Prevalence of neuropsychiatric adverse events and associated factors among adult patients on dolutegravir attending Mulago ISS clinic.

INTRODUCTION: Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor that is recommended by the World Health Organization as the preferred first-line and second-line antiretroviral therapy (ART) in patients with HIV. In 2018, Uganda started using DTG-based regimens as the preferred first-line ART. However, concerns regarding the potential neurotoxicity of DTG have been increasing. Data on the occurrence of neuropsychiatric adverse events (NPAEs) and the associated factors among adult patients who are initiated on or switched to DTG-based first-line or second-line ART in Uganda are limited. OBJECTIVE: This study aimed to determine the prevalence of NPAEs among adult patients on DTG and the factors associated with their occurrence. METHODS: We conducted a cross-sectional study using questionnaires administered by a trained research assistant between 15 November 2021 and 15 December 2021. The study included patients aged ≥18 years with HIV who were either initiated on or switched to a DTG-based ART regimen between 1 January 2018 and 31 October 2021. Informed consent and data were collected from 892 participants attending Mulago ISS clinic, including data on age, sex, marital status, disclosure status, current regimen, duration on ART, concurrent illness, concurrent medications, year of switch to DTG, duration on DTG, whether the onset of NPAEs was immediate or delayed, history of alcohol use or smoking, level of education, report of NPAEs while on DTG, and history of NPAEs while on previous regimen. Data were entered into Epidata version 4.6.0.2 then exported to Stata version 14 for analysis. RESULTS: Of the 892 adults on DTG attending Mulago ISS clinic, 41.7% (95% confidence interval [CI] 38.5%-44.9%) experienced at least one NPAE. DTG duration in years (adjusted prevalence [aPR] = 1.21, p = 0.024), disclosure status (aPR = 1.40, p = 0.042), concurrent medications (aPR = 1.31, p = 0.026), year of switch to DTG, and concurrent illness were associated with an increased occurrence of NPAEs. CONCLUSIONS: The prevalence of NPAEs was higher than that reported by any clinical trial. About 9.1% of participants had experienced severe to life-threatening NPAEs that required intervention from a healthcare professional to improve tolerability. The high prevalence requires that clinicians screen for NPAEs at very visit and reassure patients to maximize the benefits of long-term ART.

Bayesian regularization to predict neuropsychiatric adverse events in smoking cessation with pharmacotherapy.

BACKGROUND: Research on risk factors for neuropsychiatric adverse events (NAEs) in smoking cessation with pharmacotherapy is scarce. We aimed to identify predictors and develop a prediction model for risk of NAEs in smoking cessation with medications using Bayesian regularization. METHODS: Bayesian regularization was implemented by applying two shrinkage priors, Horseshoe and Laplace, to generalized linear mixed models on data from 1203 patients treated with nicotine patch, varenicline or placebo. Two predictor models were considered to separate summary scores and item scores in the psychosocial instruments. The summary score model had 19 predictors or 26 dummy variables and the item score model 51 predictors or 58 dummy variables. A total of 18 models were investigated. RESULTS: An item score model with Horseshoe prior and 7 degrees of freedom was selected as the final model upon model comparison and assessment. At baseline, smokers reporting more abnormal dreams or nightmares had 16% greater odds of experiencing NAEs during treatment (regularized odds ratio (rOR) = 1.16, 95% credible interval (CrI) = 0.95 - 1.56, posterior probability P(rOR > 1) = 0.90) while those with more severe sleep problems had 9% greater odds (rOR = 1.09, 95% CrI = 0.95 - 1.37, P(rOR > 1) = 0.85). The prouder a person felt one week before baseline resulted in 13% smaller odds of having NAEs (rOR = 0.87, 95% CrI = 0.71 - 1.02, P(rOR < 1) = 0.94). Odds of NAEs were comparable across treatment groups. The final model did not perform well in the test set. CONCLUSIONS: Worse sleep-related symptoms reported at baseline resulted in 85%-90% probability of being more likely to experience NAEs during smoking cessation with pharmacotherapy. Treatment for sleep disturbance should be incorporated in smoking cessation program for smokers with sleep disturbance at baseline. Bayesian regularization with Horseshoe prior permits including more predictors in a regression model when there is a low number of events per variable.

