Le numéro de mai 2025 du Journal of Child and Adolescent Psychopharmacology est consacré à la psychopharmacologie dans les TND.

1. Croarkin PE. From the Editor-in-Chief’s Desk: Special Issue on the Psychopharmacology of Neurodevelopmental Disorders. Journal of Child and Adolescent Psychopharmacology. 2025; 35(4): 173-4.

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2. Kevelson SD. The Curious Case of Therapist Self-Disclosure During Pharmacotherapy Visits in an Autism Center. J Child Adolesc Psychopharmacol. 2025; 35(4): 175-7.

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3. Thom RP, Warren TL, Khan S, Muhle RA, Wang PP, Brennand K, Zürcher NR, Veenstra-VanderWeele J, Hoffman EJ. A Blueprint for Translational Precision Medicine in Autism Spectrum Disorder and Related Neurogenetic Syndromes. J Child Adolesc Psychopharmacol. 2025; 35(4): 178-93.

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

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4. Ward C, Childress A, Martinko K, Chen D, Larsen KG, Shah A, Sheridan P, Hefting N, Knutson J. Safety and Efficacy of Brexpiprazole in the Treatment of Irritability Associated with Autism Spectrum Disorder: An 8-Week, Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial and 26-Week Open-Label Extension in Children and Adolescents. J Child Adolesc Psychopharmacol. 2025; 35(4): 194-201.

Introduction: The effective management of irritability is a key need in young people with autism spectrum disorder (ASD). We evaluated the efficacy and safety of brexpiprazole in children and adolescents with irritability associated with ASD. Methods: This was an 8-week, phase 3, randomized, double-blind, placebo-controlled trial (NCT04174365) and 26-week, open-label extension (OLE, NCT04258839) of brexpiprazole (0.25-3 mg/day based on body weight) in children and adolescents (5-17 years) with a diagnosis of ASD, score ≥18 on the Aberrant Behavior Checklist-Irritability (ABC-I) subscale, and score ≥4 on the Clinical Global Impressions-Severity scale. Results: Of the 119 randomized participants (brexpiprazole = 60, placebo = 59), 104 completed double-blind treatment, and 95 enrolled and 70 completed the OLE. Similar reductions in mean ABC-I subscale score were seen in both groups (least-squares mean ± standard error reduction from double-blind baseline of -10.1 ± 1.3 with brexpiprazole vs -8.9 ± 1.3 with placebo). Thus, the primary endpoint did not show a significant treatment effect (LS-mean [95% confidence interval] treatment difference: -1.22 [-4.49, 2.05], p = 0.46) and the hierarchical efficacy analysis ended at this point. At the end of the OLE, participants had a mean ± SD reduction from open-label baseline of -6.1 ± 8.2 in ABC-I subscale score. During double-blind treatment, 51.7% participants treated with brexpiprazole had ≥1 treatment-emergent adverse event (TEAE) versus 35.1% with placebo; no severe or serious TEAEs were reported. The only potentially treatment-related TEAE that occurred in ≥5% of participants was somnolence (12.1% for brexpiprazole vs 5.3% for placebo). During the OLE, the most commonly reported TEAE was increased weight (n = 13, 13.7%). Conclusions: Treatment with brexpiprazole did not demonstrate significant efficacy versus placebo for the treatment of irritability associated with ASD. The safety profile was consistent with that observed in adult and adolescent patients with schizophrenia.

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5. Verdes A, Bhattachan S, Kolevzon A, King BH, McDougle CJ, Sanders KB, Kim SJ, Spanos M, Chandrasekhar T, Rockhill C, Palumbo M, Minjarez M, Nowinski L, Marler S, Siecinski S, Giamberardino S, Gregory SG, Veenstra-VanderWeele J, Sikich L, Jutla A. Predictors of Placebo Response in the Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors. J Child Adolesc Psychopharmacol. 2025; 35(4): 202-10.

