Prospective open-label trial. The objective of this study was to determine whether buspirone showed preliminary evidence of effectiveness, safety, and tolerability in individuals with Williams syndrome (WS). This is a...Prospective open-label trial. The objective of this study was to determine whether buspirone showed preliminary evidence of effectiveness, safety, and tolerability in individuals with Williams syndrome (WS). This is a 16-week, prospective, flexibly dosed, open-label trial of buspirone in 20 individuals with WS aged 5-65 years. The primary outcome measure was the Pediatric Anxiety Rating Scale (PARS). Buspirone use (mean dose, 22.6 mg per day) was associated with a reduction in anxiety severity, with Cohen's estimate of -4.02 for the PARS. All 18 participants who completed the study received the Clinical Global Impression-Improvement subscale score for anxiety of "much improved" or "very much improved." No serious or severe adverse events occurred during the trial, and no participants discontinued the study due to adverse events. Buspirone was safe and well tolerated. It was also associated with a reduction in anxiety severity. Given these findings, a double-blind, placebo-controlled study of buspirone in WS is warranted.
McKinney WS, Schmitt LM, De Stefano LA
… +14 more, Ethridge L, Norris JE, Horn PS, Dauterman S, Rosselot H, Pedapati EV, Reisinger DL, Dominick KC, Shaffer RC, Chin D, Friedman NR, Hong M, Sweeney JA, Erickson C
J Child Adolesc Psychopharmacol
· 2025 May · PMID 39651602
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Treatment studies in knockout rodent models have found that minocycline and lovastatin each improve synaptic, neurological, and behavioral functioning, and open-label chronic dosing studies in human patients with fragil...Treatment studies in knockout rodent models have found that minocycline and lovastatin each improve synaptic, neurological, and behavioral functioning, and open-label chronic dosing studies in human patients with fragile X syndrome (FXS) have demonstrated modest clinical improvements. Findings from blinded studies are mixed, and there is a limited understanding of electrophysiological target engagement that would facilitate cross-species translational studies. Smaller-scale, acute (e.g., single-dose) drug studies may speed treatment identification by detecting subtle electrophysiological and behavioral changes. Twenty-nine participants with FXS (31% female) ages 15-45 years completed a randomized, double-blind, crossover study in which they received a single oral dose of 40 mg of lovastatin, 270 mg of minocycline, or placebo, with a 2-week washout period between dosing visits. Participants completed a comprehensive neuropsychological battery and three EEG paradigms (resting state; auditory chirp; auditory habituation) before and 4 hours after dosing. No serious adverse events were reported, and both drugs were well-tolerated. Compared with placebo, there were no overall treatment effects for any outcomes, including EEG, but several modest drug responses varied as a function of sex and age. Lovastatin treatment was associated with improved spatial awareness in older participants and females compared with minocycline and placebo. We show that single-dose drug studies are highly feasible in FXS and that patients with FXS can complete a range of EEG and behavioral tasks, many of which have been shown to be reliable and may therefore be sensitive to subtle drug target engagement. Acute single doses of lovastatin or minocycline did not lead to changes in electrophysiological or performance-based measures. This may be due to the limited effects of these drugs in human patients or limited acute effects relative to chronic dosing. However, the study design was further validated for use in neurodevelopmental populations.
