Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

Trends in Discharge Prescription of Digoxin After Norwood Operation: An Analysis of Data from the Pediatric Health Information System (PHIS) Database.

Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.

Keeping the Pharmacology in Pharmacoepidemiology.

The treatment of many medical conditions requires the use of multiple drugs. A study published recently in this journal nicely illustrates the need to consider the pharmacology of potentially interacting drugs when conducting pharmacoepidemiologic studies of patient safety outcomes associated with such interactions. By examining multiple streams of data, we can piece together the risks and the mechanisms of action underlying those risks, and provide useful information for clinicians and patients to use multiple pharmacotherapies safely.

Pharmacy students' intentions to utilize pharmacoeconomics, pharmacoepidemiology, and health outcomes in future jobs.

INTRODUCTION: The objectives of this study were to explore factors associated with pharmacy students' intentions to utilize health outcomes by: (1) understanding opinions on health outcomes, (2) understanding the likelihood of using health outcomes in different settings, and (3) predicting pharmacy students' intentions to utilize health outcomes in future jobs. METHODS: This study surveyed second-year pharmacy students over two years. The survey contained four components: the theory of planned behavior, opinions on health outcomes, the likelihood of using health outcomes in different settings, and demographics. To predict pharmacy students' intentions to utilize health outcomes in future jobs, a multiple linear regression model was used with behavioral intention as the dependent variable. RESULTS: Of the 376 second-year pharmacy students surveyed, 229 responded (60.90%). Pharmacy students had a positive attitude (mean: 0.77, SD: 0.16), high level of subjective norm (mean: 0.75, SD: 0.18), high level of perceived behavioral control (mean: 0.74, SD: 0.15), and high level of behavioral intention (mean: 0.74, SD: 0.21). They thought health outcomes were important for their future jobs (mean: 0.76, SD: 0.22), and equally important as other courses in the doctor of pharmacy curriculum (mean: 0.49, SD: 0.23). Significant predictors of utilizing health outcomes in future jobs were attitude (0.21; 95% CI: 0.03, 0.40), subjective norm (0.38; 95% CI: 0.23, 0.54), and perceived behavioral control (0.45, 95% CI: 0.27, 0.63). CONCLUSIONS: The second-year pharmacy students in the program studied had positive opinions and expressed high likelihood of applying their health outcomes knowledge and skill after graduation.

Pharmacoepidemiology.

At the time of their marketing authorization, the effects of drugs and especially their efficacy have been mostly studied in randomized controlled clinical trials (RCT), comparing them to placebo or to existing drugs. However, RCT are by nature limited in their extent, and the often stringent inclusion and exclusion criteria destined to provide for homogeneous study populations reduce the generalizability of RCT results.The post-authorization evaluation of drugs (pharmacoepidemiology or real-world evidence (RWE)) covers the description of drug utilization and population risks or benefits of these drugs after they have been marketed and provided to their target populations. Though field studies have existed for a long time, modern pharmacoepidemiology has been made possible essentially by the emergence of large population databases compiled from claims data or electronic health records. The methods can be exposure or disease-based cohorts or event-driven case-based studies, tailored to the specific questions to be answered. They rely on scrupulous analysis and execution of impeccable methodology, to ensure the most reliable results possible.Pharmacoepidemiology requires knowledge of the pharmacology of drugs, of the clinical aspects of diseases and disease management, and of the epidemiological methods that can apply.

Pharmacovigilance - The next chapter.

The discovery and quantification of adverse drug reactions has long relied on the careful analysis of spontaneously reported cases. Causality assessment (imputation) was a fundamental feature of individual case report analysis. This was complemented by analysis of aggregated cases, and of disproportionality analyses in spontaneous reports databases. In the absence of more specific information sources, these have resulted in the discovery of many new adverse reactions, altering drug information. It has led to the withdrawal from the market of many drugs, but its use for risk quantification remains fraught with uncertainty. The recent access to population-wide claims or electronic health records databases have confirmed for spontaneous reporting a predominant role in hypothesis generation for serious adverse drug reactions, notably those that result in hospital admission or death. In these cases, the events are identifiable at the population level, and can be quantified precisely using the tools of modern pharmacoepidemiology, to generate specific benefit-risk analyses. Spontaneous reporting remains irreplaceable in signal and alert generation in drug safety, despite its inherent limitations. For signal strengthening and assessment, more systematic and quantitative methods should be sought, such as claims databases for reactions resulting in hospital admissions.

