Similarities and Differences Across Bipolar Disorder Subtypes Among Adolescents.

Objectives: To compare demographic, clinical, and familial characteristics across bipolar disorder (BD) subtypes in adolescents. Methods: A total of 168 participants, 13 to 19 years of age, with BD-I (n = 41), BD-II (n = 68), or operationalized BD-not otherwise specified (NOS) (n = 59) were recruited from a tertiary subspecialty clinic at an academic health sciences center. Diagnoses were determined using the semistructured K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) interview. Omnibus analyses were followed up with post hoc pairwise comparisons. Results: After controlling for age, race, and living with both natural parents, BD-I was associated with greater functional impairment, increased rates of psychiatric hospitalization, psychosis, and lifetime exposure to second-generation antipsychotics and lithium, less self-injurious behavior, less anxiety disorders, and less severe worst lifetime depression and lower levels of emotional dysregulation and lability compared with both BD-II and BD-NOS. Lifetime most severe manic symptoms were highest in BD-I, lowest in BD-NOS, with BD-II intermediate. Lifetime exposure to psychosocial treatment followed the opposite pattern: lowest in BD-I, highest in BD-NOS, with BD-II intermediate. Variables for which there were no significant between-group differences included suicidal ideation, suicide attempts, comorbidities other than anxiety, or family history of BD. Conclusion: Among observed differences, most distinguish BD-I from other subtypes, whereas few variables differed between BD-II and BD-NOS. Different BD subtypes share important similarities in multiple clinical and familial characteristics, including family history of BD. Present findings support and extend knowledge regarding the course and outcome of bipolar youth study operationalized definition of BD-NOS. Further research is warranted to evaluate intermediate phenotypes and treatment strategies that address these subtype-related differences.

Dimensional and Categorical Correlates of Substance Use Disorders among Canadian Adolescents with Bipolar Disorder.

OBJECTIVES: Despite increasing evidence of excessive substance use disorder (SUD) prevalence among adolescents with bipolar disorder (BP), little is known about this topic among Canadian adolescents with BP. We therefore sought to examine the clinical characteristics and dimensional measures of psychopathology associated with comorbid SUD among Canadian BP adolescents. METHOD: Participants were 100 adolescents, ages 13-19 years, with BP I, II, or not otherwise specified (NOS). Diagnoses (current and lifetime) were determined via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime version (KSADS-PL). Participants were considered to have lifetime SUD if they met DSM-IV criteria for abuse of or dependence on alcohol or any drug other than nicotine. Chi-square analyses and independent samples t-tests were followed by logistic regression analyses. RESULTS: The lifetime prevalence of SUD was 33% (primarily alcohol and cannabis use disorders). In univariate analyses, SUD was associated with greater lifetime prevalence of conduct disorder, oppositional defiant disorder, panic disorder, assault of others, and a greater number of stressful life events. SUD was significantly associated with greater self-reported impulsivity and parent-report of anger/depression in the adolescent. In multivariable analyses, SUD was associated with panic disorder and oppositional defiant disorder. CONCLUSION: SUD is highly prevalent among Canadian adolescents with BP and is associated with anxiety disorders, behavioural disorders, and trait impulsivity. Targeting these clinical characteristics may help guide preventative and treatment strategies for this population.

OBJECTIFS: Malgré des preuves croissantes de la prévalence excessive du trouble d'utilisation de substances (TUS) chez des adolescents souffrant de trouble bipolaire (TB), ce sujet est très peu connu des adolescents canadiens souffrant de TB. Nous avons donc cherché à examiner les caractéristiques cliniques et les mesures dimensionnelles de la psychopathologie associée au TUS comorbide chez les adolescents canadiens souffrant de TB. MÉTHODE: Les participants étaient 100 adolescents de 13 à 19 ans souffrant de TB I, II, ou non spécifié ailleurs (NSA). Les diagnostics (actuels et de durée de vie) ont été déterminés par le tableau des troubles affectifs et de la schizophrénie pour les enfants d'âge scolaire, version actuelle et de durée de vie (KSADS-PL). Les participants étaient évalués avoir un TUS de durée de vie s'ils satisfaisaient aux critères du DSM-IV en matière d'abus ou de dépendance à l'alcool ou à toute autre drogue que la nicotine. Les analyses chi-carré et les tests t d'échantillons indépendants ont été suivis d'analyses de régression logistique. RÉSULTATS: La prévalence de durée de vie du TUS était de 33 % (principalement des troubles d'utilisation d'alcool et de cannabis). Dans les analyses univariées, le TUS était associé à une prévalence de durée de vie plus marquée du trouble des conduites, du trouble oppositionnel avec provocation, du trouble panique, d'agression physique et d'un plus grand nombre d'événements de la vie stressants. Le TUS était significativement associé à une plus grande impulsivité auto-déclarée et à des rapports des parents sur la colère/dépression de l'adolescent. Dans les analyses multivariées, le TUS était associé au trouble panique et au du trouble oppositionnel avec provocation. CONCLUSION: Le TUS est hautement prévalent chez les adolescents canadiens souffrant de TB et est associé aux troubles anxieux, aux troubles du comportement, et à l'impulsivité. Cibler ces caractéristiques cliniques peut aider à guider l'élaboration de stratégies préventives et de traitement pour cette population.

