Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2026 Sep 9;41(5):e70059. doi: 10.1002/hup.70059

A Systematic Review and a VigiBase Study of Accidental Clozapine Intoxications in Children and Adolescents

Sara Jiménez‐Fernández 1,2,✉, Carlos De las Cuevas 3, Emilio J Sanz 4,5, Jose de Leon 6,7
PMCID: PMC13555656  PMID: 42713824

ABSTRACT

Objectives

This study aimed to: (1) systematically review published cases of accidental clozapine poisoning in children and adolescents, and (2) study accidental pediatric clozapine intoxications reported to VigiBase, the global pharmacovigilance database.

Methods

A systematic review was conducted following PRISMA guidelines, and a retrospective analysis of accidental pediatric clozapine intoxication cases was performed using VigiBase.

Results

A systematic review identified 5 studies describing 8 cases of accidental clozapine ingestion in children aged 10 months to 10 years. The most common clinical manifestations were acute neuro‐respiratory complications. One fatality was reported, in a two‐year‐old child. The VigiBase observational analysis included 32 accidental intoxication cases, 3 in adolescents and 29 in children under seven years of age. Among adolescents, all cases resulted from in‐hospital medication administration errors; none were fatal. In the children, nearly half required prolonged hospitalization, and 2 resulted in death due to aspiration pneumonia or cardiopulmonary failure.

Conclusions

Accidental clozapine poisoning in pediatric populations, although rare, can result in severe and potentially life‐threatening outcomes, particularly in very young children. At home, preventive strategies are essential to reduce accidental overdose. The 3 cases of hospitalized adolescents are relatively recent, and many hospitals currently have systems in place to prevent medication errors.

Keywords: adolescent, child, clozapine/adverse effects, clozapine/toxicity, drug overdose

1. Introduction

Clozapine was developed between the 1960s and the 1980s without the comprehensive studies currently required by the Food and Drug Administration (FDA); its story is marked by post‐marketing pharmacovigilance identifying potentially lethal adverse drug reactions (ADRs) (de Leon 2022). In the 1970s, clozapine was marketed in some European countries with very limited trials and almost no pharmacokinetic studies. In 1974, the first United States (US) study, a small open trial, was published (Simpson and Varga 1974). Then a pharmacovigilance study described 8 deaths associated with agranulocytosis, which almost led to its complete withdrawal from the market (Idänpään‐Heikkilä et al. 1975). In the 1980s, some US experts continued to use clozapine under humanitarian regulations. The US company, encouraged by this experience, started negotiating again with the FDA about marketing clozapine.

The risk of agranulocytosis led the FDA to require a randomized clinical trial (RCT) for treatment‐resistant schizophrenia (TRS) which led to its approval in 1989 (Kane et al. 1988). A later RCT led to the 2002 approval of clozapine in the US for suicide prevention in schizophrenia and schizoaffective disorder (Meltzer et al. 2003). Currently, many studies of various designs support the finding that clozapine may have a unique anti‐suicidal effect when compared with other antipsychotics (De Las Cuevas, de, et al. 2025). However, this clinical success inherently increases the availability of the drug within households, inadvertently raising the risk of environmental exposure for vulnerable family members, particularly young children.

1.1. Clozapine in Children and Adolescents

The current US package insert states, “Safety and effectiveness in pediatric patients have not been established.” Most clozapine studies are limited to small samples and case reports (Adnan et al. 2022; da Rosa et al. 2024). The clozapine studies in children and adolescents are limited and paid little attention to pharmacokinetics (Jiménez‐Fernández et al. 2024) and developmental safety data. Understanding how antipsychotics like clozapine behave when accidently ingested by a developing central nervous system is critical for establishing real‐world safety boundaries.

In spite of clozapine's demonstrated ability to save lives, it is associated with severe ADRs that can be potentially lethal (De Las Cuevas et al. 2025). VigiBase is the global pharmacovigilance database for potential ADRs to medicinal products. In a recent analysis of 2825 clozapine ADRs in populations of children and adolescents from VigiBase data, three most novel and important findings were seen: (1) a lower percentage of fatal outcomes (1.5%) than in samples that included all ages (11.8%); (2) only one fatal outcome associated with agranulocytosis, which provided a very low percentage of 0.1% fatal outcomes among 934 patients with decreased white blood cell (WBC) count; and (3) suicide was the most frequent cause of death with 7 non‐duplicated fatal cases among 27 non‐duplicated fatal outcomes (De Las Cuevas et al. 2024).