Time trends in oral bisphosphonate initiation in Ontario, Canada over 20 years reflect drug policy and healthcare delivery changes.

Characteristics of patients starting oral bisphosphonate therapy changed over time, reflecting trends in osteoporosis management (e.g., new drugs to market), and general healthcare delivery (e.g., benzodiazepine use declined, statin use increased). When designing studies that examine osteoporosis drug effects, potential time-related biases must be considered. INTRODUCTION: To describe the type of oral bisphosphonate initiated and characteristics of patients starting oral bisphosphonate therapy over time. METHODS: We identified community-dwelling older adults (ages ≥ 66 years) initiating oral bisphosphonate therapy from April 1996 to March 2016 (1996 to 2015 fiscal years) using healthcare administrative data in Ontario. Patients with conditions other than osteoporosis that may impact bisphosphonate prescribing were excluded. The bisphosphonate initiated and patient characteristics were summarized by fiscal year and stratified by sex. RESULTS: We identified 560,817 eligible patients (81% women). Most patients initiated cyclical etidronate from 1996 until 2005, and then weekly regimens became dominant. In 2008, risedronate became the main oral bisphosphonate (46% risedronate, 43% alendronate, 11% etidronate); with its use increasing after availability of monthly and delayed-release risedronate formulations. In 2015, 71% of patients started risedronate, 28% started alendronate, and less than 2% started etidronate. Characteristics of patients changed over time, reflecting changes in osteoporosis management and general healthcare delivery. Over time, a larger proportion of men (9% to 28%) and patients with diabetes (women 10% to 17%, men 14% to 22%) initiated therapy; benzodiazepine (women 22% to 13%, men 20% to 10%) and estrogen-based hormone replacement therapy (12% to 15% of women 1996-2002 to 3% since 2008) decreased, while statin use increased (women 15% to 39%, men 14% to 52%). CONCLUSIONS: The characteristics of patients starting oral bisphosphonate therapy have changed over time. Consideration must be given to these time trends when designing studies that examine osteoporosis drug effects.

The Pharmacoepidemiology of Psychotropic Medication Use in Canadian Children from 2012 to 2016.

Objective: The goal of this study was to characterize the frequency and trends of psychotropic drug prescribing in Canadian children from 2010 to 2016 and to compare these results with a previous study conducted between 2005 and 2009. Methods: Using a national physician panel survey database from IQVIA Canada, aggregated frequencies of written prescriptions and therapeutic indications for antipsychotics, attention-deficit/hyperactivity disorder (ADHD) medications (psychostimulants and nonstimulants), and antidepressants were analyzed in children. Changes in frequency of written prescriptions and therapeutic indications are presented using descriptive statistics. Results: Written prescriptions for antipsychotics decreased by 10% from 2010 to 2016, in contrast to a 114% increase in written prescriptions for antipsychotics observed between 2005 and 2009. Written prescriptions for psychostimulants and antidepressants rose by 35% and 27%, respectively, between 2012 and 2016, comparable with previous results. The most common reasons for recommending an antipsychotic were ADHD and conduct disorder, although there appears to be a downward trend for ADHD compared with other conditions. In contrast, the share of written prescriptions for antipsychotics for autism increased 34% over the study period. Within the second-generation antipsychotics, written prescriptions for aripiprazole increased. An increase in the use of guanfacine extended release for ADHD was also observed. Conclusion: Several factors may be involved in stabilization and small decrease in antipsychotic use in recent years, including physician and patient awareness of adverse effects related to antipsychotic use, knowledge implementation strategies advocating short-term and judicious use of antipsychotics in children, and the approval of guanfacine extended release for use in Canada for ADHD in 2013.

