Reporting of harms in clinical trials of esketamine in depression: a systematic review.

While previous systematic reviews of trials evaluating conventional antidepressants highlighted inadequacies and inconsistencies in adverse event (AE) reporting, no evaluation is available on esketamine in resistant depression. The objective of this review was to assess quality of reporting AEs in all published clinical trials studying esketamine. It also aimed to compare the proportions of AEs reported in journal articles to those recorded in the ClinicalTrial.gov Registers. Clinical trials evaluating the efficacy and safety of esketamine in depression were searched using Medline and ClinicalTrials.gov. The quality of reporting harms was assessed using a 21-item checklist from the CONSORT Extension of Harms (1 point by item). The total quality score was graded into four categories: high (17-21), moderate (12-16), low (7-11) and very low (0-6). Ten clinical trials were included in the analysis. Nine trials were classified as 'low quality' with regard to safety, one trial was classified as 'moderate quality'. Compared to AEs recorded in ClinicalTrials.gov, we found that 41.5% of serious AEs and 39% of non-serious AEs were not reported in the published articles. Among them, the majority were psychiatric events but also cardiovascular events and 94% concerned patients from esketamine groups. Quality of AEs reporting in published clinical trials of esketamine was poor and harms were reported less frequently in journal publications than in ClinicalTrial.gov Registers. The study suggests that an assessment of the benefits/risks balance of esketamine based on the results reported in trial publications is flawed due to the poor accuracy and completeness of harm data.

Testosterone treatment and the risk of osteonecrosis: a pharmacovigilance analysis in Vigibase.

PURPOSE: Recent reports have raised concerns about a potential risk of osteonecrosis associated with testosterone treatment (TT). The aim of this pharmacovigilance study was to assess the risk of reporting osteonecrosis associated with the use of TT compared with use of any other medication. METHODS: We performed a disproportionality analysis to investigate the risk of reporting osteonecrosis with TT using the WHO database VigiBase®. We estimated the reporting odds ratio (ROR) and 95% confidence interval (CI) of reporting osteonecrosis with use of TT vs all other drugs, and the adjusted ROR with use of TT vs use of drugs for benign prostatic hyperplasia (BPH). RESULTS: Among men at least 18 years of age between January 1, 2000, and December 31, 2019, we identified 3479 reports of osteonecrosis, 84 of which were associated with TT use, out of a total of 4,667,754 adverse event reports. Reports of osteonecrosis in TT users occurred with both transdermal and injectable forms, and the mean age at report was 55.4 years. TT use was associated with a greater risk of reporting osteonecrosis compared to all other drugs (ROR, 5.13; 95% CI, 4.13-6.37) and compared with use of drugs for BPH (ROR, 3.00; 95% CI, 2.08-4.30). Half of the osteonecrosis reports associated with TT indicated concomitant use of corticosteroids. CONCLUSION: TT was associated with a greater risk of reports of osteonecrosis compared to use of any other drug and use of drugs for BPH. This signal should be confirmed in complementary studies.

Will artificial intelligence chatbots replace clinical pharmacologists? An exploratory study in clinical practice.

PURPOSE: Recently, there has been a growing interest in using ChatGPT for various applications in Medicine. We evaluated the interest of OpenAI chatbot (GPT 4.0) for drug information activities at Toulouse Pharmacovigilance Center. METHODS: Based on a series of 50 randomly selected questions sent to our pharmacovigilance center by healthcare professionals or patients, we compared the level of responses from the chatbot GPT 4.0 with those provided by specialists in pharmacovigilance. RESULTS: Chatbot answers were globally not acceptable. Responses to inquiries regarding the assessment of drug causality were not consistently precise or clinically meaningful. CONCLUSION: The interest of chatbot assistance needs to be confirmed or rejected through further studies conducted in other pharmacovigilance centers.

Drug-related catatonia in youths: real-world insights from the WHO Safety Database.

