general psychopathology factor in Chinese adolescents and its correlation with trans-diagnostic protective psycho-social factors.

BACKGROUND: Comorbidity in mental disorders is prevalent among adolescents, with evidence suggesting a general psychopathology factor ("p" factor) that reflects shared mechanisms across different disorders. However, the association between the "p" factor and protective factors remains understudied. The current study aimed to explore the "p" factor, and its associations with psycho-social functioning, in Chinese adolescents. METHODS: 2052 students, aged 9-17, were recruited from primary and secondary schools in Shanghai, China. Multiple rating scales were used to assess psychological symptoms and psycho-social functioning. Confirmatory factor analysis was conducted to verify the fit of models involving different psychopathology domains such as externalizing, internalizing, and the "p" factor. Subsequently, structural equation models were used to explore associations between the extracted factors and psycho-social functioning, including emotion regulation, mindful attention awareness, self-esteem, self-efficacy, resilience, and perceived support. RESULTS: The bi-factor model demonstrated a good fit, with a "p" factor accounting for 46 % of symptom variation, indicating that the psychological symptoms of Chinese adolescents could be explained by internalizing, externalizing, and the "p" factor. Psychologically, a higher "p" was positively correlated with emotion suppression and negatively correlated with mindful attention awareness, emotion reappraisal, self-esteem, and resilience. Socially, a higher "p" was associated with decreased perceived support. LIMITATIONS: Only common symptoms were included as this study was conducted at school. Furthermore, the cross-sectional design limited our ability to investigate causal relationships. CONCLUSIONS: A "p" factor exists among Chinese adolescents. Individuals with higher "p" factor levels were prone to experience lower levels of psycho-social functions.

Association between anxiety, depression symptoms, and academic burnout among Chinese students: the mediating role of resilience and self-efficacy.

BACKGROUND: To explore the associations between anxiety and depression symptoms and academic burnout among children and adolescents in China, and to examine the role of resilience and self-efficacy in addressing academic burnout. METHODS: A total of 2,070 students in grades 4-8 were recruited from two primary and three middle schools in Shanghai, completed the Elementary School Student Burnout Scale (ESSBS), the Multidimensional Anxiety Scale for Children-Chinese (MASC-C), the Center for Epidemiological Studies Depression Scale (CES-D), the Connor-Davidson Resilience Scale (CD-RISC), and the General Self-Efficacy Scale (GSES), with 95.04% effective response rate. Multivariable regression analyses examining the associations between anxiety / depression symptoms and academic burnout (as well as the associations between resilience / self-efficacy and academic burnout) were performed using STATA 16.0 and SmartPLS 3.0. RESULTS: Anxiety symptoms (ß = 0.124, p < 0.01) and depression symptoms (ß = 0.477, p < 0.01) were positively correlated with academic burnout. Resilience partially mediated the association between depression symptoms and academic burnout (ß = 0.059, p < 0.01), with a mediation rate of 12.37%. Self-efficacy partially mediated the associations between anxiety symptoms and academic burnout (ß = 0.022, p < 0.01) and between depression symptoms and academic burnout (ß = 0.017, p < 0.01), with mediation rates of 17.74% and 3.56%, respectively. Resilience and self-efficacy together (ß = 0.041, p < 0.01) formed a mediating chain between depression symptoms and academic burnout, with a mediation rate of 8.6%. CONCLUSIONS: Anxiety and depression symptoms were positively associated with academic burnout. Resilience and self-efficacy were found to mediate the associations partially.

Consensus Paper: Cerebellum and Reward.