Current evidence for adjunct pyridoxine (vitamin B6) for the treatment of behavioral adverse effects associated with levetiracetam: A systematic review.

BACKGROUND: Levetiracetam (LVT), while an effective treatment for multiple seizure types, is associated with a high incidence of neuropsychiatric adverse events (NPAEs). In predominantly retrospective studies, supplementation with pyridoxine/vitamin B6 (PN) was associated with improvement in NPAEs in some people. A previous review highlighted a lack of double-blind, controlled trials of PN for the treatment of NPAEs in individuals treated with LVT. The current paper updates the findings from the previous review to include evidence from studies published since June 2019. METHODS: An updated systematic review of the published literature was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies published between June 2019 and 2nd November 2022 in which supplementary PN was initiated for the treatment of LVT-associated NPAEs. All study types were eligible. The risk of bias in randomized trials was assessed using the Cochrane risk-of-bias tool. RESULTS: Seven additional studies were identified: two double-blind, randomized controlled trials (RCTs), four retrospective studies, and one retrospective case series. One RCT reported significant improvements from baseline in behavioral adverse events (BAEs) in both the intervention (PN) group and the low-dose control group (both p < 0.05), with a significantly greater improvement in the intervention group (p < 0.001). In the second RCT, differences in BAE severity between PN and placebo groups at the endpoint were not statistically significant. In one retrospective study, subjective irritability was reported to have improved from baseline in 9/20 individuals (45%) treated with supplementary PN. Data for systematic assessments (PHQ-9 and GAD-7) were available for 10 individuals. Assessment by PHQ-9 showed that six individuals improved, two worsened and two had no change. Based on the GAD-7, three people improved, two worsened and five had no change. In the second retrospective study, 18/41 individuals (44%) who commenced PN following the emergence of BAEs showed "significant" improvement. In a separate group of individuals with pre-existing behavioral problems in whom PN treatment was initiated at the same time as commencing LVT, 3/18 (16.7%) developed BAEs. This compared with 79/458 people (17.2%) who were initially treated only with LVT. The third retrospective study compared treatment-related irritability in individuals who had been treated with both LVT and perampanel, either sequentially or concomitantly. Two people who developed irritability while receiving LVT monotherapy were able to continue treatment with the addition of PN. The fourth study reported a significantly lower LVT discontinuation rate in individuals taking PN and a higher rate of improved behavior in those who were able to continue LVT. The case series reported improvements in behavioral symptoms in six people within two to three weeks of commencing supplementary PN. CONCLUSION: Data published within the last three years add to earlier evidence suggesting that PN might be effective in the treatment of NPAEs associated with LVT. However, the quality of evidence remains poor and only a few prospective trials have been published. Data from placebo-controlled trials are still largely lacking. Currently, there is insufficient evidence to justify any firm recommendation for PN supplementation to treat NPAEs associated with LVT. Further well-designed, prospective trials are warranted.

Risk of neuropsychiatric adverse events associated with varenicline treatment for smoking cessation among Dutch population: A sequence symmetry analysis.

