Using artificial intelligence to create diverse and inclusive medical case vignettes for education.

AIMS: Medical case vignettes play a crucial role in medical education, yet they often fail to authentically represent diverse patients. Moreover, these vignettes tend to oversimplify the complex relationship between patient characteristics and medical conditions, leading to biased and potentially harmful perspectives among students. Displaying aspects of patient diversity, such as ethnicity, in written cases proves challenging. Additionally, creating these cases places a significant burden on teachers in terms of labour and time. Our objective is to explore the potential of artificial intelligence (AI)-assisted computer-generated clinical cases to expedite case creation and enhance diversity, along with AI-generated patient photographs for more lifelike portrayal. METHODS: In this study, we employed ChatGPT (OpenAI, GPT 3.5) to develop diverse and inclusive medical case vignettes. We evaluated various approaches and identified a set of eight consecutive prompts that can be readily customized to accommodate local contexts and specific assignments. To enhance visual representation, we utilized Adobe Firefly beta for image generation. RESULTS: Using the described prompts, we consistently generated cases for various assignments, producing sets of 30 cases at a time. We ensured the inclusion of mandatory checks and formatting, completing the process within approximately 60 min per set. CONCLUSIONS: Our approach significantly accelerated case creation and improved diversity, although prioritizing maximum diversity compromised representativeness to some extent. While the optimized prompts are easily reusable, the process itself demands computer skills not all educators possess. To address this, we aim to share all created patients as open educational resources, empowering educators to create cases independently.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Neurodevelopmental Outcomes among Brazilian Children with Cyanotic Congenital Heart Disease and Its Associated Factors.

Objectives: The aim of this study was to evaluate neurodevelopmental outcomes (motor development, nonverbal intelligence, and attention) in children with cyanotic congenital heart disease (CHD) compared with healthy children from a public hospital in southern Brazil. Materials and Methods: This was a cross-sectional study with pediatric patients of both sexes: 37 children with cyanotic CHD and a control group with 38 healthy children. Parents/guardians undertook a questionnaire and the SNAP IV scale (to evaluate attention) was applied. Two instruments were applied to each child: the R-2 Non-Verbal Intelligence test and the motor development scale. To assess the factors associated with insufficient performance in the three fields of neurodevelopment, a Poisson regression analysis was performed with a robust estimate. Results: There were no significant differences between children with cyanotic CHD and the control group for any of the neurodevelopmental outcomes studied. Low socioeconomic class was a factor associated with worse performance on the intelligence test and inattention. Furthermore, age was a factor for performance on the intelligence test, while a greater number of siblings was a factor associated with worse performance on the attention test. Conclusions: Public policies regarding child health must involve prioritizing the improvement of families' social conditions.

EurOP2E - the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers.

PURPOSE: Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. METHODS: CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. RESULTS: Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. CONCLUSION: Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system.

Fentanyl treatment for end-of-life dyspnoea relief in advanced cancer patients.

PURPOSE: We assessed the effects of subcutaneous-endovenous fentanyl on dyspnoea in a cohort of advanced cancer patients. METHODS: We performed a retrospective study in a cohort of advanced cancer patients with dyspnoea at rest who received subcutaneous or intravenous fentanyl. Patients with no shortness of breath at rest or at minimal exertion, no rescue doses per 24 h, were deemed to be responders to fentanyl. The period of assessment was 6 days from the beginning of fentanyl treatment. RESULTS: Seventy-two patients were evaluated: 65% males, 50% ≥ 75 years, Palliative Performance Scale (PPS) median of 30%. Seventy-six percent of the patients were responders to fentanyl. Fentanyl efficacy was not statistically related to age, gender, cancer type, previous opioid treatment, steroid and midazolam doses and PPS. The median fentanyl dose in responders was 25 mcg/h (interquartile range 12-70). It was significantly related to age (37 vs 12 mcg/h, for ≤ 75 vs > 75 years, respectively; p = 0.02). There was not a significant difference between fentanyl doses of responders and non-responder patients. Thirty-six, 23 and 15 patients had sustained improvements in dyspnoea over 48, 72 and 96 h. Fentanyl had no significant toxicity. The length of inclusion in the study and exclusion were related to low performance status (hazard ratio 0.961; 95%CI 0.927-0.996; Cox-regression) but not to fentanyl doses (hazard ratio 0.875; 95%CI 0.620-1.234; Cox-regression). CONCLUSION: Our preliminary data suggest that subcutaneous-endovenous fentanyl may be associated with dyspnoea relief in dying patients. Further research is needed to confirm these findings.

