Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.     

Declarative memory impairment in pediatric bipolar disorder

OBJECTIVES: Impaired verbal declarative memory has been proposed as a trait marker for adult bipolar disorder. However, similar impairments in juvenile-onset bipolar disorder have not been yet documented. Here, we assessed declarative memory in a large sample of clinically well-characterized children with bipolar disorder. METHODS: Forty-one children and adolescents with bipolar disorder [21 bipolar I disorder (BP-I), 10 bipolar II disorder (BP-II), and 10 bipolar disorder, not otherwise specified (BP-NOS)] and 17 demographically matched healthy participants completed a standardized learning and memory test. RESULTS: BP-I children recalled and recognized significantly fewer words than healthy subjects, whereas children with BP-II and BP-NOS did not differ from controls. However, individuals with BP-NOS made more perseverative errors and intrusions than the other groups. Severity of mood symptomatology was not associated with memory performance in any bipolar subtype. CONCLUSIONS: Findings suggest that declarative memory impairments in juvenile BP-I are similar to those seen in the adult form of the illness. These impairments do not appear to be secondary to clinical state; rather, they may reflect trait-related impairments. Distinct performance patterns in BP-I, BP-II, and BP-NOS suggest that the broadly defined phenotype is significantly heterogeneous, and may not be informative for pathogenetic investigations of bipolar disorder.     

Structural brain and neuropsychometric changes associated with pediatric bipolar disorder with psychosis

James A, Hough M, James S, Burge L, Winmill L, Nijhawan S, Matthews PM, Zarei M. Structural brain and neuropsychometric changes associated with pediatric bipolar disorder with psychosis.
Bipolar Disord 2011: 13: 16–27. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: To identify neuropsychological and structural brain changes using a combination of high‐resolution structural and diffusion tensor imaging in pediatric bipolar disorder (PBD) with psychosis (presence of delusions and or hallucinations). Methods: We recruited 15 patients and 20 euthymic age‐ and gender‐matched healthy controls. All subjects underwent high‐resolution structural and diffusion tensor imaging. Voxel‐based morphometry (VBM), tract‐based spatial statistics (TBSS), and probabilistic tractography were used to analyse magnetic resonance imaging data. Results: The PBD subjects had normal overall intelligence with specific impairments in working memory, executive function, language function, and verbal memory. Reduced gray matter (GM) density was found in the left orbitofrontal cortex, left pars triangularis, right premotor cortex, occipital cortex, right occipital fusiform gyrus, and right crus of the cerebellum. TBSS analysis showed reduced fractional anisotropy (FA) in the anterior corpus callosum. Probabilistic tractography from this cluster showed that this region of the corpus callosum is connected with the prefrontal cortices, including those regions whose density is decreased in PBD. In addition, FA change was correlated with verbal memory and working memory, while more widespread reductions in GM density correlated with working memory, executive function, language function, and verbal memory. Conclusions: The findings suggest widespread cortical changes as well as specific involvement of interhemispheric prefrontal tracts in PBD, which may reflect delayed myelination in these tracts.     

Examination of concordance between maternal and youth reports in the diagnosis of pediatric bipolar disorder

Objective:  While concordance between mother and child report continues to be the gold standard in the assessment of pediatric bipolar disorder, uncertainty develops when a mother's report is not endorsed by the youth. To this end we compared discordant (mother positive and youth negative) and concordant (mother and youth positive) cases.
Methods:  Subjects were 98 adolescents (12–19 years of age) derived from family studies of bipolar disorder in youth who had both self-reported and mother-reported assessments. Comparisons were made between discordant (n = 35) and concordant (n = 59) cases on a wide range of clinical correlates.
Results:  Mothers in both groups reported similar rates of symptoms of mania and depression. Within the concordant group, mothers and youth reported similar rates of symptoms of mania. There were no differences between the concordant and discordant groups in onset, duration, or impairment of mania, rates of psychiatric hospitalization, cognitive variables, or rates of disorders in family members.
Conclusions:  The similarities between discordant and concordant reports in symptomatology of mania and depression, rates of comorbidities, treatment needs, and other clinical correlates suggest that a mother-based diagnosis of mania should not be discounted in discrepant cases in which the youth fails to endorse the diagnosis.     

Neuropsychological functioning in youth with bipolar disorder.

