Accurate assessment of treatment outcomes in patients with Tourette syndrome (TS) is essential for evidence-based clinical care. This report determined the minimal clinically important difference (MCID) on the Yale Globa...Accurate assessment of treatment outcomes in patients with Tourette syndrome (TS) is essential for evidence-based clinical care. This report determined the minimal clinically important difference (MCID) on the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (YGTSS-TTS) and YGTSS Impairment Scale (YGTSS-I), using the Clinical Global Impression of TS Severity (CGI-TS-S) and Improvement (CGI-TS-I) as anchors, in pediatric patients with TS receiving pharmacotherapy. Analyses used data from two clinical trials of ecopipam (a randomized controlled trial and its open-label extension). Receiver operating characteristic (ROC) analysis determined the percentage reduction in YGTSS scores that distinguished patients with improvement from those with no change or worsening on the CGI-TS-S and CGI-TS-I. Spearman's correlation, empirical cumulative distribution function, and probability distribution function analyses examined relationships between YGTSS-TTS and CGI-TS-S or CGI-TS-I. Overall, 133 patients (75.2% male; mean [SD] age, 12.7 [2.8]) were included; 63.2% had improvement on the CGI-TS-S, and 78.2% showed improvement on the CGI-TS-I. Percentage reduction in YGTSS scores that distinguished improvement from no change or worsening on the CGI-TS-S and CGI-TS-I ranged from 18.6%-33.3% (area under the ROC curve range, 0.71-0.81). Improvement on the YGTSS-TTS was correlated with posttreatment CGI-TS-S ( = -0.65; < 0.001) and CGI-TS-I ( = -0.61; < 0.001) scores. The MCID for YGTSS-TTS was achieved by 67% and 62% of patients with improvement on the CGI-TS-S and CGI-TS-I, respectively. This analysis is the first to determine the MCID for YGTSS in a pediatric population with TS receiving pharmacotherapy. Whether using CGI-TS-S or CGI-TS-I as the anchor, a 25% reduction in YGTSS scores was a generally appropriate minimum threshold to define clinically meaningful improvement in this population. Findings offer an objective threshold for classifying clinically meaningful improvement in children and adolescents receiving pharmacotherapy for TS in clinical practice.
variants are thought to affect the scaffolding that protects the axonal segment of neurons as well as neuronal synapses. The gene is located in the 9q34.11 genomic region and encodes the cytoskeletal protein alpha II sp...variants are thought to affect the scaffolding that protects the axonal segment of neurons as well as neuronal synapses. The gene is located in the 9q34.11 genomic region and encodes the cytoskeletal protein alpha II spectrin. Epilepsy, encephalopathy, and motor neuropathy are most commonly associated with variants. An informed consent and questionnaire were developed in order to gather information from caregivers regarding their family members' variant. Survey results are summarized descriptively, in order of frequency. The results of a questionnaire filled out by the caregivers of loved ones who have a mutation are summarized for 25 individuals, 14 males and 11 females, who have the mutation. The results of this survey mirror those reported by other authors and include epilepsy, intellectual and motor delays, encephalopathy, and motor neuropathy. Additional effects of the mutation reported here include absent or difficult speech, happy personality, decline in cognitive and motor skills with age, vision and hearing abnormalities, organ and skeletal effects, autoimmune diseases, and weakened immune systems.
Weight loss is a well-documented adverse effect of psychostimulants. Given their frequent coprescription with second-generation antipsychotics (SGA) in pediatric patients, this study aims to examine whether concomitant u...Weight loss is a well-documented adverse effect of psychostimulants. Given their frequent coprescription with second-generation antipsychotics (SGA) in pediatric patients, this study aims to examine whether concomitant use of psychostimulants mitigates SGA-associated weight gain in children and adolescents. This study utilized the IQVIA Ambulatory electronic medical record-U.S. database (2016-2021) to identify patients aged 6-17 years who initiated an SGA. Those who started psychostimulants within 7 days of SGA initiation and maintained ≥90 days of use were classified as concomitant users, while those who initiated psychostimulants later with ≥90 days of overlap were add-on users. Patients never prescribed psychostimulants were SGA-only users. After adjusting for the baseline covariates using propensity scores, 6- and 12-month body mass index (BMI) -score trends following psychostimulant initiation were compared between (1) concomitant and SGA-only users and (2) add-on and SGA-only users, using a linear mixed-effects regression model. The results of linear mixed effect regression models indicate that concomitant users experienced a 0.0143 less monthly BMI -score increase ( = 0.0063) compared with the SGA-only users over the 6 months following psychostimulant initiation. Similarly, add-on users had a significantly lower rate of weight gain compared with SGA-only users ( = -0.0463, < 0.0001). When the follow-up period was extended to 12 months, the sensitivity analyses for both concomitant and add-on users were consistent with their primary analyses. Concomitant and add-on psychostimulants appear to mitigate SGA-associated weight gain in children and adolescents. Further investigation is needed to understand their effectiveness and safety relative to other interventions for antipsychotic-associated weight gain.
Many individuals with autism spectrum disorder (ASD) experience gastrointestinal (GI) symptoms, which can impact social interactions, exacerbate social communication deficits, and decrease the quality of life. GI symptom...Many individuals with autism spectrum disorder (ASD) experience gastrointestinal (GI) symptoms, which can impact social interactions, exacerbate social communication deficits, and decrease the quality of life. GI symptoms have been shown to be correlated with the autonomic nervous system and endocrine response to stress in some people with ASD. Furthermore, propranolol, a central and peripheral beta-adrenergic antagonist that inhibits the stress response, has been shown to provide GI relief for some individuals with ASD, but not others. This pilot study examined whether baseline (i.e., resting) heart rate variability (HRV), a biomarker that is sensitive to the stress response, predicted the response to propranolol in decreasing GI symptoms. In this pilot study, a sample of 37 individuals with ASD participated in a 12-week open-label trial of propranolol. The Gastrointestinal Severity Index and HRV were collected at baseline (i.e., prior to taking propranolol) and again at the end of the 12-week trial period. Higher HRV was associated with the greatest reduction in GI symptoms, with a strong effect size, but only for adolescents and young adults (15-24 years old). Baseline HRV and GI change scores were not significantly correlated for younger children (7-14 years old). The results from this open-label pilot trial suggest that autistic adolescents and young adults with higher baseline HRV, indicating greater parasympathetic tone, may respond better to propranolol and show the greatest reduction in GI symptoms. The data from this pilot should be interpreted with caution until larger, randomized, double-blinded, placebo-controlled trials of propranolol for GI symptoms in ASD are completed.
Thom RP, Warren TL, Khan S
… +6 more, Muhle RA, Wang PP, Brennand K, Zürcher NR, Veenstra-VanderWeele J, Hoffman EJ
J Child Adolesc Psychopharmacol
· 2025 May · PMID 40138183
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Despite growing knowledge of the underlying neurobiology of autism spectrum disorder (ASD) and related neurogenetic syndromes, treatment discovery has remained elusive. In this review, we provide a blueprint for translat...Despite growing knowledge of the underlying neurobiology of autism spectrum disorder (ASD) and related neurogenetic syndromes, treatment discovery has remained elusive. In this review, we provide a blueprint for translational precision medicine in ASD and related neurogenetic syndromes. The discovery of trofinetide for Rett syndrome (RTT) is described, and the role of nonmammalian, mammalian, and stem cell model systems in the identification of molecular targets and drug screening is discussed. We then provide a framework for translating preclinical findings to human clinical trials, including the role of biomarkers in selecting molecular targets and evaluating target engagement, and discuss how to leverage these findings for future ASD drug development. Multiple preclinical model systems for ASD have been developed, each with tradeoffs with regard to suitability for high-throughput small molecule screening, conservation across species, and behavioral face validity. Future clinical trials should incorporate biomarkers and intermediate phenotypes to demonstrate target engagement. Factors that contributed to the approval of trofinetide for RTT included replicated findings in mouse models, a well-studied natural history of the syndrome, development of RTT-specific outcome measures, and strong engagement of the RTT family community. The translation of our growing understanding of the neurobiology of ASD to human drug discovery will require a precision medicine approach, including the use of multiple model systems for molecular target selection, evaluation of target engagement, and clinical trial design strategies that address heterogeneity, power, and the placebo response.