Risk factors for non-adherence to antidepressant treatment in patients with mood disorders.

PURPOSE: Adherence to antidepressant therapy by patients with depressive disorders is essential not only to achieve a positive patient outcome but also to prevent a relapse. The aim of this study was to identify potential modelling factors influencing adherence to antidepressant treatment by patients with mood disorders in the community mental health care setting METHODS: A total of 160 consecutive psychiatric outpatients attending two Community Mental Health Centres on Tenerife Island between September 2011 and May 2012 were asked to participate in the study; of these, 145 accepted. The Morisky self-report scale was used to assess adherence. The potential predictors examined included socio-demographic, clinical and therapeutic variables. The Clinical Global Impression-Severity and -Improvement scales and the Beck Depression Inventory were used for clinical assessment. Drug treatment side-effects were assessed using the "Self-report Antidepressant Side-Effect Checklist." All participants were also asked to complete the "Drug Attitude Inventory" (DAI), "Beliefs about Medicine Questionnaire" (BMQ), and "Leeds Attitude towards concordance Scale". Discriminant analyses were performed to predict non-adherence. RESULTS: There was no clear correlation between adherence and the socio-demographic variables examined, but adherence was related to a positive attitude of the patients towards his/her treatment (DAI) and low scores in the BMQ-Harm and -Concern subscales. Non-adherence was also related to an increasing severity of depression and to the presence and severity of side-effects. CONCLUSIONS: Among our study cohort, the profiles of adherent patients to antidepressant treatment were more closely associated with each patient's attitudes and beliefs than to objective socio-demographic variables. The severity of depression played a relevant role in adherence, but whether this role is direct or an interaction with several concurrent factors is not yet clear. Side-effects were also closely related to adherence, as conditioned by frequent polypharmacy.

The relationship of psychological reactance, health locus of control and sense of self-efficacy with adherence to treatment in psychiatric outpatients with depression.

BACKGROUND: Although non-adherence to antidepressant medications is a significant barrier to the successful treatment of depression in clinical practice, few potentially modifiable predictors of poor adherence to antidepressant treatment are known. The aim of this study was to examine the relationship of psychological reactance, health locus of control and the sense of self-efficacy on adherence to treatment regimen among psychiatric outpatients with depression. METHODS: One hundred and forty-five consecutive psychiatric outpatients suffering from depressive disorders were invited to participate in a cross-sectional study and 119 accepted. Patients completed a series of self-reported questionnaires assessing psychological reactance, health locus of control, self-efficacy, and adherence to prescribed medication in addition to socio-demographic and clinical variables. Logistic regression analyses were performed to determine which factors better correlate to treatment adherence. RESULTS: Age was found to be the best correlate of adherence to prescribed treatment. As regards psychological dimension studied, medication adherence was negatively associated with both cognitive and affective psychological reactance; patients with higher psychological reactance were more likely to be noncompliant than patients showing a low level of psychological reactance. Regarding health locus of control, only the external dimension of doctor-attributed health locus of control was positively associated with medications adherence. No effect on adherence was observed for the self-efficacy scale. CONCLUSIONS: Psychological reactance is an important correlate of adherence to treatment in patients with depressive disorders and this needs to be considered when giving clinical advice in order to avoid inducing reactance and thus non-adherence to prescribed treatments. Mental health professionals need to learn about communication techniques and counseling skills that enable them to deal with the psychological reactance of their patients.

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.

