Journal of child and adolescent psychopharmacology最新文献

Objectives: To describe the Sertraline Pediatric Registry for the Evaluation of Safety (SPRITES) safety results, including adverse events (AEs) (serious and nonserious, including suicide-related events) following long-term treatment with sertraline in children and adolescents aged 6-16 years. Methods: SPRITES was a multicenter, prospective, observational study designed to compare cognitive, emotional, and physical development in pediatric patients exposed to sertraline or psychotherapy alone in routine care for up to 3 years. Safety outcomes included AEs collected on the Pediatric Adverse Event Rating Scale and suicidal ideation/behavior (SIB), as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). AEs (unadjusted and adjusted for exposure) and C-SSRS data were summarized descriptively, and a marginal structural model (MSM) was applied to the C-SSRS results. Results: Between April 2012 and September 2020, 941 patients participated in SPRITES. At baseline, per treating physician discretion, 695 patients were administered sertraline, 243 patients were administered psychotherapy alone, and 3 patients were administered an antidepressant other than sertraline. At postbaseline timepoints, patients receiving sertraline reported higher overall rates of AEs relative to the other antidepressants and nonpharmacologic treatment groups. The most common AEs in the sertraline group were related to psychiatric and gastrointestinal disorders. In all exposure groups, the incidence of AEs and SIB decreased across study timepoints. MSM analyses did not demonstrate an effect of sertraline treatment on new onset or worsening SIB. Conclusion: The safety profile of sertraline in a long-term, real-world setting is similar to that of prior pediatric sertraline studies. A greater proportion of AEs and SIB events reported in the sertraline group compared with the nonpharmacologic therapy group is not unexpected given the safety profile of sertraline and observation of baseline differences in psychiatric disease severity between exposure groups. With prolonged sertraline treatment, incidence rates of AEs and SIB events decreased, and worsening of SIB was not observed.

Introduction: The effective management of irritability is a key need in young people with autism spectrum disorder (ASD). We evaluated the efficacy and safety of brexpiprazole in children and adolescents with irritability associated with ASD. Methods: This was an 8-week, phase 3, randomized, double-blind, placebo-controlled trial (NCT04174365) and 26-week, open-label extension (OLE, NCT04258839) of brexpiprazole (0.25-3 mg/day based on body weight) in children and adolescents (5-17 years) with a diagnosis of ASD, score ≥18 on the Aberrant Behavior Checklist-Irritability (ABC-I) subscale, and score ≥4 on the Clinical Global Impressions-Severity scale. Results: Of the 119 randomized participants (brexpiprazole = 60, placebo = 59), 104 completed double-blind treatment, and 95 enrolled and 70 completed the OLE. Similar reductions in mean ABC-I subscale score were seen in both groups (least-squares mean ± standard error reduction from double-blind baseline of -10.1 ± 1.3 with brexpiprazole vs -8.9 ± 1.3 with placebo). Thus, the primary endpoint did not show a significant treatment effect (LS-mean [95% confidence interval] treatment difference: -1.22 [-4.49, 2.05], p = 0.46) and the hierarchical efficacy analysis ended at this point. At the end of the OLE, participants had a mean ± SD reduction from open-label baseline of -6.1 ± 8.2 in ABC-I subscale score. During double-blind treatment, 51.7% participants treated with brexpiprazole had ≥1 treatment-emergent adverse event (TEAE) versus 35.1% with placebo; no severe or serious TEAEs were reported. The only potentially treatment-related TEAE that occurred in ≥5% of participants was somnolence (12.1% for brexpiprazole vs 5.3% for placebo). During the OLE, the most commonly reported TEAE was increased weight (n = 13, 13.7%). Conclusions: Treatment with brexpiprazole did not demonstrate significant efficacy versus placebo for the treatment of irritability associated with ASD. The safety profile was consistent with that observed in adult and adolescent patients with schizophrenia.

Background: Although randomized clinical trials (RCTs) have investigated several treatments for social communication difficulties and repetitive behavior in autism, none has yet shown consistent superiority over placebo. Placebo response in autism RCTs may impede the ability to detect meaningful treatment effects. Objective: We sought to identify individual-level predictors of placebo response in Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B), a 24-week RCT of intranasal oxytocin for social impairment in autistic youth. In our primary analysis, we examined predictors of change in the Aberrant Behavior Checklist-modified Social Withdrawal (ABC-mSW) score at 24 weeks in SOARS-B participants taking placebo. Secondary analyses examined predictors of ABC-mSW change at 12 weeks and of Clinical Global Impressions-Improvement at 24 and 12 weeks. We also examined predictors of response among SOARS-B participants taking oxytocin. Methods: For each analysis, we first used lasso (least absolute shrinkage and selection operator) regression to identify potentially influential predictors from a large group that included demographic factors, rating scale data, and prescribed medications. We then estimated an unpenalized linear regression model for the outcome of interest that included only variables retained by the optimal lasso. We considered variables with statistically significant coefficients to be influential predictors. Results: Higher baseline ABC-mSW score was the only significant predictor of greater ABC-mSW change in the placebo group at 24 and 12 weeks. Conclusions: In SOARS-B, higher baseline severity on a measure of reciprocal social communication predicted greater placebo response. This is consistent with the finding that lower social communication adaptive functioning was associated with greater placebo response in recent RCTs of balovaptan for social impairment in autism. However, it contrasts with findings from a trial of citalopram for repetitive behavior in autism, in which lower baseline severity of a composite of autistic and mood symptoms predicted greater placebo response. This may indicate that different factors contribute to placebo response in different symptom domains.

