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Background: Multiple clinical trials of modern antipsychotics have failed in pediatric samples. One possibility for these failures is the use of a primary outcome measure that was developed for adults. Surprisingly, the psychometric properties of primary outcome measures have never been reported for a pediatric sample using modern methods. The present study’s aim is to use a pediatric sample to evaluate the psychometrics of the most used primary outcome measure in pediatric schizophrenia trials, the Positive and Negative Syndrome Scale (PANSS). Methods: To evaluate the factor structure, item characteristics, and treatment sensitivity of the PANSS in a pediatric sample, secondary analyses of PANSS data at baseline and weekly throughout an 8-week randomized double-blind study of three antipsychotic agents (registered and previously published) were conducted. Subjects were 118 youths receiving outpatient psychiatric treatment for schizophrenia spectrum disorders (Mage=14.26(2.41) years). Outcomes: A 10-item short form, keeping two strongest items for each factor, had r=.89 with the full-length scale. Each of the 5 2-item subscales has alphas ranging from .66 to .84. Item Response Theory (IRT) found that the 10-item scale and 2-item subscores had high reliability across the severity range typical of clinical trials. Criterion validity was high, with equal sensitivity to treatment effects. Interpretation: The short version eliminates weaker items in the pediatric population without loss of sensitivity to treatment effects and thus may be more appropriate for subsequent pediatric trials. Funding: NIMH funded the original protocol; NDA archived the data; Signant paid for secondary statistical analyses. Declaration of Interest: Dr. Findling receives or has received research support, acted as a consultant and/or has received honoraria from Acadia, Adamas, Aevi, Afecta, Akili, Alkermes, Allergan, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies, Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life Sciences,NIH, Neurim, Otsuka, PaxMedica, PCORI, Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx, Takeda, Teva, Tris, and Validus. Dr. Youngstrom has received royalties from the American Psychological Association and Guilford Press, consulted with Signant Health about psychological assessment, and received funding from NIMH. He is the founder and Executive Director of Helping Give Away Psychological Science (HGAPS.org). Dr. Sikich receives or has received research support from NIMH, NICHD, and Roche. She has received partial salary support from Tris. She has a patent submission through Duke University for a new formulation of intranasal oxytocin. Dr. Frazier receives or has received funding from NIMH, NICHD, Autism Speaks, Roche pharmaceuticals, and Fulcrum. Dr. McClellan receives or has received funding from NIMH. Dr. Daniel is an employee and equity holder in Signant Health. Dr. Busner is an employee and equity holder in Signant Health. Ethical Approval: The secondary analyses were reviewed and approved by the UNC Chapel Hill IRB.

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.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.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.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.

Objectives: This study benchmarks quality of life (QoL) of youth with bipolar disorder (BD) against healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. The relative impacts of depressive, (hypo)manic, mixed, and externalizing symptoms on QoL is tested for youth with BD. Method: 657 youth completed the Schedule for Affective Disorders and Schizophrenia for Children (KSADS), the KSADS depression and mania scales, the Parent General Behavior Inventory (PGBI), and the Child Behavior Checklist (CBCL). Youth-reported QoL was determined by the Revised Children Quality of Life Questionnaire (KINDL) and was compared to healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. Results: Youth with BD reported poorer QoL overall and on most subscales compared to healthy youth, youth with chronic medical conditions, youth with behavior disorders, and youth with other non-behavior/non-mood disorders. QoL in youth with BD did not differ significantly from QoL in youth with unipolar depression. Parent-report and interview-rated depressive symptoms were associated with decreases in Total QoL and all QoL subscales except Family. Externalizing symptoms were associated with decreases in Family QoL and increases in Friend QoL, and (hypo)manic symptoms were associated with increases in Emotional Well-Being QoL. Conclusions: Depressive symptoms may drive the decline in QoL causing youth with BD to rate their QoL worse than healthy youth, youth with chronic medical conditions, and youth with behavior disorders, but not worse than youth with unipolar depression.

