André Luiz Schuh Teixeira da Rosa

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet in children and adolescents it remains off-label and underused, constrained by safety concerns and scarce pediatric-specific evidence. Its benefits may extend beyond any single diagnostic category to severe, treatment-resistant dimensions of psychopathology that recur across diagnoses. This review traces clozapine’s history in youth, synthesizes the current evidence, and organizes it by domains of treatment resistance: psychosis, aggression, affective symptoms, suicidality and self-directed harm, and catatonia, with sections on real-world outcomes, clinical management, and safety. Randomized controlled data are confined to treatment-resistant early-onset schizophrenia and to one small trial in conduct disorder, with the first prospective open-label trial now available in autistic youth. Elsewhere the evidence is observational and of lower certainty, although convergent for aggression, suicidality, mood, and catatonia. The strongest transdiagnostic evidence is register-based and within-individual, drawn from cohorts aged 16 years and older, and spans psychotic and affective disorders; the pediatric gap concerns study design as well as sample size. Because pharmacovigilance data show that mortality is not concentrated in the hematological domain, safe use requires surveillance beyond blood counts, therapeutic drug monitoring, and safeguards over drug supply when suicide risk is present. Viewing clozapine as a treatment option defined by symptom severity and refractoriness may support rational use in severely ill youth, but the proposal remains preliminary: a conceptual framework that requires prospective, dimensionally designed pediatric studies. Clozapine’s potential transdiagnostic anti-suicidal effect merits priority investigation, given that suicide is a leading cause of death in adolescence.

Objective: Severe disruptive behaviors in youth with autism spectrum disorder (ASD) frequently persist despite conventional treatments, contributing to functional impairment. Although clozapine has antiaggressive properties, evidence guiding its use in treatment-resistant cases in autistic youth remains predominantly observational and retrospective. This study aimed to evaluate systematically and prospectively the effectiveness and safety of clozapine for treatment-resistant disruptive behaviors (TR-DB) in youth with ASD under routine conditions. Methods: This single-arm, open-label trial enrolled participants aged 10–17 with ASD. Inclusion required TR-DB after ≥2 antipsychotic trials and a Clinical Global Impression–Severity score ≥5. Following flexible titration, clozapine was maintained for 12 weeks. The primary outcome was change on the caregiver-rated Aberrant Behavior Checklist–Irritability (ABC-I). Secondary measures included global improvement, autism symptom severity, adaptive behavior, and caregiver quality of life. Response was defined as ≥30% ABC-I reduction plus a CGI–Improvement (CGI-I) of 1 to 2; remission required ≥80% ABC-I reduction and a CGI-I of 1. Results: Thirty-one participants initiated clozapine treatment (mean age 13.4 years; 90.3% male), and 28 completed the trial. ABC-I scores decreased from 32.0 ± 7.7 to 7.4 ± 5.1 (Cohen’s d _z −2.5; p < 0.001). Overall, 83.9% responded, and 38.7% remitted. Global severity improved from 6.1 ± 0.6 to 3.8 ± 1.6 ( p < 0.001). Significant improvements were observed in daily living skills, caregiver quality of life, and reduced polypharmacy. Adverse drug reactions were mostly mild-to-moderate; however, metabolic changes comprised significant weight gain and triglyceride elevation (both p < 0.05). Serious events included seizures ( n = 4) and pneumonia ( n = 1). Conclusions: Clozapine was associated with robust, rapid TR-DB reductions and high retention in autistic youth. However, safety risks mandate rigorous monitoring. Controlled trials are needed to confirm efficacy and refine the benefit–risk profile.

