The aim of this study was to develop and validate manic and depressive scales carved from the full length General Behavior Inventory. The brief version was designed to be applicable for youths and adults, and to improve separation between mania and depression dimensions. Data came from nine studies (two youth clinical samples, aggregate N = 738 and seven non-clinical adult samples, aggregate N = 1756). Items with high factor loadings on the two extracted dimensions of mania and depression were identified from both data sets, and final item selection was based on internal reliability criteria. Confirmatory factor analyses described the two-factor model's fit. Criterion validity was compared between mania and depression scales, and with the full length GBI scales. For both mania and depression factors, seven items produced a psychometrically adequate measure applicable across both aggregate samples. Internal reliability of the Mania scale was .81 (youth) and .83 (adult) and for Depression was .93 (youth) and .95 (adult). By design, the brief scales were less strongly correlated with each other than were the original GBI scales. Construct validity of the new instrument was supported in observed discriminant and convergent relationships with external correlates and discrimination of diagnostic groups. The new brief GBI, the 7 Up 7 Down Inventory (7U7D) demonstrates sound psychometric properties across a wide age range, showing expected relationships with external correlates. The new instrument provides a clearer separation of manic and depressive tendencies than the original.
bipolar disorder; measurement; self-report; two-dimensional; spectrum
The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder.
Subjects 10–17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40–160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings.
In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were −13.83 (ziprasidone) and −8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was −3.3 (95% confidence interval, −5.0 to −1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥460 ms.
These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile.
Clinical Trials Registry
NCT00257166 and NCT00265330 at ClinicalTrials.gov.
The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia.
Subjects ages 13–17 years with schizophrenia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40–160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale–Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings.
Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS–A score decrease from baseline at week 6 was not significantly different (p=0.15; −14.16 [0.78] for ziprasidone and −12.35 [1.05] for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was −6.9 (8.9). The most common treatment-emergent adverse events (≥10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericia's corrected QT (QTcF) ≥500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures.
Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile.
Clinical Trials Registry
NCT00257192 and NCT00265382 at ClinicalTrials.gov.
To compare clinical variables in patients with rapid-cycling bipolar I or II disorder and a recent history of substance use disorder (SUD).
Cross-sectional data from 2 studies of patients with rapid-cycling bipolar I disorder or rapid-cycling bipolar II disorder and a recent history of SUD were used to retrospectively assess the differences in clinical variables between the subtypes. The studies were conducted from November 1997 to February 2007 at University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Extensive clinical interview and the Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid-cycling bipolar disorder, SUDs, and other Axis I disorders and to collect clinical variables. The Addiction Severity Index (ASI), Global Assessment Scale (GAS), and the Medical Outcomes Study 36-ltem Short-Form Health Survey were used to measure the severity of impairment at the initial assessment. One-way analysis of variance or χ2 was used for significance tests. A Bonferroni adjustment was applied for multiple comparisons.
Of 245 patients with rapid-cycling bipolar disorder (rapid-cycling bipolar I disorder, N = 191; rapid-cycling bipolar II disorder, N = 54) and a recent history of SUD, the demographics were similar. A significantly higher rate of panic disorder was observed in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder (odds ratio = 3.72, 95% CI = 1.66 to 8.32, p = .008). A significantly higher psychiatric composite score on the ASI was also found in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder even after Bonferroni adjustment (p = .0007). There were no significant differences between the subtypes in the rates of previous hospitalization or suicide attempt, early childhood verbal, physical, or sexual abuse, lifetime substance abuse or dependence, the number of SUDs or mood episodes in the last 12 months, and total or other subscale scores on ASI and GAS.
Except for the significantly higher rate of comorbid panic disorder and higher psychiatric composite scores on the ASI in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder, the other clinical variables were similar between the 2 groups.
Although combination pharmacotherapy is common in child/adolescent psychiatry, there has been little research evaluating it. We tested the value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression
We randomized 168 children age 6–12 years (mean 8.89 ±2.01) with severe physical aggression to a 9-week trial of PT, stimulant, and placebo (Basic treatment; n=84) or PT, stimulant, and risperidone (Augmented treatment; n=84). All had diagnoses of attention-deficit/ hyperactivity disorder (ADHD) and either oppositional defiant (n= 124) or conduct disorder (n= 44). Children received psychostimulant (usually OROS methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of Week 3, either placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (NCBRF; Disruptive-Total subscale = Primary outcome) and Antisocial Behavior Scale (ABS); blinded clinicians rated change on the Clinical Global Impressions (CGI) scale.
