A 52-Week Study of Olanzapine with a Randomized Behavioral Weight Counseling Intervention in Adolescents with Schizophrenia or Bipolar I Disorder

Objectives: To evaluate the 52-week safety/tolerability of oral olanzapine for adolescents with schizophrenia or bipolar mania and compare effectiveness of a standard versus intense behavioral weight intervention in mitigating risk of weight gain. Methods: Patients 13?17 years old with schizophrenia (Brief Psychiatric Rating Scale for Children [BPRS-C] total score >30; item score ≥3 for hallucinations, delusions, or peculiar fantasies) or bipolar I disorder (manic or mixed episode; Young Mania Rating Scale [YMRS] total score ≥15) received open-label olanzapine (2.5?20?mg/day) and were randomized to standard (n?=?102; a single weight counseling session) or intense (n?=?101; weight counseling at each study visit) weight intervention. The primary outcome measure was mean change in body mass index (BMI) from baseline to 52 weeks using mixed-model repeated measures. Symptomatology was also assessed. Results: No statistically significant differences between groups were observed in mean baseline-to-52-week change in BMI (standard: +3.6?kg/m2; intense: +2.8?kg/m2; p?=?0.150) or weight (standard: +12.1?kg; intense: +9.6?kg; p?=?0.148). Percentage of patients at endpoint who had gained ≥15% of their baseline weight was 40% for the standard group and 31% for the intense group (p?=?0.187). Safety/tolerability results were generally consistent with those of previous olanzapine studies in adolescents, with the most notable exception being the finding of a mean decrease in prolactin. On symptomatology measures, patients with schizophrenia had a mean baseline-to-52-week change in BPRS-C of ?32.5 (standard deviation [SD]?=?10.8), and patients with bipolar disorder had a mean change in YMRS of ?16.7 (SD?=?8.9), with clinically and statistically significant improvement starting at 3?4 days for each. Conclusions: Long-term weight gain was high in both groups, with no statistically significant differences between the standard or intense behavioral weight interventions in BMI or weight. Safety, tolerability, and effectiveness findings were generally consistent with the known profile of olanzapine in adolescents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140324/1/cap.2016.0010.pd

An application programming interface implementing Bayesian approaches for evaluating effect of time-varying treatment with R and Python

IntroductionMethods and tools evaluating treatment effect have been primarily developed for binary type of treatment. Yet, treatment is rarely binary outside the experimental setting, varies by dosage, frequency and time. Treatment is routinely adjusted, initiated or stopped when being administered over a period of time.MethodsBoth Gaussian Process (GP) regression and Bayesian additive regression tree (BART) have been used successfully for handling complex setting involving time-varying treatments that is either adaptive or non-adaptive. Here, we introduce an application programming interface (API) that implements both BART and GP for estimating averaged treatment effect (ATE) and conditional averaged treatment (CATE) for the two-stage time-varying treatment strategies.ResultsWe provide two real applications for evaluating comparative effectiveness of time-varying treatment strategies. The first example evaluates an early aggressive treatment strategies for caring children with newly diagnosed Juvenile Idiopathic Arthritis (JIA). The second evaluates the persistent per-protocol treatment effectiveness in a large randomized pragmatic trial. The examples demonstrate the use of the API calling from R and Python, for handling both non-adaptive or adaptive treatments, with presences of partially observed or missing data issues. Summary tables and interactive figures of the results are downloadable

AACAP 2006 Research Forum--Advancing research in early-onset bipolar disorder: barriers and suggestions

OBJECTIVE: The 2006 Research Forum addressed the goal of formulating a research agenda for early-onset bipolar disorder (EOBP) and improving outcome by understanding the risk and protective factors that contribute to its severity and chronicity. METHOD: Five work groups outlined barriers and research gaps in EOBP genetics, neuroimaging, prodromes, psychosocial factors, and pharmacotherapy. RESULTS: There was agreement that the lack of consensus on the definition and diagnosis of EOBP is the primary barrier to advancing research in BP in children and adolescents. Related issues included: the difficulties in managing co-morbidity both statistically and clinically; acquiring adequate sample sizes to study the genetics, biology, and treatment; understanding the EOBP\u27s developmental aspects; and identifying environmental mediators and moderators of risk and protection. Similarly, both psychosocial and medication treatment strategies for children with BP are hamstrung by diagnostic issues. To advance the research in EOBP, both training and funding mechanisms need to be developed with these issues in mind. CONCLUSIONS: EOBP constitutes a significant public health concern. Barriers are significant but identifiable and thus are not insurmountable. To advance the understanding of EOBP, the field must be committed to resolving diagnostic and assessment issues. Once achieved, with adequate personnel and funding resources, research into the field of EOBP will doubtless be advanced at a rapid pace

Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode

Objectives: The aim of the present study was to systematically evaluate the prodrome to mania in youth. Methods: New-onset/worsening symptoms/signs of \u3e= moderate severity preceding first mania were systematically assessed in 52 youth (16.2 +/- 2.8 years) with a research diagnosis of bipolar I disorder (BD-I). Youth and/or caregivers underwent semi-structured interviews, using the Bipolar Prodrome Symptom Scale-Retrospective. Results: The mania prodrome was reported to start gradually in most youth (88.5%), with either slow (59.6%) or rapid (28.8%) deterioration, while a rapid-onset-and-deterioration prodrome was rare (11.5%). The manic prodrome, conservatively defined as requiring \u3e= 3 symptoms, lasted 10.3 +/- 14.4 months [95% confidence interval (CI): 6.3-14.4], being present for \u3e= 4 months in 65.4% of subjects. Among prodromal symptoms reported in \u3e= 50% of youth, three were subthreshold manic in nature (irritability: 61.5%, racing thoughts: 59.6%, increased energy/activity: 50.0%), two were nonspecific (decreased school/work functioning: 65.4%, mood swings/lability: 57.7%), and one each was depressive (depressed mood: 53.8%) or subthreshold manic/depressive (inattention: 51.9%). A decreasing number of youth had \u3e= 1 (84.6%), \u3e= 2 (48.1%), or \u3e= 3 (26.9%) \u27specific\u27 subthreshold mania symptoms (i.e., elation, grandiosity, decreased need for sleep, racing thoughts, or hypersexuality), lasting 9.5 +/- 14.9 months (95% CI: 5.0-14.0), 3.5 +/- 3.5 months (95% CI: 2.0-4.9), and 3.0 +/- 3.2 months (95% CI: 1.0-5.0) for \u3e= 1, \u3e= 2, or \u3e= 3 specific symptoms, respectively. Conclusions: In youth with BD-I, a relatively long, predominantly slowonset mania prodrome appears to be common, including subthreshold manic and depressive psychopathology symptoms. This suggests that early clinical identification and intervention may be feasible in bipolar disorder. Identifying biological markers associated with clinical symptoms of impending mania may help to increase chances for early detection and prevention before full mania

Escitalopram in Adolescents with Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study

Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. Methods: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. Results: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. Conclusions: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research

Objectives: Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. Methods: An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. Results: Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic