The burden of adverse drug reactions reported by patients in the Dutch ADR monitor: a proof of concept.

BACKGROUND: We aimed to describe the burden of adverse drug reactions (ADRs) reported by patients participating in the Dutch ADR Monitor using a multifactorial burden measurement instrument. METHODS: The Dutch ADR Monitor is a cohort event monitoring system that collects information on ADR experiences, including burden. This study includes the initial data (November 2022 until May 2023). Patients were asked if experienced ADRs impacted 7 domains of burden: appearance, medical treatment, daily life, fatigue, physical consequences, mental consequences and the course of ADRs. Burden was scored from 0 to 10 on impacted domains. The distributions of these burden scores were demonstrated in Likert plots. The burden between persistent and recurrent ADRs was compared. RESULTS: 92 patients reported 199 ADRs. Impact on the domains fatigue and daily life were experienced most frequently, except for skin and subcutaneous tissue ADRs, where impact on appearance and mental consequences were experienced most frequently. Fatigue was considered the most burdensome domain. No difference in burden was found between persistent (median = 7, IQR = 4) and recurrent ADRs (median = 6, IQR = 4, p = 0.59). CONCLUSIONS: This is the first study investigating burden of ADRs on 7 domains in patients with chronic diseases. Impact on the domain fatigue was considered most burdensome.

Patients with skin and subcutaneous ADRs experienced impact on appearance and mental consequences most often, but found impact on fatigue most burdensome.For most reported ADRs, patients scored the highest burden on the domain fatigue and thus found impact on this domain to be the most burdensome.Patients with skin and subcutaneous ADRs experienced impact on appearance and mental consequences most often, but found impact on fatigue most burdensome.

Quantification of Longitudinal Patient-Reported Burden of Adverse Drug Reactions Attributed to the Use of TNF-α Inhibitors in inflammatory rheumatic diseases: an observational prospective cohort study.

BACKGROUND: There is a lack of knowledge on patient perspectives on adverse drug reactions (ADRs) attributed to the use of biologics. The aim of this study is to quantify the burden over time of ADRs attributed to TNF-α inhibitors in patients with inflammatory rheumatic diseases (IRDs) and investigate whether the burden over time differs between different types of ADRs. RESEARCH DESIGN AND METHODS: Data were used from the Dutch Biologic Monitor (DBM), an observational prospective cohort study for patient-reported ADRs attributed to biologics. Patients with an IRD using a TNF-α inhibitor reporting an ADR, lasting for three consecutive questionnaires, were included. Questionnaires were sent every two months and burden was scored on a 5-point Likert-type scale. Burden scores were analyzed using linear mixed models. RESULTS: Data from 166 unique patients reporting 274 ADRs were included. The burden score decreased every month by 0.29 points (95% CI -0.34 - -0.24) on average on a 5-point Likert-type scale. The burden score for infections and infestations decreased significantly faster than the burden score for injection site reactions. CONCLUSIONS: Patient-reported burden of ADRs attributed to the use of a TNF-α inhibitor in patients with IRDs decreased significantly over time, especially for infections and infestations.

Drug-Gene Risk Stratification in Patients with Suspected Drug-Induced Interstitial Lung Disease.

BACKGROUND: Pulmonary toxicity has been associated with drug use. This is often not recognized in clinical practice, and underestimated. OBJECTIVE: We aimed to establish whether polymorphisms in certain genes corresponding with a metabolic pathway of drug(s) used are associated with pulmonary toxicity in patients with suspected drug-induced interstitial lung disease (DI-ILD). METHODS: This retrospective observational study explored genetic variations in three clinically relevant cytochrome P450 (CYP) iso-enzymes (i.e., CYP2D6, CYP2C9, and CYP2C19) in a group of patients with a fibroticinterstitial lung disease, either non-specific interstitial pneumonia (n = 211) or idiopathic pulmonary fibrosis (n = 256), with a suspected drug-induced origin. RESULTS: Of the 467 patients, 79.0% showed one or more polymorphisms in the tested genes accompanied by the use of drug(s) metabolized by a corresponding affected metabolic pathway (60.0% poor metabolizers and/or using two or more drugs [likely DI-ILD], 37.5% using three or more [highly likely DI-ILD]). Most commonly used drugs were statins (63.1%) with a predominance among men (69.4 vs 47.1%, p < 0.0001). Nitrofurantoin, not metabolized by the tested pathways, was prescribed more frequently among women (51.9 vs 4.5%, p < 0.00001). CONCLUSIONS: In our cohort with suspected DI-ILD, 79% carried one or more genetic variants accompanied by the use of drugs metabolized by a corresponding affected pathway. In 60%, the diagnosis of DI-ILD was likely, whereas in 37.5%, it was highly likely, based on CYP analyses. This study underlines the importance of considering both drug use and genetic make-up as a possible cause, or at least a contributing factor, in the development and/or progression of fibrotic lung diseases. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00267800, registered in 2005.