Compared to Basic treatment (PT + stimulant[STIM][44.8±14.6 mg/day] + placebo [1.88±0.72]), Augmented treatment (PT + STIM[46.1±16.8 mg/day] + risperidone[1.65±0.75]) showed statistically significant improvement on the NCBRF Disruptive–Total subscale (treatment-by-time interaction p= 0.0016), the NCBRF Social Competence subscale (p= 0.0049), and ABS Reactive Aggression (p= 0.01). CGI scores were substantially improved for both groups but did not discriminate between treatments (CGI-I ≤ 2, 70% for Basic treatment vs. 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented; other adverse events differed modestly from Basic treatment; weight gain within the Augmented treatment group was minor.
Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behavior when added to PT and optimized stimulant treatment. Clinical trial registration information—Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302.
disruptive behavior disorders; parent training; physical aggression; psychostimulants; risperidone
The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder.
Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13–17 years) or a manic episode of bipolar I disorder (ages 10–17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400–800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs.
Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥0.5 standard deviations from baseline).
In this 26-week study, quetiapine flexibly dosed at 400–800 mg/day, with options to reduce dosing based on tolerability, was generally safe and well tolerated in youth. Clinicians should monitor lipid profiles and weight gain in youth with schizophrenia or bipolar disorder during treatment with quetiapine.
Clinical trial registration information
Quetiapine Fumarate (Seroquel) in the Treatment of Adolescent Patients With Schizophrenia and Bipolar I Disorder (ANCHOR 150). Available at: http://clinicaltrials.gov/ct2/show/NCT00227305
The purpose of this study was to evaluate the extended efficacy, safety, and tolerability of escitalopram relative to placebo in adolescents with major depressive disorder (MDD).
Adolescents (12–17 years) who completed an 8-week randomized, double-blind, flexible-dose, placebo-controlled, lead-in study of escitalopram 10–20 mg versus placebo could enroll in a 16–24-week, multisite extension trial; patients maintained the same lead-in randomization (escitalopram or placebo) and dosage (escitalopram 10 or 20 mg/day, or placebo) during the extension. The primary efficacy was Children's Depression Rating Scale-Revised (CDRS-R) change from the lead-in study baseline to treatment week 24 (8-week lead-in study plus 16-week extension); the secondary efficacy was Clinical Global Impressions-Improvement (CGI-I) score at week 24. All efficacy analyses used the last observation carried forward (LOCF) approach; sensitivity analyses used observed cases (OC) and mixed-effects model for repeated measures (MMRM). Safety was evaluated via adverse event (AE) reports and the clinician-rated Columbia-Suicide Severity Rating Scale (C-SSRS).
Following lead-in, 165 patients enrolled in the double-blind extension (82 placebo; 83 escitalopram); 40 (48.8%) placebo and 37 (44.6%) escitalopram patients completed treatment. CDRS-R total score improvement was significantly greater for escitalopram than for placebo (p=0.005, LOCF; p=0.014; MMRM). Response rates (CDRS-R ≥40% reduction from baseline [adjusted and unadjusted] and CGI-I ≤2) were significantly higher for escitalopram than for placebo (LOCF); remission rates (CDRS-R ≤28) were 50.6% for escitalopram and 35.7% for placebo (p=0.002). OC analyses were not significantly different between groups. The most frequent escitalopram AEs (≥5% and more frequent than placebo) were headache, nausea, insomnia, vomiting, influenza-like symptoms, diarrhea, and urinary tract infection. Most AEs were mild/moderate and not related to the study drug. AEs suggestive of self-harm occurred in 5.7% and 7.1% of placebo and escitalopram patients. Occurrence of suicidal behavior and/or suicidal ideation assessed by C-SSRS was 10.9% (14/128) for placebo and 14.5% (19/131) for escitalopram.
Extended use of escitalopram was generally safe and resulted in modest improvement in efficacy in adolescents with MDD.