Objectives: Pediatric studies of schizophrenia have relied on the 30-item Positive and Negative Syndrome Scale (PANSS30) as a primary outcome measure. There have been many efforts to create shorter versions of it to reduce costs and burden while keeping good reliability and validity. The present aim is to conduct a confirmatory investigation of the reliability and validity of 10 and 20 item abbreviated versions developed in a US-based NIMH pediatric sample that reflects the five-factor structure underlying the PANSS, adding more detailed examination of patient-level score reproducibility and extending the examination to a large, placebo-controlled, international pediatric trial. Methods: We applied the same psychometric and treatment sensitivity analyses as in Findling et al., (2023) to an adolescent schizophrenia paliperidone randomized placebo-controlled clinical trial, accessed via the YODA secure data environment (described in Singh et al., 2011). Analyses included confirmatory factor analyses, graded response models, ω reliability coefficients, tests of convergent criterion validity, sensitivity to change, and Bland-Altman plots to evaluate score reproducibility. Results: Using the paliperidone RCT dataset, the PANSS10 or 20-item vs. 30-item versions had similar average interitem correlations (.11 to .15), ωTotal reliabilities of .78 to .89 with reliability >.80 across patient presentations from mild residual symptoms to severe pathology, correlations of .92 and .98 with the 30-item total, partial eta-squared values for time, treatment, and time x treatment, and similar correlations with CGI-severity and CGAS ratings. Per-item scores differed by 0.04 points on average on the PANSS10 and 0.01 for the PANSS20 versus the PANSS30, all not significant.Conclusions: Strong reliability and validity findings for the PANSS10 and PANSS20 short forms were replicated in this large international placebo-controlled pediatric RCT. In addition to replication and generalization to an international sample, the findings extend prior work by being the first to apply modern reliability models (ω) for multi-factor composites, also using Bland-Altman methods to evaluate patient-level score reproducibility. Scores based on the PANSS10 or PANSS20 reproduce traditional scores with high fidelity, offering substantial savings in terms of time, cost, and burden, especially when used for tracking progress or outcomes.

Aggressive behavior is one of the most common reasons for referrals of youth to mental health treatment. While there are multiple publications describing different types of aggression in children, it remains challenging for clinicians to diagnose and treat aggressive youth, especially those with impulsively aggressive behaviors. The reason for this dilemma is that currently several psychiatric diagnoses include only some of the common symptoms of aggression in their criteria. However, no single diagnosis or diagnostic specifier adequately captures youth with impulsive aggression (IA). Here we review select current diagnostic categories, including behavior and mood disorders, and suggest that they do not provide an adequate description of youth with IA. We also specifically focus on the construct of IA as a distinct entity from other diagnoses and propose a set of initial, provisional diagnostic criteria based on the available evidence that describes youth with IA to use for future evaluation.

Identifying substance use disorders (SUDs) early and accurately improves case formulation and treatment. Previous studies have investigated validity and reliability of the Child and Adolescent Symptom Inventory (CASI) for anxiety, mood, and behavior problems. The present study's aim was to test if the embedded CASI Substance Use (SU) subscale can discriminate adolescents and young adults (AYA) with and without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework.

