Neuropsychiatric Adverse Events Research Articles

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.

Influenza-associated Neurologic Complications in Hospitalized Pediatric Patients: A Multicenter Retrospective Study in Republic of Korea.

The rates of influenza-associated neurologic complications are variable among studies, and a difference has been observed between the Western and Asian countries. The study aims to evaluate the frequency and characteristics of influenza-associated neurologic complications. We performed a retrospective review of hospitalized cases of influenza infection from October 2010 to April 2017 from 3 referral hospitals. A total of 1988 influenza cases were identified. Influenza-associated neurologic complications were 161 cases (8.1%); influenza virus A was detected in 113 (70.2%) cases, B in 47 (29.2%) cases and both A and B in 1 case (0.6%). Twenty-four patients (15%) had underlying neurologic diseases. The most common diagnosis was a simple febrile convulsion (44%), followed by complex febrile convulsion (29%), fever-provoked seizure under pre-existing neurologic disease or afebrile seizure (14%), encephalopathy/encephalitis (8%) and meningitis (5%). Most of the patients fully recovered (96%). Three patients (1.9%) died of myocarditis (n = 1), encephalopathy (n = 1), and simultaneous encephalitis and myocarditis (n = 1). Pre-existing neurologic disease, age groups of 6 months to 6 years and 6-12 years were a risk factor of influenza-associated neurologic complications with an adjusted odds ratio of 5.41 (95% confidence interval [CI] 3.23-9.06, P < 0.001), 12.99 (95% CI 1.77-95.19, P = 0.01) and 8.54 (95% CI 1.14-64.79, P = 0.04), respectively. There was no association between neuropsychiatric adverse events and oseltamivir prescription (P = 0.17). Influenza-associated neurologic complications are not uncommon, and most patients fully recovered. The frequency of influenza-associated neurologic complications in Korean children was not significantly different from that of children in Western countries.

An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors.

Neuropsychiatric adverse effects (NPAE) associated with integrase strand transfer inhibitors (INSTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a growing concern, with higher rates in the real-world compared to phase III trials. This paper reviews the incidence, risk factors, and management of NPAE with second-generation INSTIs, INSTI/rilpivirine dual therapy, and doravirine. Recent cohort data confirm up to 8% NPAE-associated discontinuations for dolutegravir; NPAE with dolutegravir/rilpivirine therapy are higher than with dolutegravir alone, whereas bictegravir appears similar to dolutegravir. In contrast, NPAE with cabotegravir alone or with rilpivirine appears to be low. Doravirine has NPAE rates similar to rilpivirine and lower than efavirenz. Risk factors for NPAE include female gender, concurrent abacavir use, Sub-Saharan African descent, and age, whereas underlying psychiatric conditions do not appear to increase risk. Strategies to manage NPAE include changing administration time, therapeutic drug monitoring, or regimen modification including within-class INSTI changes. People experiencing NPAE with dolutegravir may tolerate bictegravir. Overall, mild to moderate NPAE are associated with INSTIs and newer NNRTIs. Rarely, more severe symptoms may occur and lead to treatment discontinuation. Clinicians should be aware of NPAE to identify and manage drug-related adverse effects.

Clarithromycin-induced Seizures and Status Epilepticus.

ABSTRACTClarithromycin is a commonly used antibiotic. Neuropsychiatric adverse effects are recognized, but the occurrence of seizures and status epilepticus (SE) has been rarely reported. We report the case of an elderly patient who developed generalized tonic-clonic seizures (GTCS) followed by nonconvulsive status epilepticus (NCSE), 2 days after starting clarithromycin. Other causes of seizures were excluded by magnetic resonance imaging (MRI) of the brain, CSF analysis, and routine laboratory studies, thus establishing the causal role of clarithromycin. Clarithromycin was stopped and parenteral antiepileptic drugs started, which controlled the status. In the elderly, symptoms like delirium, drowsiness, confusion, or seizures can occur due to an underlying systemic disease, brain pathology, or adverse effects of medications, all of which must be correctly differentiated. This case illustrates the occurrence of seizures and SE due to clarithromycin. Awareness about this possibility will help physicians recognize and treat such situations promptly.How to cite this article: Seetharam R, Iyer RB, Nooraine J, Ramachandran J. Clarithromycin-induced Seizures and Status Epilepticus. Indian J Crit Care Med 2021;25(8):945–947.

Safety of Memantine in Combination with Potentially Interactive Drugs in the Real World: A Pharmacovigilance Study Using the Japanese Adverse Drug Event Report (JADER) Database.