Cerebellum is a key-structure for the modulation of motor, cognitive, social and affective functions, contributing to automatic behaviours through interactions with the cerebral cortex, basal ganglia and spinal cord. The predictive mechanisms used by the cerebellum cover not only sensorimotor functions but also reward-related tasks. Cerebellar circuits appear to encode temporal difference error and reward prediction error. From a chemical standpoint, cerebellar catecholamines modulate the rate of cerebellar-based cognitive learning, and mediate cerebellar contributions during complex behaviours. Reward processing and its associated emotions are tuned by the cerebellum which operates as a controller of adaptive homeostatic processes based on interoceptive and exteroceptive inputs. Lobules VI-VII/areas of the vermis are candidate regions for the cortico-subcortical signaling pathways associated with loss aversion and reward sensitivity, together with other nodes of the limbic circuitry. There is growing evidence that the cerebellum works as a hub of regional dysconnectivity across all mood states and that mental disorders involve the cerebellar circuitry, including mood and addiction disorders, and impaired eating behaviors where the cerebellum might be involved in longer time scales of prediction as compared to motor operations. Cerebellar patients exhibit aberrant social behaviour, showing aberrant impulsivity/compulsivity. The cerebellum is a master-piece of reward mechanisms, together with the striatum, ventral tegmental area (VTA) and prefrontal cortex (PFC). Critically, studies on reward processing reinforce our view that a fundamental role of the cerebellum is to construct internal models, perform predictions on the impact of future behaviour and compare what is predicted and what actually occurs.

Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Measurement of flourishing: a scoping review.

Introduction: Flourishing is an evolving wellbeing construct and outcome of interest across the social and biological sciences. Despite some conceptual advancements, there remains limited consensus on how to measure flourishing, as well as how to distinguish it from closely related wellbeing constructs, such as thriving and life satisfaction. This paper aims to provide an overview and comparison of the diverse scales that have been developed to measure flourishing among adolescent and adult populations to provide recommendations for future studies seeking to use flourishing as an outcome in social and biological research. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we conducted a scoping review across PubMed and EMBASE of studies introducing original flourishing scales (defined as a previously unpublished measure of mental health or wellbeing that used "flourishing" in its definition). Studies focusing on adult populations that were published before April 28, 2023 were considered eligible for inclusion. Results: Out of 781 studies retrieved, we identified seven eligible studies covering seven unique flourishing scales. We find that all seven scales are multidimensional and assess features over monthly or yearly intervals. While most of the scales (six out of seven) include indicators of both hedonic and eudaimonic wellbeing, the operationalization of these dimensions of wellbeing varies considerably between scales. Several of the scales have been translated and validated across multiple geographical contexts, including higher- and lower-income countries. Discussion: Complementing self-report measures with other social, economic, regional, and biological indicators of flourishing may be useful to provide holistic and widely applicable measures of wellbeing. This review contributes to concept validation efforts that can guide strategies to sustain flourishing societies.

Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task-based fMRI connectome study.

BACKGROUND: Youth with a family history of bipolar disorder (BD) may be at increased risk for mood disorders and for developing side effects after antidepressant exposure. The neurobiological basis of these risks remains poorly understood. We aimed to identify biomarkers underlying risk by characterizing abnormalities in the brain connectome of symptomatic youth at familial risk for BD. METHODS: Depressed and/or anxious youth (n = 119, age = 14.9 ± 1.6 years) with a family history of BD but no prior antidepressant exposure and typically developing controls (n = 57, age = 14.8 ± 1.7 years) received functional magnetic resonance imaging (fMRI) during an emotional continuous performance task. A generalized psychophysiological interaction (gPPI) analysis was performed to compare their brain connectome patterns, followed by machine learning of topological metrics. RESULTS: High-risk youth showed weaker connectivity patterns that were mainly located in the default mode network (DMN) (network weight = 50.1%) relative to controls, and connectivity patterns derived from the visual network (VN) constituted the largest proportion of aberrant stronger pairs (network weight = 54.9%). Global local efficiency (Elocal , p = .022) and clustering coefficient (Cp , p = .029) and nodal metrics of the right superior frontal gyrus (SFG) (Elocal : p < .001; Cp : p = .001) in the high-risk group were significantly higher than those in healthy subjects, and similar patterns were also found in the left insula (degree: p = .004; betweenness: p = .005; age-by-group interaction, p = .038) and right hippocampus (degree: p = .003; betweenness: p = .003). The case-control classifier achieved a cross-validation accuracy of 78.4%. CONCLUSIONS: Our findings of abnormal connectome organization in the DMN and VN may advance mechanistic understanding of risk for BD. Neuroimaging biomarkers of increased network segregation in the SFG and altered topological centrality in the insula and hippocampus in broader limbic systems may be used to target interventions tailored to mitigate the underlying risk of brain abnormalities in these at-risk youth.

