Exposure to a range of stressful life events (SLE) is implicated in youth psychopathology. Previous studies point to a discrepancy between parents'/children's reports regarding stressful life events. No study systematically assessed the correlation between such discrepancies and psychopathology in depressed youth. This study was designed to assess parent-youth discrepancies regarding stressful life events and its association with severity of psychopathology at baseline and response to selective serotonin reuptake inhibitor (SSRI) treatment in depressed youth. Reports regarding stressful life events were assessed in children/adolescents suffering from depressive/anxiety disorders using the life events checklist (LEC), a self-report questionnaire measuring the impact of negative life events (NLE) and positive life events (PLE), as reported by the children and their parents. The severity of depression/anxiety disorders and response to antidepressant treatment were evaluated and correlated with both measures of LEC. Participants were 96 parent-child dyads (39 boys, 57 girls) aged 6-18 years (mean = 13.90 years, SD = 2.41). Parents reported more NLE and higher severity of NLE events than their children (number of NLE: 7.51 ± 4.17 vs. 6.04 ± 5.32; Cumulative severity of NLE: 24.95 ± 14.83 vs. 17.24 ± 12.94). Discrepancy in PLE, but not NLE, was associated with more severe psychopathology and reduced response to treatment. Discrepancy in informant reports regarding life events in depressed/anxious youth, especially regarding PLE, is associated with more severe psychopathology and reduced response to pharmacotherapy. It is essential to use multiple reporters in assessing stressful life events in children.

Recent survey data suggest that a high proportion of patients with Tourette syndrome (TS) experience pain, yet pain features in TS have not been previously investigated in a systematic manner. This article reviews the current understanding and impact of pain in TS as well as identifies possible areas for emphasis for future research on pain in TS. Using a comprehensive search strategy in two relevant research databases (PubMed and Scopus), we searched for relevant peer-reviewed, primary research articles, and review articles. Search terms used were Tourette syndrome, tic disorder, pain, pain management, sensory, and sensory gating. A total of 116 pertinent articles were identified. Pain is reported by 47%-60% of individuals with TS and may relate to different aspects of tic phenomenology or other causes. Pain is more prevalent among TS patients than in the general population and negatively impacts quality of life. To standardize future research efforts, we propose the following classification: tic-related immediate pain, tic-related delayed injury/pain, suppression-related pain, premonitory urge-related pain, and associated primary pain syndromes. Altered sensory gating and interoceptive processing abnormalities are possible mechanisms contributing to pain in TS but warrant further study. Despite pain prevalence, most TS clinical rating scales and outcome measures used in therapeutic studies do not incorporate sufficient information regarding pain. Therapies known to improve pain in non-TS conditions that are also reported to improve tics have not been investigated for their effects on pain among TS patients. TS can be associated with a chronic pain syndrome that negatively affects quality of life. Future research using a systematic framework is needed to better understand pain cause(s) and prevalence, develop appropriate assessment methods, establish outcome measures, and understand mechanisms of pain in TS. Such investigations are likely to lead to therapeutic options for this troublesome symptom.

It is essential not to delay behavior management and control for aggression, violence, and impulsive behavior in young people. Clozapine has been widely used in adolescents and adults to manage violence and aggression in Schizophrenia. However, there are limited data on the use of clozapine in children, and no systematic review has addressed its use in this population. To better understand the conditions under which clozapine is used as a therapeutic alternative for nonschizophrenic diagnoses and to assess the current evidence supporting its prescription to children, a systematic review was conducted. The review followed PRISMA guidelines and was registered in PROSPERO under the ID CRD42024537707. The review identified that all the studies used clozapine to address externalizing behavior, particularly aggressive behavior, and found positive outcomes supporting its use for treating children with treatment-resistant aggression. The studies also found that clozapine was well-tolerated in all cases. However, the studies were limited and mainly consisted of open trials without a control group. Further high-quality research is needed to establish precise guidelines for using clozapine in children.

The incidence of neuroleptic malignant syndrome (NMS), a rare, potentially fatal adverse effect of antipsychotics, among children and youth is unknown. This cohort study estimated NMS incidence in antipsychotic users age 5-24 years and described its variation according to patient and antipsychotic characteristics. We used national Medicaid data (2004-2013) to identify patients beginning antipsychotic treatment and calculated the incidence of NMS during antipsychotic current use. Adjusted hazard ratios (HRs) assessed the independent contribution of patient and antipsychotic characteristics to NMS risk. The 1,032,084 patients had 131 NMS cases during 1,472,558 person-years of antipsychotic current use, or 8.9 per 100,000 person-years. The following five factors independently predicted increased incidence: age 18-24 years (HR [95% CI] = 2.45 [1.65-3.63]), schizophrenia spectrum and other psychotic disorders (HR = 5.86 [3.16-10.88]), neurodevelopmental disorders (HR = 7.11 [4.02-12.56]), antipsychotic dose >200mg chlorpromazine-equivalents (HR = 1.71 [1.15-2.54]), and first-generation antipsychotics (HR = 4.32 [2.74-6.82]). NMS incidence per 100,000 person-years increased from 1.8 (1.1-3.0) for those with none of these factors to 198.1 (132.8-295.6) for those with 4 or 5 factors. Findings were essentially unchanged in sensitivity analyses that restricted the study data to second-generation antipsychotics, children age 5-17 years, and the 5 most recent calendar years. In children and youth treated with antipsychotics, five factors independently identified patients with increased NMS incidence: age 18-24 years, schizophrenia spectrum and other psychotic disorders, neurodevelopmental disorders, first-generation drugs, and antipsychotic doses greater than 200 mg chlorpromazine-equivalents. Patients with 4 or 5 of these factors had more than 100 times the incidence of those with none. These findings could improve early identification of children and youth with elevated NMS risk, potentially leading to earlier detection and improved outcomes.

To evaluate the comparative efficacy of pharmacological interventions for children and adolescents with a dual diagnosis of persistent tic disorders or Tourette disorder and attention-deficit/hyperactivity disorder (TD + ADHD). We searched CENTRAL, Embase, PubMed, PsycInfo, Web of Sciences, ClinicalTrials.gov, and WHO ICTRP up to September 2023 to identify double-blinded randomized controlled trials (RCTs) assessing pharmacological interventions for children and adolescents with TD + ADHD. Outcomes were change in ADHD symptoms (primary) and tics (secondary) severity. Standardized mean difference (SMD) was calculated and pooled in random-effects network meta-analysis. The Confidence in Network Meta-Analysis framework was adopted to determine certainty of evidence. We included 8 RCTs involving 575 participants. Network meta-analyses demonstrated that α2 agonists (SMD, 95% confidence interval [CI] ADHD: -0.72 [-1.13 to -0.31]; TD: -0.70 [-0.96 to -0.45]) and stimulants + α2 agonists (ADHD: -0.84 [-1.54 to -0.13]; TD: -0.60 [-1.04 to -0.17]) were more efficacious than placebo for ADHD symptoms and tics severity. Stimulants alone were more efficacious than placebo for ADHD symptoms severity only, but they did not worsen tics (ADHD: -0.54 [-1.05 to -0.03]; TD: -0.22 [-0.49 to 0.05]). There were no significant differences between any pairs of medications that were found efficacious against placebo for ADHD symptoms or tics severity. Certainty in the evidence varied from low to very low. Stimulants are efficacious for ADHD symptoms severity and do not increase tics severity in TD + ADHD. α2 agonists are efficacious for both ADHD symptoms and tics severity in TD + ADHD. These findings should inform guidelines and help guide shared decision-making to choose a medication for children with TD + ADHD.

To assess quality of life and outcomes associated with adverse effects (AEs) in pediatric patients receiving pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and their parents/caregivers. An online survey was conducted (10/13/2023-10/20/2023) among parents/caregivers recruited from Dynata's U.S. panel who lived with a pediatric patient (6-17 years) currently treated for ADHD. Patient and parent/caregiver characteristics and outcomes were descriptively reported. Patients were considered to have AEs if they experienced symptoms/complications in the past 30 days that appeared, worsened, or remained unchanged after initiating their latest ADHD treatment. Regression analyses were used to estimate correlations between the number of AEs and key outcomes, including patients' health-related quality of life (HRQoL; based on the Pediatric Quality of Life Inventory) and parents/caregivers' work and activity impairments (based on Work Productivity and Activity Impairment: Caregiver) and mental health (based on Patient Health Questionnaire-4). A total of 401 parents/caregivers from all U.S. regions completed the survey (caregiver median age: 38 years, 58.9% female; patient median age: 11 years; 37.7% female). In the 30 days prior to data collection, 66.8% of patients had AEs (overall mean: 1.2 AEs), with insomnia/sleep disturbances and decreased appetite/weight loss being the most frequently reported (14.2% and 11.7%, respectively). The number of AEs was significantly correlated with reduced patient's HRQoL (including reduced physical, emotional, and school functioning), increased parent/caregiver's work and activity impairment, and a higher likelihood of parents/caregivers having generalized anxiety disorder or major depressive disorder, respectively (all < 0.001). AEs are common among pediatric patients receiving pharmacological treatment for ADHD and are associated with poorer quality of life and outcomes in pediatric patients and their parents/caregivers. Therapies with better safety profiles may help improve patient's HRQoL and parent/caregiver outcomes.

Children with autism often present with comorbid anxiety disorders. Cognitive behavioral therapy (CBT) is an effective, evidence-based approach to treating anxiety, but information on youth with autism and anxiety is limited. Coping Cat is a 16-week CBT intervention for children with anxiety but its use in a group telehealth format in an urban, predominantly Hispanic population is limited. (a) To examine the feasibility and preliminary effectiveness of a short-term CBT telehealth group for youth with autism and anxiety disorders in an urban, predominantly Hispanic population and (b) to examine satisfaction with the intervention. Single-arm pilot study that consisted of a 16-week telehealth CBT group therapy was based on a modified Coping Cat curriculum. Youth with autism and anxiety disorders who were on a waitlist for psychotherapy at an urban developmental center were invited to participate. Anxiety was assessed pre- and posttreatment using the Screen for Child Anxiety Related Emotional Disorders, parent and self-report. Eighteen children were enrolled; 16 children completed the program. Mean age was 11 ± 2.5 years (8-15 years); 89% males, 61% Hispanic. There was a significant reduction in pre-post intervention in symptoms of overall anxiety (parent: 41.0 ± 18.5 to 31.0 ± 16.3 ≤ 0.003, self: 25.9 ± 12.8 to 14.1 ± 7.8 ≤ 0.001), panic disorder (parent: 8.1 ± 7.0 to 4.1 ± 4.2 = 0.013, self: 5.1 ± 4.8 to 0.8 ± 0.9 = 0.004), and separation anxiety disorder (parent: 7.5 ± 4.8 to 5.7 ± 4.4 = 0.041, self: 5.8 ± 3.3 to 3.8 ± 2.4 = 0.018) as per parent and self-reports. Self-report data also revealed a significant reduction in symptoms of social anxiety disorder (6.5 ± 3.5 to 3.9 ± 2.7 ≤ 0.001). Parents and children reported satisfaction with the group. In this small, predominantly Hispanic population of youth with autism and anxiety disorder, 89% of families were compliant with a group telehealth CBT intervention. Parents and youth reported a significant reduction in anxiety symptoms and program satisfaction. A modified group CBT program via telehealth represents a feasible intervention for youth with autism and anxiety disorders.

Professor Alessandro Zuddas, from the University of Cagliari (Italy), passed away prematurely in July 2022. As a prominent figure in child and adolescent neuropsychiatry, he substantially influenced the fields of neurodevelopmental disorders and neuropsychopharmacology both nationally and internationally. Professor Zuddas was a renowned expert in basic and clinical research in child and adolescent psychopharmacology, an enlightened and stimulating educator, and a mentor to many students, residents, and senior colleagues. With his enthusiasm and unique ability to network, he contributed enormously to trace a path in the field that we continue to follow. His name will remain in the textbooks and articles he authored. Here, as colleagues and friends who had the honor to work with him, we provide our personal views of Alessandro's impact and legacy, which go far beyond his publications.

The Positive and Negative Syndrome Scale (PANSS) is a widely accepted outcome measure for pediatric schizophrenia trials; however, it has notable limitations. Psychometric investigations have shown a multifactorial structure and some items have limited utility assessing symptom severity in children. To address these issues, we developed and evaluated optimized 10- and 20-item PANSS short-forms (PANSS10 and PANSS20) using patient-level clinical trial data. This study further assesses these optimized forms using independent clinical trial data. We examined patient-level data from a randomized pediatric schizophrenia trial comparing paliperidone ER to aripiprazole. Data were accessed through the Yale Open Data Access (YODA) secure platform. Analyses included confirmatory factor analyses, graded response models, ω score reliability, internal consistency, sensitivity to change, and criterion validity versus the Clinical Global Impressions of Severity (CGI-S). Bland-Altman analyses examined score calibration versus the 30-item PANSS and inclusion cut scores. Participants ( = 288) were ages 12 to 17 years ( = 15.3, SD = 1.46; 66% male). Total scores for the PANSS10 and PANSS20 showed strong correlations with the 30-item PANSS (0.90 and 0.97, respectively). Average inter-item correlations were 0.10 and 0.14 and ω reliabilities were 0.74 and 0.85. Both PANSS10 and PANSS20 scores showed reliability >0.80-2.3 to 4.5 SD and -3.0 to 6.0 SD about mean symptom severity, respectively. Sensitivity to treatment was also similar (partial squared 0.23 and 0.22), as was correlation with CGI-S at baseline (0.45 and 0.48; not significantly different). The mean item-average discrepancy with the 30-item PANSS was 0.095 for PANSS10 and 0.033 for PANSS20. The optimized PANSS forms continue to show impressive reliability, validity, and calibration compared with the 30-item PANSS. Researchers should consider replacing the 30-item PANSS with the PANSS10 as a clinical outcome and screening measure due to its length and psychometric performance.

Despite advances in obstetric care, postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Prior reviews of studies published through 2016 suggest an association of antidepressant use during late pregnancy and increased risk of PPH. However, a causal link between prenatal antidepressants and PPH remains controversial. This systematic literature review aimed to synthesize the empirical evidence on the association of antidepressant exposure in late pregnancy with the risk of PPH, including studies published before and after 2016. A systematic literature search was conducted using PubMed, OVID Medline, EMBASE, SCOPUS, PsycINFO, and CINAHL from inception to September 9, 2023. Original, peer-reviewed studies (published in English) that reported on the frequency or risk of PPH in women with evidence of antidepressant use during pregnancy and included at least one control group were included. Twenty studies (eight published after 2016) met inclusion criteria, most of which focused on the risks of PPH associated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The main findings from the individual studies were mixed, but the majority documented statistically significant associations of PPH with late prenatal exposure, especially for exposures occurring within 30 days of delivery, compared with unexposed deliveries. Fourteen studies addressed underlying antidepressant indications or their correlates. Few studies focused on prenatal antidepressants and the risk of well-defined severe PPH or on antidepressant dose changes and general PPH risk. None examined competing risks of antidepressant discontinuation on mental health outcomes. Late pregnancy exposure to antidepressants may be a minor risk factor for PPH, but it is unclear to what extent reported associations are causal in nature, as opposed to correlational (effects related to nonpharmacological factors including maternal indication). For patients needing antidepressants during pregnancy, current evidence does not favor routinely discontinuing antidepressants specifically to reduce the risk of PPH.

Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive disorders in youth. Yet, data on discontinuing these medications, withdrawal symptoms, and strategies to switch between them are limited. We searched PubMed and ClinicalTrials.gov through June 1, 2024, to identify randomized controlled trials assessing antidepressant discontinuation in youth. We summarized pediatric pharmacokinetic data to inform tapering and cross-titration strategies for antidepressants and synthesized these data with reports of antidepressant withdrawal. Our search identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), including SSRIs (K = 10), SNRIs (K = 4), and TCAs (K = 1), ranging from 4 to 35 weeks. Deprescribing antidepressants requires considering clinical status, treatment response, and, in cross-titration cases, the pharmacokinetics and pharmacodynamics of both medications. Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. Although approaches to deprescribing antidepressants in pediatric patients are frequently empirically guided, accumulating data related to the course of relapse and withdrawal symptoms, as well as the pharmacokinetic and pharmacodynamic properties of medications, should inform these approaches. Recommendations within this review support data-informed discussions of deprescribing-including when and how-that are critically important in the clinician-family-patient relationship.

