Psychopharmacological Treatment Algorithms of Manic/Mixed and Depressed Episodes in Pediatric Bipolar Disorder.

Introduction: Pediatric bipolar disorder (PBD) is a severe psychiatric illness diagnosed before the age of 18, which is associated with extreme shifts in mood characterized by manic and depressive episodes. In 2005, AACAP published algorithms to guide pharmacological treatment of manic/mixed episodes associated with PBD. At that time, lithium was the only Food and Drug Administration (FDA)-approved treatment for pediatric bipolar manic/mixed episodes. The goal of this article is to review evidence that has emerged since the AACAP algorithm in 2005. Methods: Literature searches were conducted through PubMed and limited to studies published between 2005 and 2021, using keywords that focused on randomized controlled trials (RCTs) for available psychopharmacological medications. In addition, the authors conducted in-depth searches for articles providing evidence for agents included in the 2005 AACAP algorithm. Results: Since the publication of the AACAP algorithm in 2005, multiple RCTs have been conducted in PBD, leading to FDA approval of five medications (aripiprazole, asenapine, olanzapine, quetiapine, and risperidone) for the treatment of manic/mixed episodes and two medications (lurasidone and olanzapine-fluoxetine combination) for the treatment of depressed episodes. Divalproex sodium and oxcarbazepine were studied in pediatric RCTs and failed to separate from placebo. Conclusions: We offer an update to the 2005 AACAP algorithms for the treatment of pediatric bipolar mixed/manic episodes and added an evidence-based algorithm for the treatment of depression in PBD. In addition to treatment algorithms, we review current evidence for efficacy of agents proposed in the AACAP algorithm and provide tables summarizing medication side effects and efficacy.

Development of a Symptom-Focused Model to Guide the Prescribing of Antipsychotics in Children and Adolescents: Results of the First Phase of the Safer Use of Antipsychotics in Youth (SUAY) Clinical Trial.

OBJECTIVE: To develop a new approach to prescribing guidelines as part of a pragmatic trial, Safer Use of Antipsychotics in Youth (SUAY; ClinicalTrials.gov Identifier: NCT03448575), which supports prescribers in delivering high-quality mental health care to youths. METHOD: A nominal group technique was used to identify first- to nth-line treatments for target symptoms and potential diagnoses. The panel included US pediatricians, child and adolescent psychiatrists, and psychopharmacology experts. Meeting materials included information about Medicaid review programs, systematic reviews, prescribing guidelines, and a description of the pragmatic trial. Afterward, a series of 4 webinar discussions were held to achieve consensus on recommendations. RESULTS: The panel unanimously agreed that the guideline should focus on target symptoms rather than diagnoses. Guidance included recommendations for first- to nth-line treatment of target mental health symptoms, environmental factors to be addressed, possible underlying diagnoses that should first be considered and ruled out, and general considerations for pharmacological and therapeutic treatments. CONCLUSION: Prescribing guidelines are often ignored because they do not incorporate the real-world availability of first-line psychosocial treatments, comorbid conditions, and clinical complexity. Our approach addresses some of these concerns. If the approach proves successful in our ongoing pragmatic trial, Safer Use of Antipsychotics in Youth (SUAY), it may serve as a model to state Medicaid programs and health systems to support clinicians in delivering high-quality mental health care to youths. CLINICAL TRIAL REGISTRATION INFORMATION: Safer Use of Antipsychotics in Youth; http://clinicaltrials.gov/; NCT03448575.

In Reply.

Thank you for the opportunity to respond to the letter, "Thoughtful Clinical Use of Pharmacogenetics in Child and Adolescent Psychopharmacology." We appreciate the thoughtful consideration by Ramsey et al.1 of the American Academy of Child and Adolescent Psychiatry (AACAP) policy statement on the Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adolescents.2 In this reply, we will highlight many of the important points that the authors have included and will also express our concerns regarding some of the authors' conclusions in light of the current level of evidence.

Closing the gap: unmet needs of individuals with impulsive aggressive behavior observed in children and adolescents.