Impact of Vision Impairment and Ocular Morbidity and Their Treatment on Quality of Life in Children: A Systematic Review.

TOPIC: This review summarizes existing evidence of the impact of vision impairment and ocular morbidity and their treatment on children's quality of life (QoL). CLINICAL RELEVANCE: Myopia and strabismus are associated with reduced QoL among children. Surgical treatment of strabismus significantly improves affected children's QoL. METHODS: We conducted a systematic review and meta-analysis by screening articles in any language in 9 databases published from inception through August 22, 2022, addressing the impact of vision impairment, ocular morbidity, and their treatment on QoL in children. We reported pooled standardized mean differences (SMDs) using random-effects meta-analysis models. Quality appraisal was performed using Joanna Briggs Institute and National Institutes of Health tools. This study was registered with the International Prospective Register of Systematic Reviews (identifier, CRD42021233323). RESULTS: Our search identified 29 118 articles, 44 studies (0.15%) of which were included for analysis that included 32 318 participants from 14 countries between 2005 and 2022. Seventeen observational and 4 interventional studies concerned vision impairment, whereas 10 observational and 13 interventional studies described strabismus and other ocular morbidities. Twenty-one studies were included in the meta-analysis. The QoL scores did not differ between children with and without vision impairment (SMD, -1.04; 95% confidence interval [CI], -2.11 to 0.03; P = 0.06; 9 studies). Myopic children demonstrated significantly lower QoL scores than those with normal vision (SMD, -0.60; 95% CI, -1.09 to -0.11; P = 0.02; 7 studies). Children with strabismus showed a significantly lower QoL score compared with those without (SMD, -1.19; 95% CI, -1.66 to -0.73; P < 0.001; 7 studies). Strabismus surgery significantly improved QoL in children (SMD, 1.36; 95% CI, 0.48-2.23; P < 0.001; 7 studies). No randomized controlled trials (RCTs) concerning refractive error and QoL were identified. Among all included studies, 35 (79.5%) were scored as low to moderate quality; the remaining met all quality appraisal tools criteria. DISCUSSION: Reduced QoL was identified in children with myopia and strabismus. Surgical correction of strabismus improves the QoL of affected children, which supports insurance coverage of strabismus surgery. Further studies, especially RCTs, investigating the impact of correction of myopia on QoL are needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Genetics, epigenetics, and neurobiology of childhood-onset depression: an umbrella review.

Depression is a serious and persistent psychiatric disorder that commonly first manifests during childhood. Depression that starts in childhood is increasing in frequency, likely due both to evolutionary trends and to increased recognition of the disorder. In this umbrella review, we systematically searched the extant literature for genetic, epigenetic, and neurobiological factors that contribute to a childhood onset of depression. We searched PubMed, EMBASE, OVID/PsychInfo, and Google Scholar with the following inclusion criteria: (1) systematic review or meta-analysis from a peer-reviewed journal; (2) inclusion of a measure assessing early age of onset of depression; and (3) assessment of neurobiological, genetic, environmental, and epigenetic predictors of early onset depression. Findings from 89 systematic reviews of moderate to high quality suggest that childhood-onset depressive disorders have neurobiological, genetic, environmental, and epigenetic roots consistent with a diathesis-stress theory of depression. This review identified key putative markers that may be targeted for personalized clinical decision-making and provide important insights concerning candidate mechanisms that might underpin the early onset of depression.

Editors' Note: Third Annual Report Regarding JAACAP's Antiracist Journey.

In 2020, we wrote to you of our dedication and vision for JAACAP "to be antiracist at every level."1 Over the last 3 years, we have pursued initiatives "to reshape the Journal to pursue this vision."2,3 In this article, we provide an update on these goals and initiatives (Figure 1). With the launching of our new open access journal, JAACAP Open,4 in late 2022, we now extend these initiatives to both scientific journals in the JAACAP family and aspire to be a leader among mental health journals in our intentional pursuit of antiracist policies and practices.