Objectives: Irritability and anhedonia are cardinal symptoms of depression for children and adolescents. However, anhedonia may be more strongly associated with illness severity compared with irritability. The present study evaluated the impact of irritability and anhedonia on symptom severity and functional impairment among depressed children and adolescents. Methods: Participants were 383 children and adolescents presenting for outpatient treatment at a community mental health center or academic medical center. Children and adolescents were diagnosed with unipolar depression or bipolar disorder. Regression models predicted depression severity and functional impairment from irritability and anhedonia after covarying age, gender, depressive and hypomanic symptoms, and diagnosis. Results: Greater irritability and anhedonia were associated with more severe depression symptoms. Greater irritability, but not anhedonia, was associated with lower global functioning and family quality of life (QoL), and more externalizing problems. Greater anhedonia was associated with lower overall, emotional, self-esteem, and social QoL. Neither irritability nor anhedonia was associated with school or physical QoL, nonsuicidal self-injury, suicidal ideation, number of comorbid diagnoses, or internalizing problems. Conclusions: Irritability was associated with more markers of depression severity, whereas anhedonia was associated with indicators of functional impairment. This study used a cross-sectional observational design and therefore cannot provide information about cause and effect relationships between variables. Irritability and anhedonia were derived from their respective subscales of the General Behavior Inventory and included only caregiver-reported symptoms but not child- or adolescent-reported symptoms. Identifying the impact of specific symptoms of depression may assist clinicians in delivering more individualized interventions to target symptoms that result in greater impairment.

Although hopelessness has been linked to depression for centuries, the diagnostic criteria for depression are inconsistent with regard to the status of hopelessness. Most research on hopelessness and depression has focused on adults. The current study examined this relation in children and adolescents. Integrative data analyses with a pooled sample (N = 2466) showed that clinical levels of hopelessness multiplied the odds of having a clinical diagnosis of depression 10-fold. Conversely, not having clinical levels of hopelessness multiplied the odds of endorsing no clinical level of depressive symptoms 28-fold. Moreover, results differed by levels of depression: (a) among youths with clinical levels of depression, hopelessness was associated with six depressive symptoms; (b) among youths without clinical levels of depression, hopelessness was associated with nine depressive symptoms. We found that hopelessness helps to explain the heterogeneity of depressive presentations. Our finding supports the consideration of hopelessness in the diagnosis (if not treatment and prevention) of depression in children and adolescents. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

biObjective:/i/bTo describe the longer-term effectiveness, safety, and tolerability of open-label ziprasidone in children and adolescents with bipolar I disorder (BD-I).biMethods:/i/bA subset of 23 participants aged 10-17 years, who were previously treated in a multi-site, 4-week randomized controlled trial received open-label ziprasidone (20-80 mg twice a day) for up to 26 weeks.biResults:/i/bThe most common adverse events (AEs) were fatigue (30%), somnolence (17%), and nausea (13%). Effects on weight, body mass index, and metabolic parameters (glucose, cholesterol, and triglycerides) were minimal. No participant had a Fridericia-corrected QT interval ≥ 460 msec or a change from baseline of ≥60 msec, and there were no cardiac-related AEs. Both the participants who continued ziprasidone and those who initiated ziprasidone in the open-label extension showed improvements in their symptoms of mania.biConclusions:/i/bThe overall findings of the study are consistent with the accumulating knowledge on the safety profile of ziprasidone in the acute and long-term treatment of children and adolescents with BD-I, in the midst of a manic episode. ClinicalTrial.gov ID: NCT03768726.

Sleep is crucial to overall health, and its disruption is both associated with and a diagnostic symptom of multiple mental illnesses. Several broad assessment instruments embed sleep-related items in scales about other constructs. Using these items as their own scale has not yet been validated for differentiating among psychiatric disorders or measuring severity of associated sleep problems. This study reports evidence of reliability and validity for using sleep items on the Child Behavior Checklist (CBCL) and Parent General Behavior Inventory (P-GBI) as extracted scales across two distinct clinical contexts.Participants were youth aged 5-18 years and their parents recruited from both an academic medical center (N=759) and an urban community health center (N=618). Primary caregivers completed the CBCL and P-GBI as part of a more comprehensive outpatient evaluation.Across both community and academic samples, P-GBI sleep subscales were more reliable and consistent than CBCL sleep subscales, showed greater coverage of sleepiness and insomnia constructs, were better at discriminating individuals within a wider range of sleep complaints, and showed significant correlation with mood disorder diagnoses. P-GBI Insomnia had the highest accuracy for identifying bipolar disorders, while Lassitude was better at identifying unipolar depression. The CBCL sleep items did not form a cohesive scale.The P-GBI sleep items provide a brief, reliable measure for assessing distinct dimensions of sleep complaints and detecting mood symptoms or diagnoses related to the youth’s sleep functioning, making them a useful addition to clinical practice.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Supplemental digital content is available in the text., Purpose This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12–17 years). Methods Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression—Improvement score at EOS, CFB at EOS in Conners 3—Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale—Parent Total average score. Results In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression—Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3—Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale—Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event–related discontinuation rates were

Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyper-activity disorder (ADHD), represent a group of conditions that manifest early in child development and produce impairments across multiple domains of functioning. Although a number of pharmacological and psychosocial treatments exist to improve the symptoms associated with these syndromes, treatment advances have lagged. The Precision Medicine Initiative was launched with the goal of revolutionizing medicine by progressing beyond the historical one-size-fits-all approach. In this review, we evaluate current research efforts to personalize treatments for ASD and ADHD. Most pharmacogenetic testing has focused on the cytochrome P450 enzyme family with a particular focus on CYP2D6 and CYP2C19 , which are genes that produce an enzyme that acts as a key metabolizer of many prescribed medications. This article provides an update on the state of the field of pharmacogenetics and “therapy-genetics” in the context of ASD and ADHD, and it also encourages clinicians to follow US Food and Drug Administration recommendations regarding pharmacogenetic testing. [ Psychiatr Ann . 2021;50(4):175–184.]

The present study examines the relationship between Perceived Criticism (PC) and Sensitivity to Criticism (SC) in youth with Bipolar Spectrum Disorder (BPSD), their symptomatic experiences, and family functioning. We hypothesized that findings for youth would be consistent with findings for adults indicating that PC and SC would be associated with a worse clinical presentation, and that associations between family criticism and sensitivity and youth symptoms would be stronger for youth with BPSD than with other clinical diagnoses. We examined 828 youths ages 4-18 years (M=10.9, SD=3.4) and their caregivers from diverse ethnic and socioeconomic backgrounds using the Longitudinal Expert evaluation of All Data (LEAD) diagnoses (Spitzer, 1983), the parent-reported General Behavior Inventory (Youngstrom et al., 2001), The Perceived Criticism Scale (Hooley & Teasdale, 1989), and the Family Assessment Device (Epstein et al., 1983). We found significant positive association between parent reports of youth criticalness and more severe manic and depression symptoms, greater mood lability, higher suicidality, and worse overall functioning. Youth with BPSD were significantly more critical and had higher SC than youth without BPSD. Interactions between BPSD and family criticalness and sensitivity were found in their links with youth symptoms. Negative associations between criticism and sensitivity and youth global family functioning were significant only for youth with BPSD. The positive association between criticism and youth mood lability was significant only for youth with BPSD. Our findings suggest that family factors and interactional patterns impact and are influenced by functioning in youth with BPSD and that family-based treatments should be considered routinely with these youth.

Rates of treatment utilization decline as adolescents make the transition to adulthood even though young adults are particularly vulnerable to the negative outcomes of untreated mental illness. Although a variety of factors have been explored to explain decreased treatment utilization in this age group, previous research has almost exclusively employed cross-sectional methods rather than following a group of youth as they enter adulthood. The current study aims to address this methodological limitation by assessing treatment utilization in emerging adults who began participating in a longitudinal study during childhood. One hundred and thirty seven youth who turned 18 during the 96-month follow-up period were included in the current analyses. Demographic and socioeconomic variables such as sex, race, and insurance status and clinical variables such as psychiatric diagnoses and perceptions of treatment effectiveness were investigated as factors potentially associated with outpatient treatment use before and after age 18. Prior to age 18, youth reported using outpatient services at 75% of their visits, but after age 18, outpatient treatment utilization dropped to around 50%. White race, increased parental stress, and increased parental perception of treatment usefulness were associated with greater treatment use prior to age 18, whereas only increased youth perception of symptom-related dysfunction were associated with increased treatment use after age 18. Findings point to the importance of including youth preferences and perceptions of dysfunction in treatment decisions across adolescence in order to optimize treatment use following the transition to adulthood.

