Systematic review and meta-analysis: Season of birth and schizophrenia risk.

OBJECTIVE: Winter birth has been hypothesized to be associated with increased schizophrenia risk for nearly a century. Major hypotheses regarding the potential etiological risk factors for schizophrenia such as vitamin D deficiency and virus exposure in utero are predicated based on the observation that risk of schizophrenia is higher in children born in winter months. METHODS: We conducted a systematic review and meta-analysis to examine the association between season and month of birth and risk of schizophrenia. We further investigated this relationship stratified by hemisphere. RESULTS: Forty-three studies spanning 30 countries and territories and 440,039 individuals with schizophrenia were included in this meta-analysis. Winter births were associated with a small but statistically significant increased risk of schizophrenia (OR 1.05, 95 % CI 1.03-1.07, p < 0.0001) and summer births were associated with a small but statistically significant decreased risk of schizophrenia (OR 0.96, 95 % CI 0.94-0.98, p = 0.0001). Stratified subgroup analysis demonstrated no significant difference between hemispheres in the risk of schizophrenia for either winter or summer births. CONCLUSIONS: Analysis using birth month data demonstrated a clear seasonal trend towards increased risk of schizophrenia being associated with winter birth months and decreased risk of schizophrenia in summer-to-fall months in the Northern but not Southern Hemisphere. These data suggest a small-but-substantial increased risk of schizophrenia in winter birth month. Further research needs to examine potential etiologic causes for this association.

Acute medical workup for new-onset psychosis in children and adolescents: A retrospective cohort.

No consensus exists about which medical testing is indicated for youth with new-onset psychotic symptoms. We conducted a chart review of youths aged 7-21 years who were medically hospitalized for workup of new-onset psychotic symptoms from January 2017 through September 2020 in a free-standing children's hospital. The sample included 131 patients. At discharge, 129 (98.5%; 95% confidence interval [CI]: 94.5-99.8) were diagnosed with a primary psychiatric condition, 1 was diagnosed with levetiracetam-induced psychosis, and 1 with seronegative autoimmune encephalitis. Notably, 33 (25.2%; 95% CI: 18.0-33.5) had incidental findings unrelated to psychosis, 14 (10.7%; 95% CI: 6.0-17.3) had findings that required medical intervention but did not explain the psychosis, 12 (9.2%; 95% CI: 4.8-15.5) had a positive urine drug screen, and 4 (3.1%; 95% CI: 0.8-7.6) had a neurological exam consistent with conversion disorder. In conclusion, extensive medical testing in the acute setting for psychosis had a low yield for identifying medical etiologies of new-onset psychotic symptoms.

Characterizing Youth-Caregiver Concordance and Discrepancies in Psychopathology Symptoms in a US Community Sample.

Evidence shows that reports of psychopathology symptoms by youth and their caregiver informants differ. To quantify youth-caregiver discrepancies in psychopathology symptoms and factors associated with such discrepancies, we investigated differences in how youth and their caregivers rated psychopathology symptoms. The sample (N = 5094) was extracted from the Philadelphia Neurodevelopmental Cohort, a community-based sample of youth and included participants ages 11-17 years old with both youth and caregiver reported symptom scores. Across psychopathology symptoms, youth-caregiver concordance was poor to fair (Cohens kappa for symptom items ranged between 0.03-0.41). Psychosis symptoms had the lowest concordance-Cohen's kappa ranged from 0.03 to 0.17 across psychosis symptoms. Discrepancies between youth and caregiver symptom reports were greater than average for Black youth and for youth of low socioeconomic status; discrepancies were also higher than average in youth with any psychiatric disorder when compared to typically developing youth. Network analysis of difference scores obtained by subtracting youth symptom scores from caregiver reported symptom scores showed that network connectivity (i.e., correlated difference scores) was sparsest for psychosis spectrum compared to other psychiatric disorders. Using a large sample, we show that youth and their caregiver informants tend to report psychopathology symptoms differently. Youth-caregiver discrepancies were the most pronounced for Black youth and youth of low socio-economic status. Race and socioeconomic status contribute to significant differences in how youth and their caregivers report such symptoms and are important factors that should be accounted for to facilitate accurate mental health symptom assessment and evaluation.

Association between racial/ethnic discrimination and pubertal development in early adolescence.