Rare cases of Talaromyces pneumonia in individuals with underlying cancer and no travel to endemic areas.

Introduction: Talaromyces marneffei causes a systemic fungal infection, referred to as talaromycosis, in immunocompromised individuals. Talaromycosis is an AIDS (acquired immunodeficiency syndrome) defining illness for patients living in the Southeast Asian region. Here we present two rarely reported cases of pulmonary talaromycosis in Southern California in patients with active cancer, negative HIV status, and no prior travel history to endemic regions. Case description: Case 1: A 76-year-old male with a past medical history of emphysema and latent tuberculosis status post rifampin treatment, presented with a necrotic lung mass. He was diagnosed with squamous cell lung carcinoma and bronchoalveolar lavage cultures grew Talaromyces marneffei. He had no animal exposure or prior travel history to Asia. Due to a transfusion reaction to liposomal amphotericin (the mainstay of treatment), he required a transition to posaconazole. He was HIV-negative and expired due to underlying cancer and infection complications.Case2: A 63-year-old male with a past medical history of tuberculosis, diabetes, and cavitary pneumonia with bronchoscopy positive for Talaromyces presented with worsening back pain and was found to have multiple sites of poorly differentiated adenocarcinoma likely originating from gastric adenocarcinoma. He was HIV-negative and expired due to complications from underlying cancer and infection. Conclusion: We demonstrate that patients with pulmonary Talaromyces are becoming more prominent outside of endemic areas even in the setting of no prior travel. In addition, since patients with this infection are severely immunosuppressed, they require extensive workup for other comorbidities such as possible underlying cancer or tuberculosis.

Active Medical Learner Engagement Results in the Discovery That One Size Does Not Fit All in Overcoming COVID-19 Vaccine Hesitancy.

Vaccine hesitancy is an ongoing public health concern defined as the refusal of a vaccine that is readily available. Therefore, we developed a project to explore why patients in a safety net medical center were hesitant or refused the COVID-19 vaccine. The project was conducted by healthcare learners to promote "learning by doing". Responses were collected through a previously developed and ongoing survey among both hospitalized and ambulatory patients that had no previous history of COVID-19 infection, were currently infected, or had recovered from COVID-19. Results were analyzed using a priori power analysis and Chi-squared test. We discovered that different self-reported ethnic groups had different reasons for vaccine hesitancy; specifically, 69% of Black/African American respondents stated that their main reason for hesitancy was vaccine safety compared to 13.9% of non-Hispanic Whites (p = 0.005). Furthermore, our cohort was significantly more likely to disagree rather than agree with the statement: "getting vaccinated is important for the health of others in my community"(p = 0.016). The learners discovered that a more specific approach to vaccine education would be required to understand and overcome vaccine hesitancy in our cohort of socioeconomic and ethnically diverse groups.

Could blunt trauma lead to a double lumen esophagus?

INTRODUCTION AND IMPORTANCE: Esophageal rupture and perforation are serious complications of blunt abdominal trauma. Early diagnosis and intervention is key for patient survival. Studies have reported that mortality of patients with esophageal perforation can be as high as 20-40 % (Schweigert et al., 2016; Deng et al., 2021 [1, 2]). We present a patient with suspected esophageal perforation after a blunt trauma identified by esophagogastroduodenoscopy (EGD) as the presence of a second gastroesophageal lumen concerning for esophagogastric fistula. CASE PRESENTATION: Our patient is a 17-year-old male with no past medical history who was brought in from an outside facility status post electric bike accident. CT imaging from an outside hospital showed concern for possible esophageal rupture. On arrival, he was in no acute distress. Patient underwent a fluoroscopy upper GI series which showed extravasation of fluid outside the lumen, indicating an esophageal injury. Patient was evaluated by Gastroenterology and Cardiothoracic surgery, who agreed on an empiric course of piperacillin/tazobactam and fluconazole for prophylaxis in the setting of suspected esophageal rupture. Patient underwent an esophagram with EGD which demonstrated a 2nd false lumen from 40 to 45 cm. This appeared to be from incomplete avulsion of the submucosal space. No contrast extravasation was seen with the esophagram. CLINICAL DISCUSSION: To date, there has been no published case of trauma induced formation of a double lumen esophagus. Our patient presented with no previous history to suggest chronic or congenital double lumen of the esophagus. CONCLUSION: When considering esophageal rupture, the possibility of the formation of an esophago-gastric fistula should be considered via external traumatic insult.