The Longitudinal Assessment of Manic Symptoms (LAMS) study was designed to investigate phenomenology and establish predictors of functional outcomes in children with elevated manic symptoms. The purpose of this series of analyses was to determine whether the participants demonstrated different trajectories of parent-reported manic and biphasic symptoms over the first 24 months of follow-up and to describe the clinical characteristics of the trajectories.
The 707 participants were initially aged 6–12 years and ascertained from outpatient clinics associated with the four university-affiliated LAMS sites. There were 621 children whose parents/guardians’ ratings scored ≥ 12 on the Parent General Behavior Inventory–10-item Mania Form (PGBI-10M) and a matched random sample of 86 children whose parents/guardians’ ratings scored ≤ 11 on the PGBI-10M. Participants were seen every six months after the baseline and their parents completed the PGBI-10M at each visit.
For the whole sample, manic symptoms decreased over 24 months (linear effect B = -1.15, standard error = 0.32, t = -3.66, p < 0.001). Growth Mixture Modeling revealed four unique trajectories of manic symptoms. Approximately 85% of the cohort belonged to two classes in which manic symptoms decreased. The remaining ≈ 15% formed two classes (high and rising and unstable) characterized by the highest rates of diagnostic conversion to a bipolar disorder (all p-values < 0.001).
Outcomes are not uniform among children with symptoms of mania or high risk for mania. A substantial minority of clinically referred children shows unstable or steadily increasing manic symptoms, and these patterns have distinct clinical correlates.
children; longitudinal course; manic symptoms
To assess the safety and effectiveness of open-label treatment with extended-release carbamazepine (ERC) in pediatric subjects suffering from bipolar I disorder.
Medically healthy youths aged 10–17 years suffering from an acute manic or mixed episode were eligible. After screening for study eligibility, the youths began a 5-week titration period in which doses of ERC were adjusted in order to optimize benefit whilst minimizing adverse events, at doses between 200–1,200 mg/day. Thereafter, subjects could continue to receive treatment during a subsequent 21-week period. Safety measures included spontaneously reported adverse events (AEs) and laboratory assessments. The primary efficacy measure was the Young Mania Rating Scale (YMRS).
A total of 60 children (ages 10–12) and 97 adolescents (ages 13–17), with an overall average age of 13.4 years (standard deviation [SD] 2.0 years) received ERC. The mean duration of study participation was 109.6 days (SD 70.2 days), with 66 (42%) completing the entire study. At end of study participation (end point), the most prevalent dose of ERC was 1,200 mg: 31.7% of children and 24.7% of adolescents reached the 1,200 mg dose. The YMRS decreased from a mean of 28.6 (SD 6.2) at baseline to a mean of 13.8 (SD 9.4) (P<0.0001) at end point. A total of 26 subjects discontinued study participation because of AEs, the most common of which were rash (n=6), white blood cell count decreased (n=5), nausea (n=3), and vomiting (n=3). No deaths were reported. The most commonly reported AEs were headache (n=41), somnolence (n=30), nausea (n=22), dizziness (n=21), and fatigue (n=19).
Open-label administration of ERC might be a safe and effective intervention in this subject population. More definitive studies are warranted.
bipolar disorder; children; adolescents; treatment; carbamazpine
Pediatric bipolar disorder involves poor social functioning, but the neural mechanisms underlying these deficits are not well understood. Previous neuroimaging studies have found deficits in emotional face processing localized to emotional brain regions. However, few studies have examined dysfunction in other regions of the face processing circuit. This study assessed hypoactivation in key face processing regions of the brain in pediatric bipolar disorder.
Youth with a bipolar spectrum diagnosis (n=20) were matched to a nonbipolar clinical group (n=20), with similar demographics and comorbid diagnoses, and a healthy control group (n=20). Youth participated in a functional magnetic resonance imaging (fMRI) scanning which employed a task-irrelevant emotion processing design in which processing of facial emotions was not germane to task performance.
Hypoactivation, isolated to the fusiform gyrus, was found when viewing animated, emerging facial expressions of happiness, sadness, fearfulness, and especially anger in pediatric bipolar participants relative to matched clinical and healthy control groups.