Racial health disparities in the United States are a major concern, with Black or African Americans experiencing more morbidity and mortality at earlier ages compared to White Americans. More data is needed on the biological underpinnings of this phenomenon. One potential explanation for racial health disparities is that of accelerated aging, which is associated with increased stress exposure. Black Americans face disproportionate levels of environmental stress, specifically racial/ethnic discrimination. Here we investigated associations between self-reported experiences of discrimination and pubertal development (PD) in a diverse sample of young American adolescents (N = 11,235, mean age 10.9 years, 20.5% Black participants) from the Adolescent Brain Cognitive Development (ABCD) Study. Compared to their non-Black counterparts, Black youth experienced more racial/ethnic discrimination in the past year (10.4% vs 3.1%) and had a greater likelihood of being in late/post-pubertal status (3.6% vs 1.5% in boys, 21.3% vs 11.4% in girls). In both sexes, multivariable regression models run in the full sample revealed a cross-sectional association of experiences of racial/ethnic discrimination with pubertal development (boys: standardized beta [ß]=0.123, P < .001; girls: ß = 0.110, P < .001) covarying for demographics, BMI, and dietary habits. Associations remained significant when controlling for multiple other environmental confounders including other forms of (non-racial/ethnic) discrimination and other environmental adversities including poverty and negative life events, and when using parent-reported assessment of pubertal development. Furthermore, racial/ethnic discrimination was associated with elevated estradiol levels in girls (ß = 0.057, P = .002). Findings suggest an association between experiences of discrimination and pubertal development that is independent of multiple environmental stressors. Future longitudinal studies are warranted to establish causal mechanism.

Making Evidence-Based Knowledge Accessible to Parents to Promote Child Mental Health Care.

Parenting is often described as one of the most complicated life challenges, and the complexity increases in the presence of child developmental and/or mental health conditions. In the field of child psychiatry, parental psychoeducation-including guidance, support, and skill building-is an integral part of treatment that improves both the child patient's wellbeing and the quality of life of the family. Parents are the primary agent of care delivery for the child patient, which means that parental beliefs, attitudes, and knowledge about mental health care fundamentally influence service use and treatment adherence. Parents' and caregivers' access to accurate and up-to-date information regarding child development and mental health conditions can be critical in helping families optimize their use of mental health services, feel more confident in managing their child's symptoms, and make informed decisions about treatment strategies, which ultimately improve mental health outcomes in children.1.

Association Between Discrimination Stress and Suicidality in Preadolescent Children.

OBJECTIVE: Youth suicide rates in the United States have been increasing in recent years, especially in Black Americans, the reasons for which are unclear. Environmental adversity is key in youth suicidality; hence there is a need to study stressors that have a disproportionate impact on Black youths. We aimed to disentangle the unique contribution of racial/ethnic discrimination from other adversities associated with childhood suicidal ideation and attempts (suicidality). METHOD: We analyzed data from the Adolescent Brain Cognitive Development (ABCD) Study, which included a large, diverse sample of US children (N = 11,235, mean age 10.9 years, 20.2% Black), assessed for multiple environmental adversities including discrimination. Multivariate regression models tested the association of self-reported racial/ethnic discrimination with suicidality, covarying for multiple confounders including other discrimination types (toward non-US-born individuals, sexual orientation-based, and weight-based). Matched analyses contrasted effects of racial/ethnic discrimination and racial identity on suicidality. RESULTS: Black youths reported more discrimination and higher suicidality rates than non-Black youths. High racial/ethnic discrimination was positively and significantly associated with suicidality, adjusting for other discrimination types (odds ratio = 2.6, 95% CI = 2.1-3.2). Findings remained significant after adjusting for multiple suicidality risk factors. Once experienced, racial/ethnic discrimination was similarly associated with suicidality in White, Black, and Hispanic youths. Matched analyses revealed that racial/ethnic discrimination was associated with suicidality (relative risk = 2.7, 95% CI = 2-3.5), whereas Black race was not (relative risk = 0.9, 95% CI = 0.7-1.2). CONCLUSION: Racial/ethnic discrimination is disproportionately experienced by Black children, and is associated with preadolescent suicidality, over and above other adversities. Findings highlight the need to address discrimination as part of suicide prevention strategies. Cross-sectional design hampers causal inferences.

Association Between Discrimination Stress and Suicidality in Preadolescent Children.