Interest of pharmacoepidemiology in pharmacovigilance: Post-authorization safety studies in regulatory pharmacovigilance activity.

During the past few decades, it has been stated that a paradigm shift has occurred in the assessment and management of patient related drug safety. Some of these changes have resulted in a significant increase in the importance of pharmacoepidemiology and its use in pharmacovigilance. For European member states, the Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols and results of imposed and non-imposed post-authorization safety studies (PASS). Between 2013 and 2017, the total number of PASS during this 5-years period of the different products, including protocols and results, was 1062. The number of protocols of PASS is increasing over time, except in 2017 where a 25% decrease has been observed. Whereas, PASS results steadily increased over the 5years period. Between 2014 and 2017, about 29% (n=137) of PRAC reviewed protocols were imposed. The number of imposed PASS was almost constant over time with a mean of 34.3±7.6 imposed protocols per year and 3.5±1.74 imposed results per year. The need for the implementation of PASS for pharmacovigilance regulatory activities is increasing. Nevertheless, conducting such studies remains difficult.

Serious Adverse Drug Events Reported to the FDA: Analysis of the FDA Adverse Event Reporting System 2006-2014 Database.

BACKGROUND: Data on adverse drug events (ADEs) observed at the population level provide important evidence regarding the safety of a pharmaceutical product in real-world settings. Recent patterns in serious and fatal ADE reporting have not been documented. OBJECTIVE: To assess recent patterns in serious and fatal ADE reports in the United States. METHODS: We conducted a retrospective analysis of the publicly available 2006-2014 FDA Adverse Event Reporting System database. Non-U.S. reports, reports from clinical trials, and reports with missing outcome data were excluded. The annual numbers of ADEs with reported outcome of death, disability, and other serious outcomes were determined. Types (direct, manufacturer expedited, or manufacturer periodic) and sources (consumer, health professional, or other) of these serious ADE reports were also identified. The distribution of serious ADE reports by patient age groups (< 18, 18-44, 45-64, and ≥ 65 years) was determined. Drugs listed as primary suspects in serious ADEs (death, disability, and other serious outcomes) were identified and ranked. Descriptive statistics were used to characterize the patterns in serious or fatal ADE reporting. RESULTS: From 2006 to 2014, the number of serious ADEs reported to the FDA increased 2-fold. A total of 902,323 serious outcomes were reported over the 9-year study period: 244,408 deaths, 72,141 disabilities, and 585,774 other serious outcomes. The relative percentage of reports of deaths was highest during 2012 (32.4%). The percentage of reports of disability was highest during 2006 (12.1%). Overall, the "other serious outcomes" category accounted for almost 65% of serious ADEs reports. Expedited reports from drug manufacturers were most common (about 72%) of the serious ADEs with available data on report type. Health professionals (47.3%) were the most common source of report followed by consumers (36.1%) and other sources (16.6%). A disproportionately high number of reported ADEs was among patients aged 45-64 years (40%) and ≥ 65 years (32.6%). Antineoplastic drugs were more frequently reported with deaths. Three antidepressant drugs were among the top 10 drugs reported with disability. During 2006-2014, there were 38 drugs with more than 1,000 reports of serious ADEs in a given year: 2 drugs currently withdrawn from the market (rofecoxib and parecoxib), 10 drugs with an FDA risk evaluation and mitigation strategies (REMS) program, 13 biologic or specialty drugs, and 14 others. CONCLUSIONS: An overall increase in the trend of the number of serious ADE reports was observed from 2006 to 2014. Drugs with a REMS program and biologic and specialty drugs were involved in a significant number of reported serious ADEs. Data on reporting patterns can guide surveillance and pharmacoepidemiological studies to understand the public health burden of serious ADEs. DISCLOSURES: No outside funding supported this study. Hansen has received consulting fees from and has provided expert testimony for Daichii Sankyo and Takeda. The other authors have nothing to disclose.

