Association between antidepressant use and delirium in older adults: an analysis of the World Health Organization's global pharmacovigilance database.

BACKGROUND: Psychoactive drugs frequently cause delirium adverse events in older adults. However, few data on the relationship between antidepressants and delirium are available. Here, we investigated the association between antidepressant prescription and pharmacovigilance reports of delirium in older adults. METHODS: Using the World Health Organization's VigiBase® global pharmacovigilance database from 1967 to 2022, we performed a disproportionality analysis in order to probe the putative associations between each antidepressant class (non-selective monoamine reuptake inhibitors (NSMRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), alpha-2-adrenergic receptor antagonists, and other antidepressants) and reports of delirium in people aged 65 or over. We calculated the reporting odds ratios (r-OR) and their 95% confidence interval ([95%CI]) with logistic regression models before and after adjustment for confounding factors. Secondary analyses were performed for each drug and within each class by age group (65-74, and 75 and over). We also studied the reports of concomitant delirium and hyponatremia. RESULTS: Our main analysis included 87,524 cases of delirium. After adjustment for confounders, a significant association was found between delirium and all antidepressant classes other than SNRIs. Intraclass disparities were found for the association between the most frequently prescribed antidepressants and reports of delirium. An elevated risk of reports of concomitant delirium and hyponatremia was found for SSRIs (4.46 [4.01-4.96]), SNRIs (1.25 [1.07-1.46]), MAOIs (1.72 [1.41-2.09]), and the "other antidepressants" class (1.47 [1.30-1.65]). CONCLUSIONS: There was a significant association between reports of delirium and antidepressant classes (other than SNRIs). However, this association varied from one drug to another within a given antidepressant class. Moreover, this association could not always be explained by antidepressant-induced hyponatremia.

Safety of perioperative intravenous lidocaine in liver surgery - A pilot study.

Background and Aims: Perioperative lidocaine infusion has many interesting properties such as analgesic effects in the context of enhanced recovery after surgery. However, its use is limited in liver surgery due to its hepatic metabolism. Material and Methods: This prospective, monocentric study was conducted from 2020 to 2021. Patients undergoing liver surgery were included. They received a lidocaine infusion protocol until the beginning of hepatic transection (bolus dose of 1.5 mg kg-1, then a continuous infusion of 2 mg kg-1 h-1). Plasma concentrations of lidocaine were measured four times during and after lidocaine infusion. Results: Twenty subjects who underwent liver resection were analyzed. There was 35% of preexisting liver disease before tumor diagnosis, and 75% of liver resection was defined as "major hepatectomy." Plasmatic levels of lidocaine were in the therapeutic range. No blood sample showed a concentration above the toxicity threshold: 1.6 (1.3-2.1) µg ml-1 one hour after the start of infusion, 2.5 (1.7-2.8) µg ml-1 at the end of hepatic transection, 1.7 (1.3-2.0) µg ml-1 one hour after the end of infusion, and 1.2 (0.8-1.4) µg ml-1 at the end of surgery. Comparative analysis between the presence of a preexisting liver disease or not and the association of intraoperative vascular clamping or not did not show significant difference concerning lidocaine blood levels. Conclusion: Perioperative lidocaine infusion seems safe in the field of liver surgery. Nevertheless, additional prospective studies need to assess the clinical usefulness in terms of analgesia and antitumoral effects.

Transverse Myelitis Following SARS-CoV-2 Vaccination: A Pharmacoepidemiological Study in the World Health Organization's Database.

BACKGROUND: Transverse myelitis (TM) has recently been associated by health authorities with Ad26.COV2.S (Janssen/Johnson & Johnson), one of the 5 US Food and Drug Administration (FDA) or European Medicines Agency (EMA) labeled severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. It is unknown whether a similar association exists for the other FDA or EMA labeled SARS-CoV-2 vaccines (BNT162b2 [Pfizer/BioNTech], mRNA-1273 [Moderna], ChAdOx1nCov-19 [Oxford-AstraZeneca], and NVX-CoV2373 [Novavax]). This study aimed to evaluate the association between SARS-CoV-2 vaccine class and TM. METHODS: This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from VigiBase, the World Health Organization's pharmacovigilance database. We first conducted a disproportionality analysis with the information component (IC) using the reports of TM that occurred within 28 days following exposure to the FDA or EMA labeled SARS-CoV-2 vaccines, from December 1, 2020 (first adverse event related to a SARS-CoV-2 vaccine) to March 27, 2022. Second, we analyzed the clinical features of SARS-CoV-2 vaccine-associated TM cases reported in VigiBase. RESULTS: TM was significantly associated both with the messenger ribonucleic acid (mRNA)-based (n = 364; IC025  = 0.62) and vector-based (n = 136; IC025  = 0.52) SARS-CoV-2 vaccines that are authorized by the FDA or the EMA. CONCLUSIONS: Findings from this observational, cross-sectional pharmacovigilance study showed that mRNA-based and vector-based FDA/EMA labeled SARS-CoV-2 vaccines can be associated with TM. However, because TM remains a rare event, with a previously reported rate of 0.28 cases per 1 million vaccine doses, the risk-benefit ratio in favor of vaccination against SARS-CoV-2 virus remains unchallenged. Rather, this study suggests that clinicians should consider the diagnosis of TM in patients presenting with early signs of spinal cord dysfunction after SARS-CoV-2 vaccination. ANN NEUROL 2022;92:1080-1089.

Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase®.

BACKGROUND: Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database. METHODS: We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report. RESULTS: Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75-10.77) and leukaemia (aROR 3.54, 95% CI 2.97-4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2-9.9) for malignant lymphoma and 2.5 years (IQR 0.6-7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association. CONCLUSIONS: Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease.

Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). METHODS: Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. RESULTS: We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5  M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 µM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. CONCLUSION: We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.

Could N-acetylcysteine improve the safety of clozapine?

Clozapine is an atypical antipsychotic indicated in patients with treatment-resistant schizophrenia which remains underused due to safety issues. Mechanisms behind these adverse effects are complex and not fully understood. They may involve immune-related mechanisms, direct toxic effects and oxidative stress. Clozapine-induced oxidative stress might indeed notably be involved in the onset of neutropenia, agranulocytosis, myocarditis, sialorrhea, and metabolic alterations. Therefore, the association of N-acetylcysteine (NAC), an easily accessible, low-cost and well tolerated antioxidant drug could be of interest in clozapine-treated patients to improve clozapine safety. Furthermore, according to recent studies NAC could help to improve schizophrenia symptoms. We believe that the use of NAC in the context of clozapine prescribing merits further study, as it could improve clozapine safety which may lead to a wider use and ultimately improve the healthcare of thousands of patients. NAC could also secondarily show positive knock-on effects for the patients by improving clinical symptoms of schizophrenia in synergy with clozapine, and by reducing substance abuse and thus by improving the patient's overall condition. However, given the rarity of clozapine-induced severe adverse effects, only a large volume of data (e.g., National adverse events monitoring) could assess the benefits of NAC on clozapine safety.

Long-Lasting Effects of Chronic Intermittent Alcohol Exposure in Adolescent Mice on Object Recognition and Hippocampal Neuronal Activity.

BACKGROUND: Binge drinking is popular and highly prevalent in teenagers. However, the long-term cognitive and neurobiological consequences of such practices are not yet fully understood. In this context, we therefore assessed in mice whether a chronic intermittent alcohol (CIA) exposure in adolescence had long-term consequences on object discrimination and memory performances, emotional behaviors, brain activity, and morphology. METHODS: C57BL/6JRj mice were treated with either saline or ethanol (EtOH) (2 g/kg/d, i.p., from postnatal days [PND] 30 to PND 44 every other day). The day following the last administration or later in adulthood (PND 71) mice were tested for different behavioral tests (novel object recognition, spontaneous alternation, light-dark box, elevated plus-maze, actimeter test), to assess object recognition, working memory performances, anxiety-like behavior, and locomotor activity. We also investigated neuronal activation of hippocampus, prefrontal and perirhinal cortices, and anatomical changes using immediate-early gene expression and longitudinal brain magnetic resonance imaging. RESULTS: Our results showed that adolescent mice exposed to CIA present a critical and persistent impairment of short-term object recognition performances. By contrast, spatial working memory was not impaired, nor was anxiety-like behavior. This altered object discrimination was associated with a biphasic change in neuronal activity in the hippocampus but without morphological changes. Indeed, c-Fos expression was specifically increased in the dorsal dentate gyrus (DG) of the hippocampus after the binge exposure, but then became significantly lower in adulthood both in the DG and the CA1 part of the hippocampus compared with adult saline pretreated mice. CONCLUSIONS: These findings provide evidence for adolescent vulnerability to the effects of intermittent binge EtOH exposure on object discrimination and hippocampal activity with long-lasting consequences.

Vestibular loss promotes procedural response during a spatial task in rats.