Objective: Youth suicide rates in the United States have been increasing in recent years, especially in Black Americans, the reasons for which are unclear. Environmental adversity is key in youth suicidality; hence there is a need to study stressors that have a disproportionate impact on Black youths. We aimed to disentangle the unique contribution of racial/ethnic discrimination from other adversities associated with childhood suicidal ideation and attempts (suicidality). Method: We analyzed data from the Adolescent Brain Cognitive Development (ABCD) Study, which included a large, diverse sample of US children (N = 11,235, mean age 10.9 years, 20.2% Black), assessed for multiple environmental adversities including discrimination. Multivariate regression models tested the association of self-reported racial/ethnic discrimination with suicidality, covarying for multiple confounders including other discrimination types (toward non-US-born individuals, sexual orientation-based, and weight-based). Matched analyses contrasted effects of racial/ethnic discrimination and racial identity on suicidality. Results: Black youths reported more discrimination and higher suicidality rates than non-Black youths. High racial/ethnic discrimination was positively and significantly associated with suicidality, adjusting for other discrimination types (odds ratio = 2.6, 95% CI = 2.1-3.2). Findings remained significant after adjusting for multiple suicidality risk factors. Once experienced, racial/ethnic discrimination was similarly associated with suicidality in White, Black, and Hispanic youths. Matched analyses revealed that racial/ethnic discrimination was associated with suicidality (relative risk = 2.7, 95% CI = 2-3.5), whereas Black race was not (relative risk = 0.9, 95% CI = 0.7-1.2). Conclusion: Racial/ethnic discrimination is disproportionately experienced by Black children, and is associated with preadolescent suicidality, over and above other adversities. Findings highlight the need to address discrimination as part of suicide prevention strategies. Cross-sectional design hampers causal inferences.Reprinted from J Am Acad Child Adolesc Psychiatry, Argabright et al., Association Between Discrimination Stress and Suicidality in Preadolescent Children, S0890-8567(21)01355-1, copyright 2021, with permission from Elsevier.

Association between traumatic stressful events and schizotypal symptoms among a community-based sample of adolescents: A 2-year longitudinal study.

BACKGROUND: Traumatic stressful events (TSEs) are among the most studied risk factors for subsequent schizotypal symptoms. However, specificity and aggregate effects of trauma exposure on schizotypal symptoms remain unclear. This study investigates these relationships among a community-based sample of US adolescents. MATERIAL AND METHODS: A sub-sample of 426 adolescents (51.6% female) from the Philadelphia Neurodevelopmental Cohort study were selected for longitudinal follow-up based on presence (n = 209) or absence (n = 217) of psychosis spectrum symptoms (PSS). At baseline, they completed assessments of demographic, TSEs, other psychopathology (e.g., PSS, anxiety, depression, and behavioral disorder) and family history of psychopathology. Schizotypal symptom dimensions (cognitive-perceptual, interpersonal and disorganized) were evaluated approximately two years later. RESULTS: More than half of adolescents experienced at least one type of TSE. Adolescents with assaultive trauma reported about 1.5 times as many symptoms on all three schizotypal symptom dimensions, compared to adolescents with non-assaultive TSE, adjusting for demographic and family history variables. No statistical significance was found after further adjusting for other baseline psychopathology (p > 0.05). There was a significant aggregate effect of TSEs on cognitive-perceptual symptoms with small effect size (p < 0.001, Cohen's f2 = 0.034). CONCLUSIONS: We found evidence of an association between aggregate TSEs and cognitive-perceptual symptoms, but trauma type was not associated with schizotypal symptom dimensions when controlling for potential confounders. Our findings highlight the importance of considering aggregate TSE effects and potential confounds when examining associations between TSEs and schizotypy. Trauma and psychosis spectrum screening may be important in the effort to provide trauma-informed care.

Commentary: Schizophrenia prevention and prodromal psychosis in children and adolescents.

Catalan and colleagues aggregated findings related to detection, prognosis, and intervention in Clinical High Risk for Psychosis (CHR-P) children and adolescents through October 7, 2019 (Catalan et al., 2020). While a sufficient number of studies were available to meta-analytically summarize evidence on detection and prognosis, the authors highlight the need for more studies on interventions, including cognitive behavioral therapy for psychosis, in CHR-P youth. Further research on the biological and neural correlates of CHR-P in children and adolescents is also needed. Though results from the few existing biomarker studies in CHR-P youth were included in the systematic review, disparate study methodologies and outcomes prohibited biomarker study meta-analysis.

Editors' Note and Special Communication: Research Priorities in Child and Adolescent Mental Health Emerging From the COVID-19 Pandemic.