Catatonia is characterized by psychomotor alterations and reduced contact with the environment. Initially linked to schizophrenia, it also occurs in mood disorders or organic conditions. In children, catatonia remains poorly delineated, despite dramatically increasing the risk of premature death. As data on pediatric drug-induced catatonia bears many uncertainties, we aimed to characterize its age-dependent patterns, using real-world data from the WHO safety database (VigiBase®).VigiBase® was queried for all reports of catatonia registered up to December 8th 2022. Reports involving patients <18 years were classified into 3 groups: ≤23 months, 2-11 years, and 12-17 years. Disproportionality analyses relied on the Reporting Odds Ratio (ROR), and the positivity of the lower end of the 95% confidence interval of the Information Component (IC) was required to suspect a signal. Catatonia was evoked in 421 pediatric reports. In infants, vaccines were leading. In children, the main signals involved haloperidol (ROR 104.3; 95% CI 45.6-238.5), ondansetron (ROR 40.5; 95% CI 16.5-99.5), and ciclosporin (ROR 27.4; 95% CI 13.8-54.1). In adolescents, chlorpromazine (ROR 199.1; 95% CI 134.8-294.1), benzatropine (ROR 193; 95% CI 104.1-361.6), and olanzapine (ROR 135.7; 95% CI 104.6-175.9) reached the highest RORs. In infants, catatonia was related to vaccines, it was ascribed to multiple drugs in children, and mainly to psychotropic drugs in adolescents. Less suspected drugs, such as ondansetron, were highlighted. Despite limitations inherent in spontaneous reporting systems, this study supports that a careful anamnesis is warranted to separate catatonia associated with medical conditions from drug-induced catatonia in pediatric patients.

[Funding of psychiatry in France, the problem of expensive drugs. Example of Esketamine in the case of resistant depressive episodes]. / Financement de la psychiatrie en France, la question des médicaments onéreux : exemple de l'Esketamine dans l'épisode dépressif caractérisé résistant.

In France, the funding of mental health institutions relies on an annual budget allocation. Esketamine, a non-competitive NMDA glutamate receptor antagonist, has been approved for adults with treatment-resistant major depressive disorder since 2019. However, due to its high cost (€200 per 28 mg device, excluding tax), the aim of this work was to evaluate whether the income received by an institution for the management of a patient treated with Esketamine could cover the purchase of devices, based on real clinical data. Within our institution, seven patients underwent treatment with Esketamine during the study period resulting in a total usage of 714 devices, amounting to a purchase cost of €142,800. Over the course of the follow-up period, the institution received €149,054 in revenue for the treatment of these patients. Our analysis reveals that the expense associated with Esketamine constitutes 95.8 % of the income generated from caring for these patients. This not only raises questions about the pricing of this drug but also highlights the lack of a funding system for costly psychiatric drugs. This concern extends to somatic treatments associated with psychiatric care.

Aromatase inhibitors and the incidence of Parkinson disease: A population-based cohort study.

BACKGROUND: Current guidelines recommend the treatment of hormone receptor-positive breast cancer with aromatase inhibitors (AIs) and tamoxifen in the adjuvant setting. Some observational studies have raised concerns that tamoxifen may be associated with an increased risk of Parkinson disease (PD). However, no studies have directly compared the risk of PD between AIs and tamoxifen in women diagnosed with breast cancer. METHODS: Using the UK Clinical Practice Research Datalink, the authors assembled a cohort of women newly diagnosed with breast cancer and newly treated with either AIs or tamoxifen between January 1, 1995, and December 31, 2017. Patients were followed 1 year after treatment initiation (ie, a 1-year lag) until an incident diagnosis of PD or were censored at death from any cause, the date of transfer out of the practice, or the end of the study period (December 31, 2018). Cox proportional hazards models with inverse probability of treatment weights were used to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for PD comparing AIs with tamoxifen and accounting for more than 30 confounders. RESULTS: In all, 30,140 women with nonmetastatic breast cancer were identified: 13,838 initiated AIs, and 16,302 initiated tamoxifen. Compared with tamoxifen, AIs were not associated with an increased risk of PD (HR, 0.94; 95% CI, 0.60-1.47). Consistent results were observed across all secondary and sensitivity analyses. CONCLUSIONS: In this large observational study, the use of AIs, in comparison with tamoxifen, was not associated with an increased risk of PD in women diagnosed with nonmetastatic breast cancer in a real-world setting. LAY SUMMARY: Previous studies have indicated that tamoxifen may increase the risk of Parkinson disease in the treatment of breast cancer. However, no studies have directly compared the risk of Parkinson disease between aromatase inhibitors and tamoxifen. This study included 30,140 women diagnosed with breast cancer and treated with aromatase inhibitors or tamoxifen. Overall, compared with tamoxifen, aromatase inhibitors were not associated with an increased risk of Parkinson disease in women diagnosed with breast cancer. This study provides an important addition to the comparative safety profile of aromatase inhibitors and tamoxifen in the treatment of breast cancer.