Declarative memory refers to a spatial strategy using numerous sources of sensory input information in which visual and vestibular inputs are assimilated in the hippocampus. In contrast, procedural memory refers to a response strategy based on motor skills and familiar gestures and involves the striatum. Even if vestibular loss impairs hippocampal activity and spatial memory, vestibular-lesioned rats remain able to find food rewards during complex spatial memory task. Since hippocampal lesions induce a switch from declarative memory to procedural memory, we hypothesize that vestibular-lesioned rats use a strategy other than that of hippocampal spatial response to complete the task and to counterbalance the loss of vestibular information. We test, in a reverse T-maze paradigm, the types of strategy vestibular-lesioned rats preferentially uses in a spatial task. We clearly demonstrate that all vestibular-lesioned rats shift to a response strategy to solve the spatial task, while control rats use spatial and response strategies equally. We conclude that the loss of vestibular informations leading to spatial learning impairments is not offset at the hippocampus level by integration process of other sense mainly visual informations; but favors a response strategy through procedural memory most likely involving the striatum, cerebellum, and motor learning.

NSAIDs for Pain Control During the Peri-Operative Period of Hip Fracture Surgery: A Systematic Review.

BACKGROUND: Hip fracture (HF) mostly affects older adults and is responsible for increased morbidity and mortality. Non-steroidal anti-inflammatory drugs (NSAIDs) are part of the peri-operative multimodal analgesic management, but their use could be associated with adverse events in older adults. This systematic review aimed to assess outcomes associated with NSAIDs use in the peri-operative period of HF surgery. METHODS: This systematic review was conducted according to the PRISMA guidelines. Three databases (PubMed/EMBASE/Cochrane Central) were used to search for clinical trials and observational studies assessing efficacy, safety and impact of NSAIDs use on non-specific post-operative outcomes, such as functional status and post-operative complications. RESULTS: Among the 1320 references initially identified, four provided data on efficacy, four on safety and six on non-specific post-operative outcomes (three randomized controlled clinical trials, three observational studies). Mean study population ages ranged from 68 to 87 years. Two studies found that NSAIDs were effective on pain control, but two studies found conflicting results on opioid sparing. No increased risk of acute kidney injury was observed, while results concerning bleeding risk and delirium were conflicting. No study has found any effect of NSAIDs use on walk recovery. Quality of evidence was high for pain control, but low to very low for all the other studied outcomes. CONCLUSIONS: The use of NSAIDs may be effective for pain control in the peri-operative period of HF surgery. However, safety data were conflicting with low levels of certainty. Further studies are needed to assess their benefit-risk balance in this context. The research protocol was previously registered on PROSPERO (registration number: CRD42021237649).

A biological pharmacology network to secure the risk of drug-drug interaction with nirmatrelvir/ritonavir.

Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent risk of adverse drug reaction and lack of efficacy. In this study, we aimed at describing the expert advices provided by the biological pharmacology network of the SFPT (i.e., the therapeutic drug monitoring specialists working in the laboratories of the pharmacology departments in France/Belgium). From February to August 2022, we collected all specialized advices provided by the biological pharmacology network of the SFPT. Seven pharmacology departments actively participated in the study (Brussels Saint-Luc Hospital in Belgium, Caen, Dijon, Nantes, Nancy, Rennes and Toulouse in France). We collected the following data: patient's age, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments, and advice provided. One hundred and six expert advice on 753 drugs were provided during the seven months of data collection. Two centers provided 83% of all the expert advice (around 8/month). Patients originated form a transplantation department in 65% of the cases. The most common request were for cardiac drugs (28%), immunosuppressive drugs (24%) and endocrine drugs (18%). The advice were distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment, and treatment switch in 59%, 28%, 11%, and 1.6% of the cases, respectively. Only 2 pieces of advice (0.3%) constituted treatment contra-indications. Drug monitoring was proposed in 10% of prescription lines. Expert advice provided by the biological pharmacology network of the SFPT allows securing the combination of nirmatrelvir/ritonavir with other concomitant drugs. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction.

Micropipette-guided Drug Administration (MDA) as a non-invasive chronic oral administration method in male rats.