Background:Memantine, an NMDA receptor antagonist, is used for the treatment of Alzheimer’s disease. There is a caution to refrain from administrating memantine in combination with some specific drugs such as amantadine or dextromethorphan due to potential interactions that might augment the adverse effects of memantine.Objective:This notification has not been validated in real-world data, which we aim to address using a large self-reporting database from Japan.Methods:We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database reported between April 2004 and March 2019 for detecting the neuropsychiatric adverse event (AE) signals associated with memantine and other potentially interactive drugs including amantadine, dextromethorphan, cimetidine, ranitidine, procainamide, quinidine, acetazolamide, citrate, and bicarbonate. Drug-drug interactions between memantine and these drugs were assessed using multiplicative and additive models.Results:There was no statistically robust evidence to support multiplicative or additive interactions between memantine and the aforementioned drugs to increase the reporting of any included neuropsychiatric AEs or AE categories.Conclusion:The real-world JADER data did not raise the concern about the interactive increase in the neuropsychiatric AEs in patients with dementia taking memantine in combination with amantadine or dextromethorphan, suggesting there may be no urgent need to prohibit the co-administration of these drugs presently.

Prolonged efavirenz exposure reduces peripheral oxytocin and vasopressin comparable to known drugs of addiction in male Sprague Dawley rats.

IntroductionSeveral drugs of abuse (DOA) are capable of modulating neurohypophysial hormones, such as oxytocin (OT) and vasopressin (VP), potentially resulting in the development of psychological abnormalities, such as cognitive dysfunction, psychoses, and affective disorders. Efavirenz (EFV), widely used in Africa and globally to treat HIV, induces diverse neuropsychiatric side effects while its abuse has become a global concern. The actions of EFV may involve neurohypophysial system (NS) disruption like that of known DOA. This study investigated whether sub-chronic EFV exposure, at a previously-determined rewarding dose, alters peripheral OT and VP levels versus that of a control, ∆9-tetrahydrocannabinol (∆9-THC), methamphetamine (MA) and cocaine.Materials and methodsTo simulate the conditions under which reward-driven behavior had previously been established for EFV, male Sprague Dawley rats (n = 16/exposure) received intraperitoneal vehicle (control) or drug administration across an alternating sixteen-day dosing protocol. Control administration (saline/olive oil; 0.2 ml) occurred on odd-numbered and drug administration (EFV: 5 mg/kg, ∆9-THC: 0.75 mg/kg, MA: 1 mg/kg, or cocaine: 20 mg/kg) on even-numbered days followed by euthanasia, trunk blood collection and plasma extraction for neuropeptide assay. Effect of drug exposure on peripheral OT and VP levels was assessed versus controls and quantified using specific ELISA kits. Statistical significance was determined by Kruskal-Wallis ANOVA, with p < 0.05. Ethics approval: NWU-00291-17-A5.ResultsDelta-9-THC reduced OT and VP plasma levels (p < 0.0001, p = 0.0141; respectively), cocaine reduced plasma OT (p = 0.0023), while MA reduced plasma VP levels (p = 0.0001), all versus control. EFV reduced OT and VP plasma levels (p < 0.0001; OT and VP) versus control, and similar to ∆9-THC.ConclusionEFV markedly affects the NS in significantly reducing both plasma OT and VP equivalent to DOA. Importantly, EFV has distinct effects on peripheral OT and VP levels when assessed within the context of drug dependence. The data highlights a possible new mechanism underlying previously documented EFV-induced effects in rats, and whereby EFV may induce neuropsychiatric adverse effects clinically; also providing a deeper understanding of the suggested abuse-potential of EFV.

Efficacy and Tolerability of Quinacrine Monotherapy and Albendazole Plus Chloroquine Combination Therapy in Nitroimidazole-Refractory Giardiasis: A TropNet Study.

Giardiasis failing nitroimidazole first-line treatment is an emerging problem in returning European travelers. We present data on the efficacy and tolerability of 2 second-line treatment regimens. This prospective, open-label, multicenter study assessed the efficacy and tolerability of quinacrine monotherapy (100 mg 3 times per day for 5 days) and albendazole plus chloroquine combination therapy (400 mg twice daily plus 155 mg twice daily for 5 days) in nitroimidazole-refractory giardiasis. The defined end points were the clinical outcome, assessed at week 5 after treatment and the parasitological outcome, assessed using microscopy of 2 stool samples, ≥2 to ≤5 weeks after treatment. A total of 106 patients were included in the study. Quinacrine achieved clinical and parasitological cure in 81% (59/73) and 100% (56/56), respectively. Albendazole plus chloroquine achieved clinical and parasitological cure in 36% (12/33) and 48% (12/25), respectively. All patients (9/9) who clinically and parasitologically failed albendazole plus chloroquine treatment and opted for retreatment with quinacrine achieved clinical cure. Mild to moderate treatment-related adverse events were reported by 45% and 30% of patients treated with quinacrine and albendazole plus chloroquine, respectively. One patient treated with quinacrine developed severe neuropsychiatric side effects. The majority of nitroimidazole-refractory Giardia infections (57%) were acquired in India. Quinacrine was a highly effective treatment in nitroimidazole-refractory giardiasis, but patients should be cautioned on the low risk of severe neuropsychiatric adverse event. Albendazole plus chloroquine had a low cure rate in nitroimidazole-refractory giardiasis. Nitroimidazole-refractory giardiasis was primarily seen in travelers returning from India.