This highlights the potential toxicity of clozapine during overdose, despite its strong, specific anti‐suicidal effect compared with other antipsychotics. Thus, child and adolescent psychiatrists worldwide need to use extreme precautions to avoid intentional or accidental overdose when prescribing clozapine to patients at risk for suicide (De Las Cuevas et al. 2024).

1.2. Accidental Poisoning in Children and Adolescents

Unintentional pediatric poisoning is a common problem in children. In Spain, over 250–300 visits to a pediatric emergency department occur because of exposure to a potentially toxic substance, most of them being mild in nature (Martínez Sánchez and Mintegi Raso 2020). In the United States, among children younger than 6 years, poison exposures increased by 12.4% from 2000 to 2010, including a 33% increase in pharmaceutical‐related exposure (Spiller et al. 2013).

In general, these poisonings are much more frequent in young children under 7 years of age, who are very curious, enjoy exploring, and, lacking a sense of danger, often grab medications within their reach. In other cases—especially during the first months of life—poisonings result from dosage errors in the medication given to the child or from the administration of the wrong drug. In older children and adolescents, drug poisonings are more often associated with suicidal intent (Martínez Sánchez and Mintegi Raso 2020).

1.3. Accidental Poisoning in Children and Adolescents With Clozapine

Atypical antipsychotics represent a non‐negligible proportion of pharmaceutical exposures reported to poison control centers (Wang et al. 2025). While the toxicological profile of several second‐generation antipsychotics has been described, epidemiological and clinical data specific to clozapine in pediatric accidental ingestion are scarce; only a limited number of cases were published (Borzutzky et al. 2003; Mady et al. 1996) and clinical manifestations may range from mild neurological symptoms to potentially life‐threatening events. This gap is clinically relevant because clozapine may be increasingly prescribed to adults of reproductive age, many of whom live in households with young children.

The present study had two aims: (a) to systematically review published cases of accidental clozapine intoxication in children and adolescents, and (b) to analyze spontaneous reports from VigiBase, the World Health Organization global pharmacovigilance database, to characterize severity patterns, clinical manifestations, and contextual risk factors. We hypothesized that acute accidental clozapine intoxications in children would predominantly present with neurocardiovascular toxicity and that clinical context would differ substantially between young children and adolescents.

2. Methods

2.1. Systematic Review

The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statements of quality (Moher et al. 2009). A systematic electronic literature search without language restrictions was conducted using MEDLINE/PubMed, databases from inception until May 30, 2025. The search terms used were “Clozapine/poisoning[Mesh]” with the following filters: Humans, Child: birth – 18 years. Given the rarity of cases, a MeSH‐focused strategy was used to maximize specificity. The inclusion criterion for the studies was young people (children and adolescents) with accidental clozapine intoxication. Records considered potentially relevant by the first author were selected for full‐text reading. Disagreements arising during this phase were resolved through discussion and consensus between the first and the last authors. The selected data were extracted and entered by the first author and verified by the last author. All inconsistencies regarding study inclusion and data abstraction were resolved by consensus.

To assess the methodological quality of a study and to determine the extent to which a study has addressed the possibility of bias in its design, conduct and analysis, Joanna Briggs Institute (JBI) tools were used for case reports and case series (Moola et al. 2020; Munn et al. 2020).

2.2. VigiBase Observational Study

VigiBase is the global pharmacovigilance database of reported potential ADRs of medicinal products. It receives data from all national drug/pharmacovigilance agencies including the FDA. The reporting agent (many times a clinician) sometimes classifies ADRs, but usually those who report enter free text information and the pharmacovigilance staff at a regional or national center or pharmaceutical company do the encoding, using the categories provided by the database.

A prior VigiBase study included an observational, retrospective analysis conducted from onset of clozapine use through June 1, 2022; it found 2825 ADRs in patients younger than 18 years with 27 non‐duplicated fatal outcomes (De Las Cuevas et al. 2024). That study of fatal outcomes eliminated accidental overdoses; thus, unpublished data from accidental intoxication in children were selected, leading to 32 non‐duplicated cases with completed data.