SARS-CoV-2 (COVID-19) infection has been implicated in the onset of neuropsychiatric symptoms in adults and children. While outcomes of COVID-19 infection and vaccination have been tracked in the general pediatric popula...SARS-CoV-2 (COVID-19) infection has been implicated in the onset of neuropsychiatric symptoms in adults and children. While outcomes of COVID-19 infection and vaccination have been tracked in the general pediatric population, little is known of their impact on children with preexisting neuropsychiatric syndromes, including pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). The aim of this study is to understand the prevalence and severity of COVID-19 symptoms and PANS/PANDAS symptoms following COVID-19 infection or vaccination in children with PANS/PANDAS. We analyzed retrospective COVID-19 survey data from caregivers of youth with PANS/PANDAS at Massachusetts General Hospital (MGH; = 57) and the International PANS Registry (IPR; = 478). Surveys were conducted online between late 2021 and early 2022 to collect COVID-19 infection and vaccination histories, side effects, and changes in PANS/PANDAS symptoms. Descriptive results are reported, stratified by case and sibling groups within the IPR sample. Among patients with test-confirmed COVID-19 (MGH: = 20, IPR: = 65 cases, = 16 siblings), mild/minor COVID-19 symptoms were common (62-75%). All patients with preexisting PANS/PANDAS-related symptoms at the time of COVID-19 infection experienced an exacerbation of PANS/PANDAS symptoms, while remitted patients did not report any PANS/PANDAS symptoms. Following the first COVID-19 vaccine dose (MGH: = 45, IPR: = 150 cases, = 44 siblings), fatigue was the predominant side effect (30-56%). Most patients did not report new (59-81%) or worsened (71-82%) PANS symptoms post-vaccination, irrespective of symptomatic status at vaccination. Vaccine hesitancy often stemmed from concerns that the vaccination would cause an exacerbation of PANS/PANDAS symptoms. In two samples of children with PANS/PANDAS, symptoms of COVID-19 following infection and vaccination were common and generally mild to moderate. Children experiencing PANS/PANDAS symptoms at the time of COVID-19 infection experienced an increase in PANS/PANDAS symptom severity.
The purpose of this article was to review the safety, tolerability, and effectiveness of clozapine in youth and young adults with autism spectrum disorder (ASD) and/or intellectual disability. An IRB-approved retrospect...The purpose of this article was to review the safety, tolerability, and effectiveness of clozapine in youth and young adults with autism spectrum disorder (ASD) and/or intellectual disability. An IRB-approved retrospective chart review of youth and young adults with autism and/or intellectual disability who were prescribed clozapine between January 2012 and June 2020 was completed. Information was collected from 1 year before through 1 year after clozapine initiation related to medications prescribed, hospitalizations, emergency department (ED) visits, and Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement (CGI-I) ratings. Adverse effects and reasons for stopping clozapine were documented. Fifty-eight patients were included in analysis. Forty patients remained on clozapine through June 2020 and 18 did not. Most patients were prescribed clozapine for treatment of irritability. Reasons for stopping clozapine included side effects, continued behavior concerns, difficulty with blood draws, and improvement in symptoms. For those who remained on clozapine for the duration of the review period, the number of hospitalizations and ED presentations for psychiatric concerns or medical concerns potentially related to clozapine significantly decreased in the year following clozapine initiation compared with the year prior (2.13 vs. 3.48, = 0.010). There was a significant reduction in CGI-I scores from 3.96 to 2.53 ( < 0.001) from clozapine initiation to 1 year later. There was a nonsignificant trend toward reduction in use of multiple antipsychotics simultaneously from time of clozapine initiation to 1 year later in those who remained on clozapine (38.5% vs. 25%, = 0.232). Use of clozapine for treatment-refractory irritability in youth and young adults with ASD and/or intellectual disability is generally well-tolerated. Observed benefits included a decrease in number of hospitalizations and ED visits and a decrease in CGI-I score in the year after clozapine initiation.