Randomized controlled trials (RCTs) have shown that attention-deficit/hyperactivity disorder (ADHD) medications significantly reduce symptomatology at a group level, but individual response to ADHD medication is variable. Thus, developing prediction models to stratify treatment according to individual baseline clinicodemographic characteristics is crucial to support clinical practice. A potential valuable source of data to develop accurate prediction models is real-world clinical data extracted from electronic healthcare records (EHRs). Yet, systematic information regarding EHR data on ADHD is lacking. We conducted a comprehensive review of studies that included EHR reporting data regarding individuals with ADHD, with a specific focus on treatment-related data. Relevant studies were identified from PubMed, Ovid, and Web of Science databases up to February 24, 2024. We identified 103 studies reporting EHR data for individuals with ADHD. Among these, 83 studies provided information on the type of prescribed medication. However, dosage, duration of treatment, and ADHD symptom ratings before and after treatment initiation were only reported by a minority of studies. This review supports the potential use of EHRs to develop treatment response prediction models but emphasizes the need for more comprehensive reporting of treatment-related data, such as changes in ADHD symptom ratings and other possible baseline clinical predictors of treatment response.

Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter- also commonly known as ) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 ) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Genetic variations in and were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: = 0.058, Methylphenidate [MPH]: = 0.044). There was also a trend for the 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine ( = 0.029). Participants with 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Most children with ADHD who were CYP2D6 normal metabolizers or had 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of and with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

Long-acting injectable (LAI) antipsychotic medications are being prescribed to children and adolescents along a broad age range from 2 to 17 years old. However, there is no U.S. Food and Drug Administration (FDA) approved indication for the use of any LAI in a pediatric population. The goal of this article is to perform a systematic literature review regarding the use of LAIs in a pediatric population, to obtain pediatric LAI safety data, and to survey prescriber attitudes regarding LAI use in youth. A search for relevant articles between June 1986 and June 2021 was conducted. Safety data were obtained from FDA MedWatch postmarketing adverse event reports regarding LAI use in children and adolescents. A survey of practicing Child and Adolescent Psychiatrists in Wisconsin was done regarding the use of LAIs in youth. The predominant reasons for LAI use in youth were illness severity and treatment noncompliance. Twenty-six of 30 identified studies and reports favored LAI use in youth, but were of low to very low quality. Overall, 587 FDA MedWatch reports between June 1986 and June 2021 were identified. Most adverse events occurred in modest numbers. Extrapyramidal symptoms accounted for 18% of all MedWatch reports, neuroleptic malignant syndrome accounted for 3% of all reports, and deaths accounted for 2% of all reports. The concern for safety was reflected in prescriber survey results along with a recognition that LAIs can be helpful to target severe psychiatric symptoms and address treatment noncompliance. No randomized controlled studies were found. Identified published studies and reports were of low to very low quality. However, it appeared reasonable that the use of LAIs in a select group of pediatric patients can be helpful to target severe psychiatric symptoms and to enhance treatment compliance.

To provide an evidence-based review of the Comprehensive Behavioral Intervention for Tic (CBIT) disorders. For close to a century, behavioral interventions for managing tics associated with Tourette and other tic disorders (TDs) were incorrectly considered ineffective and dangerous by the professional community, due, in large part, to unfounded fears that efforts to suppress tics would lead to a host of negative psychological, and even physical, outcomes (e.g., symptom substitution, tic rebound). Spurred by a growing body of research to the contrary, the Comprehensive Behavioral Treatment for Tics (CBIT) was developed to provide a tolerable and effective nonpharmacological treatment option, alone or in combination with medication, for youth and adults with tics associated with Tourette or other TDs. CBIT combines two evidence-based practices, habit reversal training (HRT) to address the urge-tic relationship and a functional intervention to identify and neutralize tic-related environmental factors. Based on positive findings from two large-scale randomized controlled trials that involved a total of 248 8-69-year olds with Tourette or chronic TD, CBIT has been designated as a first-line treatment, when available, for treating tics by the American Academy of Neurology and the European and Canadian medical academies. CBIT has demonstrated acute and durable efficacy when delivered alone or in combination with medication, in person, or via telehealth, and in the presence or absence of common comorbid conditions. Additional research is needed to develop and test treatment guidelines for the use of CBIT in combination with pharmacologic, neuromodulatory, and other intervention modalities.