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition emerging in early childhood, characterized by core features such as sociocommunicative deficits and repetitive, rigid behaviors, interests, and activities. In addition to these, disruptive behaviors (DB), including aggression, self-injury, and severe tantrums, are frequently observed in pediatric patients with ASD. The atypical antipsychotics risperidone and aripiprazole, currently the only Food and Drug Administration–approved treatments for severe DB in patients with ASD, often encounter therapeutic failure or intolerance. Given this, exploring pharmacological alternatives for more effective management of DB associated with ASD is essential. Clozapine, noted for its unique antiaggressive effects in schizophrenia and in various treatment-resistant neuropsychiatric disorders, independent from its antipsychotic efficacy, remains underexplored in youths with ASD facing severe and persistent DB. Objective: This study aimed to evaluate the efficacy, tolerability, and safety of clozapine for treatment-resistant DB in youths with ASD. Methods: This is a prospective, single-center, noncontrolled, open-label trial. After a cross-titration phase, 31 patients with ASD aged 10-17 years and with treatment-resistant DB received a flexible dosage regimen of clozapine (up to 600 mg/day) for 12 weeks. Standardized instruments were applied before, during, and after the treatment, and rigorous clinical monitoring was performed weekly. The primary outcome was assessed using the Irritability Subscale of the Aberrant Behavior Checklist. Other efficacy measures include the Clinical Global Impression Severity and Improvement, the Swanson, Nolan, and Pelham questionnaire-IV, the Childhood Autism Rating Scale, and the Vineland Adaptive Behavior Scale. Safety and tolerability measures comprised adverse events, vital signs, electrocardiography, laboratory tests, physical measurements, and extrapyramidal symptoms with the Simpsons-Angus Scale. Statistical analysis will include chi-square tests with Monte Carlo simulation for categorical variables, paired t tests or Wilcoxon tests for continuous variables, and multivariate linear mixed models to evaluate the primary outcome, adjusting for confounders. Results: Recruitment commenced in February 2023. Data collection was concluded by April 2024, with analysis ongoing. This article presents the protocol of the initially planned study to provide a detailed methodological description. The results of this trial will be published in a future paper. Conclusions: The urgent need for effective pharmacological therapies in mitigating treatment-resistant DB in pediatric patients with ASD underscores the importance of this research. Our study represents the first open-label trial to explore the anti-aggressive effects of clozapine in this specific demographic, marking a pioneering step in clinical investigation. Adopting a pragmatic approach, this trial protocol aims to mirror real-world clinical settings, thereby enhancing the applicability and relevance of our findings. The preliminary nature of future results from this research has the potential to pave the way for more robust studies and emphasize the need for continued innovation in ASD treatment. Trial Registration: Brazilian Clinical Trials Registry RBR-54j3726; https://ensaiosclinicos.gov.br/rg/RBR-54j3726 International Registered Report Identifier (IRRID): DERR1-10.2196/58031

Background: Patients with autism spectrum disorder (ASD) may experience severe psychiatric symptoms, often unresponsive to conventional pharmacological therapies, highlighting the need for more effective alternatives. Aims: This study aims to map and synthesize evidence on the use of clozapine as a therapeutic option for managing severe psychiatric symptomatology co-occurring with ASD. Methods: We conducted a scoping review on multiple sources following the JBI guidelines. The search strategy was inclusive, targeting both peer-reviewed publications and gray literature presenting empirical data on the use of clozapine therapy for patients with ASD accompanied by comorbid psychiatric symptoms. Two independent evaluators performed the selection of studies, data extraction, and critical appraisal. Results: The review included 46 studies, encompassing 122 ASD individuals who received clozapine therapy. The sources of evidence comprise 31 case reports, 8 case series, 6 retrospective observational studies, and 1 quasi-experimental prospective study. The tables present the findings along with a narrative summary. Clozapine treatment demonstrated benefits in four groups of severe and treatment-resistant psychiatric symptoms in ASD patients: disruptive behaviors, psychotic symptoms, catatonia, and mood symptoms. Although side effects were common, tolerability was generally satisfactory. However, severe adverse events, such as seizures, moderate neutropenia, and myocarditis, underscore the need for intensive clinical monitoring. Conclusions: While clozapine shows promise as a pharmacological intervention for severe psychopathologies in ASD, more rigorous clinical studies are required to elucidate its efficacy and safety in this population. The limited robustness of the evidence calls for caution, signaling an early research stage into this topic.