Rates of mental illness among young people remain elevated, and the utilization of youth mental health services is expected to increase. Yet, there is limited knowledge on real-world medication usage and prescribing at t...Rates of mental illness among young people remain elevated, and the utilization of youth mental health services is expected to increase. Yet, there is limited knowledge on real-world medication usage and prescribing at these services. Hence, the aim of this study was to explore the medication prescribing patterns at a center, an Australian youth mental health service. A retrospective cross-sectional study of medical records was conducted. Demographic data, clinical information, prescribed medications, and reasons for use of young people who attended an intake assessment at Camperdown over a 13-month period, February 2021-February 2022, were analyzed. Data collection focused on medication molecule, strength, dose, prescriber designation, and indication. Data were analyzed descriptively. Records for 608 participants were included. The median age at intake was 19.9 years old (interquartile range: 16.1-22.4), and most participants identified as female ( = 372, 61.2%). Anxiety ( = 246, 40.5%) and low mood ( = 95, 15.6%) were the most common presenting concerns. Almost half of participants ( = 291, 47.9%) reported using medication/s at intake, and almost one in five participants ( = 119, 19.6%) were prescribed a medication at the service. The most prescribed medications at were melatonin (24.0%) and quetiapine (12.3%), as well as the antidepressants escitalopram (15.1%), sertraline (11.2%), and fluoxetine (7.3%). This study provides insights into the prescribing practices at a single center. Further investigations are needed to explore the impacts of off-label prescribing for young people, particularly in relation to melatonin and quetiapine, where safety and efficacy in young people have not been well established.
Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood...Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood symptoms in youth with BD. This study included 246 youth of European ancestry with BD (7-20 years old at intake) from the Course and Outcome of Bipolar Youth study and Centre for Youth Bipolar Disorder. Mood symptom severity was assessed at intake and, for 168 participants, prospectively for a median of 8.7 years. PRSs for BD, schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were constructed using genome-wide summary statistics from independent adult cohorts. Higher BD-PRS was significantly associated with lower most severe lifetime depression score at intake ( = -0.14, = 0.03). Higher SCZ-PRS and MDD-PRS were associated with significantly less time spent in euthymia (SCZ-PRS: = -0.21, = 0.02; MDD-PRS: = -0.22, = 0.01) and more time with any subsyndromal mood symptoms (i.e., any mania, mixed, or depression symptoms; SCZ-PRS: = 0.15, = 0.04; MDD-PRS: = 0.17, = 0.01) during follow-up. PRSs for BD and ADHD were not significantly associated with any longitudinal mood variable. This exploratory analysis was the first to examine psychiatric PRSs in relation to the prospective course of mood symptoms among youth with BD. Results from the current study can serve to guide future youth BD studies with larger sample sizes on this topic.