3. Results

3.1. Systematic Review

Figure 1 shows our method for identifying 22 potential articles and the subsequent exclusion of 16 articles, yielding 5 articles describing accidental clozapine intoxication in children and adolescents (Borzutzky et al. 2003; Isbister et al. 2005; Mady et al. 1996; Toepfner et al. 2013; Wong and Curtis 2004). Extracted data is presented in detail in the Supporting Information S1 and summarized in Supporting Information S1. There were 8 case reports between 13 months and 10 years old, who ingested between 50 and 200 mg of clozapine. Neurological ADRs were the most common (Supporting Information S1). Two cases documented clozapine serum concentrations between 544 and 736 ng/mL in girls aged 18 and 31 months after ingestion of 100–200 mg, corresponding to estimated exposures of approximately 10–20 mg/kg. Nevertheless, neurological and cardiovascular manifestations resolved within approximately 40 hours, supporting a predominantly reversible toxic effect.

FIGURE 1.

FIGURE 1

Open in a new tab

Flow chart.

Overall, the quality of the studies included was moderate. Supporting Information S1 shows that, according to the corresponding JBI checklist (selected based on the study type—case report, case series, or review synthesis), two studies showed a low risk of bias, one a moderate risk, and two a high risk.

3.2. VigiBase Observational Study

VigiBase initially reported 33 cases; however, one was excluded from the analysis due to missing age information. Moreover, with the limited available information an intentional overdose could not be ruled out (see Supporting Information S1, Case 33). Among the remaining 32 patients, the mean age was 3.65 years, and 50% were female (n = 16). There were two clearly independent subgroups of accidental overdoses of clozapine: 3 intoxications during hospitalization in adolescents and 29 intoxications in children under 7 years of age. These two distinct clusters also reflect different developmental and behavioral stages: exploration‐driven environmental exposure in toddlers versus system‐level vulnerabilities in adolescents.

3.2.1. Accidental Intoxications in Hospitalized Adolescents

The three cases in adolescents (2 females and 1 male) appeared to be explained by hospital medication administration errors in Europe (n = 2) and Asia (Supporting Information S1). None of these cases resulted in a fatal outcome; however, a 16‐year‐old European female required prolonged hospitalization after the administration of 100 mg of clozapine and a 15‐year‐old European male showed severe sedation.

3.2.2. Accidental Intoxications in Children Under 7 Years of Age

Table 1 describes the 29 cases in children under 7 years of age with a mean age of 2.3 years; 52% (15/27 with data) were female. Two cases in infants aged 12 and 13 months were categorized under the database label “suicide”. We hypothesize that these cases could potentially be secondary to a maternal overdose transmitted possibly through breastfeeding; however, this remains speculative and unconfirmed, as VigiBase provided us with access only to pediatric records and not to linked maternal data.

TABLE 1.

Accidental clozapine intoxications in 29 children (< 7 years old).

Total n = 29 a Female n = 15 Male n = 12
Seriousness
Not serious 8 (28%) 4 (27%) 4 (33%)
Serious, but not fatal 17 (58%) 7 (47%) 8 (67%)
Fatal 2 (7%) 2 (13%)
Not reported 2 (7%) 2 (13%)
Clinical manifestations
Sedation and somnolence 14 (48%) 8 (44%) 6 (50%)
Tachycardia 5 (17%) 3 (19%) 2 (17%)
↑ white blood cell count 2 (7%) 2 (12%)
Aspiration pneumonia 1 (3%) 1 (6%)
Seizure 1 (3%) 1 (7%)
Vomiting and nausea 1 (3%) 1 (6%)
Pyrexia 1 (3%) 1 (6%)
Cardiopulmonary failure 1 (3%) 1 (6%)
Open in a new tab
a

Two children with missing gender data.

More than a half of the patients (52%, 15/29) required prolonged hospitalization. In three patients, clozapine intoxication was life‐threatening. There were 2 deaths. A 24‐month‐old girl from North America died of aspiration pneumonia, which did not overlap with previously published cases by Wong and Curtis (2004). A 12‐month‐old European girl died of cardiopulmonary failure. Detailed descriptions indicated that almost one‐third (31%, 9/29) were counted as medication errors, including reports labeled as “wrong product administered,” “medication error,” or “administered drug to incorrect patient”. Others (41%, 12/29) were described as accidental, although the exact circumstances were not described (Supporting Information S1).

Regarding symptomatology, none of the patients in this subgroup presented with pericarditis or myocarditis. The most frequently reported ADRs were sedation and somnolence (n = 14), tachycardia (n = 5), and elevated white blood cell count/leukocytosis (n = 2). Other symptoms occurring in single cases are described in Table 1.