PURPOSE: Varenicline is an effective treatment for smoking cessation. While clinical trials did not confirm a causal role, case reports suggested a possible link of varenicline with neuropsychiatric adverse drug events (NPAEs). This study aims to investigate the risk of NPAEs associated with varenicline initiation among the general population in a real-world setting. METHODS: We conducted a sequence symmetry analysis (SSA) based on the University of Groningen IADB.nl prescription database. We selected incident users of both varenicline and marker drugs for NPAEs, including depression, anxiety and sleep disorder within different time-intervals. Adjusted sequence ratios (aSR) were calculated for each time-interval. RESULTS: Within 365-days' time-interval 1066 patients were incident users of both varenicline and NPAE marker drugs. In total, 505 patients were prescribed varenicline before NPAE marker drugs and 561 vice versa (crude sequence ratio [cSR] 0.90, 95% CI: 0.80-1.02). After adjustments for trends in prescriptions, overall a null association was found (aSR 1.00, 95% CI: 0.89-1.13). Regarding specific NPAEs, no increased risks were found for depression nor anxiety within any time-interval. A small transient increased risk was found for sleep disorders, particularly in earlier time-intervals 3 and 6 months (aSRs 1.52, 95% CI: 1.10-2.11 and 1.45, 95% CI: 1.15-1.83, respectively). Subgroup and sensitivity analyses showed similar findings. CONCLUSIONS: Varenicline initiation was unlikely to be associated with an increased risk of taking anti-depressants nor anti-anxiety drugs. Yet a small, but statistically significant, transient association with drugs for sleep disorders was noticed, possibly associated with withdrawal symptoms caused by smoking cessation.

Neuropsychiatric outcomes before and after switching to dolutegravir-based therapy in an acute HIV cohort.

INTRODUCTION: Dolutegravir (DTG)-based antiretroviral therapy (ART) is currently the first-line treatment for people living with HIV. Neuropsychiatric adverse events (NP-AEs) have been reported with DTG but neuropsychiatric symptoms have not been systemically quantified using structured scales. This study examined mood and cognitive parameters before and after a planned transition from non-DTG to DTG-based ART within a longitudinal study of acute HIV infection (AHI). METHODS: RV254 AHI cohort participants on ≥ 24 weeks of ART initiated at AHI underwent sequential assessments before and after the switch including: (1) Patient Health Questionnaire-9 (PHQ-9), a 9-item survey (scores 0-27) that evaluates somatic and affective/cognitive symptoms of depression; (2) a 2-Questions screening that has been validated locally for depression; (3) Distress Thermometer (scores 0-10); and 4) administration of a 4-test neurocognitive battery sensitive to HIV. RESULTS: 254 individuals (95% male, median age 30) switched to a DTG-based regimen after a median 144 weeks of ART. Serial assessments were completed at a median of 19 weeks before and 37 weeks after DTG. There was a modest but statistically significant increase in PHQ-9 scores after DTG (pre-switch: 5 [IQR 1-7] vs. Post-switch: 5 [IQR 2-8], p = 0.009). The percentage of participants with at least moderate depression (PHQ-9 ≥ 10) increased from 10 to 16% (p = 0.006), but the frequency of moderate-severe depression (PHQ-9 ≥ 15) remained unchanged (3%). No volunteer reported NP-AEs within the study period. Somatic symptoms of depression increased more than cognitive/affective symptoms. Plasma viral suppression (HIV-1 RNA < 50; p = 0.005) and PHQ-9 ≥ 10 (p < 0.001) before switch were linked to lower PHQ-9 scores after DTG in multivariable analysis. Performance on all neuropsychological tests, except grooved pegboard test, improved modestly after DTG (all p < 0.05). CONCLUSION: After a median duration of 37 weeks of DTG use, there was a modest increase in the higher quartile of PHQ-9. This increase was associated with a rise in moderate depression symptoms but not the more severe forms of depression on PHQ-9. No clinically relevant NP-AEs were reported. Pre-existing depression was not associated with subsequent worsening of symptoms after DTG. Cognitive test performance improved post-DTG but could be due to practice effect.

Simulation of the Pharmacokinetics of Oseltamivir and Its Active Metabolite in Normal Populations and Patients with Hepatic Cirrhosis Using Physiologically Based Pharmacokinetic Modeling.

Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated in patients with severe hepatic impairment. A physiologically based pharmacokinetic (PBPK) model of the prodrug oseltamivir and its active metabolite, oseltamivir carboxylate (OC), was established and validated to simulate their disposition in adults and predict the exposure in patients with Child-Pugh C cirrhosis (CP-C). The simulated results from PBPK modeling and the observed data after oral administration of various oseltamivir regimens were consistent according to the fold error values of less than 2. Furthermore, the clinical observations published in the literature were comparable with our pharmacokinetic predictions. In patients with CP-C, the oseltamivir Cmax was approximately 2-fold increased, and its AUC was approximately 6-fold higher compared with those in normal subjects. In contrast, the AUC of OC in CP-C patients did not differ significantly from that in normal subjects, whereas its Cmax was reduced by approximately 30% in the patients. Examination of drug exposure in different health conditions indicated that the oseltamivir exposure was significantly increased in conditions with elevated cirrhosis severity, which might be associated with a higher risk of adverse drug effects, e.g., neuropsychiatric adverse events (NPAEs). In conclusion, the pharmacokinetics of oseltamivir and OC were correctly predicted by PBPK modeling. The model further predicted that the pharmacokinetics of oseltamivir might be altered in liver cirrhosis, depending on the degree of severity.

Neuropsychiatric adverse events of antiepileptic drugs in brain tumour-related epilepsy: an Italian multicentre prospective observational study.

BACKGROUND AND PURPOSE: We assessed the prevalence and magnitude of neuropsychiatric adverse events (NPAEs) associated with antiepileptic drugs (AEDs) among patients with brain tumour-related epilepsy (BTRE). METHODS: This observational, prospective, multicentre study enrolled 259 patients with BTRE after neurosurgery. All patients received AED monotherapy. Efficacy was assessed through clinical diaries, whereas NPAEs were collected using the Neuropsychiatric Inventory Test-12 questionnaire at baseline and after 5 months. RESULTS: Tumour localization in the frontal lobe was associated with a higher prevalence of NPAEs (odds ratio, 7.73; P < 0.001). Independent of tumour localization, levetiracetam (LVT) treatment was associated with higher prevalence and magnitude of NPAEs (odds ratio, 7.94; P < 0.01) compared with other AEDs. Patients with oligodendroglioma reported more NPAEs than patients with other tumour types. NPAEs were not influenced by chemotherapy, radiotherapy or steroid treatment. Evaluating non-neurobehavioural adverse events of AEDs, no significant differences were found among AEDs, although patients treated with old AEDs had a higher prevalence of adverse events than those treated with new AEDs. CONCLUSIONS: Both tumour localization in the frontal lobe and LVT treatment are associated with a higher risk of NPAEs in patients with BTRE. LVT is regarded as a first-line option in patients with BTRE because of easy titration and few significant drug-to-drug interactions. Thus, as NPAEs lead to poor compliance and a high dropout rate, clinicians need to accurately monitor NPAEs after AED prescription, especially in patients with frontal lobe tumours receiving LVT.

Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1.

BACKGROUND: Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. METHODS: The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. RESULTS: The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 µg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 µg/mL) than in those without NP-AEs (1.01 µg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454). CONCLUSION: In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs.

Has the time come to abandon efavirenz for first-line antiretroviral therapy?

Efavirenz has been recommended as a preferred third agent together with two nucleos(t)ides for first-line combination antiretroviral therapy (ART) for >15 years. The availability of efavirenz in a fixed-dose combination makes it very attractive. However, because of (i) adverse events associated with efavirenz, (ii) a poorer overall efficacy of efavirenz compared with newer antiretrovirals, (iii) the ranking of efavirenz as FDA Pregnancy Category D and (iv) the relatively high prevalence of transmitted drug-resistance mutations, there is a need to reconsider the role of efavirenz in first-line ART. We review the available evidence that challenges efavirenz's current position in first-line HIV treatment guidelines. Apart from its animal teratogenic potential, and moderate neuropsychiatric adverse events associated with its use, efavirenz has recently been associated with an increased risk of suicidality when compared with other antiretroviral drugs. Most importantly, efavirenz has demonstrated overall inferior efficacy to various comparator drugs, which include rilpivirine, raltegravir and dolutegravir, in antiretroviral-naive patients. Furthermore, epidemiological data indicate that the prevalence of non-nucleoside reverse transcriptase inhibitor resistance has reached 5%-8% in various parts of the world, and minority transmitted non-nucleoside reverse transcriptase inhibitor resistance-associated mutations can have a negative impact on the outcome of first-line efavirenz-based ART. Based on considerations of efficacy, toxicity and resistance, it is time to reconsider the routine use of efavirenz in ART. This, of course, presupposes that other antiretrovirals will be available in place of efavirenz, and may not be applicable in certain developing country settings where this is not the case.