The Association Between Screen Time and Outdoor Time on Adolescent Mental Health and Academic Performance: Evidence from Rural China.

Purpose: We examine how adolescent free time allocation-namely, screen time and outdoor time-is associated with mental health and academic performance in rural China. Methods: This paper used a large random sample of rural junior high school students in Ningxia (n = 20,375; age=13.22), with data collected from self-reported demographic questionnaires (to assess free time allocation), the Strengths and Difficulties Questionnaire (to assess mental health), and a standardized math test (to measure academic performance). We utilized a multivariate OLS regression model to examine associations between free time allocation and adolescent outcomes, controlling for individual and family characteristics. Results: Our sample's screen time and outdoor time both averaged around 1 hour. About 10% of the sample adolescents reported behavioral difficulties, while a similar percentage (11%) reported abnormal prosocial behaviors. Adolescents with higher levels of screen time (>2 hours) were 3 percentage points more likely to have higher levels of behavioral difficulties (p<0.001), indicating that excessive screen time was associated with worse mental health. Meanwhile, outdoor time was associated with better mental health, and positive correlations were observed at all levels of outdoor time (compared to no outdoor time, decreasing the likelihood of higher levels of behavioral difficulties by between 3 and 4 percentage points and of lower prosocial scores by between 6 and 8 percentage points; all p's<0.001). For academic performance, average daily screen times of up to 1 hour and 1-2 hours were both positively associated with standardized math scores (0.08 SD, p<0.001; 0.07 SD, p<0.01, respectively), whereas there were no significant associations between outdoor time and academic performance. Conclusion: Using a large sample size, this study was the first to examine the association between adolescent free time allocation with mental health and academic performance, providing initial insights into how rural Chinese adolescents can optimize their free time.

Early Family Intervention for Youth at Risk for Bipolar Disorder: Psychosocial and Neural Mediators of Outcome.

BACKGROUND: The impairing neurodevelopmental course of bipolar disorder (BD) suggests the importance of early intervention for youth in the beginning phases of the illness. OBJECTIVE: We report the results of a 3-site randomized trial of family-focused therapy for youth at high-risk (FFT-HR) for BD, and explore psychosocial and neuroimaging variables as mediators of treatment effects. METHODS: High-risk youth (<18 years) with major depressive disorder or other specified BD, active mood symptoms, and a family history of BD were randomly assigned to 4 months of FFT-HR (psychoeducation, communication and problem-solving skills training) or 4 months of enhanced care psychoeducation. Adjunctive pharmacotherapy was provided by study psychiatrists. Neuroimaging scans were conducted before and after psychosocial treatments in eligible participants. Independent evaluators interviewed participants every 4-6 months over 1-4 years regarding symptomatic outcomes. RESULTS: Among 127 youth (mean 13.2 ± 2.6 years) over a median of 98 weeks, FFT-HR was associated with longer intervals prior to new mood episodes and lower levels of suicidal ideation than enhanced care. Reductions in perceived family conflict mediated the effects of psychosocial interventions on the course of mood symptoms. Among 34 participants with pre-/post-treatment fMRI scans, youth in FFT-HR had (a) stronger resting state connectivity between ventrolateral PFC and anterior default mode network, and (b) increased activity of dorsolateral and medial PFC in emotion processing and problem-solving tasks, compared to youth in enhanced care. CONCLUSION: FFT-HR may delay new mood episodes in symptomatic youth with familial liability to BD. Putative treatment mechanisms include neural adaptations suggestive of improved emotion regulation.

Narrative Review: Impairing Emotional Outbursts: What They Are and What We Should Do About Them.