Objectives: The objective of this study was to explore the safety and clinical effects of amisulpride in children and adolescents with psychiatric disorders. Methods: This case series included six patients, aged 11 to 19 years, diagnosed with affective disorder, autism, anxiety, psychosis, and obsessive-compulsive disorder, and treated with amisulpride at doses ranging from 100 to 400 mg per day. Results: Amisulpride appeared to reduce psychotic and behavioral symptoms. Observed side effects included increased appetite, weight gain, sedation, and mild extrapyramidal symptoms. Conclusion: Amisulpride may have promise for study and future use in children and adolescents with psychiatric disorders and severe symptoms.

Objective: Self-report questionnaires are common for measuring posttraumatic stress disorder (PTSD). The experience of life threat-Criterion A-serves a gatekeeper function for diagnosing PTSD, and evidence suggests false positives are common on questionnaires. It remains unknown how common they are and whether extra instructions can reduce them. Methods: The present study assessed 42 youths, 10-17 years of age, from a clinic setting. Youths and parents completed regular PTSD questionnaires and then enhanced versions with more detailed instructions and examples of Criterion A and non-Criterion A events. Parents completed a semistructured interview as the verification of true versus false positives. Results: In the full sample, parents endorsed 41 and children endorsed 45 false positive events. The mean was significantly greater than zero for both parents and children. Parents endorsed 59 and children endorsed 138 false positive symptoms. When false positive events were endorsed, this was significantly associated with more false positive symptoms for both parents and children. An enhanced questionnaire failed to reduce false positive events for the full sample. Discussion: The common occurrence of false positives suggests caution is warranted when interpreting estimates from questionnaire-based research about the prevalence of PTSD. While this attempt to eliminate false positives was not fully successful, there may be other useful enhancements to consider in future research.

Objective: The current intense period of drug development for fragile X syndrome (FXS) and other neurodevelopmental disorders (NDDs) indications has highlighted the importance of behavioral outcome measures with strong psychometric properties and specifically content validity. The Aberrant Behavior Checklist-Community Edition (ABC-C), which has successfully been applied to autism spectrum disorder drug trials, has been revised for FXS (ABC_FX) and is widely used for both clinical and research purposes. Despite its strong psychometric validation, the ABC_FX and its parent measure have not been subjected to qualitative content validity evaluations. The present study intended to fill this gap. Methods: Using two surveys administered sequentially and developed with guidance and review from the Food and Drug Administration (FDA), we asked 10 clinicians experienced in FXS and related NDDs to determine the adequacy of the ABC_FX for assessing its behavioral constructs, its relevance to FXS, and its potential for detecting response to interventions. Various descriptive statistic parameters and ad hoc metrics were used to analyze categorical and Likert-like scale responses. Results: Experts considered that most items and all six ABC_FX subscales indeed evaluated their explicit or implicit behavioral constructs. However, item and subscale specificity were relatively low (∼25%-30%). Relevance of items of the Hyperactivity subscale was relatively high while low for many items of the Socially Unresponsive/Lethargic subscale. These items were also considered of low responsiveness potential. Irritability, Hyperactivity, Stereotypy, and Social Avoidance were the subscales with the strongest profiles, although the experts estimated that Stereotypy items may not be that responsive to treatment. A novel Anxiety construct, representing mainly recently reported observable behaviors, contributed mainly by Irritability items, emerged as a potential measure. Conclusions: The present study demonstrated the overall adequacy of the ABC_FX for its behavioral constructs, its relevance to FXS, and its potential for detecting response to treatment. It also showed that anxiety, a distinctive feature of FXS and other genetic NDDs, can also be measured by the ABC_FX. These findings can help with the implementation and interpretation of the ABC_FX, as well as with potential improvements to the measure in FXS and other NDDs.