Burden of non-serious infections during biological use for rheumatoid arthritis.

INTRODUCTION: Biologicals have become a cornerstone in rheumatoid arthritis (RA) treatment. The increased risk of serious infections associated with their use is well-established. Non-serious infections, however, occur more frequently and are associated with a high socioeconomic burden and impact on quality of life but have not received the same attention in the literature to date. The aim of this study was to gain insight into the various non-serious infections reported in RA patients using biologicals and their experienced burden. MATERIALS AND METHODS: The Dutch Biologic Monitor was a prospective observational study that included adults with rheumatoid arthritis and biological use who answered bimonthly questionnaires on the adverse drug reactions (ADRs) they experienced from their biological and reported the associated impact score (ranging from 1, no impact, to 5, very high impact). ADRs were assigned a MedDRA code by pharmacovigilance experts and labeled as definite, probable, possible or no infection by infectious disease professionals. Descriptive statistics were performed using medians and interquartile ranges. RESULTS: A total of 586 patients were included in the final analysis. Eighty-five patients (14.5%) reported a total of 421 ADRs labeled as probable or definite infections by the experts. Patient-assigned burden was ADR-specific. Upper respiratory tract infections were most frequently reported and had a high rate of recurrence or persistence, with a median impact score of 3.0 (IQR 2.0-3.0) which remained stable over time. DISCUSSION: Non-serious infections significantly outnumbered serious infections in this real-life cohort of RA patients using biologicals (77.1 non-serious infections and 1.3 serious infections per 100 patient years, respectively). Infections in the upper respiratory tract were rated as having an average burden, which remained constant over a long period of time. Awareness of the impact of recurrent and chronic non-serious infections may enable healthcare professionals to timely treat and maybe even prevent them, which would lessen the associated personal and socioeconomic burden.

Hospital registration of adverse drug reactions in electronic health records: importance and contribution to pharmacovigilance.

BACKGROUND: Information on registered adverse drug reactions (ADRs) in hospitals may provide a large real-world data source that can be used to ensure patients' safety. This study aimed to assess the potential contribution of hospital registration of ADRs in electronic health records (EHR) to pharmacovigilance. RESEARCH DESIGN AND METHODS: An observational retrospective descriptive study using data from the Jeroen Bosch Hospital in the Netherlands in 2019. 'Serious and/or severe' and 'previously unknown' ADRs registered systematically in the corresponding field of EHRs were assessed. RESULTS: ADR data concerning 1010 patients were included. In total, 1630 ADRs were registered in EHRs. Fifty-eight serious and/or severe ADRs (5.2%) were registered. Tubulointerstitial nephritis was the most frequently registered severe ADR and was mainly associated with antibacterials for systemic use. A total of 82 previously unknown ADRs (5%) were registered. 'Migraine' and 'chest pain' were the most frequently registered unknown ADRs. Additionally, 25 ADRs (1.5%) were registered that may be attributable to 10 drugs 'under additional monitoring.' CONCLUSIONS: Hospital registrations of ADRs in EHRs provide information on ADRs, which are challenging to assess during clinical trials. However, improvements are required to optimize this registration before it can serve as a valuable data source for pharmacovigilance purposes.

The effect of corticosteroids, antibiotics, and anticoagulants on the development of post-COVID-19 syndrome in COVID-19 hospitalized patients 6 months after discharge: a retrospective follow up study.