Srinivasan A, Luccarelli J, Tamargo R
… +2 more, Adegoke T, Smith JR
J Child Adolesc Psychopharmacol
· 2025 May · PMID 40040484
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Catatonia is a severe psychomotor and mood-related disorder, which can significantly impact the quality of life for autistic individuals. Often, electroconvulsive therapy (ECT) is required for treatment of catatonia in a...Catatonia is a severe psychomotor and mood-related disorder, which can significantly impact the quality of life for autistic individuals. Often, electroconvulsive therapy (ECT) is required for treatment of catatonia in autism. However, hyperactive, impulsive, and aggressive symptoms are common in this subpopulation. Thus, pharmacologic agents are needed to assist in obtaining intravenous (IV) access and placement of necessary monitoring leads when ECT is pursued. Here we report six patients with autism and hyperactive catatonia who successfully and safely received intramuscular (IM) ketamine to obtain IV access for ECT while prescribed high-dose benzodiazepines for catatonia. Using SlicerDicer software found within Epic Systems electronic medical record, we conducted a single-site retrospective analysis. All patients had a diagnosis of autism, were treated for hyperactive catatonia with ECT, and required the use of ketamine for safe IV placement. Diagnoses of autism and catatonia were confirmed per the fifth edition of the . Six patients were identified. All patients met criteria for autism, intellectual disability, and catatonia. The patient's ages ranged from 10 to 30 years, and all were prescribed high doses of benzodiazepines for treatment of catatonia, with a mean dose of 24 mg per day in lorazepam equivalents. The patients' symptoms of hyperactive catatonia impaired the ability to obtain IV access. Thus, IM ketamine was received by all patients to facilitate this process. All patients were able to receive ECT. In all cases, IM ketamine was successfully used to obtain IV access and allow patients to receive ECT uneventfully. No serious adverse events were reported despite the coadministration of ketamine with high-dose benzodiazepines in this patient subpopulation.
Viloxazine extended-release (VLX-ER) is effective as monotherapy for attention-deficit/hyperactivity disorder (ADHD), and is often tried as an add-on treatment when psychostimulant therapy fails to provide an adequate tr...Viloxazine extended-release (VLX-ER) is effective as monotherapy for attention-deficit/hyperactivity disorder (ADHD), and is often tried as an add-on treatment when psychostimulant therapy fails to provide an adequate treatment response. This phase 4, open-label study evaluated safety, tolerability, and efficacy of VLX-ER with optimized psychostimulants in pediatric participants with ADHD. Morning versus evening VLX-ER use was also evaluated. Children and adolescents (6-17 years) experiencing inadequate psychostimulant response (investigator-assessed ADHD Rating Scale-5 [ADHD-RS-5] score ≥24 and Clinical Global Impression-Severity of Illness [CGI-S] scores ≥3) during a 4-week screening period received flexibly-dosed VLX-ER, taken once daily in the morning (weeks 14) or evening (weeks 5-8), concomitantly with a psychostimulant. Safety (primary outcome) and efficacy were evaluated relative to baseline. Fifty-six participants (26 children; 30 adolescents) enrolled, and 48 (85.7%) completed the study. Combination therapy was well tolerated, with only two participants (3.6%) withdrawing due to adverse events (AEs). The most commonly reported AEs were headache (17.9%), decreased appetite (12.5%), and upper respiratory tract infection (10.7%). Mean ± standard deviation investigator-assessed ADHD-RS-5 scores (baseline: 37.2 ± 8.4) improved progressively by -13.5 ± 9.7 points at week 4 and -18.2 ± 10.0 points at week 8 ( < 0.0001 each). Likewise, CGI-S scores (baseline: 4.4 ± 0.6) improved by -0.9 ± 0.9 at week 4 and -1.4 ± 1.1 at week 8 ( < 0.0001 each). Parent-assessed scales, including ratings of morning and evening ADHD behaviors and sleep disturbances, showed significant improvement relative to baseline regardless of morning (week 4) or evening (week 8) VLX-ER dosing. Combined treatment with VLX-ER and psychostimulant therapy showed acceptable safety and tolerability, with improvement in morning and evening ADHD behaviors and sleep disturbances relative to stimulant monotherapy. Timing of VLX-ER administration (morning or evening) did not appear to affect safety, drug response, or sleep improvement.