A Science and Risk-Based Pragmatic Methodology for Blend and Content Uniformity Assessment.

This paper describes a pragmatic approach that can be applied in assessing powder blend and unit dosage uniformity of solid dose products at Process Design, Process Performance Qualification, and Continued/Ongoing Process Verification stages of the Process Validation lifecycle. The statistically based sampling, testing, and assessment plan was developed due to the withdrawal of the FDA draft guidance for industry "Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment." This paper compares the proposed Grouped Area Variance Estimate (GAVE) method with an alternate approach outlining the practicality and statistical rationalization using traditional sampling and analytical methods. The approach is designed to fit solid dose processes assuring high statistical confidence in both powder blend uniformity and dosage unit uniformity during all three stages of the lifecycle complying with ASTM standards as recommended by the US FDA.

Inflammatory Markers and Brain-Derived Neurotrophic Factor as Potential Bridges Linking Bipolar Disorder and Cardiovascular Risk Among Adolescents.

OBJECTIVE: Bipolar disorder (BD) is associated with increased rates of cardiovascular disease (CVD). Brain-derived neurotrophic factor (BDNF) and inflammatory markers are leading biomarkers in BD. We examined whether these biomarkers underlie the link between BD and CVD proxies among adolescents with bipolar spectrum disorders. METHODS: Subjects were 60 adolescents, 13-19 years old (40 with BD and 20 healthy controls [HCs]). Semistructured interviews determined diagnoses based on DSM-IV. Serum was assayed for BDNF, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Carotid intima media thickness (cIMT) and flow-mediated dilation were assessed using ultrasound. Procedures were conducted at a subspecialty clinic (January 2011-May 2014). RESULTS: Adolescents with BD had significantly greater waist circumference (BD: 81.72 cm [11.67 cm], HC: 75.64 cm [8.63 cm]; U = 547.5, P = .021), body mass index (BMI) (BD: 25.50 kg/m²undefined[5.29 kg/m²], HC: 21.76 kg/m² [3.43 kg/m²]; U = 608.5, P < .0001), pulse pressure (BD: 42.31 mm Hg [10.57 mm Hg], HC: 33.84 mm Hg [6.69 mm Hg]; U = 561.5, P < .001), and IL-6 (BD: 8.93 pg/mL [7.71 pg/mL], HC: 4.96 pg/mL [6.38 pg/mL]; U = 516.0, P < .0001) than HC adolescents. Subjects with BD-I (n = 14) and BD-II (n = 16) had greater IL-6 versus HCs (F3,51 = 5.29, P = .003). Controlling for BMI and age did not alter these findings. IL-6 was higher in symptomatic (n = 19) and asymptomatic BD (n = 21) versus that found in HCs (F2,52 = 7.96, P = .001). In symptomatic BD, lower BDNF was associated with greater mean cIMT (ρ = -0.507, P = .037). CONCLUSIONS: This study found evidence of increased inflammation among adolescents with BD. While present findings suggest a potential interplay between symptomatic status, biomarkers, and atherosclerosis proxies, there were no significant differences in cIMT or flow-mediated dilation in adolescents with BD compared to HCs. This may indicate that there is potential opportunity for CVD prevention strategies in adolescents with BD.

Controlled Study of Obesity Among Adolescents with Bipolar Disorder.