Over the last year, the coronavirus disease 2019 (COVID-19) pandemic has resulted in profound disruptions across the globe, with school closures, social isolation, job loss, illness, and death affecting the lives of children and families in myriad ways. In an Editors' Note in our June 2020 issue,1 our senior editorial team described this Journal's role in advancing knowledge in child and adolescent mental health during the pandemic and outlined areas we identified as important for science and practice in our field. Since then, the Journal has published articles on the impacts of the pandemic on child and adolescent mental health and service systems,2-5 which are available in a special collection accessible through the Journal's website.6 Alongside many opinion papers, the pace of publication of empirical research in this area is rapidly expanding, covering important issues such as increased frequency of mental health symptoms among children and adolescents3,5,7-10 and changes in patterns of clinical service use such as emergency department visits.11-14 As the Senior Editors prepared that Editors' Note, they were acutely aware that the priorities that they identified were broad and generated by only a small group of scientists and clinicians. Although this had the advantage of enabling us to get this information out to readers quickly, we decided that a more systematic approach to developing recommendations for research priorities would be of greater long-term value. We were particularly influenced by the efforts of the partnership between the UK Academy of Medical Scientists and a UK mental health research charity (MQ: Transforming Mental Health) to detail COVID-19-related research priorities for "Mental Health Science" that was published online by Holmes et al. in The Lancet Psychiatry in April 2020.15 Consistent with its focus on mental health research across the lifespan, several recommendations highlighted child development and children's mental health. However, a more detailed assessment of research priorities related to child and adolescent mental health was beyond the scope of that paper. Furthermore, the publication of that position paper preceded the death of George Floyd at the hands of Minneapolis police on May 25, 2020, which re-energized efforts to acknowledge and to address racism and healthcare disparities in the United States and many other countries. To build upon the JAACAP Editors' Note1 and the work of Holmes et al.,15 we conducted an international survey of professionals-practitioners and researchers-working on child and adolescent development and pediatric mental health to identify concerns about the impact of the pandemic on children, adolescents, and their families, as well as what is helping families navigate these impacts, and the specific research topics that are of greatest importance.

Racial Implicit Associations in Psychiatric Diagnosis, Treatment, and Compliance Expectations.

OBJECTIVE: Racial and ethnic disparities are well documented in psychiatry, yet suboptimal understanding of underlying mechanisms of these disparities undermines diversity, inclusion, and education efforts. Prior research suggests that implicit associations can affect human behavior, which may ultimately influence healthcare disparities. This study investigated whether racial implicit associations exist among medical students and psychiatric physicians and whether race/ethnicity, training level, age, and gender predicted racial implicit associations. METHODS: Participants completed online demographic questions and 3 race Implicit Association Tests (IATs) related to psychiatric diagnosis (psychosis vs. mood disorders), patient compliance (compliance vs. non-compliance), and psychiatric medications (antipsychotics vs. antidepressants). Linear and logistic regression models were used to identify demographic predictors of racial implicit associations. RESULTS: The authors analyzed data from 294 medical students and psychiatric physicians. Participants were more likely to pair faces of Black individuals with words related to psychotic disorders (as opposed to mood disorders), non-compliance (as opposed to compliance), and antipsychotic medications (as opposed to antidepressant medications). Among participants, self-reported White race and higher level of training were the strongest predictors of associating faces of Black individuals with psychotic disorders, even after adjusting for participant's age. CONCLUSIONS: Racial implicit associations were measurable among medical students and psychiatric physicians. Future research should examine (1) the relationship between implicit associations and clinician behavior and (2) the ability of interventions to reduce racial implicit associations in mental healthcare.

Time to Clinical Response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study.

Objectives: We investigated the time course of clinical response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study (TEOSS). Methods: TEOSS randomized 119 predominantly outpatient youth ages 8-19 years with schizophrenia or schizoaffective disorder to 8 weeks of treatment with molindone, risperidone, or olanzapine. We used proportional hazards regression to determine whether these three antipsychotics differed in the time until clinical response, defined as the time from treatment initiation to the point of achieving a Clinical Global Impressions-Improvement (CGI-I) scale score of 1 ("very much improved") or 2 ("much improved") that was maintained until week 8. Results: Of the 116 youth who initiated treatment, 56 (48%) achieved clinical response. Among clinical responders, the median (±interquartile range) time until clinical response was 4.0 (±4.0) weeks for olanzapine, 4.5 (±4.0) weeks for risperidone, and 6.0 (±4.0) weeks for molindone. There were no significant differences in time course for clinical response between medications (p = 0.84). Youth without symptom improvement (CGI-I ≥ 4) after 3 weeks were more likely to be clinical nonresponders at week 8 (relative risk ratio = 1.98, 95% confidence interval 1.29-3.05), compared with youth with at-least-minimal symptom improvement after 3 weeks when looking at all antipsychotics combined. Conclusion: To our knowledge, our study is the first to investigate medication differences in treatment response timing in early onset schizophrenia spectrum disorders. Clinical response times for molindone, risperidone, and olanzapine were not significantly different. Furthermore, while lack of early improvement predicted clinical nonresponse, whether or not to continue antipsychotic treatment after 3 or more weeks without symptom improvement should be based on clinical judgment after weighing potential risks, benefits, and alternatives. ClinicalTrials.gov Identifier: NCT00053703.