Trends in new prescription of gabapentinoids and of coprescription with opioids in the 4 nations of the UK, 1993-2017.

We explored potential differences in time trends of gabapentinoid prescription and of opioid coprescription between 1993 and 2017 in the 4 UK nations using the Clinical Practice Research Datalink, a UK primary care database. There were distinct trends in annual rates of new gabapentin and pregabalin prescriptions in Northern Ireland. The rate of new gabapentin prescriptions rapidly increased after 2010 and exceeded that of the other nations by 2017 (rate of 836 [95% confidence interval: 787-887] per 100 000 person-years). Additionally, the rate of new pregabalin prescriptions was higher during the entire study period, reaching a peak of 1139 (95% confidence interval: 1088-1193) per 100 000 person-years in 2010, 5-fold higher than the other nations. Findings in Northern Ireland may be partly attributable to the high burden of anxiety disorders, an indication for pregabalin. Further exploration of reasons for discrepancies in gabapentinoid prescribing between UK nations is warranted.

Fatal adverse drug reactions: A worldwide perspective in the World Health Organization pharmacovigilance database.

AIMS: Adverse drug reactions (ADRs) are important causes of death. However, the main involved drugs are relatively unknown. The present study was performed to characterise death-related drugs recorded in a large pharmacovigilance database during the last 10 years. METHODS: A retrospective analysis of VigiBase, the World Health Organization pharmacovigilance database, was performed investigating fatal ADRs registered between 1 January 2010 and 31 December 2019 in male and female patients aged ≥18 years and reported by physicians. Analyses were descriptive investigating age, sex and suspected drugs. Differences in reporting according to sex, age and continents were investigated using disproportionality analysis with calculation of reporting odds ratio and its 95% confidence interval. RESULTS: Among the 23 millions ADRs recorded in VigiBase, 3 250 967 were included with 43 685 fatal. They were reported mainly in patients older than 75 years. The 3 most frequently involved drug classes were antineoplastic/immunomodulating drugs followed by nervous system and cardiac drugs. The top 3 individual drugs were denosumab, lenalidomide and thalidomide with marked differences according to age, sex, continents and countries. The risk of reporting fatal ADRs was higher in males, in the Americas and in patients ≥65 years. CONCLUSION: Fatal ADRs registered in a large pharmacovigilance database during the last 10 years correspond to just over 1% of the total number of ADRs. They occurred more in males, after 65 years and with antineoplastic/immunomodulating drugs in general. Our study also highlighted, for the first time, important differences in fatal ADRs between continents and countries.

Hepatic Disorders With the Use of Remdesivir for Coronavirus 2019.

Remdesivir is a nucleotide analog prodrug with antiviral activity against a broad spectrum of human coronavirus in cell cultures and mouse models including severe acute respiratory syndrome-associated coronavirus 2. Recently, the Food and Drug Agency (FDA) and the European Medicines Agency (EMA) recommended remdesivir for the treatment of patients hospitalized with severe coronavirus disease 2019 (COVID-19) infection.1,2 In the remdesivir clinical development program, some cases have raised concerns regarding potential hepatobiliary disorders associated with remdesivir, including in healthy volunteers and patients with COVID-19.3 In cohort studies of patients hospitalized for severe COVID-19 who were treated with compassionate-use remdesivir, elevated hepatic enzymes were the most frequent adverse drug reaction reported.4,5 In the first randomized, double-blind, placebo-controlled clinical trial assessing the effect of intravenous remdesivir in adults admitted to hospital with severe COVID-19 (n = 237), a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped by the investigators because of adverse events including aminotransferase or bilirubin increases (3 versus 0).6 Although there is no signal from the available data of severe hepatotoxicity or drug-induced liver injury in clinical trials, the number of patients exposed to remdesivir was too limited. Therefore, there is an urgent need to investigate the hepatic safety profile associated with remdesivir in COVID-19 patients.

Abatacept in rheumatoid arthritis and the risk of cancer: a world observational post-marketing study.

OBJECTIVES: We aimed to investigate whether abatacept used in patients for RA was associated with an increased risk of reporting overall cancer and specific cancers, including breast, lung, lymphoma, melanoma and non-melanoma skin cancer when compared with other biologic DMARDs (bDMARDs). METHODS: We performed an observational study within VigiBase, the World Health Organization's global database of individual case safety reports, from 2007 to 2017 to compare the cases of cancer reported in RA patients exposed to abatacept with those reported in RA patients exposed to other bDMARDs. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CIs of the exposure odds among spontaneous reporting of cancers to the exposure odds among other reported adverse effects. RESULTS: We identified 15 846 adverse effects reported in RA patients who received abatacept and 290 568 adverse effects reported in RA patients treated with other bDMARDs. Compared with other bDMARDs, the use of abatacept was not associated with an increased risk of reporting cancer overall [ROR 0.98 (95% CI 0.91, 1.05)]. Analyses by specific cancer sites showed a significantly increased ROR for melanoma [1.58 (95% CI 1.17, 2.08)], but not for other specific cancer sites. CONCLUSION: Compared with other bDMARDs, exposure to abatacept in RA patients was only significantly associated with an increased risk of reporting melanoma. This increased risk is consistent with the properties of abatacept (CTLA-4 agonist) since it has an opposite action than ipilimumab, an antibody that blocks CTLA-4 and is approved for the treatment of malignant melanoma. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT03980639.

Parkinsonism associated with gabapentinoid drugs: A pharmacoepidemiologic study.

BACKGROUND: Use of gabapentinoids is increasing. Following recent case reports, we investigated a putative risk of parkinsonism with pregabalin or gabapentin. METHODS: A disproportionality analysis of 5,653,547 individual case safety reports in the World Health Organization individual case safety report database, VigiBase, compared all patients with parkinsonism who were receiving gabapentinoids with other patients. Results are shown as reporting odds ratios and the information component, an indicator of disproportionate Bayesian reporting. Sensitivity analyses included comparisons with drugs used for similar indications (amitriptyline, duloxetine) and exclusion of drugs that induce parkinsonism. RESULTS: Among 5,653,547 reports, 4925 parkinsonism reports were found with pregabalin and 4881 with gabapentin. Gabapentin and pregabalin were associated with increased reporting odds ratio (2.16 [2.10-2.23], 2.43 [2.36-2.50]). Similar trends were found using information components after excluding drugs that induce parkinsonism and for pregabalin compared with amitriptyline or duloxetine. CONCLUSIONS: This study found that gabapentinoids (particularly pregabalin) can be associated with parkinsonism. © 2019 International Parkinson and Movement Disorder Society.

Role of serotonin and norepinephrine transporters in antidepressant-induced arterial hypertension: a pharmacoepidemiological-pharmacodynamic study.

PURPOSE: Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI- and SNRI-induced AH. METHODS: The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs. RESULTS: A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x - 2.55, R2 = 0.68, Pearson coefficient correlation = 0.82). CONCLUSION: The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect.