BACKGROUND: In preclinical studies resorting to rodents, the effects of prolonged oral intake of active substances are difficult to evaluate. Indeed, to get closer to clinical reality, oral gavage (OG) is frequently used but the repetition of administrations induces risks of lesions of the digestive tract, and stress for animals which can compromise the quality of the results. NEW METHOD: This study describes the development of a non-invasive oral administration method in male Sprague Dawley rats, as a safe alternative of OG, more faithful to clinical reality and limiting biases in pharmacokinetics and/or pharmacodynamics interpretation. Micropipette-guided Drug Administration (MDA) is based on the administration by micropipette of a sufficiently palatable vehicle for the animals to voluntarily take its contents. RESULTS: MDA was not demonstrated as less stressful than OG. A pharmacokinetics equivalence between MDA and OG was demonstrated for pregabalin administration but not for aripiprazole. Despite the use of a sweet vehicle, the MDA method does not result in weight gain or significant elevation of blood glucose and fructosamines level. Regarding the time needed to administrate the solution, the MDA method is significantly faster than OG. COMPARISON WITH EXISTING METHOD(S): Contrastingly to procedures using food or water, this method allows for a rigorous control of the time and dose administered and is delivered in discrete administration windows which is therefore closer to the clinical reality. This method appears particularly suitable for pharmacological evaluation of hydrophilic compounds. CONCLUSIONS: The MDA procedure represents a respectful and adapted pharmacological administration method to study the effects of chronic oral administration in rats.

Infections associated with clozapine: a pharmacovigilance study using VigiBase®.

Introduction: Clozapine is primarily reserved for treatment-resistant schizophrenia due to safety concerns associated with its use. Infections have been reported with clozapine, which may lead to elevated serum levels of the drug. However, the existing literature on this topic is limited. Therefore, we conducted a study using VigiBase® to investigate the potential over-reporting of infections associated with clozapine, to explore the presence of dose-dependency, and to investigate the underlying mechanism. Methods: Disproportionality analyses were performed using VigiBase to assess the association between clozapine and all types of infections, the association between clozapine-associated infections and neutropenia, the association between clozapine-associated infections and agranulocytosis, the dose-effect relationship between clozapine and infections, and the interaction between clozapine and the main strong CYP450 inhibitors using reports carried out until 11 April 2023. Results: A statistically significant signal of infections was observed with clozapine, as indicated by an information component of 0.43 [95% CI: (0.41-0.45)]. The most commonly reported infections were respiratory and gastrointestinal in nature. Neutropenia showed weaker association with clozapine-associated reports of infections compared to other clozapine-associated reports [X2 (1, N = 204,073) = 454; p < 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p < 0.005]. No evidence of dose-dependency was observed. Among the 17 tested CYP inhibitors, significant drug-drug interactions were found with clarithromycin, metronidazole, valproic acid, lansoprazole, omeprazole, amiodarone, and esomeprazole. Discussion: Our study revealed a significant safety signal between clozapine use and infections, predominantly respiratory and gastrointestinal infections. The co-administration of clozapine with valproic acid or proton pump inhibitors may potentially contribute to an increased risk of infection. Further vigilance is warranted in clinical practice, and consideration of therapeutic drug monitoring of clozapine in cases involving concomitant use of these drugs or in the presence of infections may be beneficial.

Neurocognitive impairment in females with breast cancer treated with endocrine therapy and CDK4/6 inhibitors: a pharmacovigilance study using the World Health Organization's database.

Importance: Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive impacts remain inconsistent for ET and are scarce for iCDK4/6s. Objective: To evaluate whether ET and iCDK4/6s are associated with neurocognitive impairment (NCI). Methods: We used observational, real-world cases of NCI from the World Health Organization's database VigiBase® to perform disproportionality analysis. Cases were defined as any symptom of NCI in females treated with ETs or iCDK4/6s. The study period was from the date of the first adverse event reported in VigiBase® with iCDK4/6s (1 January 2014) until the date of data extraction (16 March 2022). In our primary analysis, we calculated the reporting odds ratio (ROR) adjusted for age to identify a potential association between NCI and individual ETs in isolation or in combination with iCDK4/6s. We also performed subgroup analyses by the NCI class. Results: We identified 2.582 and 1.943 reports of NCI associated with ETs and iCDK4/6s, respectively. NCI was significantly associated with each ET [anastrozole: n = 405, aROR = 1.52 (95% CI: 1.37-1.67); letrozole: n = 741, aROR = 1.37 (95% CI: 1.27-1.47); exemestane: n = 316, aROR = 1.37 (95% CI: 1.22-1.53); tamoxifen: n = 311, aROR = 1.25 (95% CI: 1.12-1.40); and fulvestrant: n = 319, aROR = 1.19 (95% CI: 1.06-1.33)] and only with palbociclib for iCDK4/6s [n = 1,542, aROR = 1.41 (95% CI: 1.34-1.48)]. Conclusion: These findings suggest that in females treated for breast cancer, all ETs may be associated with NCI. However, amongst iCDK4/6s, NCI may be specific to palbociclib. NCI most frequently involved learning and memory as well as language. Neurocognitive impact of treatments requires better consideration and management.

An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.