Association of anxiety phenotypes with risk of depression and suicidal ideation in community youth.

BACKGROUND: Anxiety symptoms are common in adolescence and are often considered developmentally benign. Yet for some, anxiety presents with serious comorbid nonanxiety psychopathology. Early identification of such "malignant" anxiety presentations is a major challenge. We aimed to characterize anxiety symptoms suggestive of risk for depression and suicidal ideation (SI) in community youths. METHODS: Cross-sectional associations were evaluated in community youths (n = 7,054, mean age: 15.8) who were assessed for anxiety, depression, and SI. We employed factor and latent class analyses to identify anxiety clusters and subtypes. Longitudinal risk of anxiety was evaluated in a subset of 330 youths with longitudinal data on depression and SI (with baseline mean age of 12.3 years and follow-up mean age of 16.98 years). OUTCOMES: Almost all (92%) adolescents reported anxiety symptoms. Data-driven approaches revealed anxiety factors and subtypes that were differentially associated with depression and SI. Cross-sectional analyses revealed that panic and generalized anxiety symptoms show the most robust associations with depression and SI. Longitudinal, multivariate analyses revealed that panic symptoms during early adolescence, not generalized anxiety symptoms, predict depression and SI for later adolescent years, particularly in males. INTERPRETATION: Anxiety is common in youths, with certain symptom clusters/subtypes predicting risk for depression and SI. Panic symptoms in early adolescence, even below disorder threshold, predict high risk for late adolescent depression and SI.

Markers of Psychosis Risk in the General Population.

The categorical approach to defining schizophrenia spectrum disorders requires meeting established criteria. To advance early identification and intervention in young people, the field has progressed to studying help-seeking individuals who are at clinical high risk based on subthreshold psychosis spectrum symptoms, and criteria have been articulated for qualifying individuals as at risk. A broader dimensional examination of psychosis has been applied to population-based studies on non-help seekers. This review highlights the ascertainment and assessment approaches to such population-based studies. Most studies are cross-sectional and rely on questionnaires with limited overlap of tools. However, several consistent findings emerge on symptoms, neurocognitive deficits, and neuroimaging parameters and other biomarkers associated with emergence and persistence of psychotic features. The findings are consistent with the literature on abnormalities associated with schizophrenia, including the presence of neurocognitive deficits; abnormalities in brain structure, function, and connectivity that are related to distress; impairment; and functional outcome. These findings support the validity of studying psychosis experiences during development in a way that can chart the emergence of psychosis in the context of general psychopathology. Such studies are necessary for establishing developmental trajectories that characterize this emergence and for identifying risk and resilience biomarkers moderating or modulating the full range of schizophrenia-related manifestations. More community-based studies are needed, with better standardization and harmonization of measures and incorporating longitudinal follow-up, to establish mechanistic links between cellular-molecular aberrations and specific manifestations of psychosis as envisioned by the precision medicine agenda.

Characteristics of youth with reported family history of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort.

Little is known about the impact of family history of psychosis on youth from community samples. To fill this gap, we compared youth with a first-degree relative with psychosis spectrum symptoms (i.e. family history of psychosis spectrum symptoms, FHPS) to youth without FHPS in a cross-sectional analysis of the Philadelphia Neurodevelopmental Cohort (PNC). The PNC is a racially diverse community sample of 9498 youth ages 8-21 years old, of whom 8928 completed the Family Interview for Genetic Studies to determine FHPS status. Polygenic risk score for schizophrenia (PRSS) was available for a subsample of 4433 European Americans. FHPS youth (n = 489) constituted 5.5% of the analytic sample. After adjusting for environmental risk factors (sociodemographic variables and traumatic stressful events), FHPS youth had lower functioning on the Children's Global Assessment Scale and elevated psychosis spectrum, mood, externalizing, and fear symptoms compared to non-FHPS youth (all p < .001). In the European-American subsample, FHPS status was associated with poorer functioning and greater symptom burden in all four psychopathology domains (all p < .001), even after covarying for PRSS. Thus, ascertaining FHPS is important because it is uniquely associated with symptoms and functional impairment in community youth beyond PRS-S and the environmental risk factors we investigated. Future research identifying environmental causes of FHPS-associated impairment could inform the development of interventions for the broad array of symptoms observed in FHPS youth.