BACKGROUND: Little is known about the neuropsychological status of youth with bipolar disorder (BPD) or whether cognitive deficits in this population are accounted for by comorbidity with attention deficit/hyperactivity disorder (ADHD). We compared neuropsychological and academic functioning of youth with and without DSM-IV BPD, controlling for effects of comorbid ADHD. METHODS: Fifty-seven youth with BPD and 46 healthy control subjects were assessed on a battery of clinical neuropsychological measures including subtests from the Wechsler Intelligence Scales for Children and Adults (Third Editions), the Stroop, the Wisconsin Card Sorting Test, the Rey-Osterreith Complex Figure, an auditory working memory Continuous Performance Test, a measure of verbal learning, and the Wide Range Achievement Test-Third Edition. RESULTS: Bipolar disorder was associated with impairments on subtests reflecting sustained attention, working memory, and processing speed after controlling for ADHD. Additionally, decrements of moderate effect sizes were found for measures of interference control, abstract problem solving, and verbal learning but did not meet criteria for statistical significance. CONCLUSIONS: After controlling for ADHD, youth with BPD show neuropsychological deficits similar to impairments found in adults with the disorder. Further studies are needed to understand the clinical implications of these impairments as well as their role in the underlying risk for pediatric BPD.     

History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk

BACKGROUND: Despite evidence indicating high morbidity associated with pediatric bipolar disorder (BP), little is known about the prevalence and clinical correlates of suicidal behavior among this population. OBJECTIVE: To investigate the prevalence of suicidal behavior among children and adolescents with BP, and to compare subjects with a history of suicide attempt to those without on demographic, clinical, and familial risk factors. METHODS: Subjects were 405 children and adolescents aged 7-17 years, who fulfilled DSM-IV criteria for BPI (n = 236) or BPII (n = 29), or operationalized criteria for BP not otherwise specified (BP NOS; n = 140) via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. As part of a multi-site longitudinal study of pediatric BP (Course and Outcome of Bipolar Youth), demographic, clinical, and family history variables were measured at intake via clinical interview with the subject and a parent/guardian. RESULTS: Nearly one-third of BP patients had a lifetime history of suicide attempt. Attempters, compared with non-attempters, were older, and more likely to have a lifetime history of mixed episodes, psychotic features, and BPI. Attempters were more likely to have a lifetime history of comorbid substance use disorder, panic disorder, non-suicidal self-injurious behavior, family history of suicide attempt, history of hospitalization, and history of physical and/or sexual abuse. Multivariate analysis found that the following were the most robust set of predictors for suicide attempt: mixed episodes, psychosis, hospitalization, self-injurious behavior, panic disorder, and substance use disorder. CONCLUSIONS: These findings indicate that children and adolescents with BP exhibit high rates of suicidal behavior, with more severe features of BP illness and comorbidity increasing the risk for suicide attempt. Multiple clinical factors emerged distinguishing suicide attempters from non-attempters. These clinical factors should be considered in both assessment and treatment of pediatric BP.     

Randomized,placebo‐controlled trial of flax oil in pediatric bipolar disorder

Gracious BL, Chirieac MC, Costescu S, Finucane TL, Youngstrom EA, Hibbeln JR. Randomized, placebo‐controlled trial of flax oil in pediatric bipolar disorder.
Bipolar Disord 2010: 12: 142–154. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: This clinical trial evaluated whether supplementation with flax oil, containing the omega‐3 fatty acid α‐linolenic acid (α‐LNA), safely reduced symptom severity in youth with bipolar disorder. Methods: Children and adolescents aged 6–17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg α‐LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale‐Revised, and Clinical Global Impressions‐Bipolar ratings using Kaplan‐Meier survival analyses. Results: There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician‐rated Global Symptom Severity was negatively correlated with final serum omega‐3 fatty acid compositions: %α‐LNA (r = ?0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = ?0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n‐6 (r = 0.48, p < 0.004). The mean duration of treatment for α‐LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for α‐LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms. Conclusions: Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n‐6 levels, individual variations in conversion of α‐LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone.     

Self‐esteem in remitted bipolar disorder patients: a meta‐analysis

Nilsson KK, Jørgensen CR, Craig TKJ, Straarup KN, Licht RW. Self‐esteem in remitted bipolar disorder patients: a meta‐analysis.
Bipolar Disord 2010: 12: 585–592. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Low self‐esteem has been found to be a risk factor for depression in major depressive disorder (MDD). In contrast, the role of self‐esteem in bipolar disorder (BD) is still uncertain. In order to examine the characteristics of self‐esteem in BD, we synthesized studies comparing self‐esteem in BD patients with self‐esteem in MDD patients and in normal controls. Methods: Database searches and identification of studies were conducted by two of the authors independently. Remission of BD and MDD was a major selection criterion. The results were generated through meta‐analyses. Results: Random‐effects models of 19 between‐group comparisons (N = 1,838) suggested that the self‐esteem of remitted BD patients was significantly lower than that of normal controls (Cohen’s d = ?0.83), while significantly higher than that of remitted MDD patients (Cohen’s d = 0.54). Fail‐safe numbers and tests for funnel plot asymmetry indicated that the results were robust and unlikely to reflect publication biases. Additional studies indicated that self‐esteem may take a fluctuating course during remission of BD. Conclusions: By revealing that BD patients do experience low self‐esteem, the findings implicate a need for further understanding the causes and therapeutic impact of such abnormality in BD.     