208-LB: Peripheral CB1 Inverse Agonism Improves Metabolism in DIO Mice Independent of Hepatic FGF21

Obesity is associated with an overactive endocannabinoid system, and selective blockade of CB1R in peripheral tissues, including the liver, reverses HFD-induced metabolic abnormalities by restoring normal lipid and glucose homeostasis and avoid unwanted adverse neuropsychiatric effects. The CB1R inverse agonist JD5037 has been shown equal effective with its brain-penetrant compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance. Fibroblast growth factor-21 (FGF21) has emerged as a major endocrine regulator derived from the liver that reduces adiposity and hepatic steatosis and improves glucose tolerance and insulin sensitivity, with changes similar to those induced by CB1R blockade. Here we investigated whether FGF21 mediate the metabolic effects of CB1R blockade by JD5037 in DIO mice. In C57BL/6J wild-type mice, HFD caused a robust increase in hepatic Fgf21 mRNA and serum FGF21 levels, which were reversed by chronic peripheral CB1R antagonist JD5037 treatment to levels observed in STD or vehicle-treated hepatocyte-specific CB1R-/- (hCB1-/-) mice, indicating activation of CB1R in the liver is largely involved in HFD-induced “FGF21-resistant” state. In contrast, the expression of the FGF21 receptor Fgfr1 and co-receptor β-klotho (Klb) were dramatically reduced by HFD in both epididymal fat and brain tissue in wild-type mice, and these effects were reversed by JD5037 treatment. To address whether FGF21 mediated the metabolic effects of CB1R blockade, we repeated JD5037 treatment in liver-specific FGF21-/- (hFGF21-/-) mice. Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in hFGF21-/- mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB1R blockade by inverse agonist in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21. Disclosure J. Liu: None. Funding National Institutes of Health

Comparative safety review of recommended, first-line single-tablet regimens in patients with HIV

ABSTRACT Introduction Different single-tablet regimens (STRs), containing one or two nucleoside reverse transcriptase inhibitors (NRTIs) plus an anchor drug, are available for the use in naïve, HIV-infected patients. Despite some restrictions in the use of particular regimens in certain situations (e.g., HBV coinfection), International guidelines do not provide indications to prefer any regimen over others concerning the tolerability profile. We aimed to assess advantages and disadvantages of the most prescribed STRs. Areas covered An extensive review of articles published in English language was conducted on PubMed, looking for evidence about STRs in naïve, HIV-infected population. Safety outcomes of registrational trials were assessed, giving priority to studies directly comparing STRs included in our research (abacavir/lamivudine/dolutegravir, tenofovir alafenamide/emtricitabine/bictegravir, lamivudine/dolutegravir, tenofovir alafenamide/emtricitabine/darunavir/cobicistat, tenovofir disoproxil fumarate/lamivudine/doravirine). Data from cohort studies and meta-analyses were also assessed, extrapolating the main evidence about the combinations of interest. Expert opinion Integrase inhibitors (InsTIs)-based regimens have few interruptions for adverse events and few drug-related adverse events, with tenofovir alafenamide/emtricitabine/dolutegravir and lamivudine/dolutegravir being the most tolerable ones. However, neuropsychiatric adverse events and metabolic issues could prompt the alternative use of darunavir or doravirine-based combinations, even if a superior safety profile of these combinations over InSTIs has yet to be demonstrated.

Neuropsychiatric safety of varenicline in the general and COPD population with and without psychiatric disorders: a retrospective cohort study in a real-world setting

ObjectivesTo evaluate the real-world association between varenicline and neuropsychiatric adverse events (NPAEs) in general and chronic obstructive pulmonary disease (COPD) population with and without psychiatric disorders compared with nicotine replacement...

New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.

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.