To assess the effect of pharmacotherapeutic interventions commonly employed in the management of COVID-19 hospitalized patients on the development of post-COVID-19 syndrome. This study employed two distinct databases, the Medisch Spectrum Twente (MST) clinical database comprising electronic health records of COVID-19 patients hospitalized at MST, and the Post-COVID cohort database which contains follow-up information on the same patients. These databases were integrated to establish the potential relationship between the administration of corticosteroids, antibiotics, or anticoagulants during hospitalization and the occurrence of post-COVID-19 syndrome after a 6-month interval following discharge. A total of 123 patients who were hospitalized due to COVID-19 infection were included in this study. Among these patients, 33 (26.8%) developed post-COVID-19 syndrome which persisted even 6 months after hospital discharge. Multivariate analysis revealed that patients who received treatment with corticosteroids had a significantly lower likelihood (OR 0.32, 95% CI 0.11-0.90) of developing post-COVID-19 syndrome, while no significant association was observed for treatment with antibiotics (OR 1.26, 95% CI 0.47-3.39) or anticoagulants (OR 0.55, 95% CI 0.18-1.71). The findings of this study indicate that corticosteroids exert a significant protective effect against the development of post-COVID-19 syndrome in patients who were hospitalized due to COVID-19 infection. Although a trend towards a protective effect of anticoagulants was observed, it did not reach statistical significance. On the contrary, patients treated with antibiotics were shown to have increased chances of developing post-COVID-19 syndrome, although this effect was also not statistically significant.

Development of a Framework Structuring Themes in the Course of Adverse Drug Reactions from a Patient's Perspective.

INTRODUCTION: There is a need for more extensive information about adverse drug reactions (ADRs) for patients than currently available, including information on the course of ADRs. Aspects characterising the course of ADRs from the patient perspective have not been identified before. OBJECTIVE: We aimed to develop a framework based on common themes in the course of ADRs identified from patient descriptions in patient-reported ADRs. METHODS: In this qualitative study, patient descriptions of the course of patient-reported ADRs were analysed by a thematic analysis with an inductive approach using three different existing datasets containing patient-reported ADRs. Two datasets included patient-reported ADRs from cohort event monitoring of biologics and direct oral anticoagulants and one dataset included spontaneous reports from patients concerning medication for lower urinary tract symptoms. A conceptual framework was developed from the identified main themes and subthemes. RESULTS: Patient-reported data concerning 3888 ADRs were analysed. Six main themes with multiple subthemes were identified from patient descriptions of the course of ADRs. Four themes were descriptive: frequency of an ADR episode, duration of an ADR episode, moment or period of ADR occurrence, and development in the intensity of the ADR. Two themes concerned factors influencing the course of ADRs: triggering factors and improving factors. CONCLUSIONS: The presented framework illustrates that patients describe extensive details on the course and timeframe of ADRs. The identified themes provide a basis for improving the systematic data collection of more extensive details about ADRs from patients as a first step towards the provision of more comprehensive ADR information to patients.

Recurring Fatigue After Biologic Administration: Patient-Reported Data from the Dutch Biologic Monitor.

BACKGROUND: Fatigue is a common problem in immune-mediated inflammatory disease (IMID) patients, significantly impacting their quality of life. OBJECTIVES: In this study, we describe the pattern and characteristics of fatigue as a patient-reported adverse drug reaction (ADR) of biologics, and compared patient and treatment characteristics with patients reporting other ADRs or no ADRs. METHODS: In this cohort event monitoring study, the description and characteristics of fatigue reported as a possible ADR in the Dutch Biologic Monitor were assessed and analysed for commonly recurring themes or patterns. Baseline and treatment characteristics of patients with fatigue and patients reporting other ADRs or no ADRs were compared. RESULTS: Of 1382 participating patients, 108 patients (8%) reported fatigue as an ADR of a biologic. Almost half of these patients (50 patients, 46%) described episodes of fatigue during or shortly after biologic injection, which often recurred following subsequent injections. Patients with fatigue were significantly younger than patients with other ADRs or patients without ADRs (median age for patients with fatigue, 52 years; median age for patients with other ADRs, 56 years; and median age for patients without ADRs, 58 years); significantly more often smoked (25% vs. 16% and 15%); used infliximab (22% vs. 9% and 13%), rituximab (9% vs. 3% and 1%) or vedolizumab (6% vs. 2% and 1%); and significantly more often had Crohn's disease (28% vs. 13% and 13%) and other comorbidities (31% vs. 20% and 15%). Patients with fatigue significantly less frequently used etanercept (12% vs. 29% and 34%) or had rheumatoid arthritis (30% vs. 45% and 43%). CONCLUSIONS: IMID patients may experience fatigue as a postdosing effect of biologics.