4. Discussion

This systematic review and pharmacovigilance analysis provide a comprehensive characterization to date of accidental clozapine intoxications in the pediatric population, a rare but clinically significant phenomenon. Our findings contribute valuable real‐world evidence regarding the post‐marketing safety profile of clozapine. While clinical trials offer highly controlled safety data, spontaneous reporting registries like VigiBase capture the true, messy landscape of domestic accidents and medication errors.

The three main findings resulting from the combined literature review and VigiBase data are as follows: (1) In acute accidental overdose cases involving children under 7 years of age, the most frequent ADRs were neurological and cardiovascular symptoms. Importantly, no cases of agranulocytosis, myocarditis or pericarditis were identified in either the published literature or VigiBase cohort. (2) Severity appears age dependent. Fatal outcomes occurred exclusively in children younger than 2 years. Nearly half of young children required prolonged hospitalization, and a subset experienced life‐threatening complications. These findings suggest increased vulnerability in very early childhood. (3) The context of intoxication differs markedly by developmental stage. In children under seven, most cases involved accidental household exposure. In contrast, all adolescent cases identified in VigiBase were related to medication administration or dispensing errors in hospital settings. (4).

4.1. Clinical Manifestations of Accidental Overdoses in Children Under 7 Years of Age

Pediatric intoxications involving atypical antipsychotics are relatively frequent; however, data on the clinical effects of acute exposure to this drug class in young children remain limited. Specifically, epidemiological evidence regarding acute clozapine intoxication is scarce (Meli et al. 2014). More broadly, intoxication with atypical antipsychotics appears to follow a clinical course similar to that observed in older age groups, with neurological and cardiovascular symptoms predominating (Meli et al. 2014).

In cases of clozapine accidental overdose in children, the most reported ADRs were neurological and cardiovascular symptoms in both the systematic review and the VigiBase dataset, whereas agranulocytosis and leukopenia were not observed. Only two cases in children under 6 years of age in the VigiBase cohort presented leukocytosis with elevated white blood cell counts. This latter finding is consistent with the inflammatory reactions commonly observed after aggressive clozapine titrations. To prevent clozapine‐induced inflammation, baseline and weekly C‐reactive protein (CRP) monitoring has been recommended (de Leon et al. 2022). More recently, some studies have also suggested monitoring the neutrophil‐to‐lymphocyte ratio (NLR) as an additional marker of inflammatory response (de Leon et al. 2025; Kikuchi et al. 2026). These two cases did not provide CRP nor absolute lymphocyte counts and only described leukocytosis.

Children under 7 years of age (particularly those younger than two) appeared to be at increased risk of severe outcomes. In the systematic review, a death was reported in a 2‐year‐old boy after taking 100 mg of clozapine. The increased vulnerability may be related to age‐dependent pharmacokinetic and pharmacodynamic differences (Giangreco and Tatonetti 2022), for example, immature hepatic metabolism, reduced physiologic reserve in respiratory function, greater susceptibility to aspiration during sedation. Additionally, rare but severe manifestations—such as hallucinations, respiratory depression, and neuromotor abnormalities—were described in some cases, highlighting the complexity and unpredictability of clozapine toxicity in early childhood, potentially influenced by neurodevelopmental factors (Morrison et al. 2025; Ross et al. 2010) because central nervous system (CNS) is still undergoing critical neurodevelopmental pruning and receptor maturation. This would explain why even low doses trigger profound neuro‐cardiovascular shifts, such as severe sedation and reflex tachycardia, in toddlers compared to older patients.

Two cases in infants ages 12 and 13 months, were interpreted as associated with a maternal overdose, but other data that would confirm this interpretation were not available. Clozapine is a highly lipophilic agent with a low molecular weight (Baumann et al. 2004), a profile consistent with its moderate transfer into breast milk (Schoretsanitis et al. 2020).

Serum clozapine concentrations were unavailable for this fatal outcome. Clozapine serum levels were reported in two reports, with initial serum levels ranging from 544 ng/mL (C/D 2.72) (Mady et al. 1996) to 736 ng/mL (C/D 7.4) (Toepfner et al. 2013) in two girls of 18 and 31 months after taking 100–200 mg of clozapine. The concentration is higher than the recommended therapeutic levels in adults with schizophrenia (350–600 ng/mL) and C/D ratio could be much higher than the published mean values for nonsmoking adult patients of European ancestry (de Leon 2022).