Current literature shows a benefit in clinical outcomes when long-acting injectable antipsychotics (LAIAs) are utilized in adult patients with psychiatric disorders such as schizophrenia, schizoaffective disorder, and bi...Current literature shows a benefit in clinical outcomes when long-acting injectable antipsychotics (LAIAs) are utilized in adult patients with psychiatric disorders such as schizophrenia, schizoaffective disorder, and bipolar disorder. Literature regarding LAIA use in pediatric patients is sparse. The objective of this study is to compare the number of acute psychiatric admissions, psychiatric emergency services (PES) visits, and total number of days admitted to an acute psychiatric hospital 1 year prior to and 1-year post-mirror point of index hospitalization and LAIA initiation. This was a single-site retrospective mirror-image review of patients <18 years of age initiated on an LAIA during an acute psychiatric hospitalization between October 1, 2015, and October 31, 2022. The number of admissions to the acute psychiatric hospital, number of PES visits, and total number of days hospitalized at the acute psychiatric hospital were captured 1-year pre-index hospitalization admission and 1-year post-index hospitalization discharge, with LAIA administration during index hospitalization being the mirror point. Descriptive statistics and a two-tailed paired -test were utilized to analyze the data. There were 45 unique pediatric patients initiated on an LAIA during the specified timeframe. Across these 45 patients, there were 47 psychiatric admissions 1-year pre-index hospitalization and 38 psychiatric admissions 1-year post-index hospitalization discharge ( = 0.37). Additionally, there were 24 PES visits 1-year pre-index hospitalization admission and 16 PES visits 1-year post-index hospitalization discharge ( = 0.25). Finally, across the 45 patients, there were a total of 1040 days admitted to the acute psychiatric hospital in the 1-year prior to index hospitalization admission compared with 774 days admitted to the acute psychiatric hospital in the 1-year post-index hospitalization discharge ( = 0.48). In this cohort of pediatric patients initiated on an LAIA, there was a positive trend favoring LAIA therapy over oral antipsychotic therapy with LAIA injection as the mirror point; however, there was no statistically significant difference in the number of psychiatric admissions, number of PES visits, or total number of days admitted to an acute psychiatric hospital. Further studies are required to fully understand the impact of LAIA therapy on clinical outcomes for child and adolescent patients with psychiatric disorders.
Bipolar disorder (BD) in adolescence often associates with risky conducts, nonsuicidal self-injury (NSSI), and suicidal ideation. Lithium salts represent the first-line choice for BD in youth to manage manic symptoms and...Bipolar disorder (BD) in adolescence often associates with risky conducts, nonsuicidal self-injury (NSSI), and suicidal ideation. Lithium salts represent the first-line choice for BD in youth to manage manic symptoms and prevent both manic and depressive relapses. Our study aimed to assess efficacy and tolerability of extended-release lithium sulfate (ERLS) in youths with BD. A longitudinal perspective intervention study was thus conducted on a single cohort of 36 patients with BD aged 12-17 years treated with ERLS and followed up for 1 year. ERLS was titrated up to reach optimal plasma concentrations during the 3 months before baseline visit (T0). Then, patients underwent five follow-up visits after 1, 2, 3, 5, and 11 months and were administered with a battery of self- and parent-rated questionnaires and interviews to evaluate, at each timepoint, ERLS-related side effects, manic and depressive symptoms, emotional dysregulation (ED), NSSI and suicidality, and aggressiveness. Regular clinical assessments were also conducted, as well as blood tests, urinalysis, and EKG. Regression models were applied to examine the time course of outcome variables. Twenty-four patients completed the follow-up. Regressions showed a significant reduction of most dependent variables included in the models, including depressive symptoms (β = -0.0006; adj-p = 0.0007), aggressiveness (β = -0.0031; adj-p < 0.0001), ED (β = -0.0002; adj-p = 0.0497), and unstructured suicidal ideation (β = -0.0058; adj-p = 0.0340). Fine distal tremor, increased thirst, and diuresis were among the most frequently reported side effects. Findings from the present study support the use of ERLS as an effective and well-tolerated agent for the management of BD in youth, with a beneficial effect on associated severe symptoms, including NSSI and suicidality.
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 cu...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.
J Child Adolesc Psychopharmacol
· 2025 Feb · PMID 39469761
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Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive dis...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.
Bobo WV, Moore KM, Betcher HK
… +6 more, Larish AM, Stoppel CM, VandeVoort JL, Chauhan M, Athreya AP, Talati A
J Child Adolesc Psychopharmacol
· 2024 Dec · PMID 39453674
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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...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.
Langfus JA, Youngstrom EA, Daniel D
… +2 more, Busner J, Findling RL
J Child Adolesc Psychopharmacol
· 2024 Dec · PMID 39419042
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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 struc...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.
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 neurode...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.
Bishop JR, Zhou C, Gaedigk A
… +5 more, Krone B, Kittles R, Cook EH, Newcorn JH, Stein MA
J Child Adolesc Psychopharmacol
· 2024 Dec · PMID 39387268
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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 pha...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.
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 lim...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.
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...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.