Impact of adverse drug reactions on the treatment pathways of early rheumatoid arthritis patients: a prospective observational cohort study.

BACKGROUND: Several patient characteristics may be of influence on treatment pathways of rheumatoid arthritis (RA) patients in clinical practice. The aim of this study is to analyze treatment pathways of early RA patients stratified for gender and adverse drug reaction (ADR) occurrence. RESEARCH DESIGN AND METHODS: Treatment pathways of patients included in the DREAM-RA treat-to-target cohort I between 16th of July 2006-30th of April 2020 were assessed. Treatment pathways were visualized in Sankey diagrams. Follow-up time, duration per treatment and the number of treatments received were stratified for gender and ADR occurrence and analyzed. Independent t-tests and chi-square tests were performed where applicable. RESULTS: Treatment pathways of 372 patients (follow-up: 2488.4 years, mean 6.7 ± 3.7 years) were analyzed. The Sankey diagrams visualize that treatment pathways became increasingly varied and complex over time. No significant differences were found when comparing female patients and male patients. However, the average treatment duration was shorter in patients with ADRs (1.8 vs. 2.7 years, p < 0.05), and the number of treatments higher (3.5 vs. 2.5, p < 0.05). CONCLUSIONS: Treatment pathways increase in complexity over time. Differences were found between patients with and without ADRs, with patients that experience ADRs receiving more and shorter treatments.

Sex differences in adverse drug reactions from Adalimumab and etanercept in patients with inflammatory rheumatic diseases.

BACKGROUND: We examine sex differences in relation to the nature, frequency, and burden of patient-reported adverse drug reactions (ADRs) in patients with inflammatory rheumatic diseases. RESEARCH DESIGN AND METHODS: Rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis patients using etanercept or adalimumab from the Dutch Biologic Monitor were sent bimonthly questionnaires concerning experienced ADRs. Sex differences in the proportion and nature of reported ADRs were assessed. Additionally, 5-point Likert-type scales reported for the burden of ADRs, were compared between sexes. RESULTS: In total 748 consecutive patients were included (59% female). From the women 55% reported ≥1 ADR, which was significantly higher than 38% of the men that reported ≥1 ADR (p < 0.001). A total of 882 ADRs were reported comprising 264 distinct ADRs. The nature of the reported ADRs differed significantly between both sexes (p = 0.02). Women in particular reported more injection site reactions than men. The burden of ADRs was similar between sexes. CONCLUSIONS: Sex differences in the frequency and nature of ADRs, but not in ADR burden, exist during treatment with adalimumab and etanercept in patients with inflammatory rheumatic diseases. This should be taken into consideration when investigating and reporting results on ADRs and when counseling patients in daily clinical practice.

First-time adverse drug reactions, survival analysis, and the share of adverse drug reactions in treatment discontinuation in real-world rheumatoid arthritis patients: a comparison of first-time treatment with adalimumab and etanercept.