Sex effects in predictors of smoking abstinence and neuropsychiatric adverse events in the EAGLES trial.

Significance There are sex effects in abstinence outcomes across all smoking cessation medications, but there is limited information regarding sex effects on cessation-related neuropsychiatric adverse events (NPSAEs) or interactions with psychiatric status. METHODS: Secondary analysis of data from EAGLES of 8144 adults who smoke cigarettes randomized to varenicline, bupropion, nicotine patch or placebo. Design characteristics included region (within/outside US), psychiatric cohort (absent/present), and treatment. Baseline variables included demographics, smoking history, prior use of study treatments, lifetime suicide-related history, and prior psychiatric co-morbidities and medication use. Design characteristics were forced into logistic regressions models, and then interactions among sex, design elements, and baseline characteristics were evaluated for NPSAEs and 6-month cessation outcomes. RESULTS: Findings demonstrated a significant interaction of sex and race (p < 0.02); Black women were more likely to report NPSAEs than Black men. For cessation outcomes, there were no significant interactions with psychiatric cohort and sex. Women vs men with higher baseline levels of smoking had lower odds of continuous abstinence. Women vs men who used varenicline previously had lower odds of continuous abstinence. For 6-month point prevalence, sex interacted with baseline cigarettes per day (p < 0.01) similar to the interaction for continuous abstinence. Sex interacted with medication (p < 0.03), such that women vs men had relatively greater success at achieving point prevalence abstinence on varenicline. CONCLUSIONS: Overall, results demonstrated important sex and racial differences in the incidence of NPSAEs, but psychiatric status did not interact with sex on cessation outcomes. Findings did support prior work demonstrating relative increased efficacy of varenicline for women.

The Risk of Neuropsychiatric Adverse Events With Use of Leukotriene Receptor Antagonists in Patients With Asthma: Analysis of Korea's National Health Insurance Sharing Service Database.

BACKGROUND: Montelukast, a selective leukotriene receptor antagonist, is a commonly prescribed allergy medication but its potential association with neuropsychiatric adverse events is concerning. OBJECTIVE: To analyze Korea's National Health Insurance System claims records to identify the risk of neuropsychiatric adverse events in patients with asthma treated with montelukast. METHODS: This retrospective population-based study analyzed the National Health Insurance claims records of the entire Korean population between 2008 and 2015. We compared the risk of neuropsychiatric adverse events among patients with asthma using inhaled corticosteroids and/or long-acting ß2-agonists with montelukast or pranlukast and those not using leukotriene receptor antagonists (control group). RESULTS: There was no increased risk of the composite outcome of all measured neuropsychiatric adverse events in patients with asthma who were prescribed montelukast or pranlukast compared with those who were not. However, montelukast use was associated with an increased risk of hallucinations (inverse probability treatment weighting hazard ratio, 1.45; 95% CI, 1.07-1.96) and attention problems (inverse probability treatment weighting hazard ratio, 1.24; 95% CI, 1.01-1.52). Significant negative hazards for disorientation, anxiety, stress reactions, and somatic symptoms were observed in the montelukast group. When grouped by sex, the risk of hallucinations and attention problems was higher in men prescribed montelukast compared with the controls. CONCLUSIONS: We did not observe an increase in all neuropsychiatric adverse events in the leukotriene receptor antagonist-treated group; however, an increased risk of hallucinations and attention problems was observed in those taking montelukast, regardless of the medication administration period.

Increased psychomotor retardation and tension as short-term neuropsychiatric adverse events of immune checkpoint inhibitors: A prospective cohort study.