Adverse drug reactions in infants, children and adolescents exposed to antidepressants: a French pharmacovigilance study.

PURPOSE: Despite their frequent use in children and adolescents, the evidence for efficacy and safety of antidepressants (ATDs) in this population is scarce and off-label prescribing common. The aim of this study was to describe reported adverse drug reactions (ADRs) associated to ATDs over a 30-year period using the French Pharmacovigilance Database (FPVD). METHODS: We performed an analysis of ADRs registered in the FPVD from 1985 to 2016, occurred in children and adolescents receiving an ATD. Descriptive statistics were used to obtain an overview of ADRs types and characteristics, and data were stratified by age. RESULTS: Among the 45,070 pediatric cases reports registered into the FPVD, we identified 1366 reports (3.0%) in which ATDs were "suspected" as the cause of 2922 ADRs. ADRs were more frequently reported in female (n = 743; 55.5%) and adolescents (n = 627; 49.3%). Neuropsychiatric ADRs were the most reported, mainly sleepiness, agitation, and suicidal thinking and behavior, followed by gastrointestinal and hepatobiliary disorders, mainly vomiting, abdominal pain, hepatitis, nausea, and three unexpected ADRs of pancreatitis. There was an increase of annual reporting between 1986 and 2003, followed by a plateau state then a decrease from 2003 to 2012, and a rapid escalation until 2016, while an increase in the number of reporting of suicidal thinking and behavior was observed after 2003, highlighting a possible impact of black box warnings on reporting practices and ATD use. CONCLUSION: This pediatric pharmacovigilance study underscored the high prevalence of neuropsychiatric and gastrointestinal ADRs, including three unexpected cases of pancreatitis.

Antidepressants and movement disorders: a postmarketing study in the world pharmacovigilance database.

BACKGROUND: Antidepressants-induced movement disorders are rare and imperfectly known adverse drug reactions. The risk may differ between different antidepressants and antidepressants' classes. The objective of this study was to assess the putative association of each antidepressant and antidepressants' classes with movement disorders. METHODS: Using VigiBase®, the WHO Pharmacovigilance database, disproportionality of movement disorders' reporting was assessed among adverse drug reactions related to any antidepressant, from January 1967 to February 2017, through a case/non-case design. The association between nine subtypes of movement disorders (akathisia, bruxism, dystonia, myoclonus, parkinsonism, restless legs syndrome, tardive dyskinesia, tics, tremor) and antidepressants was estimated through the calculation first of crude Reporting Odds Ratio (ROR), then adjusted ROR on four potential confounding factors: age, sex, drugs described as able to induce movement disorders, and drugs used to treat movement disorders. RESULTS: Out of the 14,270,446 reports included in VigiBase®, 1,027,405 (7.2%) contained at least one antidepressant, among whom 29,253 (2.8%) reported movement disorders. The female/male sex ratio was 2.15 and the mean age 50.9 ± 18.0 years. We found a significant increased ROR for antidepressants in general for all subtypes of movement disorders, with the highest association with bruxism (ROR 10.37, 95% CI 9.62-11.17) and the lowest with tics (ROR 1.49, 95% CI 1.38-1.60). When comparing each of the classes of antidepressants with the others, a significant association was observed for all subtypes of movement disorders except restless legs syndrome with serotonin reuptake inhibitors (SRIs) only. Among antidepressants, mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan and fluvoxamine were associated with the highest level to movement disorders and citalopram, paroxetine, duloxetine and mirtazapine were the most frequently associated with movement disorders. An association was also found with eight other antidepressants. CONCLUSIONS: A potential harmful association was found between movement disorders and use of the antidepressants mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, fluvoxamine, citalopram, paroxetine, duloxetine, bupropion, clomipramine, escitalopram, fluoxetine, mianserin, sertraline, venlafaxine and vilazodone. Clinicians should beware of these adverse effects and monitor early warning signs carefully. However, this observational study must be interpreted as an exploratory analysis, and these results should be refined by future epidemiological studies.