BACKGROUND: In the United States, clozapine was first approved for treatment-resistant schizophrenia and then for suicidality in schizophrenia psychoses. Systematic reviews support clozapine's anti-suicidal effect, but the forensic literature stresses its lethality during overdoses. RESEARCH DESIGN AND METHODS: Clozapine reports to the international pharmacovigilance database (VigiBase) were analyzed for suicidal ideation, suicide attempts, intentional overdose, and completed suicides from introduction to 1 January 2024. VigiBase uses the information component (IC) as a disproportionality analysis. RESULTS: The clozapine ICs (range: other antipsychotics) were: 1) suicidal ideation IC = 0.570 with IC025 = 0.454 to IC975 = 0.680 (IC = 3.568 for aripiprazole and 1.729 for risperidone), 2) suicide attempt IC = 1.428 with IC025 = 1.323 to IC975 = 1.529 (IC = 4.150 for quetiapine and 2.968 for risperidone), 3) intentional overdose: IC = 0.995 with IC025 = 0.864 to IC975 = 1.120 (IC = 4.080 for quetiapine and 1.957 for aripiprazole), and 4) completed suicide IC = 1.133 with IC025 = 1.026 to IC975 = 1.235 (IC = 4.648 for quetiapine and 2.160 for risperidone). In summary, all clozapine ICs were significantly lower. We found 2391 clozapine-treated patients on the suicidality spectrum (627 cases with suicidal ideation, 752 with suicide attempt, 488 with intentional overdose, and 731 with completed suicide) but many were taking other antipsychotics. The most frequent reporting countries were the United States, the United Kingdom, and Croatia. CONCLUSION: This pharmacovigilance study, with all its inherent limitations, provides independent proof, not overlapping with prior literature, that clozapine may have specific strong anti-suicidal effects that do not appear to be present in other antipsychotics. Further VigiBase studies are needed to compare the lethality of an intentional overdose of clozapine (14.3%) with other antipsychotics.

Investigating in VigiBase over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.

BACKGROUND: The literature associates clozapine with pneumonia/aspiration pneumonia. RESEARCH DESIGN AND METHODS: The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023. RESULTS: There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with 1) very high titration doses, 2) very small doses in Parkinson's disease, and 3) Japan vs other countries. CONCLUSIONS: In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients with long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.

The European List of Key Medicines for Medical Education: A Modified Delphi Study.

Rational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely accessible in Europe. For this, we used a modified Delphi study method consisting of three parts. In part one, we created an initial list based on a literature search. In part two, a group of 64 coordinators in CPT education, selected via the Network of Teachers in Pharmacotherapy of the European Association for Clinical Pharmacology and Therapeutics, evaluated the accessibility of each medicine in his or her country, and provided a diverse group of experts willing to participate in the Delphi part. In part three, 463 experts from 24 European countries were invited to participate in a 2-round Delphi study. In total, 187 experts (40%) from 24 countries completed both rounds and evaluated 416 medicines, 98 of which were included in the final list. The top three Anatomical Therapeutic Chemical code groups were (1) cardiovascular system (n = 23), (2) anti-infective (n = 21), and (3) musculoskeletal system (n = 11). This European List of Key Medicines for Medical Education could be a starting point for country-specific lists and could be used for the training and assessment of CPT.

Psychiatric outpatients' self-reported adherence versus psychiatrists' impressions on adherence in affective disorders.

OBJECTIVE: The objective of this study is to explore correlation between patients' self-reported adherence to medication and their treating psychiatrists' impressions on adherence. METHODS: During a 9-month period, 140 consecutive psychiatric outpatients with affective disorders attending two community mental health centers, and their treating psychiatrists, took part. Data were collected on socio-demographic, clinical, and therapeutic variables. The Clinical Global Impression-Severity and Improvement scales and the Beck Depression Inventory were used for clinical assessment. Adherence was assessed by the psychiatrist's report and the Morisky scale from patients. In addition, "Drug Attitude Inventory," "Beliefs about Medicine Questionnaire," and "Leeds Attitude towards concordance scale" were applied to all participants. A multivariate analysis of variance (Bonferroni control) and a subsequent stepwise regression were performed. RESULTS: The allocation of patients to "adherent" or "non-adherent" categories by the patients themselves and their treating psychiatrists was divergent in more than 40% of the cases. The best agreement appears when treatment is prolonged. There is a better agreement with patients having a positive view of the medicines. When patients consider the medication harmful, this is when psychiatrists perceive more non-adherence. The agreement is also better in mild cases of depression. CONCLUSIONS: Adherence was principally compromised by patient-related factors, especially their beliefs and attitudes toward their treatment and its duration.

Analysis of deprescription strategies of proton pump inhibitors in primary care: a narrative review.