Introduction: Patients undergoing cancer treatment as well as cancer survivors commonly describe behavioral alterations. As a matter of fact, neuropsychiatric adverse events (NPAEs) have been extensively described with older immunotherapies, especially with interferon alfa. However, there are little data investigating the NPAEs of immune checkpoint inhibitors (ICIs). Therefore, the aim of this study is to evaluate the safety profile of ICI in terms of NPAEs. Materials and Methods: This is a prospective, interventional, self-controlled study. Participants receiving ICIs as unique therapy, between February and December 2019, were evaluated at the beginning of their treatment protocol, at 1 month and finally at 3 months. During the three evaluations, disease and patients' characteristics were assessed, as well as NPAEs using the Brief Psychiatric Rating Scale (BPRS) questionnaire, the psychological stress due to cancer's burden using the Herth hope index, and the performance status (PS) using the Eastern Cooperative Oncology Group (ECOG) score. Results: Forty-four patients were enrolled, of whom 24 patients completed their three evaluation visits. No changes in BPRS total score were found throughout the study period. However, two subscores of the BPRS, "motor retardation" (P = 0.008) and "tension" or "nervousness" (P = 0.002), increased starting the 1st month of treatment. Moreover, age (r = 0.426, P = 0.038) and the baseline PS (P = 0.027) were the main risk factors of such manifestations. Conclusion: This study suggests that ICI could be responsible for motor retardation and increased tension starting the 1st month of treatment, with higher ECOG score and older age being the main risk factors.

Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels.

Background: Human pentameric ligand-gated ion channels (pLGICs) comprise nicotinic acetylcholine receptors (nAChRs), 5-hydroxytryptamine type 3 receptors (5-HT3Rs), zinc-activated channels (ZAC), γ-aminobutyric acid type A receptors (GABAARs) and glycine receptors (GlyRs). They are recognized therapeutic targets of some of the most prescribed drugs like general anesthetics, anxiolytics, smoking cessation aids, antiemetics and many more. Currently, approximately 100 experimental structures of pLGICs with ligands bound exist in the protein data bank (PDB). These atomic-level 3D structures enable the generation of a comprehensive binding site inventory for the superfamily and the in silico prediction of binding site properties. Methods: A panel of high throughput in silico methods including pharmacophore screening, conformation analysis and descriptor calculation was applied to a selection of allosteric binding sites for which in vitro screens are lacking. Variant abundance near binding site forming regions and computational docking complement the approach. Results: The structural data reflects known and novel binding sites, some of which may be unique to individual receptors, while others are broadly conserved. The membrane spanning domain, comprising four highly conserved segments, contains ligand interaction sites for which in vitro assays suitable for high throughput screenings are critically lacking. This is also the case for structurally more variable novel sites in the extracellular domain. Our computational results suggest that the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) can utilize multiple pockets which are likely to exist on most superfamily members. Conclusion: With this study, we explore the potential for polypharmacology among pLGICs. Our data suggest that ligands can display two forms of promiscuity to an extent greater than what has been realized: 1) Ligands can interact with homologous sites in many members of the superfamily, which bears toxicological relevance. 2) Multiple pockets in distinct localizations of individual receptor subtypes share common ligands, which counteracts efforts to develop selective agents. Moreover, conformational states need to be considered for in silico drug screening, as certain binding sites display considerable flexibility. In total, this work contributes to a better understanding of polypharmacology across pLGICs and provides a basis for improved structure guided in silico drug development and drug derisking.

Association between oseltamivir use and neuropsychiatric adverse events in influenza patients: a nationwide population-based cohort study.