OBJECTIVE: Despite numerous studies regarding obesity (OB) in adult bipolar disorder (BP), there are few studies on this topic among adolescents. The current study attempts to extend the literature on prevalence and correlates of OB in adolescent BP by including control participants, and determining OB by direct measurement. METHODS: Participants were 75 treatment-seeking adolescents, ages 13-19 years, with BP-I, -II, or -not otherwise specified, and 47 adolescents without major psychiatric illness. Diagnoses and clinical characteristics were assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (KSADS-PL). Family psychiatric history was assessed using the Family History Screen. OB was defined as adjusted body-mass index ≥95th percentile. Variables associated with OB in univariate analyses informed variable selection for within-group logistic regression analysis among BP adolescents. RESULTS: BP participants had a significantly higher rate of OB (18%) compared to controls (4%; χ2 = 5.3; p = 0.02). BP remained a significant predictor for OB when controlling for race (odds ratio [OR] = 5.1, 95% confidence interval [CI] = 1.1-24.0, p = 0.04). In univariate analyses among BP adolescents, OB was significantly associated with suicide attempt, self-injurious behavior, and oppositional defiant disorder. In multivariable analyses, suicide attempt and antidepressants that were not selective serotonin reuptake inhibitors were significantly associated with OB. CONCLUSIONS: OB is excessively prevalent among adolescents with BP and is associated with proxies for illness severity, including suicide attempts. Additional research is warranted to identify strategies to prevent and treat OB among BP adolescents, and to elucidate processes underlying the elevated risk of suicide attempts.

Assessment Methodology for Process Validation Lifecycle Stage 3A.

The paper introduces evaluation methodologies and associated statistical approaches for process validation lifecycle Stage 3A. The assessment tools proposed can be applied to newly developed and launched small molecule as well as bio-pharma products, where substantial process and product knowledge has been gathered. The following elements may be included in Stage 3A: number of 3A batch determination; evaluation of critical material attributes, critical process parameters, critical quality attributes; in vivo in vitro correlation; estimation of inherent process variability (IPV) and PaCS index; process capability and quality dashboard (PCQd); and enhanced control strategy. US FDA guidance on Process Validation: General Principles and Practices, January 2011 encourages applying previous credible experience with suitably similar products and processes. A complete Stage 3A evaluation is a valuable resource for product development and future risk mitigation of similar products and processes. Elements of 3A assessment were developed to address industry and regulatory guidance requirements. The conclusions made provide sufficient information to make a scientific and risk-based decision on product robustness.

Impulsivity is associated with blood pressure and waist circumference among adolescents with bipolar disorder.

OBJECTIVE: Cardiovascular risk factors (CVRFs) and impulsivity are common in bipolar disorder (BD), and CVRFs are also linked with impulsivity through a number of mechanisms, both behavioral and biological. This study examines the association between CVRFs and impulsivity in adolescents with BD. METHODS: Subjects were 34 adolescents with BD and 35 healthy control (HC) adolescents. CVRFs were based on International Diabetes Federation metabolic syndrome criteria (triglycerides, high-density lipoprotein cholesterol, waist circumference, blood pressure (BP) and glucose). Impulsivity was measured using the computerized Cambridge Gambling Task (CGT). Analyses controlled for age, IQ, lifetime attention deficit hyperactivity disorder, and current antipsychotic use. RESULTS: Adolescents with BD had higher diastolic BP (73.36 ± 9.57 mmHg vs. 67.91 ± 8.74 mmHg, U = 401.0, p = 0.03), higher triglycerides (1.13 ± 0.60 mmol/L vs. 0.78 ± 0.38 mmol/L, U = 373.5, p = 0.008), and were more likely to meet high-risk criteria for waist circumference (17.6% vs. 2.9%, p = 0.04) vs. HC. Within the BD group, CGT sub-scores were correlated with CVRFs. For example, overall proportion bet was positively correlated with systolic (r = 0.387, p = 0.026) and diastolic (ρ = 0.404, p = 0.020) BP. Quality of decision-making was negatively correlated with systolic BP (ρ = -0.401, p = 0.021) and waist circumference (ρ = -0.534, p = 0.003). Significant interactions were observed, such that BD diagnosis moderates the relationship between both waist circumference and BP with CGT sub-scores. CONCLUSION: BP and waist circumference are associated with impulsivity in BD adolescents, but not in HC adolescents. Future studies are warranted to determine temporality and to evaluate whether optimizing CVRFs improves impulsivity among BD adolescents.

