Risk Of Neuropsychiatric Adverse Events Research Articles

The Use of Neuraminidase Inhibitors in Teenagers May Not Increase the Risk of Neuropsychiatric Adverse Events: A Nationwide Population-based Retrospective Study

Abstract Background: Pandemic influenza virus is a public health issue, and the neuraminidase inhibitors (NIs) “Oseltamivir” and “Zanamivir” are effective treatments. While teenagers use NIs, there are concerns regarding neuropsychiatric adverse events (NPAEs). Aim: We aimed to use the Taiwan National Health Insurance Research Database to identify the correlation between NPAEs and NIs use in teenagers aged 13–19 years. Methods: The final population between 2000 and 2015 included in this study was 3698 individuals, with 2287 individuals having received “Oseltamivir” and “Zanamivir” (study cohort group) and 9148 individuals not receiving “Oseltamivir” and “Zanamivir” (comparison cohort group). We initially used a multivariate Cox regression analysis during the tracking period to determine the cumulative incidence of NPAEs. Results: Our findings revealed no significant increase in the likelihood of developing NPAEs in the study group. The Kaplan–Meier survival curve demonstrated that individuals who received “Oseltamivir” and “Zanamivir” were not associated with statistically significantly increased NPAEs compared with controls (log-rank test, P = 0.724). Conclusion: No more risk in comparison of the normal population in our study, and the safety of “Oseltamivir” and “Zanamivir” is established treatments for influenza.

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

Montelukast, a selective leukotriene receptor antagonist, is a commonly prescribed allergy medication but its potential association with neuropsychiatric adverse events is concerning. 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. 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 β2-agonists with montelukast or pranlukast and those not using leukotriene receptor antagonists (control group). 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. 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.

More on varenicline

Murray et al have written a timely, thoughtful, and useful article (“Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events,” Current Psychiatry, July 2022, p. 41-45) about the role of the nicotinic acetylcholine receptor partial agonist varenicline for helping patients stop smoking, which is still the main preventable cause of morbidity and premature death.

Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events

Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events

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

PurposeVarenicline 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.MethodsWe 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.ResultsWithin 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.ConclusionsVarenicline 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.

Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors.

Background and AimsAnalysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors. DesignEAGLES was a randomised, double‐blind, triple‐dummy, controlled trial.SettingGlobal (16 countries across five continents), between November 2011 and January 2015.ParticipantsParticipants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders.InterventionsVarenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos.MeasurementsThe outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub‐samples using Bayes factors and corresponding robustness regions.FindingsFor all but two comparisons, Bayes factors were <1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02–0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factor = 0.52) and bupropion (Bayes factor = 0.71). Here, the robustness regions ruled out a ≥7% and ≥8% risk increase with varenicline and bupropion, respectively.ConclusionsSecondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence.

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

ABSTRACT 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.

Synaptic vesicle protein 2A tumoral expression predicts levetiracetam adverse events.

The efficacy of levetiracetam (LEV) in controlling seizures in patients with brain tumor-related epilepsy (BTRE) depends on tumoral expression of synaptic vesicle protein 2A (SV2A). Although LEV is generally well tolerated, neuropsychiatric adverse events (NPAEs) might occur, limiting compliance and seizure control. We aimed to assess the influence of tumoral SV2A expression on the occurrence of LEV-related NPAEs in patients with glioma. Specimens from patients enrolled in the multicenter COMPO study, with glioma and BTRE treated with LEV, undergoing neurosurgery were retrieved. Immunohistochemistry-based expression of SV2A in tumoral and peritumoral tissue was scored in a four-point scale from absent (score = 0) to strong (score = 3). Low immunoreactivity (IR) corresponded to scores < 2. Staining ratios (tumoral SV2A IR/peritumoral SV2A IR) were grouped into low (≤ 0.5) and high (> 0.5). NPAEs were assessed longitudinally with the Neuropsychiatry Inventory 12 test (NPI-12). Overall, 18 patients were eligible for analysis. All received LEV monotherapy, with 67% developing NPAEs. Patients with NPAEs had significantly lower median SV2A intensity score compared to patients without NPAEs (score 1 vs 0, p = 0.025). Low staining ratio (≤ 0.5) associated with higher NPAE occurrence compared to SR > 0.5 (85.7% vs 0%, p < 0.01). A SR ≤ 0.5 predicted a consistent increase in risk of NPAEs (OR 45.0; 95% CI 1.8-1128; p = 0.02). Our results suggest that SV2A expression in tumoral and peritumoral tissue correlates with the occurrence of LEV-related NPAEs. Thus, considering that SV2A expression also influences LEV effectiveness, SV2A staining might help in tailoring treatment to patients.