Predictors and Moderators of Antipsychotic-Related Weight Gain in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study.

BACKGROUND: Antipsychotic-related weight gain is a common clinically relevant side effect when treating psychotic disorders in pediatric populations, yet few predictors and no moderators of antipsychotic-related weight gain are known. METHODS: The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study randomized 119 youths (age 8-19 years) with schizophrenia or schizoaffective disorder to 8 weeks of antipsychotic treatment with molindone, risperidone, or olanzapine and assessed treatment response and side effects. In this secondary analysis, we used multivariable linear regression and receiver operating characteristic analysis to investigate predictors and moderators of weight change and percent weight change from baseline to week 8. RESULTS: Treatment assignment was the most discriminant predictor of weight change [F(2, 66) = 17.00, p < 0.001] and percent weight change [F(2, 66) = 16.85, p < 0.001]. Mean weight gain was 0.74 (standard deviation ±3.51) kg for molindone, 4.13 ± 3.79 kg for risperidone, and 7.29 ± 3.44 kg for olanzapine. After adjusting for treatment assignment, lower pretreatment hemoglobin A1C (HgbA1C) predicted more weight gain [F(1, 55) = 4.71, p = 0.03]. Diagnosis (schizoaffective vs. schizophrenia) moderated weight change [F(2, 63) = 6.02, p = 0.004] and percent weight change [F(2, 63) = 5.26, p = 0.008] such that schizoaffective diagnosis predicted larger weight gain for youths in the risperidone treatment arm. Age, sex, family income, baseline weight, and symptoms neither predicted nor moderated weight change or percent weight change. CONCLUSION: We identified prognostic subgroups and novel risk factors for antipsychotic-related weight gain. We confirmed that antipsychotic choice is extremely important for predicting future weight gain. We also found that younger age did not predict greater weight gain, in contrast to prior studies. Our findings require replication in an independent sample because we did not adjust for multiple comparisons to minimize false negatives. ClinicalTrials.gov Identifier: NCT00053703.

A Systematic Review of Pharmacologic Treatments for School Refusal Behavior.

OBJECTIVE: School refusal is an important pediatric problem with significant negative short- and long-term outcomes. Specific psychosocial treatments appear effective in reducing school refusal, but many children do not respond to these treatments. Although systematic reviews have examined the efficacy of psychological interventions for school refusal, no systematic reviews on pharmacological interventions exist. METHODS: We conducted a comprehensive literature search of MEDLINE, PsycINFO, Scopus, and Embase for randomized controlled trials (RCTs) or quasi-experimental pharmacologic trials in children and adolescents with school refusal reported in English or Spanish until July 1, 2017. Two authors screened study titles and abstracts for eligibility. Data regarding the population, intervention, comparison, and outcomes for each trial were extracted and reported. Effect sizes for school attendance are presented. RESULTS: The search identified 6 articles, including 7 trials (6 RCTs and 1 open label) and 306 youths. Pharmacologic treatments investigated for school refusal included antidepressants (imipramine, clomipramine, and fluoxetine) and benzodiazepines (alprazolam). All pharmacotherapies studied had pretreatment to posttreatment improvements on school refusal, depression, and anxiety symptoms. However, included trials were severely underpowered and did not demonstrate significant improvement compared to placebo. CONCLUSIONS: Data regarding pharmacological treatments for school refusal are sparse. Most trials in this area were conducted before development of newer antidepressants, were underpowered, and have significant methodological limitations that are characteristic of the time in which they were conducted. This systematic review highlights the need for more trials with newer pharmacologic agents, larger sample sizes, and improved systematic assessments of school refusal and comorbidities. School refusal represents an important functional outcome for many children, especially those with anxiety and depression. Future pharmacologic studies of anxiety and depression in children may benefit from incorporating specific school refusal measures as secondary outcomes.

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial.

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.