCD studies.Clinical management is also informed by an appreciation of the unique cor-relates of OCD affecting youth, especially comorbidity with chronic tic dis-orders and ADHD and their impact on treatment.The so-called "spectrum disorders" related to OCD are less prominent in children and adolescents than in adults. Although sharing some features with typical OCD, these symptoms are less clearly ego-dystonic and less anxiety producing, frequently provide a measure of gratification, and are less responsive in general to SSRIs. Often cognitive antecedents to these behaviors are less well developed than in more typical OCD, and behavioral interventions are the mainstay of treatment but with more variable success.     

Comorbid sleep disorders and suicide risk among children and adolescents with bipolar disorder

Children and adolescents with bipolar disorder are at increased risk for suicide. Sleep disturbances are common among youth with bipolar disorder and are also independently implicated in suicide risk; thus, comorbid sleep disorders may amplify suicide risk in this clinical population. This study examined the effects of comorbid sleep disorders on suicide risk among youth with bipolar disorder. We conducted secondary analyses of baseline data from the Treatment of Early Age Mania (TEAM) study, a randomized controlled trial of individuals aged 6–15 years (mean ± SD = 10.2 ± 2.7 years) with DSM-IV bipolar I disorder (N = 379). Sleep disorders (i.e., nightmare, sleep terror, and sleepwalking disorders) and suicide risk were assessed via the WASH-U-KSADS and the CDRS-R, respectively. We constructed uncontrolled logistic regression models as well as models controlling for trauma history, a generalized anxiety disorder (GAD) diagnosis, and depression symptoms. Participants with a current comorbid nightmare disorder versus those without were nearly twice as likely to screen positive for suicide risk in an uncontrolled model and models controlling for trauma history, a GAD diagnosis, and depression symptoms. Neither a current comorbid sleep terror disorder nor a sleepwalking disorder was significantly associated with suicide risk. This pattern of findings remained consistent for both current and lifetime sleep disorder diagnoses. Youth with bipolar I disorder and a comorbid nightmare disorder appear to be at heightened suicide risk. Implications for assessment and treatment are discussed.     

Treatment incidence and patterns in children and adolescents with autism spectrum disorders

This study examined the treatment rates and patterns in children and adolescents with autism spectrum disorders (ASDs). Data were collected on 353 nonreferred children and adolescents (mean age 9.5 +/- 3.9 years; range 3-21 years) with ASDs from public schools across Ohio. Parents provided information on the use of psychotropic medicines, vitamins, supplements, and modified diets. They also completed measures of social competence, problem behavior, and adaptive behavior. Results indicated that 46.7% of subjects had taken at least one psychotropic medication in the past year. In addition, 17.3% of subjects had taken some type of specially formulated vitamin or supplement, 15.5% were on a modified diet, 11.9% had some combination of psychotropic medication and an alternative treatment, and 4.8% had taken an anticonvulsant. Logistic regressions indicated that greater age, lower adaptive skills and social competence, and higher levels of problem behavior were associated with greater medication use. This was the first study to focus exclusively on a younger population, to survey patterns of modified diets, and to obtain standardized ratings of social competence, problem behaviors, and adaptive behavior in relation to medication use. The results of this study highlight the need for more research on psychotropic medication in children and adolescents with ASDs.     

Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders

Mood symptoms in adult bipolar disorder are associated with increased proinflammatory markers and decreased brain-derived neurotrophic factor (BDNF). We examined serum interleukin-6, high-sensitivity C-reactive protein (hsCRP), and BDNF among 30 bipolar disorder adolescents. Hypomanic/manic symptoms were positively associated with hsCRP. BDNF levels were negatively associated with interleukin-6. Forty percent had cardiovascular high-risk hsCRP levels. Larger longitudinal studies are warranted.     

Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders

Alcohol consumption during pregnancy can lead to a variety of cognitive and other birth defects, collectively termed fetal alcohol spectrum disorders (FASD), and including the Fetal Alcohol Syndrome (FAS). This study examined the impact of gestational alcohol exposure on the morphology of the cingulate gyrus, given this region's role in cognitive control, attention, and emotional regulation, all of which are affected in children with FASD. Thirty-one youth (ages 8–16) with histories of heavy prenatal alcohol exposure (n = 21) and demographically matched comparison subjects (n = 10) underwent structural magnetic resonance imaging. The cingulate gyrus was manually delineated, and parcellated volumes of grey and white matter were compared across groups. Alcohol-exposed individuals had significantly smaller raw cingulate grey matter, white matter, and tissue volumes compared with controls. After adjustment for respective cranial tissue constituents, only white matter volumes remained significantly reduced, and this held regardless of whether or not the child qualified for a diagnosis of FAS. A correlation between posterior cingulate grey matter volume and the WISC-III Freedom from Distractibility Index was also observed in alcohol-exposed children. These data suggest that cingulate white matter is compromised beyond global white matter hypoplasia in alcohol-exposed individuals, regardless of FAS diagnosis. The observed volumetric reductions in the cingulate gyrus may contribute to the disruptive and emotionally dysregulated behavioral profile commonly observed in this population.     

Impulsivity in children and adolescents with mood disorders and unaffected offspring of bipolar parents

Objective

Increased impulsivity seems to be present across all phases of bipolar disorder (BD). Impulsivity may therefore represent an endophenotype for BD, if it is also found among normal individuals at high genetic risk for mood disorders. In this study, we assessed impulsivity across four different groups of children and adolescents: patients with BD, major depressive disorder (MDD) patients, unaffected offspring of bipolar parents (UO), and healthy controls (HC).

Subjects and Methods

52 patients with BD, 31 with MDD, 20 UO, and 45 HC completed the Barratt Impulsiveness Scale (BIS-11), an instrument designed to measure trait impulsivity.

Results

UO displayed significantly higher total BIS-11 impulsivity scores than HC (p = 0.02) but lower scores than BD patients (F = 27.12, p < 0.01). Multiple comparison analysis revealed higher BIS-11 total scores among BD patients when compared to HC (p < 0.01) and UO (p < 0.01). MDD patients had higher BIS-11 scores when compared to HC (p < 0.01). Differences between MDD patients and UO, as well as between MDD and BD patients, were not statistically significant.

Conclusion

Our findings suggest that trait impulsivity is increased among children and adolescents with mood disorders, as well as in unaffected individuals at high genetic risk for BD.     

The spectrum of bipolar disorders

On the basis of epidemiology, neurobiology and clinical observation, the classification of bipolar disorders has shown considerable development and expansion in recent years. In particular, the recognition of mixed states, the introduction of bipolar II disorders, increasing awareness of the diagnosis of hypomania, as well as the interest in cyclothymic disorders and temperament have led to a shift in diagnostic attitudes in the USA, as well as in European countries. In this article, the possible clinical and scientific benefits of such tendencies are discussed, as are the risks of broadening bipolar disorders beyond DSM-IV.Also demonstrated is how several "modern" concepts of bipolarity have deep roots in the history of German psychiatry; a mixity scale based on Kraepelin's classification of affective mixed states is presented.     

Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders

Background

Previous research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD.

Methods

The present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI).

Results

We found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation.

Conclusions

These results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population.