Research roundup: June 2016

In brief The UK probably underestimates the prevalence of medical errors, which might now be the third leading cause of death in the USA Prescriptions for attention deficit hyperactivity disorder drugs increased by almost 800% between 2000 and 2015 Varenicline and bupropion do not seem to increase the risk of neuropsychiatric adverse events compared to nicotine patches or placebo; varenicline is more effective at helping patients quit than placebo, nicotine patches and bupropion Some studies associate sulfonylureas with cardiovascular events, but a new meta-analysis is reassuring

ACP Journal Club. Review: Varenicline does not differ from placebo for adverse neuropsychiatric events.

Source Citation Thomas KH, Martin RM, Knipe DW, Higgins JP, Gunnell D. Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis. BMJ. 2015;350:h1109....

Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis

Objective To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.Design Systematic review and meta-analysis comparing study effects using two...

Prevention of Malaria in Travelers: Bite Avoidance and Chemoprophylactic Measures

Prevention and management of malaria in travelers is dependent on awareness of risk, bite avoidance, chemoprophylaxis and early diagnosis. Prophylactic recommendations should be made based on details of travel itinerary and medical history. Travelers should be advised to use appropriate measures for avoiding mosquito bites, including insect repellent, insecticide-treated bed nets, and appropriate behavior modification. In areas of chloroquine sensitivity, chloroquine is usually the preferred chemoprophylactic agent. In areas of chloroquine resistance, atovaquone-proguanil, mefloquine or doxycycline may be used. Atovaquone-proguanil is highly effective in preventing Plasmodium falciparum malaria, is well-tolerated, and is active against both liver and blood stages, which decreases the length of time required for post-travel prophylaxis. Alternative agents include doxycycline and mefloquine. Doxycycline is also well-tolerated and is a less expensive alternative to atovaquone-proguanil, but must be taken for 4 weeks after leaving the malaria-endemic region. Mefloquine can also be considered, particularly in those who have previously demonstrated tolerance. Mefloquine is associated with increased risk of neuropsychiatric adverse events and is often started ∼ 3 weeks prior to departure to help determine tolerability. In areas of high P. vivax or P. ovale presence, the use of terminal primaquine prophylaxis can be considered to prevent relapses post-travel. As with all drug regimens, the risks and benefits of use must be weighed in each individual traveler. None of these agents are 100 % effective, and travelers should be informed to seek urgent medical attention if fever develops during or after travel, regardless of the agent used.

Post-Marketing Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir: An Updated Review

A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.

Changes in Patient-reported Neuropsychiatric Outcomes during the SENSE Trial: First-line Treatment with Two Nucleoside Analogues plus Etravirine or Efavirenz

BackgroundEfavirenz treatment has been associated with an increased risk of neuropsychiatric adverse events, some of which may last for only the first few weeks of treatment. MethodsIn this double-blind placebo-controlled trial, 157 treatment-naïve patients with human immunodeficiency virus (HIV) RNA >5000 copies/mL, were randomized 1:1 to either etravirine 400 mg once daily (n=79), or efavirenz 600 mg once daily (n=78), plus 2 nucleoside analogues. At screening, baseline, and during the trial, subjects completed the HIV-Patient Symptoms Profile (HPSP) questionnaire on the impact of adverse events associated with their treatment. There were 14 symptom domains, with 5 classified as neuropsychiatric and 9 other domains. The mean scores of each domain were compared between the arms at the Week 2 and Week 48 visits. ResultsThe treatment arms were comparable at baseline (overall median CD4 count 302 cells/uL, median HIV RNA 4.8 log10 copies/mL). In the analysis of the HPSP questionnaire, the mean score for the domains of dizziness and sleep of the etravirine arm was significantly better than the efavirenz arm at Week 2. There were no significant differences between the arms at Week 48, for any of the domains. At the baseline visit, patients with a medical history of neuropsychiatric adverse events had significantly worse scores in the neuropsychiatric domains (P < 0.01). During the trial, patients with at least one neuropsychiatric adverse event had significantly worse scores in the neuropsychiatric domains of the HPSP questionnaire (P < 0.01). ConclusionsIn the SENSE trial, dizziness and sleep disorders showed significantly worse HPSP scores in the efavirenz arm, compared with the etravirine arm at the Week 2 visit. However, at Week 48 there were no significant differences between the treatment arms in any domain of the patient HPSP. This suggests that the impact of efavirenz on quality of life may be short term for the majority of patients.