Drug-induced tics: An observational postmarketing study.

OBJECTIVES: While drug-induced tics have been described, in particular with neuroleptics, psychostimulants, or anti-epileptics, the strength and the direction of these associations are still debated. The aim of this study was to investigate the association between tics and drug exposure through a two-step analysis in two pharmacovigilance databases. METHODS: We first performed a descriptive clinical analysis of cases registered in the French pharmacovigilance database (FPVD) from January 1985 to December 2018. We then performed a disproportionality analysis in VigiBase®, the WHO pharmacovigilance database, from January 1967 to June 2019, through the calculation of reporting odds ratio (ROR). RESULTS: The drugs most frequently associated with tics in the FPVD were methylphenidate, lamotrigine, montelukast, tramadol, mirtazapine, venlafaxine, aripiprazole, and risperidone. In VigiBase®, we found a significant ROR with methylphenidate (ROR 37.54, 95% confidence interval [CI] 34.81-40.48), montelukast (ROR 12.18, 95% CI 10.29-14.41), aripiprazole (ROR 7.40, 95% CI 6.35-8.62), risperidone (ROR 4.40, 95% CI 3.72-5.21), and venlafaxine (ROR 1.52, 95% CI 1.14-2.03). CONCLUSION: This postmarketing study confirmed a potential harmful association with methylphenidate (the highest association, as expected), aripiprazole, risperidone, lamotrigine, and venlafaxine and, interestingly, found a strong signal with montelukast, which, to our knowledge, had never been published before.

Abatacept initiation in rheumatoid arthritis and the risk of cancer: a population-based comparative cohort study.

OBJECTIVE: To assess whether abatacept as initial biological DMARD (bDMARD) in the treatment of RA, when compared with other bDMARDs, is associated with an increased risk of cancer overall and by specific cancer sites (breast, lung, lymphoma, melanoma and non-melanoma skin cancer). METHODS: We performed a population-based cohort study among patients newly treated with bDMARDs within the US-based Truven MarketScan population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs of any cancer (and specific cancers) associated with initiation of abatacept, compared with initiation of other bDMARDs, adjusted for age and deciles of the propensity score. RESULTS: The cohort included 4328 patients on abatacept and 59 860 on other bDMARDs, of whom 409 and 4197 were diagnosed with any cancer during follow-up (incidence rates 4.76 per 100 per year and 3.41 per 100 per year, respectively). Compared with other bDMARDs, the use of abatacept was associated with an increased incidence of cancer overall (hazard ratioadjusted 1.17; 95% CI 1.06, 1.30). Analyses by specific cancer sites showed a significantly increased incidence of non-melanoma skin cancer (hazard ratioadjusted 1.20; 95% CI 1.03, 1.39), but no significant difference for other specific cancer sites. CONCLUSION: The use of abatacept as first bDMARD in the treatment of RA was associated with a slight increased risk of cancer overall and particularly non-melanoma skin cancer, compared with other bDMARDs. This potential signal needs to be replicated in other settings.

Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3-year analysis of the multidomain Alzheimer preventive trial (MAPT) study.

AIM: The aim of the present study was to assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over the course of 3 years. METHODS: We used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70 years and at risk of cognitive decline. Cognitive function was assessed with a composite score [Mini-Mental State Examination (MMSE) orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test] at 12, 24 and 36 months. Participants declining by more than 0.236 points on the composite score (representing the lowest quintile of 1-year cognitive change) during any 1-year period were considered to have undergone cognitive decline. Anticholinergic exposure was defined by four methods for each of four anticholinergic scales (Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, Anticholinergic Risk Scale, the Durán list). The association between cognitive decline and time-varying anticholinergic exposure [primary analysis using the Durán list and maximal anticholinergic score (0, 1 or 3)] was assessed using Cox proportional hazards models. Other cognitive decline definitions were used in sensitivity analyses. RESULTS: At baseline, among 1396 patients included, 7.4-23.5% were exposed to anticholinergic agents, depending on the anticholinergic scale used. Sixty-four per cent of participants experienced cognitive decline during follow-up. Regardless of the anticholinergic scale/exposure measurement used, no significant association was observed with cognitive decline {primary analysis: compared with non-anticholinergic agent users, hazard ratio [HR] = 1.14 [95% confidence interval (CI) = 0.95, 1.38] for anticholinergic score = 1; HR = 0.92 [95% CI = 0.65, 1.30] for score = 3}. Results were stable in sensitivity analyses. CONCLUSION: We found no significant association between anticholinergic exposure and cognitive decline in older adults using anticholinergic scales and definitions of exposure.