Impulsive aggressive (IA, or impulsive aggression) behavior describes an aggregate set of maladaptive, aggressive behaviors occurring across multiple neuropsychiatric disorders. IA is reactive, eruptive, sudden, and unplanned; it provides information about the severity, but not the nature, of its associated primary disorder. IA in children and adolescents is of serious clinical concern for patients, families, and physicians, given the detrimental impact pediatric IA can have on development. Currently, the ability to properly identify, monitor, and treat IA behavior across clinical populations is hindered by two major roadblocks: (1) the lack of an assessment tool designed for and sensitive to the set of behaviors comprising IA, and (2) the absence of a treatment indicated for IA symptomatology. In this review, we discuss the clinical gaps in the approach to monitoring and treating IA behavior, and highlight emerging solutions that may improve clinical outcomes in patients with IA.

Improving Youth Suicide Risk Screening and Assessment in a Pediatric Hospital Setting by Using The Joint Commission Guidelines.

OBJECTIVES: Hospitals accredited by The Joint Commission (TJC) are now required to use a validated screening tool and a standardized method for assessment of suicide risk in all behavioral health patients. Our aims for this study were (1) to implement a TJC-compliant process of suicide risk screening and assessment in the pediatric emergency department (ED) and outpatient behavioral health clinic in a large tertiary care children's hospital, (2) to describe characteristics of this population related to suicide risk, and (3) to report the impact of this new process on ED length of stay (LOS). METHODS: A workflow using the Columbia Suicide Severity Rating Scale was developed and implemented. Monthly reviews of compliance with screening and assessment were conducted. Descriptive statistics were used to define the study population, and multivariable regression was used to model factors associated with high suicide risk and discharge from the ED. ED LOS of behavioral health patients was compared before and after implementation. RESULTS: Average compliance rates for screening was 83% in the ED and 65% in the outpatient clinics. Compliance with standardized assessments in the ED went from 0% before implementation to 88% after implementation. The analysis revealed that 72% of behavioral health patients in the ED and 18% of patients in behavioral health outpatient clinics had a positive suicide risk. ED LOS did not increase. The majority of patients screening at risk was discharged from the hospital after assessment. CONCLUSIONS: A TJC-compliant process for suicide risk screening and assessment was implemented in the ED and outpatient behavioral health clinic for behavioral health patients without increasing ED LOS.

Psychiatric Diseases in Children and Adolescents.

Pharmacotherapy of psychiatric illnesses in children and adolescents has grown significantly over the last few decades. However, the body of research examining pharmacological treatments for psychiatric illnesses is much smaller in children and adolescents than it is in adults. As most treatments for psychiatric disorders are more effective if started early in the course of illness, treatment options for youth are especially important in order to ensure better treatment outcomes. This chapter discusses currently approved medications to treat psychiatric disorders in children and adolescents. Research on medications that may be effective treatments but are not yet FDA approved is also discussed. The medications are broken down into major categories used in youth with psychiatric disorders including antidepressants, mood stabilizers, ADHD medications, and antipsychotics.

Maladaptive Aggression: With a Focus on Impulsive Aggression in Children and Adolescents.

Objective: Aggressive behavior is among the most common reasons for referral to psychiatric clinics and confers significant burden on individuals. Aggression remains poorly defined; there is currently no consensus on the best ways to recognize, diagnose, and treat aggression in clinical settings. In this review, we synthesize the available literature on aggression in children and adolescents and propose the concept of impulsive aggression (IA) as an important construct associated with diverse and enduring psychopathology. Methods: Articles were identified and screened from online repositories, including PubMed, PsychInfo, the Cochrane Database, EMBase, and relevant book chapters, using combinations of search terms such as "aggression," "aggressive behavio(u)r," "maladaptive aggression," "juvenile," and "developmental trajectory." These were evaluated for quality of research before being incorporated into the article. The final report references 142 sources, published from 1987 to 2019. Results: Aggression can be either adaptive or maladaptive in nature, and the latter may require psychosocial and biomedical interventions when it occurs in the context of central nervous system psychopathology. Aggression can be categorized into various subtypes, including reactive/proactive, overt/covert, relational, and IA. IA in psychiatric or neurological disorders is reviewed along with current treatments, and an algorithm for systematic evaluation of aggression in the clinical setting is proposed. Conclusions: IA is a treatable form of maladaptive aggression that is distinct from other aggression subtypes. It occurs across diverse psychiatric and neurological diagnoses and affects a substantial subpopulation. IA can serve as an important construct in clinical practice and has considerable potential to advance research.