Tolerability and Efficacy of a Pediatric Granule Formulation of Artesunate-Mefloquine in Young Children from Cameroon with Uncomplicated Falciparum Malaria

A fixed-dose pediatric formulation of artesunate and mefloquine (Artequin Pediatric) has been developed. In this open, non-comparative study in Cameroonian children with uncomplicated falciparum malaria, the safety and efficacy of this formulation was tested, with a particular emphasis on the risk of neuropsychiatric adverse events (AEs). In total, 220 subjects, weighing between 10 and 20 kg, were enrolled; 213 qualified for analysis. Artesunate-mefloquine was given once daily for 3 days. Overall, 13.1% of patients reported mild to moderate neuropsychiatric AEs (elicited through a structured questionnaire or reported spontaneously) out of which 3.8% (mainly insomnia) were considered drug-related. Other drug-related AEs were infrequent (< 3%). Polymerase chain reaction-corrected cure rate (adequate clinical and parasitological response) determined by survival analysis at 28 and 63 days was 96.6%. New infections were observed in 11.2% of evaluable patients at 63 days. The new formulation was well tolerated and efficacious in the population investigated.

Low body mass index is associated with an increased risk of neuropsychiatric adverse events and concentration impairment in women on mefloquine.

We performed a prospective cohort study to gain more insight into risk factors for neuropsychiatric effects of mefloquine among tourists travelling to tropical areas. We enrolled all patients who consulted the Travel Clinic of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine prophylaxis during the period between 1 May 1999 and 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after starting weekly intake of 250 mg mefloquine. We compared the intraindividual change in scores between baseline and follow-up visit on the Dutch shortened Profile of Mood States, and on the Continuous Performance Test (CPT) which measures sustained attention. The final cohort consisted of 151 subjects with a mean age of 38 years. In this population, a significant impairment of mood state was observed in those with a body mass index (BMI) < or = 20 kg m(-2). Stratification for gender showed that the total mood disturbance in females in the lowest BMI category significantly increased by 8.42 points [95% confidence interval (CI) 3.33, 13.50], whereas BMI did not affect the risk in males. Stratification for history of use of mefloquine showed that the risks were highest in first-time users. Analyses of the CPT showed that reaction time in women with a BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95% CI 7.80, 37.20), whereas reaction time in men showed a slight and nonsignificant decrease. Risk factors for mefloquine-associated neuropsychiatric adverse events and concentration impairment are female gender, low BMI, and first-time use. The frequency of neuropsychiatric effects is highest in women with a BMI < or = 20 kg m(-2).

Neuropsychiatric events during prophylactic use of mefloquine before travelling.

It has been suggested that neuropsychiatric events during use of mefloquine are more common in females than in males and are partly explained by the psychological stress of travelling. Therefore, we investigated neuropsychiatric events in females and males on mefloquine in the 3-week prophylactic period that precedes travelling. Furthermore, we investigated whether first-time users had a higher risk of neuropsychiatric adverse events than subjects with a history of mefloquine use. We enrolled all patients who visited a Travel Clinic for mefloquine prophylaxis during the period 1 May 1999 to 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after the start of mefloquine but before travelling. We asked patients to register any adverse event in a diary and measured the intra-individual change in scores on the Dutch Shortened Profile Of Mood States (POMS) at baseline and at the end of follow-up. The final cohort consisted of 179 subjects with a mean age of 3 years. Females reported adverse events more frequently than males ( P=0.005). Overall, we observed a small but significant increase in the score on the domain fatigue [0.74 points, 95% confidence interval (CI) 0.18, 1.30]. The effect was exclusively present in females and not in males. First-time users of mefloquine increased 2.81 points (95% CI 0.70, 4.92) on the total score of the POMS, and among those, women showed the largest increase of 4.58 points (95% CI 0.74, 8.43). The use of mefloquine was associated with neuropsychiatric adverse effects. Females encountered neuropsychiatric effects more frequently than males, which could be confirmed by validated psychological tests. Neuropsychiatric effects were more common in first-time users than in individuals who had used mefloquine before.