Janet Wozniak

Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children

OBJECTIVE To examine the prevalence, characteristics, and correlates of mania among referred children aged 12 or younger. Many case reports challenge the widely accepted belief that childhood-onset mania is rare. Sources of diagnostic confusion include the variable developmental expression of mania and its symptomatic overlap with attention-deficit hyperactivity disorder (ADHD). METHOD The authors compared 43 children aged 12 years or younger who satisfied criteria for mania, 164 ADHD children without mania, and 84 non-ADHD control children. RESULTS The clinical picture was fully compatible with the DSM-III-R diagnosis of mania in 16% (n = 43) of referred children. All but one of the children meeting criteria for mania also met criteria for ADHD. Compared with ADHD children without mania, manic children had significantly higher rates of major depression, psychosis, multiple anxiety disorders, conduct disorder, and oppositional defiant disorder as well as evidence of significantly more impaired psychosocial functioning. In addition, 21% (n = 9) of manic children had had at least one previous psychiatric hospitalization. CONCLUSIONS Mania may be relatively common among psychiatrically referred children. The clinical picture of childhood-onset mania is very severe and frequently comorbid with ADHD and other psychiatric disorders. Because of the high comorbidity with ADHD, more work is needed to clarify whether these children have ADHD, bipolar disorder, or both.

Attention-Deficit Hyperactivity Disorder and Juvenile Mania: An Overlooked Comorbidity?

OBJECTIVE To evaluate the psychiatric, cognitive, and functional correlates of attention-deficit hyperactivity disorder (ADHD) children with and without comorbid bipolar disorder (BPD). METHOD DSM-III-R structured diagnostic interviews and blind raters were used to examine psychiatric diagnoses at baseline and 4-year follow-up in ADHD and control children. In addition, subjects were evaluated for cognitive, academic, social, school, and family functioning. RESULTS BPD was diagnosed in 11% of ADHD children at baseline and in an additional 12% at 4-year follow-up. These rates were significantly higher than those of controls at each assessment. ADHD children with comorbid BPD at either baseline or follow-up assessment had significantly higher rates of additional psychopathology, psychiatric hospitalization, and severely impaired psychosocial functioning than other ADHD children. The clinical picture of bipolarity was mostly irritable and mixed. ADHD children with comorbid BPD also had a very severe symptomatic picture of ADHD as well as prototypical correlates of the disorder. Comorbidity between ADHD and BPD was not due to symptom overlap. ADHD children who developed BPD at the 4-year follow-up had higher initial rates of comorbidity, more symptoms of ADHD, worse scores on the CBCL, and a greater family history of mood disorder compared with non-BPD, ADHD children. CONCLUSIONS The results extend previous results documenting that children with ADHD are at increased risk of developing BPD with its associated severe morbidity, dysfunction, and incapacitation.

CBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD.

OBJECTIVE To evaluate the discriminative ability of the Child Behavior Checklist (CBCL) to identify children with structured interview-derived diagnosis of bipolar disorder. METHOD We evaluated the convergence of CBCL scales with the diagnosis of mania in 31 children with mania, 120 children with attention-deficit hyperactivity disorder, and 77 prepubertal normal control children aged 12 years or younger. We evaluated the strength of association between each CBCL scale and structured interview-derived diagnoses with total predictive value and the odds ratio. RESULTS Excellent convergence was found between the CBCL scales of Delinquent Behavior, Aggressive Behavior, Somatic Complaints, Anxious/Depressed, and Thought Problems and the diagnosis of mania. CONCLUSIONS These findings indicate that the CBCL could serve as a rapid and useful screening instrument to identify manic children in clinical settings.

Is comorbidity with ADHD a marker for juvenile-onset mania?