The status of irritability as a feature of mood and behavior disorders in children has been a topic of much debate. From a disruptive behavior disorder (DBD) perspective, irritability has emerged as a central feature of Oppositional Defiant Disorder (ODD) and has been uniquely associated with symptoms of depression and anxiety. From the perspective of mood, in particular pediatric bipolar disorder (PBD), there is less consensus on what kind of irritability should be considered a symptom of mania or even if irritability should be considered at all. Part of the problem with characterizing irritability may be that the construct has been too narrowly defined. The present work aims to clarify the boundaries of irritability in youth by using exploratory factor analysis (EFA) on a previously unpublished measure of mood and behavior problems in youth to find which parent-reported symptoms are most closely related. Data came from the standardization sample of a previously unpublished measure – the Pediatric Bipolar and Related Disorders Scale (PBiRDS) – and comprise a nationally-representative sample (N = 1163) of parent-report items (k = 167) measuring symptoms related to irritability, hypomania, internalizing symptoms, disruptive behavior problems, and other related constructs. Parents also provided demographic and health-history information, which was used as evidence for scale validity through criterion correlations. Six factors were identified, all with high internal consistency and criterion correlations that supported the convergent validity of the scales. The factor with the most items included those related to dysregulated mood and emotions, which factored separately from hypomania, depression, and attention problems. These results suggest that irritability might be most closely associated with externalizing behavior, however high inter-factor correlations support the observation that irritability plays a role in mood disorders as well.

It is vital to identify substance use disorders (SUDs) in youths and adults early and accurately. Previous studies have investigated the validity and reliability of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR) for other related anxiety, mood, and behavior problems. The present study tested if the CBCL and YSR substance use items can discriminate adolescents with versus without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework.

BackgroundMinimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia.MethodsPatients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score.ResultsAbout 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of −15.6 at week 52 and −18.4 at week 104.ConclusionIn adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

Objective: To evaluate the efficacy and long-term safety of vilazodone in children and adolescent outpatients with major depressive disorder (MDD). Methods: Children and adolescents aged 7–17 years of age with MDD were randomized 2:2:1 to 8 weeks of double-blind placebo, vilazodone 15 or 30 mg/day or fluoxetine 20 mg/day, respectively. The primary and secondary efficacy outcomes, respectively, were change from baseline to week 8 in Children's Depression Rating Scale-Revised (CDRS-R) score total score and Clinical Global Impressions-Severity (CGI-S) score analyzed using a mixed model for repeated measurement approach. Patients who completed the 8-week randomized controlled trial (RCT), as well as new (de novo) patients, could participate in a 26-week, vilazodone-only, open-label extension (OLE) study. Results: The RCT enrolled 473 patients (60% female) with an average age of 13 years. Change in CDRS-R and CGI-S scores from baseline to week 8 did not differ between patients who received vilazodone and those randomized to placebo. The least-squares mean change from baseline in CDRS-R scores was similar for vilazodone and placebo (−20.7 vs. −20.3, p = 0.77; least-squares mean difference [LSMD] = −0.40). For fluoxetine, the LSMD versus placebo was −2.3 (p = 0.14). The OLE enrolled 330 patients (60% female) with an average age of 13–14 years. Overall, no new safety concerns were identified compared to what is known in adults. Conclusions: Similar improvements in depressive symptoms were observed in all arms. This study does not support the efficacy of vilazodone 15 or 30 mg/day for pediatric patients with MDD. No new or unexpected safety concerns were detected during the RCT or OLE studies.