Background: A potential risk of neuropsychiatric adverse events (NPAEs) of oseltamivir has remained controversial by retrospective cohort studies. This nationwide population-based cohort study aimed to assess the risk of NPAEs in influenza patients undergoing oseltamivir treatment (users) compared with a propensity score-matched cohort of patients not receiving oseltamivir (non-users). Research design and methods: Using the Korean National Health Service-Sample Cohort Database, patients diagnosed with incident influenza during 2003-2013 were divided into two cohorts: oseltamivir users and non-users. We calculated adjusted hazard ratios (aHRs) for the 5-day treatment course with oseltamivir using Cox regression analysis. Results: The incidence rate of NPAEs during 5-day oseltamivir treatment was 0.0029 and 0.0023 in oseltamivir users and non-users, respectively. The risk of NPAEs was different according to age, with an increased risk in patients aged 10-19 years (aHR 2.69, 95% CI 1.05-6.93) and a decreased risk in patients aged 0-9 years (aHR 0.46, 95% CI 0.24-0.88). The non-significant positive associations were observed in patients aged 20-64 years and those aged greater than 65 years. Conclusions: Although the reason for the inverse association in children aged 0-9 years is unknown, oseltamivir could increase the risk of NPAEs for children or adolescents aged greater than 10 years.

A Boxed Warning for Montelukast: The FDA Perspective.

The U.S. Food and Drug Administration (FDA) became aware of postmarketing reports of neuropsychiatric adverse events with Singulair (montelukast) use in 2007. Over the years, the FDA has conducted reviews of the clinical trial safety data, focused analyses of postmarketing reports, and reviews of the published literature. These activities have resulted in successive labeling updates and public communications. However, there has been continued concern among stakeholders about the risk of neuropsychiatric events and the lack of awareness among prescribers and patients/caregivers. On the basis of these concerns, the FDA embarked on another comprehensive review and also conducted a new observational study using claims data in the Sentinel Distributed Database. In September 2019, the FDA held a public Advisory Committee meeting to discuss its review and solicit recommendations from the panel regarding labeling and communication strategies. After careful consideration of the available data and feedback received during the FDA Advisory Committee meeting, the FDA required a boxed warning and a revision specifically for the allergic rhinitis indication to reserve use of montelukast to patients who have an inadequate response or intolerance to alternative therapies. Based on benefit-risk considerations, the asthma indication was not changed. To provide insight into the process and rationale for the required labeling changes, we provide an overview of the decision-making framework we used.

Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network.

Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms.

Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice. / Efectos adversos neuropsiquiátricos de dolutegravir en la práctica clínica real.

INTRODUCTION: Integrase inhibitors and especially dolutegravir (DTG) are placed as a first-line antiretroviral treatment for their efficacy and safety. Although in the pivotal trials the rate of adverse effects (AEs) was low (2-3%), in real-life studies it appears to be higher, especially neuropsychiatric AEs. The objective is to determine the percentage of AEs and discontinuation of DTG in our site and the relationship with the psychiatric background. METHODS: Retrospective descriptive study of patients starting DTG from 2015 to 2017. Discontinuation of treatment, AEs and previous psychiatric pathology were recorded. Follow-up is carried out since the beginning of the treatment, and hospitalizations and emergency room and primary care visits were registered. The study was authorized by the Ethics Committee for Clinical Research of Aragon. RESULTS: Two hundred and eighty-three patients were included, between 11 and 87 years old, 70% male. 21% were naive. 24% of the patients discontinued treatment with DTG, 10% due to AEs. Neuropsychiatric AEs were detected in 5%. This group of patients had a more frequent previous psychiatric history (62 vs. 41%; P=.002) than the ongoing treatment group and they needed more visits to primary care (18.8 vs. 8.4%; P=.016) and emergency room (8,7 vs. 3.3%; P=.061). CONCLUSION: Patients who discontinued treatment with DTG had more psychiatric history. Although more studies are required, it is necessary to assess this background before starting treatment with integrase inhibitors. Symptoms such as anxiety, insomnia or depression can be DTG AEs more frequently than expected. Being identified by primary care and emergency physicians could avoid the unnecessary prescription of other medications.

Delirium During Recovery in Patients With Severe COVID-19: Two Case Reports.