Psychiatric Comorbidity and Multimorbidity in the EAGLES Trial: Descriptive Correlates and Associations With Neuropsychiatric Adverse Events, Treatment Adherence, and Smoking Cessation.

Psychiatric and substance use disorders represent barriers to smoking cessation. We sought to identify correlates of psychiatric comorbidity (CM; 2 diagnoses) and multimorbidity (MM; 3+ diagnoses) among smokers attempting to quit and to evaluate whether these conditions predicted neuropsychiatric adverse events (NPSAEs), treatment adherence, or cessation efficacy (CE). Data were collected from November 2011 to January 2015 across sixteen countries and reflect the psychiatric cohort of the EAGLES trial. Participants were randomly assigned to receive varenicline, bupropion, nicotine replacement therapy, or placebo for 12 weeks and were followed for an additional 12 weeks posttreatment. NPSAE outcomes reflected 16 moderate-to-severe neuropsychiatric symptom categories, and CE outcomes included continuous abstinence at weeks 9-12 and 9-24. Of the 4103 participants included, 36.2% were diagnosed with multiple psychiatric conditions (20.9% CM, 15.3% MM). Psychiatric CM and MM were associated with several baseline factors, including male gender, nonwhite race or ethnicity, more previous quit attempts, and more severe mental health symptoms. The incidence of moderate-to-severe NPSAEs was significantly higher (p < .01) in participants with MM (11.9%) than those with CM (5.1%) or primary diagnosis only (4.6%). There were no significant (ps > .05) main effects or interactions with treatment condition for diagnostic grouping on treatment adherence or CE outcomes. While having multiple psychiatric diagnoses increased risk of developing moderate-to-severe NPSAEs during a quit attempt, neither CM nor MM were associated with treatment adherence or odds of quitting. These findings reassure providers to advise smokers with multiple stable psychiatric conditions to consider using Food and Drug Administration (FDA)-approved medications when trying to quit. Psychiatric MM may be associated with development of NPSAEs when smokers make a medication-assisted quit attempt, but it does not appear to be differentially associated with medication compliance or efficacy. Prescribing healthcare professionals are encouraged to not only promote use of FDA-approved pharmacotherapies by smokers with complex psychiatric presentations, but also to closely monitor such smokers for neuropsychiatric side effects that may be related to their mental health conditions. NCT01456936.

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.

Cost-Effectiveness Analysis of Smoking Cessation Interventions in the United Kingdom Accounting for Major Neuropsychiatric Adverse Events

ObjectivesSmoking is a leading cause of death worldwide. Cessation aids include varenicline, bupropion, nicotine replacement therapy (NRT), and e-cigarettes at various doses (low, standard and high) and used alone or in combination with each other. Previous cost-effectiveness analyses have not fully accounted for adverse effects nor compared all cessation aids. The objective was to determine the relative cost-effectiveness of cessation aids in the United Kingdom. MethodsAn established Markov cohort model was adapted to incorporate health outcomes and costs due to depression and self-harm associated with cessation aids, alongside other health events. Relative efficacy in terms of abstinence and major adverse neuropsychiatric events was informed by a systematic review and network meta-analysis. Base case results are reported for UK-licensed interventions only. Two sensitivity analyses are reported, one including unlicensed interventions and another comparing all cessation aids but removing the impact of depression and self-harm. The sensitivity of conclusions to model inputs was assessed by calculating the expected value of partial perfect information. ResultsWhen limited to UK-licensed interventions, varenicline standard-dose and NRT standard-dose were most cost-effective. Including unlicensed interventions, e-cigarette low-dose appeared most cost-effective followed by varenicline standard-dose + bupropion standard-dose combined. When the impact of depression and self-harm was excluded, varenicline standard-dose + NRT standard-dose was most cost-effective, followed by varenicline low-dose + NRT standard-dose. ConclusionAlthough found to be most cost-effective, combined therapy is currently unlicensed in the United Kingdom and the safety of e-cigarettes remains uncertain. The value-of-information analysis suggested researchers should continue to investigate the long-term effectiveness and safety outcomes of e-cigarettes in studies with active comparators.

Neuropsychiatric Adverse Events During 12 Months of Treatment With Efavirenz in Treatment-Naïve HIV-Infected Patients in China: A Prospective Cohort Study.