BACKGROUND: This study aims to compare nature and frequency of adverse drug reactions (ADRs), time to first ADR, drug survival, and the share of ADRs in treatment discontinuation of first-time treatment with adalimumab (ADA) and etanercept (ETN) in real-world RA patients. RESEARCH DESIGN AND METHODS: Retrospective, single-center cohort study including naïve patients treated between January 2003-April 2020. Time to first ADR and drug survival of first-time treatment were studied using Kaplan-Meier and Cox-regression models up to 10 years, with 2- and 5-year post-hoc sensitivity analysis. Nature and frequencies of first-time ADRs and causes of treatment discontinuation were assessed. RESULTS: In total, 416 patients (ADA: 255, ETN: 161, 4865 patient years) were included, of which 92 (22.1%) experienced ADR(s) (ADA: 59, 23.1%; ETN: 33, 20.4%). Adjusted for age, gender and concomitant conventional DMARD use, ADA was more likely to be discontinued than ETN up to 2-, 5- and 10-year follow-up (adjusted HRs 1.63; 1.62; 1.59 (all p<0.001)). ADRs were the second reason of treatment discontinuation (ADA 20.7%, ETN 21.4%). CONCLUSIONS: Despite seemingly different nature and frequencies, ADRs are the second reason of treatment discontinuation for both bDMARDs. Furthermore, 2-, 5-, and 10-year drug survival is longer for ETN compared to ADA.

Disease-specific ADRs of TNF-α inhibitors as reported by patients with inflammatory rheumatic diseases: a registry-based prospective multicenter cohort study.

BACKGROUND: The extent to which adverse drug reactions (ADRs) of biologics differ per immune-mediated inflammatory disease (IMID), and the relevance of tailoring ADR information per IMID is not fully investigated. We aimed to compare patient-reported ADRs attributed to adalimumab and etanercept between different inflammatory rheumatic diseases (IRDs). RESEARCH DESIGN AND METHODS: ADR reports from IRD patients were extracted from the Dutch Biologic Monitor. ADR frequencies were compared using Fischer-Freeman-Halton exact test and the influence of covariates was assessed using binomial logistic regression.A total, of 729 participants were included, of which 354 participants reported 887 unique ADRs. ADR frequencies were not significantly different between the IRDs. Rheumatoid arthritis and ankylosing spondylitis including axial spondyloarthritis patients had an increased risk of ADRs related to 'Respiratory, thoracic and mediastinal disorders' and as compared to psoriatic arthritis patients. Etanercept use, combination therapy with methotrexate and/or corticosteroids, and age also influenced the risk of reporting specific ADRs. CONCLUSIONS: There were no differences in frequencies and nature of patient-reported ADRs attributed to adalimumab and etanercept between different IRDs. However, more research is needed to align patients' and health-care professionals' perspectives to improve knowledge on disease-specific ADRs.

Patients' and health-care professionals' perspectives on adverse drug reaction burden attributed to the use of biological DMARDs: a qualitative study.

BACKGROUND: Previous studies showed a discrepancy between health-care professionals' (HCPs') and patients' perspective on adverse drug reaction (ADR) burden. However, it is unclear which factors make an ADR burdensome. We aimed to give insight into why ADRs are perceived as burdensome by inflammatory rheumatic disease (IRD) patients, and whether this differs from the HCPs' perspective. RESEARCH DESIGN AND METHODS: A qualitative study was conducted using Dutch Biologic Monitor data. Participants received bimonthly questionnaires on experienced ADRs attributed to biological DMARDs and were asked to elaborate on ADR burden using a Likert-type scale and an open-ended question for clarification. Data of 440 IRD patients were analyzed following thematic analysis. A similar analysis was done with semi-structured interviews with 13 HCPs. RESULTS: We identified seven themes associated with ADR burden: 'effect on medication prescription,' 'impact on appearance,' 'impact on autonomy,' 'impact on daily life,' 'psychological consequences,' 'distressing aspects of ADR,' and 'physical consequences.' Identical themes were identified by HCPs, although they identified most subthemes in 'psychological consequences,' and less subthemes in 'impact on daily life' and 'impact on autonomy.' CONCLUSION: Patients describe perceived ADR burden in both physical and psychological themes. The HCPs' perspective is comparable, but mostly focuses on psychological impact.

Analysis and visualization of the course and burden over time of adverse drug reactions (ADRs) attributed to TNFα-inhibitors in patients with inflammatory rheumatic diseases (IRDs).