The results of the study imply that differences exist in visual regions of the brain’s face processing system and are not solely isolated to emotional brain regions, such as the amygdala. Findings are discussed in relation to facial emotion recognition and fusiform gyrus deficits previously reported in the autism literature. Behavioral interventions targeting attention to facial stimuli might be explored as possible treatments for bipolar disorder in youth.
emotion; face processing; functional magnetic resonance imaging (fMRI); fusiform; gyrus; pediatric bipolar disorder
Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs. disorder-specific pathophysiology.
Identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that: 1) are associated with behavioral and emotional dysregulation pathological dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10 Item Mania Scale [PGBI-10M], mania, depression, anxiety); or 2) differentiate diagnostic categories(BPSD, ADHD, anxiety, disruptive behavior disorders (DBD)).
Multi-site neuroimaging study(February 2011–April 2012).
Academic medical centers: Case Western Reserve University, Cincinnati Children’s Hospital, University of Pittsburgh.
Referred sample of behaviorally and emotionally dysregulated youth(n=85) from the Longitudinal Assessment of Manic Symptoms study and healthy youth (n=20).
Main Outcome Measures
Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (Win, Loss, control conditions), symptom dimensions, and diagnostic categories.
Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical (mPFC; r=0.28), and greater levels of anxiety with greater right dorsal anterior cingulate cortical (dACC; r=0.27), activity to Win. The 20 highest (t=2.75) and 20 lowest (t=2.42) PGBI-10M scoring youth showed significantly greater left mPFC activity to Win than 20 healthy youth. DBD were associated with lower left ventrolateral prefrontal cortex(VLPFC) activity to Win (t=2.68) (all ps<0.05, corrected).
Greater PGBI-10M-related left mPFC activity, and greater anxiety-related right dACC activity, to Win may reflect heightened reward sensitivity and greater attention to reward in behaviorally and emotionally dysregulated youth, regardless of diagnosis. Reduced left VLPFC activity to Win may reflect reward insensitivity in youth with DBD. Despite a distinct reward-related neurophysiology in DBD, findings generally support a dimensional approach to studying neural mechanisms in behaviorally and emotionally dysregulated youth.
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
The purpose of this study was to investigate associations between body weight and illness characteristics, including weight gain and therapeutic efficacy, in adolescents with schizophrenia.
Adolescents ages 13–17 years (n=107) with American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) schizophrenia enrolled in a 6 week, double-blind, placebo-controlled trial comparing olanzapine and placebo. Therapeutic response was assessed by the Brief Psychiatric Rating Scale for Children (BPRS-C). Secondary outcomes included the Clinical Global Impressions-Severity (CGI-S) scale and Positive and Negative Syndrome Scale (PANSS). Obesity was defined as sex-/age-adjusted body mass index (BMI)≥95th percentile. Linear regression was used to analyze the relationship between weight gain and psychiatric symptom improvement; logistic regression was conducted to identify predictors of baseline obesity.
Weight gain was significantly correlated with greater BPRS-C reduction among olanzapine-treated subjects (r=−0.31, p<0.01), whereas a trend was observed among placebo-treated subjects (r=−0.31, p=0.08). However, this relationship became nonsignificant when analyses were controlled for duration of olanzapine treatment (p=0.12), and a treatment by weight gain interaction did not emerge in a repeated-measures mixed model analysis that included time in the study (t=1.27, p=0.21). Additionally, weight gain ≥7% was not significantly associated with response or remission. Among 17 adolescents (16%) with obesity at study entry, obesity was not significantly associated with endpoint BPRS-C illness severity. However, girls (p=0.03), individuals hospitalized within the past year (p=0.02), and those with less severe overall (p=0.03) and negative symptoms (p=0.003) according to the CGI-S and PANSS negative subscale, respectively, were more likely to be obese at baseline.
Baseline obesity was associated with lower illness severity, which could be mediated by greater treatment adherence, leading to more weight gain. Olanzapine-related weight gain was not independently associated with symptomatic outcome when controlling for treatment duration. Additional studies are needed to extend these findings to other disorders and medications.
This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions.
Outpatients, ages 7–17 years, meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnostic criteria for bipolar disorder I (BP-I) (manic or mixed) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium (Phase I) were eligible to receive open-label lithium for an additional 16 weeks (Phase II). Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions, following a standardized algorithm.
Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 (3.0) weeks during Phase II. The mean weight-adjusted total daily dose at end of Phase II was 27.8 (6.7) mg/kg/day, with an average lithium concentration of 1.0 (0.3) mEq/L. Twenty-five of the 41 patients (60.9%) were prescribed adjunctive psychotropic medications for residual symptoms. The most frequent indications for adjunctive medications were refractory mania (n=13; 31.7%) and attention-deficit/hyperactivity disorder (ADHD) (n=15; 36.6%). At the end of this phase 28 (68.3%) patients met a priori criteria for response (≥50% reduction from Phase I baseline in Young Mania Rating Scale [YMRS] summary score and a Clinical Global Impressions-Improvement [CGI-I] score of 1 or 2), with 22 (53.7%) considered to be in remission (YMRS summary score≤12 and CGI-Severity score of 1 or 2). These data suggest that patients who initially responded to lithium maintained mood stabilization during continuation treatment, but partial responders did not experience further improvement during Phase II, despite the opportunity to receive adjunctive medications. The most commonly reported (≥20%) adverse events associated with lithium treatment were vomiting, headache, abdominal pain, and tremor.
Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium. Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase, despite the possibility that adjunctive medications could be prescribed.
The current study used model-based cluster analyses to determine if there are two distinct variants of adolescents (ages 11 - 18) high on callous-unemotional (CU) traits that differ on their level of anxiety and history of trauma. The sample (n = 272) consisted of clinic-referred youths who were primarily African-American (90%) and from low income families. Consistent with hypotheses, three clusters emerged, including a group low on CU traits, as well as two groups high on CU traits that differed in their level of anxiety and past trauma. Consistent with past research on incarcerated adults and adolescents, the group high on anxiety (i.e., secondary variant) was more likely to have histories of abuse and had higher levels of impulsivity, externalizing behaviors, aggression, and behavioral activation. In contrast, the group low on anxiety (i.e., primary variant) scored lower on a measure of behavioral inhibition. On measures of impulsivity and externalizing behavior, the higher scores for the secondary cluster only were found for self-report measures, not on parent-report measures. Youths in the primary cluster also were perceived as less credible reporters than youth in the secondary or cluster low on CU traits. These reporter and credibility differences suggest that adolescents within the primary variant may underreport their level of behavioral disturbance, which has important assessment implications.
Callous Unemotional Traits; Secondary Psychopathy; Trauma; Aggression; Adolescents
This report evaluates whether classification tree algorithms (CTA) may improve the identification of individuals at risk for bipolar spectrum disorders (BPSD). Analyses used the Longitudinal Assessment of Manic Symptoms (LAMS) cohort (629 youth, 148 with BPSD and 481 without BPSD). Parent ratings of mania symptoms, stressful life events, parenting stress, and parental history of mania were included as risk factors. Comparable overall accuracy was observed for CTA (75.4%) relative to logistic regression (77.6%). However, CTA showed increased sensitivity (0.28 vs. 0.18) at the expense of slightly decreased specificity and positive predictive power. The advantage of CTA algorithms for clinical decision making is demonstrated by the combinations of predictors most useful for altering the probability of BPSD. The 24% sample probability of BPSD was substantially decreased in youth with low screening and baseline parent ratings of mania, negative parental history of mania, and low levels of stressful life events (2%). High screening plus high baseline parent-rated mania nearly doubled the BPSD probability (46%). Future work will benefit from examining additional, powerful predictors, such as alternative data sources (e.g., clinician ratings, neurocognitive test data); these may increase the clinical utility of CTA models further.
bipolar disorder; children; risk factors; clinical decision making; classification tree analysis
The study compared use of specialty outpatient mental services among children ages six and seven and children ages eight through 12 and investigated predictors of differences in the patterns of service use by age.
Eligible children were first-time patients of clinics participating in the Longitudinal Assessment of Manic Symptoms who were between ages six and 12 and who were English speaking. Children who screened positive for symptoms of mania (N=1,124) were invited to participate, and families of 621 (55%) children consented. A matched sample of 86 children without a positive screen for mania also participated. Baseline interviews assessed sociodemographic characteristics of the child and family and the child’s functioning, diagnoses, and use of services.