4.2. VigiBase Information Regarding the Context of Accidental Clozapine Overdoses in Adolescents

In the VigiBase cohort, three cases of accidental clozapine intoxication were reported in adolescents, all of which were classified as administration/dispensing errors. These findings underscore the need for stricter hospital safety and medication management systems to minimize preventable risks (Martínez Sánchez and Mintegi Raso 2020), particularly when dealing with treatments associated with a high potential for severe toxicity. Notably, no cases were documented in children aged 6–12 years. This gap may reflect the relative rarity of psychiatric hospital admissions in preadolescents.

Agranulocytosis, myocarditis, and pericarditis were not observed in cases of acute intoxication, suggesting that the mechanisms underlying acute dose‐dependent toxicity differ from those implicated in idiosyncratic immune‐mediated adverse reactions. For the clinician, this means immediate management should focus heavily on acute neuro‐respiratory support rather than expecting immediate hematological issues.

4.3. Limitations

This work has several limitations. Regarding the systematic review, the quality and level of detail in the case reports were highly variable. Many reports provided minimal clinical information and included very small sample sizes, underscoring the need for more rigorous and standardized documentation of pediatric ADRs. Regarding the VigiBase dataset, it does not report incidence rates and reporting biases are possible because not all countries report adverse events and incomplete clinical details are frequent. For example, clozapine doses were missing in several patients and other relevant variables such as body weight and inflammatory status were not reported, even though these factors may significantly influence toxicity severity and therapeutic response. No data was available on clozapine or norclozapine serum concentrations, preventing the identification of toxic thresholds and limiting the ability to correlate drug levels with clinical severity. Moreover, in four cases clozapine intoxication occurred in the context of polypharmacy, limiting the capacity to analyze potential pharmacodynamic or pharmacokinetic interactions.

Despite these limitations, this study has important strengths, particularly the breadth of information provided by VigiBase compared with the published cases included in the systematic review. VigiBase allowed us to describe the first observational study of clozapine accidental intoxication in children and adolescents. The detailed analysis of this cohort allows us to draw two meaningful conclusions regarding: (1) the varying social contexts surrounding clozapine intoxication which differ markedly between children under seven years of age and adolescents (at residential and hospital settings); and (2) interestingly, although myocarditis and pericarditis are known complications of clozapine in adults and occasionally present in children (de Filippis et al. 2024; De Las Cuevas et al. 2022), none of these accidental overdose cases developed the full‐blown syndrome and only 3 reported leukocytosis, possibly representing a mild form of clozapine‐induced inflammation associated with rapid clozapine titration and/or clozapine inflammation and co‐occurring infection (Bebawi et al. 2021).

4.4. Clinical Significance

Accidental clozapine intoxications in children are rare, but they carry a substantial risk of morbidity and mortality, with fatal outcomes exclusively reported in children under 2 years of age. In adults, clozapine saves lives according to the national registries. In children and adolescents, the evidence is limited particularly regarding pharmacokinetic issues is limited. Consequently, the likelihood of accidental household exposure has clinically relevant implications. Consequently, child and adult psychiatrists must integrate environmental safety into their routine psychoeducation. Prescribing clozapine to an adult should automatically trigger a clinical assessment of the home environment (e.g., presence of toddlers, use of locked medication boxes). Safe prescribing in psychopharmacology must extend beyond the patient to protect the household ecosystem.

5. Conclusion

Accidental clozapine intoxication in pediatric populations, although rare, carries a substantial risk of severe outcomes, including prolonged hospitalization and, in some cases, death—particularly among very young children. This review underscores the importance of increased awareness among clinicians and caregivers, especially in households where clozapine is prescribed. At home, preventive strategies such as secure medication storage, controlled dispensing, and caregiver education are essential to reducing the risk of accidental overdose, thus psychopharmacological safety in prescribing requires considering the broader household environment alongside individual patient care. The three cases of hospitalized adolescents are relatively recent (one from 2017 from Asia and two in 2020 from Europe), and many hospitals currently have systems in place to prevent medication errors.

Author Contributions

C.D.l.C. and J.d.L conceived and designed this specific study. C.D.l.C. and E.J.S. had full access to all of the data in the study and take responsibility for the integrity of the data curation. J.d.L and C.D.l.C. carried out data analysis, the first interpretation of the data. S.J.‐F. and J.d.L. drafted the first version of the manuscript. All the authors helped with the critical review and finalization of the manuscript. All authors assume responsibility for the accuracy of the data interpretation and gave final approval of the last version of the manuscript to be published.

Funding

The authors have nothing to report.