OBJECTIVE To compare the characteristics and correlates of mania in referred adolescents and to determine whether attention-deficit hyperactivity disorder (ADHD) is a marker of very early onset mania. METHOD From 637 consecutive admissions, 68 children (< or = 12 years) and 42 adolescents (> 13 years) who satisfied criteria for mania were recruited. These were compared with the 527 nonmanic referrals and 100 normal controls. RESULTS With the exception of comorbidity with ADHD, there were more similarities than differences between the children and adolescents with mania in course and correlates. There was an inverse relationship between the rates of comorbid ADHD and age of onset of mania: higher in manic children intermediate in adolescents with childhood-onset mania, and lower in adolescents with adolescent-onset mania. CONCLUSIONS ADHD is more common in childhood-onset compared with adolescent-onset cases of bipolar disorder, suggesting that in some cases, ADHD may signal a very early onset of bipolar disorder. Clinical similarities between the child- and adolescent-onset cases provide evidence for the clinical validity of childhood-onset mania.

Risperidone treatment for juvenile bipolar disorder: a retrospective chart review

OBJECTIVE To investigate the effectiveness and tolerability of the atypical neuroleptic risperidone in the treatment of juvenile mania. METHOD This is a retrospective chart review of outpatients with the diagnosis of bipolar disorder (DSM-IV) treated with risperidone at a university center. Response to treatment was evaluated using the Clinical Global Impression Scale (CGI) with separate assessments of mania, psychosis, aggression, and attention-deficit/hyperactivity disorder (ADHD). RESULTS Twenty-eight youths (mean +/- SD age, 10.4 +/- 3.8 years) with bipolar disorder (25 mixed and 3 hypomanic) who had been treated with risperidone were identified. These children received a mean dose of 1.7 +/- 1.3 mg over an average period of 6.1 +/- 8.5 months. Using a CGI Improvement score of < or = 2 (very much/much improved) to define robust improvement, 82% showed improvement in both their manic and aggressive symptoms, 69% in psychotic symptoms, but only 8% in ADHD symptoms. CONCLUSIONS Although limited by its retrospective nature, this study suggests that risperidone may be effective in the treatment of manic young people and indicates the need for controlled clinical trials of risperidone and other atypical neuroleptics in juvenile mania.

Heterogeneity of Irritability in Attention-Deficit/Hyperactivity Disorder Subjects With and Without Mood Disorders

BACKGROUND We hypothesized that irritability is a heterogeneous symptom distinguished by severity and that attending to this heterogeneity would impact the relationship between irritability and bipolar disorder. METHODS A total of 274 ADHD children were administered the Kiddie Schedule for Affective Disorders and Schizophrenia (Epidemiologic Version) structured diagnostic interview. Three measures of irritability were identified: oppositional defiant disorder (ODD)-type irritability, mad/cranky irritability, and super-angry/grouchy/cranky irritability. Subjects were stratified as having bipolar disorder (n = 30), unipolar depression (n = 100), and no history of depression or bipolar disorder (non-mood-disordered, n = 144). RESULTS Oppositional defiant disorder-type irritability was very common in all ADHD subjects, was the least impairing, and did not increase the risk of mood disorder. Mad/cranky irritability was common in only ADHD children with a mood disorder, was more impairing than the ODD-type irritability, and was predictive of unipolar depression. Super-angry/grouchy/cranky irritability was common only in ADHD children with bipolar disorder, was the most impairing, and was predictive of both unipolar depression and bipolar disorder. Two percent of the subjects with ODD-type irritability only, 6% of subjects with mad/cranky irritability, and 46% of subjects with super-angry/grouchy/cranky irritability were diagnosed with bipolar disorder. CONCLUSIONS These results challenge the conclusion that irritability is necessarily a poor diagnostic indicator of bipolar disorder in children.