A Novel Assessment Tool for Impulsive Aggression in Children with Attention-Deficit/Hyperactivity Disorder.

Objective: To establish the validity and reliability of a provisional 30-item impulsive aggression (IA) diary in children (ages 6-12 years, inclusive) with attention-deficit/hyperactivity disorder (ADHD). Methods: The provisional 30-item IA diary was administered for 14 days to parents of children with ADHD and IA symptoms (n = 103). Key inclusion criteria: confirmed ADHD diagnosis; signs of IA as measured by a Retrospective-Modified Overt Aggression Scale (R-MOAS) score ≥20 and an Aggression Questionnaire score of -2 to -5. Analyses included inter-item correlations, exploratory factor analysis (EFA), item response theory (IRT) modeling, internal consistency, test-retest reliability (TRT), concurrent validity (estimated by correlation between the IA diary and the R-MOAS/Nisonger Child Behavior Rating Form), and known-groups methods. Results: The prevalence rates of 15 (50.0%) items were found to be too low (<1%) for analysis; three items with prevalence rates ≤1% were retained, as content validity was deemed high by clinical experts. The remaining 12 behavior items had prevalence rates of 2.7%-73.6%. EFA and IRT models confirmed two subdomains in the IA diary included within a general domain of IA behavior frequency, yielding a single total behavioral frequency score (TBFS). Internal consistency was high for this TBFS (marginal reliability = 0.86 and α = 0.73). TRT for the TBFS, based on the intraclass correlation coefficient, was 0.8. Concurrent validity of TBFS with R-MOAS ranged from r = 0.49 to r = 0.62. Conclusion: The final 15-item IA diary is a reliable, psychometrically validated IA measurement tool that will allow clinicians and researchers to assess the frequency of IA behavior.

Application of the Impulsive Aggression Diary in Adolescents with Attention-Deficit/Hyperactivity Disorder.

Objective: Impulsive aggression (IA) is a maladaptive form of aggressive behavior that is an associated feature of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). As one of the most common forms of aggressive behavior, IA is a serious clinical concern. Recognition, monitoring, and management of IA symptoms are complicated by the lack of IA-specific psychometric instruments and evidence-based treatments. A recently developed electronic observer-reported outcome instrument has been validated in children for monitoring the frequency of 15 IA-related behaviors in the context of ADHD. This study seeks to first determine if the behaviors included in the pediatric IA diary are applicable to adolescents with ADHD, and second, compare the reliability of adolescent versus parent reporters. Methods: We evaluated the utility of the pediatric IA diary through concept elicitation and cognitive interviews with 17 pairs of parents and adolescents (aged 13-17 years) with IA and ADHD, supplemented with 15 new behaviors potentially applicable to adolescents. Results: The behaviors most frequently reported by adolescents included arguing (93.8%), raising their voice/shouting/yelling (93.8%), hitting others (87.5%), slamming (87.5%), pushing/shoving (81.3%), breaking (75.0%), fighting (75.0%), throwing (75.0%), and cursing (68.8%). The behaviors most commonly reported by parents included raising their voice/shouting/yelling (94.1%), arguing (88.2%), being disrespectful/mean/rude (88.2%), slamming (88.2%), throwing (88.2%), cursing (82.4%), hitting others (82.4%), pushing/shoving (82.4%), breaking (76.5%), name-calling (76.5%), and threatening (70.6%). Of all commonly reported behaviors, only being "disrespectful/mean/rude" and "breaking" are not part of the pediatric IA diary, likely due to the imprecision of these terms. No significant usability issues were found for the IA diary device. Conclusions: These findings suggest that the 15-item pediatric IA diary should be applicable to adolescent populations to appropriately characterize IA behaviors in individuals with ADHD. Furthermore, this study indicated that parents may be more reliable reporters of IA behavior than adolescents.