Background Despite the well-documented negative impact of untreated bipolar illness, approaches to early intervention in childhood-onset bipolar and related disorders are not well delineated. Methods We reviewed the extant treatment literature on children at high risk for bipolar disorder, with definitions based on family history, childhood adversity, and prodromal symptoms. Results A panoply of approaches have been described, but most interventions are based on an inadequate database to support their routine implementation. We classify early stage interventions as a function of their safety and tolerability with the hope that these might generate more rigorous study and a stronger database. Limitations Critics may rightly argue that identifying viable treatment methods is premature given our lack of ability to reliably predict illness trajectory in very young children. However, many of the psychosocial and pharmacological interventions we present could have nonspecific positive effects across a variety of symptoms, syndromes, and diagnoses, further enhancing the rationale for more rigorous study. Conclusions Early stage interventions have the potential to improve functioning in prodromal illness and exert long-term positive effects on the course of illness. Many of the safest interventions deserve consideration for implementation and dissemination studies.

Objective: To evaluate short forms of free self-report mania and depression scales, evaluating their reliability, content coverage, criterion validity, and diagnostic accuracy.Method: Youths age 11...

Objective Previous studies of Tai Chi or mindfulness-based interventions in attention-deficit/hyperactivity disorder (ADHD) have relied on self- or parent-reported outcome measures; however, there is a critical need for the validation of objective biomarkers of treatment. Therefore, we implemented a mindful movement intervention for children with ADHD, hypothesizing that an ADHD-relevant motor control measure could serve as a predictive biomarker of treatment-related improvement. Methods Thirty-four participants were included, 8 to 12 year olds diagnosed with DSM-5 ADHD. Participants engaged in the mindful movement treatment, an 8-week program with 2 classes a week for 60 minutes. At pre- and post-treatment, ADHD symptoms and associated impairment and motor control via the Physical and Neurological Examination for Subtle Signs (PANESS) were assessed. Results The results showed a significant reduction for PANESS Gaits and Station (p ≤ 0.001), total overflow (p = 0.009), and total score (p = 0.001) after treatment, with the largest effect for Gaits and Stations. The results also showed a significant reduction in symptoms of inattention (p ≤ 0.001), hyperactivity/impulsivity (p ≤ 0.001), oppositional defiant disorder (p = 0.001), and executive dysfunction (p ≤ 0.001). There were significant positive correlations between change in PANESS Gaits and Stations and change in both inattentive (p = 0.02) and hyperactive/impulsive symptoms (p = 0.02). There was also a significant positive correlation between change in the PANESS total score and change in inattentive (p = 0.007) and hyperactive/impulsive symptoms (p = 0.042). The change in the PANESS total score (β = 0.295, p = 0.002) predicted post-treatment ADHD severity above the change in inattentive or hyperactive/impulsive symptoms. Conclusion The results suggest the effectiveness of a mindful movement treatment on ADHD symptoms and suggest the PANESS as a candidate motor biomarker for future mindful movement trials. Clinical trial registration ClinicalTrials.gov, NCT02234557, https://clinicaltrials.gov/ct2/show/NCT02234557.

Objectives: Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4–5 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores ≥28 (boys) or ≥24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Results: Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were −1.1 (7.31) and 1.5 (6.93) mmHg and −0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was −26.1 (−32.2 to −20.0). Pharmacokinetic parameters of d-amphetamine, a major active metabolite of LDX, were characterized: d-amphetamine exposure increased with LDX dose; mean tmax and t1/2, respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. Conclusions: In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6–17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.