Breast cancer and spironolactone: an observational postmarketing study.

INTRODUCTION: Recent studies have discussed the risk of breast cancer with antihypertensive drugs. For spironolactone, data are conflicting. The present paper investigates this potential signal in VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database. METHODS: In VigiBase®, we performed a case/non-case study using data registered from 1981 (spironolactone's marketing authorization) to December 31, 2017. Among women ≥ 50 years, we measured the risk of reporting "Breast malignant tumors" compared with all other adverse drug reactions (as a crude and adjusted (a) reporting odds ratio (ROR 95% CI)) for spironolactone compared with first, all other drugs and second, pseudo aldosterone antagonists (amiloride, triamterene). ROR were adjusted for age, year of report, continent of report, number of drug prescribed, and completeness score. Sensitivity analyses were performed after exclusion of drug competitors (i.e., drugs like estroprogestative therapy and progestogens that could mask a putative signal) and reports from health professionals. RESULTS: During the study period, 125 ICSRs reported spironolactone exposure and breast malignant cancer in women ≥ 50 years. We failed to find a positive association between spironolactone exposure and breast cancer in comparison with exposure to other drugs (aROR = 0.63 95% CI [0.52-0.75]) or pseudo aldosterone antagonists (amiloride, triamterene) (0.56 [0.44-0.72]). Similar trends were found after exclusion of drug competitors and/or reports from health professionals. CONCLUSION: This study did not find evidence for breast cancer associated with spironolactone.

Association between anticholinergic (atropinic) drug exposure and cognitive function in longitudinal studies among individuals over 50 years old: a systematic review.

PURPOSE: With increasing age, adults are often exposed to anticholinergic drugs and are prone to potential adverse drug reaction, among which cognitive impairment. If the short-term cognitive effects of anticholinergic drugs are well established, their long-term cognitive effects have less been studied. OBJECTIVE: To provide a systematic review of longitudinal studies which assessed the effect of anticholinergic exposure on cognition in individuals over 50 years. MATERIALS: We searched the MEDLINE database for studies with a minimal 6-month follow-up, assessing anticholinergic exposure through a biological measure or a clinical list and reporting at least one cognitive outcome. We used the modified Newcastle-Ottawa scale and additional criteria regarding the anticholinergic exposure to assess studies' methodological quality. Given the heterogeneity of the studies, we performed a systematic review. RESULTS: Among the 1574 references retrieved, 25 studies were included. Anticholinergic medications were mostly defined through the Anticholinergic Cognitive Burden Scale (n = 14/25). Six studies evaluated baseline drug collection, 14 used longitudinal aggregated measure, and 5 multiple drug exposure measures over time. Seventeen studies assessed anticholinergic burden. Cognitive function was assessed by mild cognitive impairment/dementia incidence (n = 15) or neuropsychological tests (n = 14). Most studies were of poor quality and retrieved discordant results. However, studies with good quality (n = 4) suggested a relationship between anticholinergic drug exposure and/or burden and cognitive function. CONCLUSION: Our review suggests a deleterious effect of anticholinergic exposure on mid/long-term cognitive function but should be confirmed in studies with improved methodology. Meanwhile, prescription of anticholinergic drugs should remain cautious.