Of the 707 children, 30% were younger, and 50% used multiple types of specialty outpatient services. Younger children were more likely to be male, have Medicaid insurance, and have two parents with mental health problems. Use of multiple types of services was related to study site, high depression scores, fewer minor health issues, and fewer stressful life events among younger children and with parental stress, primary diagnosis, poor functioning, and not living with both parents among older children. Younger children were much more likely than older children to have used services before age six.
Younger children showed very early use of multiple types of services for mental health problems and a pattern of persistent impairment despite long-standing use of services. These data argue strongly for focusing on emotional and behavioral issues among young children.
The purpose of this study was to assess lisdexamfetamine dimesylate (LDX) treatment effects based on baseline emotional control dysfunction in children with attention-deficit/hyperactivity disorder (ADHD) categorized with or without impairments of executive function (EF) emotional control.
Post-hoc analyses of a 7 week, open-label LDX study in children with ADHD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision [DSM-IV-TR] defined) and impairments in EF control of emotional response. At baseline, participants were dichotomized by Behavior Rating Inventory of EF (BRIEF) emotional control domain T-scores of ≥65 (with impairment) or <65 (without impairment). ADHD Rating Scale-IV (ADHD-RS-IV), BRIEF Global Executive Composite and emotional control domain, Expression and Emotion Scale for Children (EESC) scores, Pearson correlations for BRIEF versus ADHD-RS-IV and EESC, and Clinical Global Impressions scores were assessed at baseline and end of study (week 7)/early termination (EOS/ET) by baseline category of BRIEF emotional control impairment. Safety assessments included treatment-emergent adverse events (TEAEs).
At baseline and EOS/ET, respectively, 53.0% and 20.7% met criteria for emotional control impairment. Participants with and without emotional control impairments had similar ADHD-RS-IV change scores. Mean (SD) change from baseline for those with and without emotional control impairments were −20.8 (12.89) and −14.6 (11.25) for BRIEF global scores and −16.0 (13.19) and −5.0 (9.48) for BRIEF emotional control domain scores. Participants with emotional control impairments had greater mean EESC total score changes. BRIEF emotional control domain and all ADHD-RS-IV scores indicated moderate correlations between change scores (all p<0.0001). Overall, 84.9% of participants had TEAEs (mostly mild-to-moderate in severity); 3.8% discontinued because of TEAEs.
The proportion of children with behavioral impairments in EF control of emotional response decreased during LDX treatment. ADHD symptoms improved in both groups. The moderate correlations between EF behaviors and ADHD symptoms suggest there may be utility in evaluating behavioral domains beyond core ADHD symptoms.
Controversy surrounds the diagnostic categorization of children with episodic moods that cause impairment, but do not meet DSM-IV criteria for bipolar I (BD-I) or bipolar II (BD-II) disorder. This study aims to characterize the degree to which these children, who meet criteria for bipolar disorder not otherwise specified (BD-NOS), are similar to those with full syndromal BD, versus those with no bipolar spectrum diagnosis (no BSD).
Children ages 6–12 years old were recruited from nine outpatient clinics, preferentially selected for higher scores on a 10-item screen for manic symptoms. Interviews with the children and their primary caregivers assessed a wide array of clinical variables, as well as family history.
A total of 707 children (9.4 ± 1.9 years old) were evaluated at baseline, and were diagnosed with BD-I (n = 71), BD-II (n = 3), BD-NOS (including cyclothymia; n = 88), or no BSD (n = 545). Compared to BD-I, the BD-NOS group had less severe past functional impairment. However, current symptom severity and functional impairment did not differ between BD-NOS and BD-I, even though both groups were significantly more symptomatic and impaired than the no BSD group. Parental psychiatric history was similar for BD-NOS and BD-I groups, and both were more likely than the no BSD group to have a parent with history of mania. Rates of elated mood did not differ between BD-NOS and BD-I youth.
Children with BD-NOS and BD-I are quite similar, but different from the no BSD group, on many phenomenological measures. These findings support the hypothesis that BD-NOS is on the same spectrum as BD-I.
adolescent; bipolar disorder; child; comorbidity; Diagnostic and Statistical Manual of Mental Disorders; differential diagnosis; mental disorders/diagnosis/epidemiology; phenotype
This study evaluated demographic and clinical correlates and predictors of polypharmacy at baseline assessment in the Longitudinal Assessment of Manic Symptoms (LAMS) sample, a cohort of children age six to 12 years at their first outpatient mental health visit at university-affiliated clinics.