Background: Although randomized clinical trials (RCTs) have investigated several treatments for social communication difficulties and repetitive behavior in autism, none has yet shown consistent superiority over placebo. Placebo response in autism RCTs may impede the ability to detect meaningful treatment effects. Objective: We sought to identify individual-level predictors of placebo response in Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B), a 24-week RCT of intranasal oxytocin for social impairment in autistic youth. In our primary analysis, we examined predictors of change in the Aberrant Behavior Checklist-modified Social Withdrawal (ABC-mSW) score at 24 weeks in SOARS-B participants taking placebo. Secondary analyses examined predictors of ABC-mSW change at 12 weeks and of Clinical Global Impressions-Improvement at 24 and 12 weeks. We also examined predictors of response among SOARS-B participants taking oxytocin. Methods: For each analysis, we first used lasso (least absolute shrinkage and selection operator) regression to identify potentially influential predictors from a large group that included demographic factors, rating scale data, and prescribed medications. We then estimated an unpenalized linear regression model for the outcome of interest that included only variables retained by the optimal lasso. We considered variables with statistically significant coefficients to be influential predictors. Results: Higher baseline ABC-mSW score was the only significant predictor of greater ABC-mSW change in the placebo group at 24 and 12 weeks. Conclusions: In SOARS-B, higher baseline severity on a measure of reciprocal social communication predicted greater placebo response. This is consistent with the finding that lower social communication adaptive functioning was associated with greater placebo response in recent RCTs of balovaptan for social impairment in autism. However, it contrasts with findings from a trial of citalopram for repetitive behavior in autism, in which lower baseline severity of a composite of autistic and mood symptoms predicted greater placebo response. This may indicate that different factors contribute to placebo response in different symptom domains.

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6. McKinney WS, Schmitt LM, De Stefano LA, 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. Results from a Double-Blind, Randomized, Placebo-Controlled, Single-Dose, Crossover Trial of Lovastatin or Minocycline in Fragile X Syndrome. J Child Adolesc Psychopharmacol. 2025; 35(4): 211-21.

Introduction: Treatment studies in FMR1 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. Materials and Methods: 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. Results: 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. Discussion: 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. Conclusions: 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.

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7. Thom RP, Renzi D, Pecukonis M, Mullett J, Ravichandran C, McDougle CJ. A Prospective Open-Label Trial of Buspirone for the Treatment of Anxiety in Williams Syndrome. Journal of Child and Adolescent Psychopharmacology. 2024; 35(4): 222-30.

Study Design: Prospective open-label trial. Objectives: The objective of this study was to determine whether buspirone showed preliminary evidence of effectiveness, safety, and tolerability in individuals with Williams syndrome (WS). Methods: 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). Results: Buspirone use (mean dose, 22.6 mg per day) was associated with a reduction in anxiety severity, with Cohen?s d 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. Conclusion: 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.

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8. Elmaghraby R, Blank E, Miyakoshi M, Gilbert DL, Wu SW, Larsh T, Westerkamp G, Liu Y, Horn PS, Erickson CA, Pedapati EV. Probing the Neurodynamic Mechanisms of Cognitive Flexibility in Depressed Individuals with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2025; 35(4): 231-43.