Double‐blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder

Pavuluri MN, Henry DB, Findling RL, Parnes S, Carbray JA, Mohammed T, Janicak PG, Sweeney JA. Double‐blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder. Bipolar Disord 2010: 12: 593–605. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: To determine the relative effects of risperidone and divalproex in pediatric mania. Methods: This is a double‐blind, randomized, outpatient clinical trial with 66 children and adolescents (mean age = 10.9 ± 3.3 years; age range = 8–18 years) with mania who were randomly assigned to either risperidone (0.5–2 mg/day, n = 33) or divalproex (60–120 μg/mL, n = 33) for a six‐week period. Measures included the Young Mania Rating Scale (YMRS) and Child Depression Rating Scale‐Revised (CDRS‐R). Results: Mixed‐effects regression models, with interaction between time and the active drug as predictors, found that the risperidone group had more rapid improvement than the divalproex group (p < 0.05), although final scores did not differ significantly between groups. Mixed models using only those subjects who completed the six‐week study found similar results. The response rate on YMRS was 78.1% for risperidone and 45.5% for divalproex (p < 0.01). The remission rate for risperidone was 62.5%, compared with 33.3% for divalproex (p < 0.05). Improvement on the CDRS‐R was significantly higher for the risperidone group relative to the divalproex group (p < 0.05). There were no significant differences between groups in safety, but subject retention was significantly higher at study endpoint in the risperidone group (p < 0.01). Dropout rate was 24% in the risperidone group and 48% in the divalproex group, with increased irritability being the most common reason for dropout in the latter. There was no significant weight gain in either group. Conclusion: Results suggest that risperidone was associated with more rapid improvement and greater reduction in manic symptoms compared to divalproex. Although the results suggest that both drugs are safe, risperidone’s lower attrition rate and lower rate of adverse events may suggest better toleration. Clinical trials with larger samples are required to confirm these preliminary findings.     

Confusion and dysphoria with low-dose topiramate in a patient with bipolar disorder

Background: Topiramate, a newer antiepileptic agent, may benefit several neurological and psychiatric states, including bipolar disorder.

Case report: A physically healthy, stockily built, 47-year-old, hypomanic Asian male with a >20-year history of uneventful use of psychotropic agents received topiramate in a dose that was stepped up to 100 mg/day across 10 days. He developed dysphoria, confusion, word-finding difficulties, and difficulties in maintaining a train of thought; the symptoms vanished within a week of drug discontinuation, and reappeared 1–2 days after rechallenge at a dose of 25 mg/day.

Conclusion: It appears that, while confusion is usually a dose-dependent adverse effect of topiramate, certain patients may idiosyncratically develop this adverse effect at very low doses.     

Cognitive decline in elderly bipolar disorder patients: a follow‐up study

Schouws SNTM, Stek ML, Comijs HC, Dols A, Beekman ATF. Cognitive decline in elderly bipolar disorder patients: a follow‐up study. Bipolar Disord 2012: 14: 749–755. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Older individuals with bipolar disorder may exhibit greater cognitive decline over time compared to mentally healthy elderly individuals. We aimed to investigate neurocognitive performance in bipolar disorder over a period of two years. Methods: A comprehensive neuropsychological test battery was applied at baseline and two years later to 65 euthymic elderly outpatients with bipolar disorder (mean age = 68.35, range: 60–90 years) and to a demographically comparable sample of 42 healthy elderly controls. A general linear model was used to measure changes over time for the two groups. The impact of baseline illness characteristics on intra‐individual change in neurocognitive performance within the bipolar group was studied by using logistic regression analysis. Results: At baseline and at follow up, bipolar disorder patients performed worse on all neurocognitive measures compared to the healthy elderly group. However, there was no significant group‐by‐time interaction between the bipolar disorder patients and the comparison group. Conclusions: Although older bipolar disorder patients have worse cognitive function than normal controls, they did not have greater cognitive decline over a period of two years.