Novel coronavirus disease (COVID-19), caused by SARS-CoV-2, has rapidly evolved into a worldwide pandemic, leaving patients with life-threatening respiratory, cardiovascular, and cerebral complications. Here we reported on two patients with severe COVID-19 who experienced delirium in the early stage of recovery and mental illness including fatigue, anxiety, and post-traumatic stress disorder in the post-illness stage of COVID-19. Two patients were admitted to hospital due to clinical symptoms and features of CT and were confirmed for COVID-19 by positive results of a throat swab for SARS-CoV-2. Due to severe respiratory symptoms and a low oxygenation index, they were transferred to the ICU and received invasive mechanical ventilation and sedation. Hyperactive delirium was observed after being transferred out of the ICU. Different treatment measures were taken in time. Delirium did not occur again in hospital, but they showed mental suffering, including fatigue, anxiety, and post-traumatic stress disorder (PTSD), during the 5 month follow-up after discharge.

HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum.

Efavirenz (EFV) is an effective antiretroviral drug with a favorable pharmacokinetic profile and widely used in combination regimens to treat HIV infection. However, there are major concerns about the safety of this drug. Patients treated with EFV often experience neuropsychiatric adverse effects, which frequently lead to switching to alternative EFV-free regimens. The mechanisms involved in the central action of EFV are intrinsically unclear. Thus, this study aimed to investigate the effects of acute and subchronic (2 weeks) EFV administration in a series of behavioral tests for anxiety-like and depression-like behavior in healthy rats. We also evaluated the effect of EFV treatment in striatal concentrations of monoamine neurotransmitters (serotonin, dopamine and noradrenaline) and their metabolites and the amino acid neurotransmitters glutamate and GABA. Our results showed that acute treatment with EFV induced an anxiogenic-like effect, while sub-chronic treatment induced both anxiogenic-like and depressive-like behavior which was dose related.. Additionally, EFV treatment caused marked alterations in the striatal concentrations of monoamines and their metabolites (and turnover rates) and the amino acid neurotransmitters glutamate and GABA. These changes were influenced by treatment duration and dose. These findings add more evidence about the neuropsychiatric adverse effects of EFV and propose potential new mechanisms for the toxic action of this drug in the central nervous system.

Trends in utilization of smoking cessation agents before and after the passage of FDA boxed warning in the United States.

BACKGROUND: In 2009, the FDA required a black box warning (BBW) on bupropion and varenicline, the two commonly prescribed smoking cessation agents due to reports of adverse neuropsychiatric events. We investigated if there was a decline in use of bupropion and varenicline after the BBW by comparing the percent using these medications before and after BBW. METHODS: We conducted a retrospective observational study using data from the Medical Expenditure Panel Survey from 2007 to 2014. The study sample consisted of adult smokers, who were advised by their physicians to quit smoking. We divided the time period into "pre-warning", "post-warning: immediate", and "post-warning: late." Unadjusted analysis using chi-square tests and adjusted analyses using logistic regressions were conducted to evaluate the change in bupropion and varenicline use before and after the BBW. Secondary analyses using piecewise regression were also conducted. RESULTS: On an average, 49.04% of smokers were advised by their physicians to quit smoking. We observed a statistically significant decline in varenicline use from 22.1% in year 2007 to 9.23% in 2014 (p value<0.001). In the logistic (Adjusted Odds Ratio=0.36, 95% CI=0.22-0.58) and piecewise regressions (Odds Ratio=0.64, 95% CI=0.41-0.99) smokers who were advised to quit smoking by their physicians were less likely to use varenicline in the immediate post-BBW period as compared to pre-BBW period. While the use of varenicline continued to be significantly low in the late post-BBW period (AOR=0.45, 95% CI=0.31-0.64) as compared to the pre-BBW period, the trend in use as seen in piecewise regression remained stable (OR=0.90, 95% CI=0.75-1.06). We did not observe significant differences in bupropion use between the pre- and post-BBW periods. CONCLUSION: The passage of the FDA boxed warning was associated with a significant decline in the use of varenicline, but not in the use of bupropion.