Use of medications in four classes (mood stabilizers, antidepressants, antipsychotics, and stimulants) was assessed, and the Service Assessment for Children and Adolescents classified lifetime and current use of various services. Analyses examined correlates of the number of medications prescribed and odds of polypharmacy, defined as use of two or more concurrent medications.
In the total sample, 201 of 698 participants (29%) were prescribed two or more medications. These participants had lower Children's Global Assessment Scale scores, more comorbid disorders, and higher baseline parent-reported mood symptoms than those prescribed no or one medication. White youths were three times as likely as nonwhite youths to be receiving two or more psychotropics, even after adjustment for other demographic and clinical characteristics. Of 262 participants (38% of sample) not being treated with medications, 252 (96%) had a diagnosis of at least one psychiatric disorder (74% had two or more).
Findings suggest that patients with greater severity and comorbidity were more likely to receive two or more medications. However, 38% of these children with serious disorders were not receiving psychotropic medication at the time of this assessment. Results counter findings suggesting overtreatment with medications of children with psychiatric disorders in the community.
Family history of mental illness provides important information when evaluating pediatric bipolar disorder (PBD). However, such information is often challenging to gather within clinical settings. This study investigates the feasibility and utility of gathering family history information using an inexpensive method practical for outpatient settings. Families (N=273) completed family history, rating scales, MINI and KSADS interviews about youths 5–18 (median=11) years presenting to an outpatient clinic. Primary caregivers completed a half page Family Index of Risk for Mood issues (FIRM). All families completed the FIRM quickly and easily. Most (78%) reported 1+ relatives having history of mood or substance issues, M=3.7 (SD=3.3). A simple sum of familial mood issues discriminated cases with PBD from all other cases, AUROC=.63, p=.006. FIRM scores were specific to youth mood disorder and not ADHD or disruptive behavior disorder. FIRM scores significantly improved the detection of PBD even controlling for rating scales. No subset of family risk items performed better than the total. Family history information showed clinically meaningful discrimination of PBD. Two different approaches to clinical interpretation showed validity in these clinically realistic data. Inexpensive and clinically practical methods of gathering family history can help to improve the detection of PBD.
pediatric bipolar disorder; family history; community mental health; assessment; screening; sensitivity and specificity
Transdermal technology is currently approved in the US for the administration of more than 20 medications. This current review describes the clinical research pertaining to the use of a methylphenidate patch in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. PubMed searches were conducted using the search term ‘methylphenidate transdermal system’, and were limited to clinical trials. No limits were set for dates of publication. A total of 21 citations were identified. Studies evaluating the safety and efficacy of the methylphenidate transdermal system (MTS) in children and adolescents were included in this review. Additional studies were identified from bibliographies and the ‘Related Citations’ section of PubMed searches. The MTS delivers a range of methylphenidate doses using a drug-in-adhesive matrix patch. According to current labeling, the patch should be applied to the hip once daily for a maximum of 9 h. Serum methylphenidate levels increase over wear time, with mean time to maximum concentration (tmax) reached between 8 and 10 h for a 9-h wear time, and the elimination half-life for methylphenidate is 3–4 h after patch removal. In clinical trials, ADHD symptoms were measured using the ADHD Rating Scale, Version IV, and several parent-, teacher-, and patient-rated scales. Treatment effects show statistically significant differences from baseline symptom scores starting at the first evaluation, 2 h after the patch is applied, with significant benefit lasting up to 12 h with a 9-h wear time. Adverse events with the MTS are similar to those seen with other formulations of methylphenidate, with the exception of skin-related reactions at the site of application, which were generally mild to moderate in severity. The incidence of contact allergic dermatitis with MTS is <1 %. Statistically significant improvements in health-related quality of life and medication satisfaction were also observed with the MTS compared with placebo, and after switching from oral extended-release (ER) methylphenidate. Transdermal drug delivery is an effective and safe means of administering methylphenidate for patients with ADHD.
Transgenerational association of bipolar spectrum disorder (BPSD) and attention deficit/hyperactivity disorder (ADHD) has been reported, but inconclusively.