Ethics Statement

This VigiBase search follows the principles of the Helsinki Declaration. It is a retrospective review of deidentified patient data worldwide that does not require the signed consent of the individual patient, according to the ethics of the institutional review board of the university of the authors who accessed the VigiBase data.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting Information S1

HUP-41-e70059-s001.pdf (292.3KB, pdf)

Acknowledgments

The authors are indebted to the national centers which make up the World Health Organization (WHO) Program for International Drug Monitoring and contribute reports to VigiBase at the Uppsala Monitoring Center. The information comes from a variety of sources, and the probability that the suspected adverse effect is drug‐related is not the same in all cases. However, the opinions and conclusions of this study are not necessarily those of the various centers nor of the WHO. The authors acknowledge Lorraine Maw, M.A., from the University of Kentucky Mental Health Research Center at Eastern State Hospital, who helped in editing the article. Open Access funding provided by Universidad de Granada / CBUA.

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

References

  1. Adnan, M. , Motiwala F., Trivedi C., Sultana T., Mansuri Z., and Jain S.. 2022. “Clozapine for Management of Childhood and Adolescent‐Onset Schizophrenia: A Systematic Review and Meta‐Analysis.” Journal of Child and Adolescent Psychopharmacology 32, no. 1: 2–11. 10.1089/cap.2021.0092. [DOI] [PubMed] [Google Scholar]
  2. Baumann, P. , Hiemke C., Ulrichm S., et al. 2004. “The AGNP‐TDM Expert Group Consensus Guidelines: Therapeutic Drug Monitoring in Psychiatry.” Pharmacopsychiatry 37: 243–265. http://doi.ort/10.1055/s‐2004‐832687. [DOI] [PubMed] [Google Scholar]
  3. Bebawi, E. , Wakim L., and Doré M.. 2021. “Clozapine Intoxication With Severe Adverse Effects Induced by an Inflammatory and Infectious Process: A Case Report.” Journal of Medical Case Reports 15, no. 1: 47. 10.1186/s13256-020-02660-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borzutzky, A. , Avello E., Rumie H., et al. 2003. “Accidental Clozapine Intoxication in a Ten‐Year‐Old Child.” Veterinary and Human Toxicology 45: 309–310. [PubMed] [Google Scholar]
  5. da Rosa, A. L. S. T. , Bezerra O. S., Rohde L. A., and Graeff‐Martins A. S.. 2024. “Exploring Clozapine Use in Severe Psychiatric Symptoms Associated With Autism Spectrum Disorder: A Scoping Review.” Journal of Psychopharmacology 38, no. 4: 324–343. 10.1177/02698811241241384. [DOI] [PubMed] [Google Scholar]
  6. de Filippis, R. , De Las Cuevas C., Sanz E. J., Schoretsanitis G., Correll C. U., and de Leon J.. 2024. “Clozapine‐Associated Pericarditis and Pancreatitis in Children and Adolescents: A Systematic Literature Review and Pharmacovigilance Study Using the Vigibase Database.” Schizophrenia Research 268: 118–130. 10.1016/j.schres.2023.10.027. [DOI] [PubMed] [Google Scholar]
  7. De Las Cuevas, C. , Arrojo‐Romero M., Ruan C. J., Schoretsanitis G., Sanz E. J., and de Leon J.. 2022. “Clozapine‐Induced Myocarditis in Children and Adolescents: A Pharmacovigilance Study Using Vigibase and a Systematic Literature Review.” Expert Opinion on Drug Metabolism & Toxicology 18, no. 11: 715–727. 10.1080/17425255.2022.2160318. [DOI] [PubMed] [Google Scholar]
  8. De Las Cuevas, C. , de Leon V. C., Blasco‐Fontecilla, et al. 2025. “Clozapine May Consistently Protect From Suicidal Behaviors While Other Antipsychotics May Lack a Specific Protective Effect: A Comprehensive Vigibase Study Interpreted in the Context of the Prior Literature.” Expert Opinion on Drug Safety 24, no. 11: 1301–1311. 10.1080/14740338.2024.2399094. [DOI] [PubMed] [Google Scholar]