A proposed anti-maladaptive aggression agent classification: improving our approach to treating impulsive aggression.

Proper drug categorization enables clinicians to readily identify the agents most appropriate for patients in need. Currently, patients with maladaptive aggression do not all always fall into a single existing diagnostic or treatment category. Such is the case for those with impulsive aggression (IA). IA is an associated feature of numerous neuropsychiatric disorders, and can be described as eruptive, aggressive behavior or a 'short fuse'. Although agents from a broad spectrum of drug classes have been used to treat maladaptive aggression, few have been tested distinctly in patients with IA, and there is no drug specifically indicated by the US Food and Drug Administration (US FDA) for IA. Further, current treatments often fail to sufficiently treat IA symptomatology. These issues create an unclear and inadequate treatment path for patients. Here we will propose the establishment of a class of anti-maladaptive aggression agents to begin addressing this clinical issue. The development of such a class would unify the various drugs currently used to treat maladaptive aggression and streamline the treatment approach towards IA. As an important case example of the range of candidate drugs that could fit into a new anti-maladaptive aggression agent category, we will review an investigational IA pharmacotherapy. SPN-810 (extended-release molindone) is currently being investigated as a novel treatment for children with IA and ADHD. Based on these studies we will review how SPN-810 may be well suited for a new, anti-maladaptive aggression drug class and more precisely, a proposed subgroup of IA modulators. The goal of this review is to begin improving the identification of and therapeutic approach for maladaptive aggression as well as IA through more precise anti-maladaptive aggression agent categorization.

A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders.

OBJECTIVES: In this 6-month open-label extension (OLE) of NCT01491035 (a 14-day, open-label, pharmacokinetic/safety lead-in study), the long-term safety and tolerability of vortioxetine (5-20 mg/day) were investigated in children and adolescents with a DSM-IV-TR™ diagnosis of depressive or anxiety disorder in the United States or Germany. The study also was designed to provide data to inform dose selection and titration in future pediatric studies with vortioxetine. METHODS: Safety evaluations included spontaneously reported adverse events (AEs), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Pediatric Adverse Events Rating Scale (PAERS; clinician administered). Clinical effectiveness was determined by Clinical Global Impressions. Comorbid attention-deficit/hyperactivity disorder was permitted, including concomitant use of stimulant medication (US sites only). RESULTS: Of the 47 patients who completed the lead-in period, 41 continued into the OLE. Most patients (n = 39 [95%]) continued their previous dose regimen. Twenty-one patients (51%) withdrew during the OLE; the most common primary reasons were administrative [n = 8], AEs [n = 4], and lack of efficacy [n = 3]. Thirty-five patients (85%) had ≥1 AE, 86% of which were mild or moderate in severity. Five patients (12%) reported a severe AE, none of which was considered related to study medication. The most common AEs (≥10%) were headache (27%), nausea (20%), dysmenorrhea (females; 19%), and vomiting (15%), with no relationship between AE intensity and age or dose. Five patients reported instances of suicidal ideation during the OLE, one of whom also reported this during the lead-in period. Two patients had nonsuicidal self-injurious behavior; one had a nonfatal suicide attempt. Throughout the study, there was a decrease over time in the incidence and intensity of AEs collected using the PAERS. Effectiveness assessment indicated a trend toward improvement based on numeric results. CONCLUSION: This OLE confirms the findings from the lead-in study, which concluded that a dosing strategy of 5-20 mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.

Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

OBJECTIVE: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. METHODS: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14-20 days with patients in the higher dose cohorts uptitrated over 2-6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. RESULTS: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration-time curve from time 0 to 24 hours, was 30%-40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. CONCLUSION: The results suggest that the dosages of vortioxetine evaluated (5-20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

Efficacy, Safety, and Tolerability of a Novel Methylphenidate Extended-Release Oral Suspension (MEROS) in ADHD.

OBJECTIVE: To test whether an optimal dose of Quillivant XR (methylphenidate extended-release oral suspension [MEROS]) would significantly reduce symptoms of ADHD in children. METHOD: A randomized, double-blind, placebo-controlled, cross-over, efficacy, safety, and tolerability study of MEROS in 45 children aged 6 to 12 years (open-label dose-optimization phase, followed by double-blind cross-over period). RESULTS: MEROS was significantly more efficacious than placebo during double-blind cross-over laboratory classroom days (Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale and Permanent Product Measure of Performance). During the open-label phase, improvements were observed in scores of ADHD Rating Scale-IV, and Clinical Global Impression-Severity and -Improvement Scales. No occurrences of suicidal ideation or behavior were recorded; the most common open-label treatment-emergent adverse events were typical of stimulant use: decreased appetite, insomnia, and abdominal pain. CONCLUSION: MEROS was efficacious in the treatment of children aged 6 to 12 years with ADHD, with a safety profile similar to that of other extended-release methylphenidate pharmacotherapies.

Atomoxetine monotherapy compared with combination therapy for the treatment of ADHD: a retrospective chart review study.

OBJECTIVE: To analyze Clinical Global Impression-Severity (CGI-S) in ADHD patients treated with atomoxetine (ATX) monotherapy versus ATX combination therapy with another ADHD-indicated medication. METHODS: This was a 2-site retrospective observational chart review study of child and adult ADHD patients, not necessarily treatment naïve, but treated ≥50 days post baseline with an endpoint assessment. To adjust for measured confounders, monotherapy (n = 77) versus combination (n = 108) cohort comparisons were performed using propensity score stratification and adjusted ANCOVA. RESULTS: There were no significant baseline cohort differences after propensity stratification. CGI-S scores after a mean 264 days of treatment were not statistically significantly different between cohorts, with no cohort differences observed in any assessed symptom subcategory. The cohorts were similar in discontinuation due to any reason, adverse event, and lack of efficacy. CONCLUSION: ATX combination therapy showed no evidence of additional benefit over ATX monotherapy in the treatment of ADHD in a community-based setting.

SSRI use during pregnancy.

The Society of Maternal and Fetal Medicine recently had a conference on the use of medications during pregnancy, delivery, and breast-feeding. One of the most important topics covered during that 2-day conference was major depression (MDD) and the use of Serotonin Selective Reuptake Inhibitors (SSRIs). This article will review the current state of knowledge about MDD during and immediately after pregnancy and treatment with SSRIs during pregnancy and breast-feeding.

Child and adolescent psychiatrists' reported monitoring behaviors for second-generation antipsychotics.

OBJECTIVE: The number of children and adolescents (hereafter referred to as "children") who have been prescribed second-generation antipsychotics (SGAs) has increased over the last decade, but little is known about monitoring practices in pediatric patients who are vulnerable to adverse effects. We examined factors associated with psychiatrists' self-reported monitoring of children who were prescribed SGAs. METHODS: A survey was mailed to a national, randomly selected sample of 1600 child and adolescent psychiatrists from the American Medical Association mailing list. Using logistic regression, we tested whether psychiatrist characteristics, attitudes, and practice characteristics were associated with monitoring (baseline and/or periodic) the following: Patient history, height and weight, blood pressure, waist circumference, lipid and glucose levels, and electrocardiogram. RESULTS: Among the analytic sample of 308, at least two thirds reported monitoring patient history, height and weight, blood pressure, and fasting plasma lipids and glucose; 23% reported monitoring waist circumference; and 12% reported conducting an electrocardiogram. More than one third stated that they routinely monitored thyroid levels and more than half reported monitoring complete blood count and electrolytes/blood urea nitrogen. Psychiatrists reporting that they were able to measure vital signs on site were more likely to measure height and weight. Those who reported feeling comfortable conducting a physical examination were more likely to measure blood pressure. Those answering that the risk of metabolic syndrome was low were less likely to measure blood pressure and waist circumference. Being board certified and able to measure vital signs on site were associated with more monitoring of glucose and lipid levels. Conversely, years in practice and feeling that patients were nonadherent with blood work were associated with less monitoring of glucose and lipid levels. CONCLUSIONS: In this sample, inconsistent monitoring patterns of children prescribed SGAs were found. Efforts to communicate guidelines' evidence base and improve office capacity to measure and track adverse effects are needed to increase appropriate adverse effect monitoring in children who have been prescribed SGAs.