OBJECTIVE: Impairing emotional outbursts, defined by extreme anger or distress in response to relatively ordinary frustrations and disappointments, impact all mental health care systems, emergency departments, schools, and juvenile justice programs. However, the prevalence, outcome, and impact of outbursts are difficult to quantify because they are transdiagnostic and not explicitly defined by current diagnostic nosology. Research variably addresses outbursts under the rubrics of tantrums, anger, irritability, aggression, rage attacks, or emotional and behavioral dysregulation. Consistent methods for identifying and assessing impairing emotional outbursts across development or systems of care are lacking. METHOD: The American Academy of Child and Adolescent Psychiatry Presidential Task Force (2019-2021) conducted a narrative review addressing impairing emotional outbursts within the limitations of the existing literature and independent of diagnosis. RESULTS: Extrapolating from the existing literature, best estimates suggest that outbursts occur in 4%-10% of community children (preschoolers through adolescents). Impairing emotional outbursts may respond to successful treatment of the primary disorder, especially for some children with attention-deficit/hyperactivity disorder whose medications have been optimized. However, outbursts are generally multi-determined and often represent maladaptive or deficient coping strategies and responses. CONCLUSION: Evidence-based strategies are necessary to address factors that trigger, reinforce, or excuse the behaviors and to enhance problem-solving skills. Currently available interventions yield only modest effect sizes for treatment effect. More specific definitions and measures are needed to track and quantify outbursts and to design and assess the effectiveness of interventions. Better treatments are clearly needed.

Editorial: Weighing Benefits and Risks While Treating Irritability and Emotional Dysregulation in Autism.

Irritability and emotional dysregulation are challenging symptoms to treat in individuals with autism spectrum disorders (ASD). Thankfully, there are several multimodal treatment approaches for which there is some empirical evidence, with the number of emerging pharmacological options growing every day. Although much progress has been made in the overall treatment of ASD, the field has eluded innovating on treatments that definitively improve irritability and emotional dysregulation without also causing untoward side effects. Sampling biases, underpowered studies, and measurement problems are challenges that are also opportunities to iterate toward better and more personalized treatments. This editorial reviews the metanalytic syntheses of extant pharmacological options to target irritability and emotional dysregulation in ASD, providing some perspectives about the impact of the current limits of our knowledge, and attempts to conclude hopefully with a horizon of many promising directions for future research.

Sleep Disturbance, Irritability, and Response to Lurasidone Treatment in Children and Adolescents with Bipolar Depression.

BACKGROUND: The presence of mixed (subsyndromal hypomanic) symptoms may influence treatment outcomes in pediatric bipolar depression. This post-hoc analysis investigated "bridge" symptoms that have cross-sectional and predictive associations with depressive and manic symptom clusters in youth with bipolar depression. METHODS: The moderating effects of these bridge symptoms on the response to flexibly dosed lurasidone 20-80 mg/d compared to placebo treatment was analyzed in children and adolescents with bipolar I depression in a six-week, placebo-controlled, double-blind study followed by a 2-year, openlabel extension study of lurasidone. RESULTS: Sleep disturbances, assessed by "difficulty with sleep" (Children's Depression Rating Scale, Revised [CDRS-R] item 4) and "decreased need for sleep" (Young Mania Rating Scale [YMRS] item 4), and "irritability" (CDRS-R item-8, YMRS item 5) were identified as "bridge" symptoms and found to have replicable causal associations with depressive (CDRS-R total) and manic symptom clusters (YMRS total) at baseline and week-6. A greater improvement in overall depression severity at week 6 with lurasidone (vs. placebo) treatment was observed in the presence (vs. absence) of decreased need for sleep at study baseline, mediated in part by significant reductions from study baseline in decreased need for sleep and manic symptom severity. The absence of sleep disturbance and irritability in patients at open-label extension study baseline was associated with higher rates of sustained recovery (symptomatic and functional remission) over 6 months compared to patients with those symptoms at baseline (68% vs. 50%, Number Needed to Treat=6). CONCLUSION: Our findings suggest that sleep disturbance and irritability are cardinal symptoms that "bridge" between depressive and manic symptom clusters and influence treatment outcomes in youth with bipolar depression.