Schizophrenia is a leading cause of disease burden in youth and can significantly impair an adolescent’s peer and familial relationships and academic functioning. Therefore, safe and effective treatments are needed. This article reviews the pharmacological treatment of adolescents with schizophrenia, when possible, with a focus on the past five years of research. There are relatively few randomized controlled trials (RCTs) and head-to-head trials informing selection of a medication in pediatric schizophrenia. However, recent literature focusing on the efficacy and tolerability of atypical antipsychotics has led to the Food and Drug Administration (FDA) approval of multiple agents, specifically risperidone, olanzapine, quetiapine, aripiprazole, paliperidone, and lurasidone, for the treatment of pediatric schizophrenia. Asenapine has also been studied in a large RCT within the past five years, but participants randomized to asenapine treatment did not do statistically significantly better than those assigned to receive placebo. Comparison RCTs on clozapine have indicated benefit in treatment-resistant pediatric schizophrenia, but at the cost of significant side effect burden. Common adverse events with atypical antipsychotics include weight gain, akathisia, hyperprolactinemia, and somnolence. Atypical antipsychotics remain first-line treatment for children and adolescents with early onset schizophrenia. However, further study is required to develop more effective and better tolerated treatment options, and in addition to pharmacologic management, current guidelines recommend combination treatment with psychotherapy and psychoeducation.

Objective: To explore blinded observational outcomes in the Treatment of Severe Childhood Aggression (TOSCA) study. Methods: During a 9-week acute trial, children with severe physical aggression and attention-deficit/hyperactivity disorder received parent training + titrated psychostimulant for 3 weeks, and those who failed to show an optimal response during Week 4 through Week 6 received in addition either randomly assigned placebo (Basic treatment) or titrated risperidone (Augmented treatment). Child and parent behaviors were videotaped in a Standardized Observation Analogue Procedure (SOAP) designed to elicit problems and strengths in child and parent interactions. SOAPs were collected at baseline and Week 9 and 52 follow-up. Results: During the acute 9-week trial, augmented treatment was associated with better outcomes than basic treatment for 3 of 13 measures: increased Child Compliance (p = 0.004; significant after correction for multiple tests), greater use of positive Parent Reinforcement (p = 0.03), and more Shared Enjoyment (p = 0.04). At follow-up, when medication was no longer by randomized assignment, parents used more Alpha Commands and displayed fewer Parent Negative Behaviors, and the dyads showed more Shared Enjoyment regardless of original randomization. Thus, there were better parent-child interactions with Augmented treatment, and interactions improved overall at follow-up regardless of original treatment assignment. Conclusions: The SOAP demonstrated sensitivity to behavior changes between short-term treatments for a few (but not most) measures. The acute treatment differences for Child Compliance and Child Negative Behavior are generally consistent with the moderate superiority of Augmented over Basic treatment previously reported for the primary study outcome.

An increasing number of antipsychotic medications have demonstrated efficacy in randomized placebo-controlled trials in the treatment of children and adolescents with schizophrenia. This review summarizes and synthesizes relevant antipsychotic medication studies, with particular emphasis on second-generation agents, and discusses other clinical considerations that may influence medication selection. With the exception of clozapine demonstrating superior efficacy in the improvement of psychotic symptoms in treatment-resistant patients, many antipsychotic agents have been shown to be similarly efficacious, including first-generation medications. Consideration of the side-effect profile, which can differ substantially from medication to medication, is essential when choosing treatment options.

Approximately 60% of patients with bipolar disorder who present with depression are misdiagnosed as having recurrent unipolar depression, which may lead to inappropriate treatment and potential worsening of symptoms. Bipolar depression in youth has a negative effect on numerous domains of life. Early treatment is crucial, yet diagnosis is difficult. The standard of treatment often requires life-long psychopharmacologic management, and treatments have various adverse effects that should be considered when the clinician tailors the regimen for each patient. By facilitating effective communication with patients, referring to diagnostic criteria, and using assessment tools before diagnosis and as treatment continues, clinicians can identify indicators of the disorder, recommend individualized treatment, and help patients work toward greater success in relationships, at home, and at school or work.