BACKGROUND: Since the introduction of omeprazole in 1989, proton pump inhibitors (PPIs) have become the mainstream of treatment for acid-related pathologies, but nowadays, it is estimated that between 20% and 80% of people worldwide who are using PPIs are doing so without an approved indication. Overusing PPIs is known to involve a tremendous cost in financial terms, and many western countries have reported high spending on these medicines. OBJECTIVE: We conducted a narrative review to evaluate PPI deprescription strategies carried out entirely or in collaboration with primary care and to identify factors that could influence the success of these strategies. METHOD: This review was conducted in November 2022, following PRISMA guidelines. Four databases were searched: PubMed, Web of Science, Scopus and CINAHL Complete, using the MeSH terms 'proton pump inhibitors' AND 'deprescriptions'. RESULTS: The search with the established criteria found eight studies. The different success rates obtained by the various studies analysed in this review may be due to the different methodologies used when establishing the protocols, sample selection and monitoring of the results. CONCLUSION: We can conclude that the two factors related to the most successful strategies were a) the clarity and simplicity of the de-escalation protocols, in which patients were instructed on the measures to follow in the event of the reappearance of symptoms, and b) the training of the physicians responsible for deprescribing. Long-term conclusions cannot be drawn about the effectiveness of these protocols, given that the studies are limited in time. Other barriers to generalizing the results are the small sample size and the absence of control groups.

Adverse drug reactions and their fatal outcomes in clozapine patients in VigiBase: Comparing the top four reporting countries (US, UK, Canada and Australia).

BACKGROUND: Pharmacovigilance findings and box warnings in the clozapine package inserts have marked the history of clozapine. OBJECTIVE: This is the largest review of clozapine adverse drug reactions (ADRs) and their associated fatal outcomes. Reports to the World Health Organization's global pharmacovigilance database, VigiBase™, were analyzed, extending from clozapine's introduction to December 31, 2022. METHODS: The analysis focused on the top four reporting countries: United States (US), United Kingdom (UK), Canada and Australia (83 % of fatal outcomes worldwide). Attempts were made to control for population and clozapine prescription in each country. RESULTS: Clozapine ADRs worldwide accounted for 191,557 reports, with the highest number (53,505) in "blood and lymphatic system disorder". Of the 22,596 fatal outcomes reported in clozapine patients, 9587 were from the US, 6567 from the UK, 3623 from Canada and 1484 from Australia. The top category worldwide in fatal outcomes was nonspecifically labeled "death" with 46 % (range 22-62 %). "Pneumonia" was second with 30 % (range 17-45 %). Agranulocytosis was numerically only the 35th top clozapine ADR associated with fatal outcomes. On average, 2.3 clozapine ADRs were reported per fatal outcome. Infections were associated with 24.2 % of the UK fatal outcomes (9.4 %-11.9 % in the 3 other countries). CONCLUSIONS: The four countries appeared to report clozapine ADRs in different ways, making comparisons difficult. We estimated higher fatal outcomes in the UK and Canada after controlling for cross-sectional estimations of population and published clozapine use. This last hypothesis is limited by the lack of precise estimation of accumulated clozapine use in each country.

Respiratory aspiration during treatment with clozapine and other antipsychotics: a literature search and a pharmacovigilance study in vigibase.

INTRODUCTION: Antipsychotics (APs), during treatment or overdose, may be associated with respiratory aspiration. AREAS COVERED: A PubMed search on 30 September 2022, provided 3 cases of respiratory aspiration during clozapine therapy and 1 case during an AP overdose. VigiBase records of respiratory aspiration associated with APs from inception until 5 September 2021, were reviewed. VigiBase, the World Health Organization's global pharmacovigilance database, uses a statistical signal for associations called the information component (IC). EXPERT OPINION: The ICs (and IC025) were 2.1 (and 2.0) for APs, 3.2 (and 3.0) for clozapine, 2.6 (and 2.4) for quetiapine, and 2.5 (and 2.2) for olanzapine. Cases of respiratory aspiration associated with APs included: 137 overdose/suicide cases (64 fatal) and 609 cases during treatment (385 fatal) including 333 taking clozapine (238 fatal). In logistic regression models of fatal outcomes, the odds ratios, OR, and (95% confidence intervals, CI) of significant independent variables were: a) 2.3-2.6 for clozapine in 3 samples of AP treatment of varying size, b) 1.9 (CI 1.0 to 3.5) for geriatric age in 284 patients on clozapine treatment, and c) 1.8 (CI 1.1-3.2) for antidepressant co-medication in 276 patients on non-clozapine APs. Multiple AP pharmacological mechanisms may explain respiratory aspiration.

Clozapine-associated pericarditis and pancreatitis in children and adolescents: A systematic literature review and pharmacovigilance study using the VigiBase database.

BACKGROUND: The literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents. METHODS: Cases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC). RESULTS: The PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC025 = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC025 = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases. CONCLUSIONS: Despite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK.

BACKGROUND: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). OBJECTIVE: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality. METHODS: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. RESULTS: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number. CONCLUSIONS: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.