  9. De Las Cuevas, C. , Sanz E. J., and de Leon J.. 2025. “Fatal Outcomes in Use of Clozapine: A Vigibase Study of 6402 Women and 11,222 Men.” Journal of Clinical Psychopharmacology 45, no. 6: 547–553. 10.1097/JCP.0000000000002088. [DOI] [PubMed] [Google Scholar]
  10. De Las Cuevas, C. , Sanz E. J., Jiménez‐Fernández M., Schoretsanitis G., Ruan C. J., and de Leon J.. 2024. “Evaluating the Adverse Drug Reactions to Clozapine in Populations of Children and Adolescents: Insights From Vigibase Data.” European Child & Adolescent Psychiatry 34: 2083–2091. 10.1007/s00787-024-02623-3. [DOI] [PubMed] [Google Scholar]
  11. de Leon, J. 2022. “The History of Clozapine in Clinical Practice: From Its Introduction to a Guideline.” Journal of Psychopharmacology 36, no. 6: 657–660. 10.1177/02698811221101059. [DOI] [PubMed] [Google Scholar]
  12. de Leon, J. , Cotes R. O., 2025. “A Neutrophil‐to‐Lymphocyte Ratio Higher Than 3 May Identify Inflammation During Clozapine Titrations: A Re‐Analysis of Five Published Cases of Myocarditis.” Neuropsychopharmacologia Hungarica 27: 296–311. https://mppt.hu/magazin/pdf/vol27issue4/v27i4p296.pdf. [PubMed] [Google Scholar]
  13. de Leon, J. , Schoretsanitis G., Smith, et al. 2022. “An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry‐Based Personalized Dosing Titrations, CRP, and Clozapine Levels.” Pharmacopsychiatry 55: 73–86. 10.1055/a-1737-1527. [DOI] [PubMed] [Google Scholar]
  14. Giangreco, N. P. , and Tatonetti N. P.. 2022. “A Database of Pediatric Drug Effects to Evaluate Ontogenic Mechanisms From Child Growth and Development.” Médica Sur 3, no. 8: 579–595.e7. 10.1016/j.medj.2022.06.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Idänpään‐Heikkilä, J. , Alhava E., Olkinuora M., et al. 1975. “Letter: Clozapine and Agranulocytosis.” Lancet 2: 611. 10.1016/s0140-6736(75)90206-8. [DOI] [PubMed] [Google Scholar]
  16. Isbister, G. K. , Balit C. R., and Kilham H. A.. 2005. “Antipsychotic Poisoning in Young Children: A Systematic Review.” Drug Safety 28, no. 11: 1029–1044. 10.2165/00002018-200528110-00004. [DOI] [PubMed] [Google Scholar]
  17. Jiménez‐Fernández, S. , Gurpegui M., de Leon J., and Schoretsanitis G.. 2024. “A Systematic Review of Clozapine Concentration‐Dose Ratio From Therapeutic Drug Monitoring Studies in Children and Adolescents Treated With Clozapine for Mental Disorders.” Therapeutic Drug Monitoring 46, no. 2: 170–180. 10.1097/FTD.0000000000001154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kane, J. , Honigfeld G., Singer J., and Meltzer H.. 1988. “Clozapine for the Treatment‐Resistant Schizophrenic. A Double‐Blind Comparison With Chlorpromazine.” Archives of General Psychiatry 45: 789–796. 10.1001/archpsyc.1988.01800330013001. [DOI] [PubMed] [Google Scholar]
  19. Kikuchi, Y. , Onodera B., Komatsu H., and Tomita H.. 2026. “Ethnicity‐Based Personalized Clozapine Titration Strategies for Prevention of Clozapine‐Induced Inflammation: Recommendations Based on Evidence From the Japanese Population.” CNS Drugs 40, no. 2: 181–197. 10.1007/s40263-025-01236-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mady, S. , Wax P., Wang D., Goetz C., Hadley C., and Love R.. 1996. “Pediatric Clozapine Intoxication.” American Journal of Emergency Medicine 14, no. 5: 462–463. 10.1016/S0735-6757(96)90152-7. [DOI] [PubMed] [Google Scholar]
  21. Martínez Sánchez, L. , and Mintegi Raso S.. 2020. “Intoxicaciones.” Protocolos Diágnosticos y Terapéuticos en Pediatria 1: 321–338. [Google Scholar]
  22. Marufu, T. C. R. N. , Bower, Hendron R. R. N., and Manning J. C. Rn. 2022. “Nursing Interventions to Reduce Medication Errors in Paediatrics and Neonates: Systematic Review and Meta‐Analysis.” Journal of Pediatric Nursing 62: e139–e147. 10.1016/j.pedn.2021.08.024. [DOI] [PubMed] [Google Scholar]