Objective: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting predominantly females and associated with variants in the MECP2 gene. Recent success in clinical trials have resulted in an expanded use of the Rett Syndrome Behaviour Questionnaire (RSBQ) for clinical and research purposes. Implementation of the RSBQ as a global clinical severity scale has raised concerns about its construct validity considering its content, structure, and psychometric features. To further understand RSBQ data, we analyzed RSBQ scores available in the literature with a focus on variability and influencing factors. Methods: We identified publications reporting RSBQ total and/or subscale scores and summarized relevant study information, such as type of investigation, administration method, and descriptive data. We then analyzed means and standard deviations, calculating variance-to-mean ratios (VMR), as a measure of variability, when raw score descriptive statistics were available. Where appropriate, we compared means and VMRs by Welch t-tests. Results: Of the 14 publications identified, raw total scores from 5 observational studies and 4 clinical trials (baseline) were available. Raw subscale scores from four of the five observational studies were also available. We found a wide but comparable range of mean total scores for observational studies and clinical trials. However, VMRs were significantly higher in observational studies. Subscale scores showed either high (i.e., General Mood, Breathing Problems) or low (e.g., Hand Behaviours, Body Rocking and Expressionless Face) variability. Available data demonstrated greater variability in pediatric than adult groups and less variability when using interviews or electronic RSBQ administration compared with paper forms. Total score changes over time did not affect variability. Although certain studies offered insight into the relationship between the RSBQ and other measures, overall, data were insufficient for characterizing how RSBQ variability relates to other factors. Conclusions: Our findings on score variability support the need for more comprehensive reporting of RSBQ data, cohort characterization, and methodology; and the deployment of standardized RSBQ administration methods, such as advanced data capture systems. There is potential for use of subscales as outcome measures, subject to further psychometric validation studies, including prospective investigations testing the stability of RSBQ scores and influencing factors. Further examining the relationship between RSBQ scores and other instruments will aid in its interpretation as a clinical outcome measure.

Objective: Pharmacoepidemiologic research shows increasing use of polypharmacy to manage behavioral treatment of youth. Methods to increase precision, for example, competing risk analysis, to capture psychotropic patterns of concomitant stimulant treatment changes over time have not been explored. Methods: A retrospective cohort study was derived from Medicaid enrollment data, prescription drug, and clinician-reported diagnosis claims data from 2007 to 2014. Youths aged 2-17 years with 1-7.5 years of continuous enrollment who were new users of stimulants were followed. Major outcomes include detailed changes of concomitant use according to the number of psychotropic classes (NPC); competing risk assessment of patient factors according to NPC; and time factors related to changes in NPC. Results: Among 30,294 new stimulant users, 75.5% remained on stimulant monotherapy and 24.5% had stimulant concomitant regimens. Among the latter, great flux was observed, revealing exposure to combinations changed substantially across time. As a proportion of all changes, retention of the maximum NPC was observed for 65.3% of 2 concomitant classes, 56.2% of 3 concomitant classes, and 57.1% and 56.2% of 4 and 5 concomitant classes, respectively. Median duration according to NPC showed a linear decrease in time from 223 days for 2 classes, 172 days for 3 classes, 141 days for 4 classes, and 113 days for 5 classes combinations. By contrast, the path to maximum NPC regimens took median times of 491-833 days as NPC increased from 2 to 4 concomitant classes. Competing risk analysis demonstrated significantly increased hazard ratios according to the number of concomitant classes for 12-17-year-olds, patients with foster care or disability coverage, and those with 3-4 years of continuous enrollment. Conclusions: Detailed NPC changes illustrate great flux in concomitant stimulant patterns among Medicaid-insured youth. Competing risk analysis brings more precise patient characteristics risk information to assess NPC changes compared with a binary model.

Importance: Selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy are the first-line treatments for pediatric obsessive-compulsive disorder (OCD) populations. Due to their limited effectiveness, additional treatment options are needed. A new potential pharmacological medication treatment avenue for OCD is intravenous (IV) ketamine. Objective: This study aimed to establish the feasibility, acceptability, and preliminary efficacy of an IV ketamine infusion for the treatment of refractory OCD in adolescents. Design: In this clinical pilot trial, every participant received IV ketamine infusion. Symptom severity and side effects were assessed daily for 2 weeks following the infusion. Setting: Study procedures were conducted at the New York State Psychiatric Institute, including a combination of in-person visits and phone calls. Participants: Five adolescents with OCD (age M, SD: 16.6 ± 1.5), who had previously failed trials of first-line treatments were enrolled. Intervention: All participants received an IV infusion of 0.5 mg/kg ketamine hydrochloride. Main Outcomes and Measures: A multimethod approach was applied, including physiological, self-report, and clinician-rated measures. To assess feasibility and acceptability, vital signs, electrocardiogram suicidality, self-reported adverse events, and dissociative symptoms were obtained. Obsessive-compulsive (OC) (Yale-Brown Obsessive Compulsive Challenge Scale, CY-BOCS) and depressive symptom severity, as well as global clinical impression, were assessed to investigate preliminary efficacy. Results: The mean (SD) pre- and 14-day posttreatment CY-BOCS were 29 (5.5) and 26.2 (5.6). There were no incidents of abnormal vital signs, mortality, or suicidal ideation in the 2 weeks following the infusion. All participants experienced mild dissociative symptoms in the 40 minutes after the IV ketamine infusion. Descriptively, OC symptom severity decreased immediately after the infusion but was not maintained over the course of the study. Conclusions and Clinical Significance: Ketamine is well-tolerated in adolescents with OCD and therefore appropriate for further efficacy testing. Trial Registration: ClinicalTrials.gov Identifier: NCT02422290.