Sports participation and quality of life in adolescents and young adults with congenital heart disease.

BACKGROUND: Adolescents and young adults with congenital heart disease (CHD) are often restricted from physical activity and sports participation, which may have adverse effects. OBJECTIVES: To determine the amount of physical activity, type of sports participation, and reasons for sports restrictions, and to evaluate the effect of sports participation on quality of life (QoL) in a cohort of patients with CHD. METHODS: Individuals with CHD aged 13-30 years were recruited at outpatient visits or via mailings. They completed a questionnaire addressing physical activity, sports participation, sports restrictions, and QoL (Pediatric Quality of Life Inventory). We also reviewed the patient's medical record. RESULTS: Of the 177 patients who responded (mean age 20 years), 31% have mild CHD, 40% have moderate CHD, and 29% have severe CHD. In the cohort, 52% participate in competitive sports, 25% recreational sports, and 23% no sports. Among patients with severe CHD, 29% participate in competitive sports that would be restricted by published guidelines (36th Bethesda Conference). After controlling for age, sex, CHD severity, residual hemodynamic disease, and comorbidities, participation in competitive sports and increased frequency of physical activity are independently associated with a higher QoL (P = .003 and P = .001, respectively). In an identical model, competitive sports participation and frequency of physical activity are associated with higher maximum predicted oxygen consumption (VO2 ) (n = 40; P = .002 and .02) and slightly lower body mass index (BMI) (P = .02 and .01). All findings were similar when analyses were stratified by recruitment method. CONCLUSIONS: Patients with CHD commonly participate in competitive sports, and such participation is associated with higher QoL, improved exercise capacity, and lower BMI.

Child and adolescent psychiatrists' attitudes and practices prescribing second generation antipsychotics.

OBJECTIVE: The purpose of this study was to examine psychiatrists' attitudes and practices in prescribing second-generation antipsychotics (SGA) to children and adolescents (referred to here as "children") and identify factors associated with off-label SGA use. METHODS: A survey was mailed to a national, randomly selected sample of 1600 child and adolescent psychiatrists identified by the American Medical Association. Multivariable logistic regression was used to identify factors, including psychiatrists' characteristics, practice characteristics, and psychiatrists' attitudes, that are associated with off-label SGA use (i.e., SGAs used in children with attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, or nonbipolar mood disorders). RESULTS: The final sample included 340 psychiatrists. Overall, respondents reported higher use and appropriateness of SGAs for United States Food and Drug Administration (FDA)-approved disorders, symptoms of aggression, and older child age. More than one third (36%) of respondents reported some off-label SGA use. Significant predictors of off-label use were: Practicing at inpatient/residential facilities (odds ratio [OR]=4.2, p=0.001); white/non-Hispanic race/ethnicity (OR=0.3, p<0.0001), agreeing that SGAs should be used for ADHD with aggression (OR=7.1, p<0.0001); and agreeing that SGAs should be used for severe delinquent behaviors (OR=1.9, p=0.03). CONCLUSIONS: Psychiatrists' attitudes about prescribing SGAs to children exhibiting aggressive symptoms were associated with off-label SGA use. Research is needed to understand the construct of aggression, potential interaction effects of aggression with diagnostic criteria, and their impact on SGA use.