  23. Meli, M. , Rauber‐Lüthy C., Walbeck H.‐, et al. 2014. “Atypical Antipsychotic Poisoning in Young Children: A Multicentre Analysis of Poisons Centres Data.” European Journal of Pediatrics 173, no. 6: 743–750. 10.1007/s00431-013-2241-y. [DOI] [PubMed] [Google Scholar]
  24. Meltzer, H. Y. , Alphs, Green L., 2003. “Clozapine Treatment for Suicidality in Schizophrenia: International Suicide Prevention Trial (Intersept).” Archives of General Psychiatry 60, no. 1: 82–91. 10.1001/archpsyc.60.1.82. [DOI] [PubMed] [Google Scholar]
  25. Moher, D. , Liberati, Tetzlaff A., and Altman D. G.. 2009. “Preferred Reporting Items for Systematic Reviews and Meta‐Analyses: The PRISMA Statement.” PLoS Medicine 6, no. 7: e1000097. 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Moola, S. , Munn Tufanaru Z.. 2020. In Systematic Reviews of Etiology and Risk, edited by Aromataris E., Lockwood C., Porritt K., JBI Manual for Evidence Synthesis JBI. 10.46658/JBIMES-24-06. [DOI] [Google Scholar]
  27. Morrison, P. D. , Jauhar S., and Young A. H.. 2025. “The Mechanism of Action of Clozapine.” Journal of Psychopharmacology 39, no. 4: 297–300. 10.1177/02698811251319458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Munn, Z. , Barker T. H., Moola S., et al. 2020. “Methodological Quality of Case Series Studies: An Introduction to the JBI Critical Appraisal Tool.” JBI Evidence Synthesis 18: 2127–2133. 10.11124/JBISRIR-D-19-00099. [DOI] [PubMed] [Google Scholar]
  29. Ross, R. G. , Stevens K. E., Proctor W. R., et al. 2010. “Research Review: Cholinergic Mechanisms, Early Brain Development, and Risk for Schizophrenia.” Journal of Child Psychology and Psychiatry 51, no. 5: 535–549. 10.1111/j.1469-7610.2009.02187.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schoretsanitis, G. , Westin A. A., Deligiannidis K. M., Spigset O., and Paulzen M.. 2020. “Excretion of Antipsychotics Into the Amniotic Fluid, Umbilical Cord Blood, and Breast Milk: A Systematic Critical Review and Combined Analysis.” Therapeutic Drug Monitoring 42, no. 2: 245–254. 10.1097/FTD.0000000000000692. [DOI] [PubMed] [Google Scholar]
  31. Simpson, G. M. , and Varga E.. 1974. “Clozapine‐A New Antipsychotic Agent.” Current Therapeutic Research Clinical and Experimental 16, no. 7: 679–686. [PubMed] [Google Scholar]
  32. Spiller, H. A. , Beuhler, Ryan M. C., Borys D. J., Aleguas A., and Bosse G. M.. 2013. “Evaluation of Changes in Poisoning in Young Children: 2000 to 2010.” Pediatric Emergency Care 29, no. 5: 635–640. 10.1097/PEC.0b013e31828e9d00. [DOI] [PubMed] [Google Scholar]
  33. Toepfner, N. , Wohlfarth Naue A., Auwärter V., Berner R., and Hermanns‐Clausen M.. 2013. “Accidental Clozapine Intoxication in a Toddler: Clinical and Pharmacokinetic Lessons Learnt.” Journal of Clinical Pharmacy and Therapeutics 38, no. 2: 165–168. 10.1111/jcpt.12022. [DOI] [PubMed] [Google Scholar]
  34. Wang, D. , Camacho‐Arteaga L., Gallarín M., Danés I., and Agustí Escasany A.. 2025. “Hospital Admissions for Acute Drug Poisoning in Adults and Children: A 7‐Year Retrospective Analysis of Hospital Discharges at a Tertiary Center.” Frontiers in Toxicology 7: 1672470. 10.3389/ftox.2025.1672470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wong, D. C. , and Curtis L. A.. 2004. “Are 1 or 2 Dangerous? Clozapine and Olanzapine Exposure in Toddlers.” Journal of Emergency Medicine 27, no. 3: 273–277. 10.1016/j.jemermed.2004.06.004. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information S1

HUP-41-e70059-s001.pdf (292.3KB, pdf)

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

Articles from Human Psychopharmacology are provided here courtesy of Wiley

RESOURCES