Further Evidence of a Bidirectional Overlap Between Juvenile Mania and Conduct Disorder in Children

OBJECTIVE To investigate systematically the overlap between mania and conduct disorder (CD) in a sample of consecutively referred youths. It was hypothesized that neither CD nor manic symptoms were secondary to the other disorder and that children with the 2 disorders would have correlates of both. METHOD Subjects were consecutively referred children and adolescents meeting DSM-III-R diagnostic criteria on structured diagnostic interview for CD (n = 116), mania (n = 110), and CD + mania (n = 76). RESULTS Of 186 children and adolescents with mania and of 192 with CD, 76 satisfied criteria for both CD and mania, representing 40% of youths with CD and 41% of youths with mania, respectively. Examination of the clinical features, patterns of psychiatric comorbidity, and functioning in multiple domains showed that children with CD and mania had similar features of each disorder irrespective of the comorbidity with the other disorder. CONCLUSIONS The data suggest that when mania and CD co-occur in children, both are correctly diagnosed. In these comorbid cases, CD symptoms should not be viewed as secondary to mania and manic symptoms should not be viewed as secondary to CD.

Clonidine for Sleep Disturbances Associated with Attention-Deficit Hyperactivity Disorder: A Systematic Chart Review of 62 Cases

OBJECTIVE Children and adolescents with attention-deficit hyperactivity disorder (ADHD), with or without psychostimulant treatment, frequently suffer from sleep disturbances. This report evaluates the use of clonidine in the treatment of sleep disturbances associated with ADHD. METHOD A systematic search of a computerized database in an outpatient pediatric psychopharmacology unit of patients treated with clonidine for ADHD-associated sleep disturbances (N = 62; 42 children and 20 adolescents) was performed. Patients were rated retrospectively about the type and severity of sleep disturbances at baseline and after treatment with clonidine. RESULTS A majority of patients (85%) treated with clonidine for ADHD-associated sleep disturbances were considered to be much to very much improved by the National Institute of Mental Health global assessment of improvement (sleep). Nighttime clonidine doses ranged from 50 to 800 micrograms (mean +/- SEM; 157 +/- 14 micrograms), and subjects received clonidine for 35.5 +/- 3.5 months. There was no association between response and age group, gender, comorbidity, or concurrent pharmacotherapy. Children and adolescents with ADHD with baseline, medicine-induced, or medicine-exacerbated sleep disturbances responded equally well to clonidine treatment. Mild adverse effects were reported in 19 subjects (31%). CONCLUSIONS These findings suggest that clonidine may be an effective agent for sleep disturbances associated with ADHD, or its treatment, and warrant further controlled investigations.

Risk for Substance Use Disorders in Youths With Child- and Adolescent‐Onset Bipolar Disorder

OBJECTIVE Previous work in adults has suggested that early-onset bipolar disorder (BPD) is associated with an elevated risk for substance use disorders (SUD). To this end, the authors assessed the risk for SUD in child- versus adolescent-onset BPD with attention to comorbid psychopathology. METHOD All youths (aged 13-18 years) with available structured psychiatric interviews were studied systematically. From clinic subjects (N = 333), 86 subjects with DSM-III-R BPD were identified. To evaluate the risk for SUD and BPD while attending to developmental issues, the authors stratified the BPD sample into those with child-onset BPD (< or = 12 years of age, n = 50) and those with adolescent-onset BPD (13-18 years of age, n = 36). RESULTS In mid-adolescence, youths with adolescent-onset BPD were at significantly increased risk for SUD relative to those with child-onset BPD (39% versus 8%; p = .001). Compared with those with child-onset BPD, those with adolescent-onset BPD had 8.8 times the risk for SUD (95% confidence interval = 2.2-34.7; chi 7(2) = 9.7, p = .002). The presence of conduct disorder or other comorbid psychopathology within BPD did not account for the risk for SUD. CONCLUSIONS Adolescent-onset BPD is associated with a much higher risk for SUD than child-onset BPD, which was not accounted for by conduct disorder or other comorbid psychopathology. Youths with adolescent-onset BPD should be monitored and educated about SUD risk. The identification and treatment of manic symptomatology may offer therapeutic opportunities to decrease the risk for SUD in these high-risk youths.

Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

OBJECTIVE Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. METHOD Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. RESULTS Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. CONCLUSIONS We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.