Pharmacoepidemiology of Tourette and Chronic Tic Disorders in Sweden 2005-2013.

BACKGROUND: Monitoring "real world" dispensation patterns over time is important to build the evidence base for safe and efficient use of psychotropic drugs. In this study, we aimed to comprehensively examine the patterns of psychotropic drug dispensations in patients with Tourette and chronic tic disorders (TD/CTD) in Sweden between 2005 and 2013. METHODS: A cohort of 6979 TD/CTD patients was identified through the Swedish National Patient Register. Their drug dispensation patterns, collected in the Swedish Prescribed Drug Register, were examined between July 1, 2005 and December 31, 2013. Frequencies of drug dispensations were further stratified by gender and comorbidities. Additionally, differences in the patterns of dispensation in children and adolescents versus adults in the last year of the follow-up were examined, as well as the time trends of the dispensations over the 8-year study period. RESULTS: A total of 5299 (75.9%) TD/CTD patients were dispensed at least one drug during the study period. The most frequently dispensed medications were attention-deficit/hyperactivity disorder (ADHD) drugs (53.8%), antidepressants (50.7%), hypnotics/sedatives (41.7%), and antipsychotics (41.5%). Most of the medicated patients (72.1%) were dispensed more than one drug during the study period. Patterns of dispensation varied according to patient's gender, associated comorbidities, and age group. Dispensation of quetiapine and aripiprazole, antiadrenergics, ADHD drugs, antiepileptics, and hypnotics/sedatives and anxiolytics (particularly the nonbenzodiazepine types) significantly increased over time, whereas dispensation of antidepressants, typical antipsychotics, and benzodiazepine-based anxiolytics significantly decreased over the study period. CONCLUSIONS: Long-term monitoring of these drug dispensation patterns and the study of both their beneficial and adverse effects is warranted.

Pattern of Antidepressant Utilization and Cost in Iran from 2006 to 2013 in Comparison with Other Countries.

Antidepressant prescribing patterns have changed globally over the past few years, with conventional drugs including tricyclic antidepressants and monoamine oxidase inhibitors being replaced by selective serotonin reuptake inhibitors (SSRIs) and novel antidepressants. The objective of this study was to assess antidepressant utilization in Iran from 2006 to 2013 and to show Iran's situation in antidepressant consumption compared with other countries. A cross-sectional study was undertaken using prescription claims data from Iranian insurance agencies. In addition, total antidepressant sales data were obtained from the databank of the national regulatory authority. Medicines were classified according to the Anatomic Therapeutic Chemical (ATC-2012 edition) System. The Organisation for Economic Co-operation and Development data were used to compare national results from Iran with other countries. Antidepressant sales were four-fold higher than those of prescribed antidepressants [24 defined daily doses (DDD)/1000 inhabitants/day were sold whereas 6 DDD/1000 inhabitants/day were prescribed in 2013]. The trend in antidepressant prescriptions and consumption showed increasing use of SSRIs (N06AB). Nortriptyline, fluoxetine, and citalopram accounted for more than 60% of all prescriptions each year. The type of adverse reactions with new expensive antidepressants may seem convincing for the growing tendency toward using these medicines, but considering their high costs, health policymakers have to be aware of the risk of overprescription of newer antidepressant. Drivers of over-the-counter purchase of antidepressants need to be explored.

Frequency and correlates of anticholinergic use among patients with schizophrenia in Denmark: A Nation-wide pharmacoepidemiological study.