Prevalence and Correlates of Disruptive Mood Dysregulation Disorder Among Adolescents with Bipolar Disorder.

OBJECTIVE: The purpose of this study was to examine the prevalence and correlates of disruptive mood dysregulation disorder phenotype (DMDDP) in a clinical population of adolescents with bipolar disorder (BD). METHODS: DMDD criteria were modified and applied to a sample of 116 adolescents with BD-I (n = 30), BD-II (n = 46) or BD-not otherwise specified (NOS) (n = 40) from a tertiary teaching hospital. Diagnoses were determined via the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime version (KSADS-PL). Diagnostic and Statistical Manual of Mental Disorders (DSM-5) DMDD Criteria A-G were derived from the KSADS oppositional defiant disorder (ODD) screening interview and supplement, as well as narrative summaries. Chi-square analyses or t tests (p < 0.05) were conducted as appropriate, followed by logistic regression. P values were adjusted using the false discovery rate (FDR) approach. RESULTS: DMDDP criteria could not be determined for 8 adolescents because of missing data from the ODD supplement. Twenty-five percent of the remainder (27/108) met criteria for DMDDP. DMDDP was not associated with BD subtype or with family history of BD. In univariate analyses, after controlling for age, sex, and race, DMDDP was associated with lower functioning, increased family conflict, assault history, and attention deficit and/or hyperactivity disorder (ADHD) (FDR adjusted p values: <0.0001, < 0.0001, 0.007, and 0.007, respectively). Lifetime substance use disorder and medication use approached significance (adjusted p = 0.05). In logistic regression, DMDDP was independently associated with greater parent-reported family conflict (odds ratio [OR] 1.17; confidence interval [CI- 1.06-1.30; p = 0.001) and greater functional impairment (OR 0.89; CI 0.82-0.97; p = 0.006). DMDDP was also associated with a threefold increase in ADHD, although ADHD was only marginally significant (OR 3.3; CI 0.98-10.94; p = 0.05). CONCLUSIONS: Despite the positioning of DMDD as phenotypically and biologically distinct from BD, these phenotypes commonly overlap in clinical settings. This overlap is not explained by BD-NOS or by nonfamilial BD. The association of ADHD with DMDDP in this sample draws into question whether arousal symptoms should have been retained as originally elaborated in the severe mood dysregulation phenotype. Strategies to mitigate the excessive functional impairment of this comorbidity are warranted.

Binge eating and emotional eating behaviors among adolescents and young adults with bipolar disorder.

BACKGROUND: This study investigates nutritional behavior among adolescents and young adults with bipolar disorder (BP) in comparison to those without history of major psychiatric disorder. METHODS: 131 participants (82 BP, 49 controls) with a mean age of 16.11 ± 1.61 years were included. The self-reported Quick Weight, Activity, Variety & Excess (WAVE) Screener was used to assess dietary habits, yielding a total nutritional score as well as Excess, Variety, and Household Food Insecurity subscale scores. Specifically, the Variety subscale was used to measure daily consumption of essential nutrients; the Excess subscale measured unhealthy eating behaviors such as binge eating and excessive intake of fat and sugar; and the Household Food Insecurity subscale was used to detect food insecurity. Within-group analysis was conducted on participants with BP to identify correlates of unhealthy diet. RESULTS: BP participants scored significantly lower than controls on the WAVE (t=2.62, p=0.010), specifically the Excess subscale (t=3.26, p=0.001). This was related to higher prevalence of binge eating and emotional eating behaviors among participants with BP compared to controls. Within-group analyses showed that self-reported emotional dysregulation/impulsivity was associated with maladaptive nutritional behaviors (t=3.38, p=0.035). LIMITATIONS: Cross-sectional design. Within-group analyses were underpowered. Diet quality was measured using a brief self-report screener. CONCLUSION: Adolescents and young adults with BP have poorer nutritional behaviors compared to controls, and this difference is related to stress-induced eating. This demonstrates the need to screen for stress-induced eating and to intervene when needed in order to optimize nutritional behaviors among adolescents and young adults with BP.