Reason for Review: The COVID-19 pandemic has affected the way healthcare services are provided and created challenges to the delivery of behavioral health in the inpatient setting. Here, we present our front-line experience of infection prevention for the psychiatric patient in the COVID era. Recent Findings: There are unique challenges surrounding COVID-19 precautions within inpatient psychiatric settings. The challenges presented to psychiatric care by COVID-19 begin in the emergency department and follow the patient through the continuum of care once admitted to the facility. Unit infrastructure, patient population, treatment modalities, staffing considerations, and discharge planning are distinct instances where COVID-19 protocols that are well-suited for other hospital settings necessitate revision for psychiatric settings. Summary: The purpose of this communication is to add to the current body of shared experience of infection prevention for the psychiatric patient in the COVID-19 era.

To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD).After 4 weeks of single-blind lead-in treatment with a Brief Psychosocial Intervention (BPI) plus placebo, patients (aged 12-17 years) with MDD (DSM-5) who did not meet response criteria (Children's Depression Rating Scale-Revised [CDRS-R]; total score ≥40 plus 40% reduction and a Parent Global Assessment score2) were randomized 1:1:1:1 to 8 weeks of BPI plus double-blind treatment with vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. The primary endpoint was change from randomization in CDRS-R total score at week 8; the primary comparison was the average effect of 2 vortioxetine doses vs placebo.Of 784 patients enrolled in the lead-in, 616 were randomized. At week 8, the mean change in CDRS-R total score averaged for vortioxetine doses was -18.01 (SE = 0.98) and the mean difference vs placebo was 0.21 (P = .878; not significant). For fluoxetine, the mean change in CDRS-R total score was -21.95 and the mean difference vs placebo was -3.73 (P = .015). Treatment-emergent adverse events occurring in ≥5% of patients in either vortioxetine arm and at least twice more frequently than placebo were nausea, headache, vomiting, and dizziness.Patients in all groups showed reduction in CDRS-R scores by the end of the study, with no difference between combined doses of vortioxetine and placebo. The primary endpoint was not met, thereby rendering the study negative. The overall favorable safety profile of vortioxetine in an adolescent patient population was consistent with that seen in adults.Active Reference (Fluoxetine) Fixed-Dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD); http://clinicaltrials.gov; NCT02709746.

Background Treatment of a child who has an anxiety disorder usually begins with the question of which treatment to start first, medication or psychotherapy. Both have strong empirical support, but few studies have compared their effectiveness head-to-head, and none has investigated what to do if the treatment tried first isn’t working well—whether to optimize the treatment already begun or to add the other treatment. Methods This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages. In Stage 1, children will be randomized to fluoxetine or Coping Cat Cognitive Behavioral Therapy (CBT). In Stage 2, remitters will continue maintenance-level therapy with the single-modality treatment received in Stage 1. Non-remitters during the first 12 weeks of treatment will be randomized to either [1] optimization of their Stage 1 treatment, or [2] optimization of Stage 1 treatment and addition of the other intervention. After the 24-week trial, we will follow participants during open, naturalistic treatment to assess the durability of study treatment effects. Patients, 8–17 years of age who are diagnosed with an anxiety disorder, will be recruited and treated within 9 large clinical sites throughout greater Los Angeles. They will be predominantly underserved, ethnic minorities. The primary outcome measure will be the self-report score on the 41-item youth SCARED (Screen for Child Anxiety Related Disorders). An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first (“Main Effect 1”). Then, among Stage 1 non-remitters, we will compare non-remitters randomized to optimization of their Stage 1 monotherapy versus non-remitters randomized to combination treatment (“Main Effect 2”). The interaction of these main effects will assess whether one of the 4 treatment sequences (CBT➔CBT; CBT➔med; med➔med; med➔CBT) in non-remitters is significantly better or worse than predicted from main effects alone. Discussion Findings from this SMART study will identify treatment sequences that optimize outcomes in ethnically diverse pediatric patients from underserved low- and middle-income households who have anxiety disorders. Trial registration This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275.