Children ages 6–12 were systematically recruited at first outpatient visit at 9 clinics at four universities and reliably diagnosed; 621 had elevated symptoms of mania (>12 on the Parent General Behavior Inventory 10-Item Mania Scale); 86 had scores below 12. We analyzed baseline data to test a familial association hypothesis: compared to children with neither BPSD nor ADHD, those with either BPSD or ADHD would have parents with higher rates of both bipolar and ADHD symptoms, and parents of comorbid children would have even higher rates of both.
Of 707 children, 421 had ADHD without BPSD, 45 BPSD without ADHD, 117 comorbid ADHD+BPSD, and 124 neither. The rate of parental manic symptoms was similar for the comorbid and BPSD-alone groups, significantly greater than for ADHD alone and “neither” groups, which had similar rates. ADHD symptoms in parents of children with BPSD alone were significantly less frequent than in parents of children with ADHD (alone or comorbid), and no greater than for children with neither diagnosis. Family history of manic symptoms, but not ADHD symptoms, was associated with parent-rated child manic-symptom severity over and above child diagnosis.
The sample was not epidemiologic, parent symptoms were based on family history questions, and alpha was 0.05 despite multiple tests.
These results do not support familial linkage of BPSD and ADHD; they are compatible with heritability of each disorder separately with coincidental overlap.
Bipolar disorder; ADHD; Family history
This study explored the demographic and diagnostic features of children who were currently receiving antipsychotics compared to children who were receiving other psychotropics in a cohort of children with and without elevated symptoms of mania (ESM). Participants were recruited from 10 child outpatient mental health clinics associated with four universities. Guardians with children between 6–12 years who presented for new clinical evaluations completed the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M). All children who scored ≥12 on the PGBI-10M and a select demographically matched comparison group of patients who scored ≤11 were invited to participate. Children were divided into two groups: those receiving at least one antipsychotic medication and those receiving other psychotropic medications. The groups were compared on demographics, diagnoses, psychiatric symptoms, functioning, and past hospitalizations. Of the 707 children enrolled in the Longitudinal Assessment of Manic Symptoms (LAMS) study, 443 (63%) were prescribed psychotropic medication at baseline: 157 (35%) were receiving an antipsychotic and 286 (65%) were prescribed other agents. Multivariate results indicated that being prescribed antipsychotics was related to being white, previous hospitalization, having a psychotic or bipolar 1 disorder and the site where the child was receiving services (p<0.001). In this sample, it is relatively common for a child to be prescribed an antipsychotic medication. However, the only diagnoses associated with a greater likelihood of being treated with an antipsychotic were psychotic disorders or unmodified DSM-IV bipolar 1 disorder.
The purpose of this open-label study was to describe the effectiveness of aripiprazole (APZ) in the treatment of children with bipolar disorders suffering from manic symptomatology.
Symptomatic outpatients (Young Mania Rating Scale [YMRS] score ≥15) meeting strict, unmodified, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic symptom criteria for a bipolar disorder, ages 4–9 years, were eligible. Subjects were treated prospectively with flexible doses of APZ (maximum daily dose of 15 mg/day), for up to 16 weeks or until a priori response criteria were met. Outcome measures included the YMRS, Clinical Global Impressions Scale-Severity, Children's Global Assessment Scale (CGAS), and the Children's Depression Rating Scale-Revised (CDRS-R). A priori response criteria consisted of 3 of 4 consecutive weeks with (1) CDRS-R <29; (2) YMRS <10; and (3) CGAS >50.
Ninety-six children (62 males; mean age of 6.9 (SD = 1.7), received APZ for an average length of treatment of 12.5 (SD = 3.9) weeks. Significant improvements in YMRS, CDRS-R, CGAS, and Clinical Global Impressions Scale-Severity scores (p < 0.001) were noted at the end of study participation. Sixty of the subjects (62.5%) met a priori response criteria at study's end. The most common side effects noted were stomachache, increased appetite, and headache. Two subjects were removed from the study due to side effects [epistaxis (n = 1); akathisia (n = 1)]. Subjects experienced an average weight gain of 2.4 (SD = 1.9) kg.
APZ may be effective in the acute treatment of symptoms of children with bipolar illnesses.