Anticholinergic medications are used to treat extrapyramidal adverse effects induced by antipsychotics. Anticholinergics are associated with adverse effects: constipation, dry mouth and worsening of cognitive function. Anticholinergics have potential for abuse and are not recommended for long term-treatment. We aimed to investigate the use of anticholinergics in patients with schizophrenia. The national health registers in Denmark were used to examine: The prevalence of anticholinergics in 1996-2012 using a cross-sectional design; geographic variations in the prescription of anticholinergics in 2012; correlates of treatment with anticholinergics. The proportion of patients using anticholinergics decreased significantly from 11.7% in 1996 to 5.7% in 2012. The prescription pattern varied considerably between national regions in 2012, ranging from 4.0% in the Capital Region to 8.1% in the Northern Denmark Region. Long-term use of anticholinergics was predicted by older age, age at debut of schizophrenia, receiving early retirement pension, typical antipsychotic use, antipsychotic polypharmacy, typical + atypical antipsychotics, antidepressant treatment, high doses of antipsychotics measured in defined-daily-dose, physical comorbidity and psychiatrists` greater caseload. Use of anticholinergics declined during the study period, and showed substantial variation across the regions in 2012. Long-term use was linked to typical antipsychotic use and variables that are associated with greater illness severity.

From a Viewpoint of Clinical Settings: Pharmacoepidemiology as Reverse Translational Research (rTR).

Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research.

Refining estimates of prescription durations by using observed covariates in pharmacoepidemiological databases: an application of the reverse waiting time distribution.

PURPOSE: The study aimed to develop an automated method to estimate prescription durations in pharmacoepidemiological studies that may depend on patient and redemption characteristics. METHODS: We developed an estimation algorithm based on maximum likelihood estimation for the reverse waiting time distribution (WTD), which is the distribution of time from the last prescription of each patient within a time window to the end of the time window. The reverse WTD consists of two distinctly different components: one component for prevalent users and one for patients stopping treatment. We extended the model to allow parameters of the reverse WTD to depend on linear combinations of covariates to obtain estimates and confidence intervals for percentiles of the inter-arrival density (time from one prescription to the subsequent). We applied the method to redemptions of warfarin, using the amount of drug filled, patient sex and patient age as covariates. RESULTS: The estimated prescription durations increased with redeemed amount and age. Women generally had longer prescription durations, which increased more with age than men. For 70-year-old women redeeming 300+ pills, we predicted a 95th percentile of the inter-arrival density of 225 (95%CI: 201, 249) days. For 50-year-old men redeeming 100 pills, the corresponding prediction was 97 (88, 106) days. CONCLUSIONS: The algorithm allows estimation of prescription durations based on the reverse WTD, which can depend upon observed covariates. Statistical uncertainty intervals and tests allow statistical inference on the influence of observed patient and prescription characteristics. The method may replace ad hoc decision rules. Copyright © 2017 John Wiley & Sons, Ltd.

Triptan use in Australia 1997-2015: A pharmacoepidemiological study.

OBJECTIVE: This study examined the use of triptan derivatives in Australia between 1997 and 2015, based on a national drug reimbursement database, and compared patterns of use with available international data. METHODS: We obtained publically available data on the number of prescriptions for triptans marketed in Australia (sumatriptan, eletriptan, rizatriptan, zolmitriptan, naratriptan). Dispensed use was measured as defined daily dose (DDD per 1000 population per day) for Australia's concessional beneficiaries (low-income earners, people with disabilities, and seniors). RESULTS: Total triptan use increased at an average annual rate of 112% over the 18-year period. Sumatriptan was the preferred triptan throughout (average annual increase 45%). Zolmitriptan and naratriptan use peaked in 2004, then decreased. Rizatriptan and eletriptan became available in 2010. There were 3.2-fold and 5.9-fold annual increases in their use from 2011 to 2105. There was some evidence suggesting that pattern of triptan use in concessional beneficiaries probably reflected pattern of overall triptan use in Australia. CONCLUSIONS: The use of triptan derivatives in Australia per head of population for treating migraine attacks continued to increase over the 18-year period studied, with use of recently introduced derivatives more than substituting for decreased use of older triptans. This suggests that the available treatments of migraine attacks had achieved what were considered less than adequate therapeutic outcomes.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis.

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.