BACKGROUND: We aimed to investigate course and burden over time of ADRs attributed to TNFα-inhibitors in IRD-patients, and whether Sankey diagrams and polar plots can visualize this. RESEARCH DESIGN AND METHODS: Data on ADRs experienced during the Dutch Biologic Monitor (January 2017 till December 2022) were used in this study. We selected IRD-patients using a TNFα-inhibitor, reporting skin reactions/infections/injection site reactions and completing ≥3 questionnaires (i.e. the initial report and ≥2 follow-ups). Course was scored as worsening/improving/remaining stable/resolving and as (non-)recurrent. Patients scored burden from 1 (no burden) to 5 (very high burden). Sankey diagrams and polar plots visualized this. RESULTS: 202 patients were included, reporting 353 ADRs. Most skin reactions were stable (25.0%). Most infections resolved (50.8%). Injection site reactions were mostly recurrent (72.3%). Skin reactions and infections tended to decrease in burden . Infections had highest burden at start, which mostly decreased over time. Injection site reactions had a low and stable burden. CONCLUSIONS: Skin reactions attributed to TNFα-inhibitors by IRD-patients are stable with a slightly decreasing burden over time. Infections have highest burden at start but resolved mostly. Injection site reactions have a low and stable burden. Sankey diagrams and polar plots are suitable to visualize this.

Drug-induced comorbidities in patients with sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized. RECENT FINDINGS: Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes. SUMMARY: A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.

Comorbidities of sarcoidosis.

Sarcoidosis is a heterogeneous disease, which can affect virtually every body organ, even though lungs and intra thoracic lymph nodes are almost universally affected. The presence of noncaseating granulomas is the histopathological hallmark of the disease, and clinical picture depends on the organs affected. Data about interaction between sarcoidosis and comorbidities, such as cardiovascular and pulmonary diseases, autoimmune disorders, malignancy and drug-related adverse events are limited. Several lung conditions can be associated with sarcoidosis, such as pulmonary hypertension and fibrosis, making it difficult sometimes the differentiation between complications and distinctive pathologies. Their coexistence may complicate the diagnosis of sarcoidosis and contribute to the highly variable and unpredictable natural history, particularly if several diseases are recognised. A thorough assessment of specific disorders that can be associated with sarcoidosis should always be carried out, and future studies will need to evaluate sarcoidosis not only as a single disorder, but also in the light of possible concomitant conditions.Key messagesComorbidities in sarcoidosis are common, especially cardiovascular and pulmonary diseases.In the diagnostic workup, a distinction must be made between sarcoidosis-related complaints and complaints caused by other separate disorders. It can be very difficult to distinguish between complications of sarcoidosis and other concomitant conditions.The coexistence of multiple conditions may complicate the diagnosis of sarcoidosis, affect its natural course and response to treatment.

Barriers and facilitators for systematically registering adverse drug reactions in electronic health records: a qualitative study with Dutch healthcare professionals.

BACKGROUND: Systematically registering ADRs in electronic health records (EHRs) likely contribute to patient safety as it enables the exchange of drug safety data. Currently, ADRs registrations by healthcare professionals (HCPs) is suboptimal. This study aimed to identify barriers and facilitators perceived by HCPs to register ADRs systematically in EHRs. RESEARCH DESIGN AND METHODS: A qualitative study with individual interviews was conducted among specialist physicians and hospital pharmacists from 10 different Dutch hospitals. A semi-structured interview guide was used to identify experienced barriers and facilitators for systematically registering ADRs. Data was analyzed following thematic analysis. Themes within barriers and facilitators were aligned with the Capability-Opportunity-Motivation-Behavior (COM-B) framework. RESULTS: In total, 16 HCPs were interviewed. Identified barriers were: lack of knowledge to recognize ADRs, time constraints, inadequate IT system, lack of support, stuck in routine, and not recognizing the importance of registering ADRs. Identified facilitators were: enhanced knowledge and awareness of ADRs, functional IT systems, expanding accountability for registration, and motivation toward registering. CONCLUSIONS: Barriers and facilitators for registering spanned all aspects of the COM-B model and occurred in individual, social and environmental domains. Addressing these aspects could improve the registration of ADRs and may contribute to patient safety.

Body weight gain in clozapine-treated patients: Is norclozapine the culprit?

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.