Introduction: Autism spectrum disorder (ASD) is characterized by deficits in social behavior and executive function (EF), particularly in cognitive flexibility. Whether transcranial magnetic stimulation (TMS) can improve cognitive outcomes in patients with ASD remains an open question. We examined the acute effects of prefrontal TMS on cortical excitability and fluid cognition in individuals with ASD who underwent TMS for refractory major depression. Methods: We analyzed data from an open-label pilot study involving nine participants with ASD and treatment-resistant depression who received 30 sessions of accelerated theta burst stimulation of the dorsolateral prefrontal cortex, either unilaterally or bilaterally. Electroencephalography data were collected at baseline and 1, 4, and 12-weeks posttreatment and analyzed using a mixed-effects linear model to assess changes in regional cortical excitability using three models of spectral parametrization. Fluid cognition was measured using the National Institutes of Health Toolbox Cognitive Battery. Results: Prefrontal TMS led to a decrease in prefrontal cortical excitability and an increase in right temporoparietal excitability, as measured using spectral exponent analysis. This was associated with a significant improvement in the NIH Toolbox Fluid Cognition Composite score and the Dimensional Change Card Sort subtest from baseline to 12 weeks posttreatment (t = 3.79, p = 0.005, n = 9). Improvement in depressive symptomatology was significant (HDRS-17, F (3, 21) = 28.49, p < 0.001) and there was a significant correlation between cognitive improvement at week 4 and improvement in depression at week 12 (r = 0.71, p = 0.05). Conclusion: These findings link reduced prefrontal excitability in patients with ASD and improvements in cognitive flexibility. The degree to which these mechanisms can be generalized to ASD populations without Major Depressive Disorder remains a compelling question for future research.

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9. Srinivasan A, Luccarelli J, Tamargo R, Adegoke T, Smith JR. Treat to Sedation: Managing Intravenous Placement for Electroconvulsive Therapy in Autism with Intellectual Disability and Hyperactive Catatonia. J Child Adolesc Psychopharmacol. 2025; 35(4): 244-8.

Purpose: 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. Methods: 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 Diagnostic and Statistical Manual of Mental Disorders. Results: 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. Conclusion: 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.

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10. Weas S, Pawlowski K, Miller M, DePillis R, Baumer N. Psychotropic Medication Prescription Patterns in Down Syndrome in a Large Pediatric Specialty Clinic. J Child Adolesc Psychopharmacol. 2025; 35(4): 249-54.

Objectives: Patterns of psychotropic medication use in children and adolescents with Down syndrome (DS) are largely unknown. Clinical decisions are often made from evidence and experience from individuals with autism spectrum disorder (ASD) or intellectual disability (ID). Methods: Longitudinal data from 670 children with DS who received care in a specialty DS clinic from March 2021 to February 2024 were collected. After each clinic visit, the clinician indicated the presence or absence of co-occurring neurodevelopmental (ND) or mental health (MH) diagnoses, as well as whether the individual was prescribed a psychopharmacological treatment. We used descriptive statistics and analyzed associations between psychotropic medication use, co-occurring ND/MH conditions, and demographic data. Results: 19.1% of patients were prescribed at least one psychotropic medication at their most recent clinical visit. Alpha-agonists were the most commonly prescribed medication class (30.8%), followed by stimulants (18.9%), and antidepressants (16.7%). There was a significant difference in psychotropic medication use by age, with older children having increased odds of being prescribed a psychotropic medication. There were no differences in psychotropic medication use across sex (p = 0.10), race (p = 0.10), or household income (p = 0.16). Conclusions: We found that one-fifth of patients with DS were prescribed psychotropic medications. Nearly every individual with DS who was prescribed a psychotropic medication had a co-occurring ND/MH condition, yet these rates were lower than what have been reported in children with ID, ASD, and attention deficit/hyperactivity disorder. Further research needs to include those with DS to further understand medication efficacy and safe dosing practices to ensure optimal outcomes.

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11. Berman L, Onyema I, Bieber E. Letter: Mirtazapine-Associated Hyperkinetic Movements in a 17-Year-Old with Autism Spectrum Disorder and Chronic Catatonia: A Case Report. J Child Adolesc Psychopharmacol. 2025; 35(4): 255-6.

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12. Beser C, Davis G, O’Connell M, Ali A. Letter: Agitation Management in a 5-Year-Old Boy with X Chromosome-Linked Monoamine Oxidase-A and Monoamine Oxidase-B Deficiency. Journal of Child and Adolescent Psychopharmacology. 2024; 35(4): 257-8.

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13. Durak M, Işık Ü. Letter: A Rare Case of Dose-Dependent Priapism in a Child with Autism Treated with Aripiprazole and Risperidone. J Child Adolesc Psychopharmacol. 2025; 35(4): 259-60.

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