BACKGROUND Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition emerging in early childhood, characterized by core features such as sociocommunicative deficits and repetitive, rigid behaviors, interests, and activities. In addition to these, disruptive behaviors (DB), including aggression, self-injury, and severe tantrums, are frequently observed in pediatric patients with ASD. The atypical antipsychotics risperidone and aripiprazole, currently the only Food and Drug Administration–approved treatments for severe DB in patients with ASD, often encounter therapeutic failure or intolerance. Given this, exploring pharmacological alternatives for more effective management of DB associated with ASD is essential. Clozapine, noted for its unique antiaggressive effects in schizophrenia and in various treatment-resistant neuropsychiatric disorders, independent from its antipsychotic efficacy, remains underexplored in youths with ASD facing severe and persistent DB. OBJECTIVE This study aimed to evaluate the efficacy, tolerability, and safety of clozapine for treatment-resistant DB in youths with ASD. METHODS This is a prospective, single-center, noncontrolled, open-label trial. After a cross-titration phase, 31 patients with ASD aged 10-17 years and with treatment-resistant DB received a flexible dosage regimen of clozapine (up to 600 mg/day) for 12 weeks. Standardized instruments were applied before, during, and after the treatment, and rigorous clinical monitoring was performed weekly. The primary outcome was assessed using the Irritability Subscale of the Aberrant Behavior Checklist. Other efficacy measures include the Clinical Global Impression Severity and Improvement, the Swanson, Nolan, and Pelham questionnaire-IV, the Childhood Autism Rating Scale, and the Vineland Adaptive Behavior Scale. Safety and tolerability measures comprised adverse events, vital signs, electrocardiography, laboratory tests, physical measurements, and extrapyramidal symptoms with the Simpsons-Angus Scale. Statistical analysis will include chi-square tests with Monte Carlo simulation for categorical variables, paired t tests or Wilcoxon tests for continuous variables, and multivariate linear mixed models to evaluate the primary outcome, adjusting for confounders. RESULTS Recruitment commenced in February 2023. Data collection was concluded by April 2024, with analysis ongoing. This article presents the protocol of the initially planned study to provide a detailed methodological description. The results of this trial will be published in a future paper. CONCLUSIONS The urgent need for effective pharmacological therapies in mitigating treatment-resistant DB in pediatric patients with ASD underscores the importance of this research. Our study represents the first open-label trial to explore the anti-aggressive effects of clozapine in this specific demographic, marking a pioneering step in clinical investigation. Adopting a pragmatic approach, this trial protocol aims to mirror real-world clinical settings, thereby enhancing the applicability and relevance of our findings. The preliminary nature of future results from this research has the potential to pave the way for more robust studies and emphasize the need for continued innovation in ASD treatment. CLINICALTRIAL Brazilian Clinical Trials Registry RBR-54j3726; https://ensaiosclinicos.gov.br/rg/RBR-54j3726 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/58031

The Brazilian Journal of Psychiatry is the official publication of Brazilian Psychiatric Association (Associação Brasileira de Psiquiatria - ABP)

Homo digitalis se refere ao homem modificado pela tecnologia. A realidade virtual (RV) e a realidade aumentada permitem ver o mundo sob a perspectiva de outras pessoas, sendo chamadas de “a máquina de empatia”. Objetivo: analisar como a RV pode ser usada na psiquiatria e na educação médica para promover empatia. Método: realizou-se uma revisão narrativa nas plataformas Medline e Embase, Google Scholar, listas de referências de artigos e em sítios eletrônicos de tecnologia. Artigos em inglês e francês foram selecionados, sem limites temporais para a busca. Resultados: uma revisão de 66 referências demonstrou que a RV pode gerar mudanças cognitivas, emocionais e comportamentais positivas, especialmente em relação a indivíduos de grupos diferentes. As narrativas imersivas com RV facilitam a compreensão empática, colocando o usuário na perspectiva de outra pessoa. A RV também está associada a jogos aplicados e estudos funcionais de atividade cerebral, que indicam potencial para gerar mudanças comportamentais positivas. Estudos maiores e ensaios clínicos são necessários para validar a efetividade dos desfechos e garantir o uso seguro e ético da tecnologia. Conclusão: a revisão demonstrou resultados promissores e um olhar otimista da RV como ferramenta para gerar empatia e promover o bem-estar mental.

Purpose Since the World Health Organization declared the coronavirus outbreak a global pandemic several million cases and more than three million deaths have been already confirmed worldwide due to COVID-19. Design and Methods Early Career Psychiatrists from all over the world present an overview of what happened in their own countries and what they have learned so far by this experience in everyday clinical practice. Practice Implication We tried to take a real time picture of this unexpected situation, drawing useful hints for now and the future.