Background: Efavirenz (EFV) is widely used in antiretroviral therapy (ART), but the incidence and risk factors of neuropsychiatric adverse events (NPAEs) after EFV treatment have rarely been studied in Chinese ART naïve patients.Methods: This prospective cohort study assessed HIV-infected patients initiating antiretroviral treatment with EFV to determine prevalence of and factors associated with NPAEs over a 12-month follow-up period using the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI).Results: A total of 546 patients were enrolled. Prevalence of anxiety, depression, and sleep disturbances at baseline were 30.4, 22.7, and 68.1%, respectively. Six patients discontinued treatment due to drug related NPAEs. Treatment was associated with improvements in HADS-A, HADS-D, and PSQI scores over the 12-month follow-up, and the frequencies of patients with anxiety, depression, and sleep disturbances significantly decreased after 12 months. Abnormal baseline HADS-A, HADS-D, and PSQI scores and other factors, including high school education or lower income, unemployment, divorce, and WHO III/IV stages, were associated with severe neuropsychiatric disorders over the 12 months.Conclusions: These findings suggested EFV discontinuation due to NAPEs was low, and the HADS-A, HADS-D, and PSQI scores after 12 months of EFV treatment were associated with several risk factors. The clinicians should keep in mind and routinely screen for the risk factors associated with neuropsychiatric disorders in HIV-infected patients.

Neurological Consequences of SARS-CoV-2 Infection and Concurrence of Treatment-Induced Neuropsychiatric Adverse Events in COVID-19 Patients: Navigating the Uncharted.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor and invade the human cells to cause COVID-19-related pneumonia. Despite an emphasis on respiratory complications, the evidence of neurological manifestations of SARS-CoV-2 infection is rapidly growing, which is substantially contributing to morbidity and mortality. The neurological disorders associated with COVID-19 may have several pathophysiological underpinnings, which are yet to be explored. Hypothetically, SARS-CoV-2 may affect the central nervous system (CNS) either by direct mechanisms like neuronal retrograde dissemination and hematogenous dissemination, or via indirect pathways. CNS complications associated with COVID-19 include encephalitis, acute necrotizing encephalopathy, diffuse leukoencephalopathy, stroke (both ischemic and hemorrhagic), venous sinus thrombosis, meningitis, and neuroleptic malignant syndrome. These may result from different mechanisms, including direct virus infection of the CNS, virus-induced hyper-inflammatory states, and post-infection immune responses. On the other hand, the Guillain-Barre syndrome, hyposmia, hypogeusia, and myopathy are the outcomes of peripheral nervous system injury. Although the therapeutic potential of certain repurposed drugs has led to their off-label use against COVID-19, such as anti-retroviral drugs (remdesivir, favipiravir, and lopinavir-ritonavir combination), biologics (tocilizumab), antibiotics (azithromycin), antiparasitics (chloroquine and hydroxychloroquine), and corticosteroids (dexamethasone), unfortunately, the associated clinical neuropsychiatric adverse events remains a critical issue. Therefore, COVID-19 represents a major threat to the field of neuropsychiatry, as both the virus and the potential therapies may induce neurologic as well as psychiatric disorders. Notably, potential COVID-19 medications may also interact with the medications of pre-existing neuropsychiatric diseases, thereby further complicating the condition. From this perspective, this review will discuss the possible neurological manifestations and sequelae of SARS-CoV-2 infection with emphasis on the probable underlying neurotropic mechanisms. Additionally, we will highlight the concurrence of COVID-19 treatment-associated neuropsychiatric events and possible clinically relevant drug interactions, to provide a useful framework and help researchers, especially the neurologists in understanding the neurologic facets of the ongoing pandemic to control the morbidity and mortality.

Evaluation of THC-Related Neuropsychiatric Symptoms Among Adults Aged 50 Years and Older

This systematic review and metaregression analysis estimates the association between the delta-9-tetrahydrocannabinol (THC) dose of cannabinoid-based medicines and neuropsychiatric adverse events among adults aged 50 years and older.

Pharmacodynamics of efavirenz 400 mg in treatment-na\xefve Chinese HIV-infected patients in a prospective cohort study

BackgroundThe plasma concentration of patients treated with efavirenz (EFV) 600 mg was found to exceed the upper limit of the proposed therapeutic window in most Chinese HIV-infected individuals; thus, dosage reduction of EFV to 400 mg daily warranted consideration. This study aimed to assess the pharmacodynamics of EFV 400 mg for HIV-1-infected patients in China.MethodTwenty cART-naïve individuals were enrolled in this study. EFV 400 mg combined with tenofovir (TDF) and lamivudine (3TC) as an initial antiretroviral regimen was administered for 48 weeks. EFV concentration and T cell subsets as well as HIV RNA load were evaluated at baseline and at 4, 12, 24, and 48 weeks. Moreover, neuropsychiatric adverse effects were also assessed by the Hamilton depression (HAMD) scale and Pittsburgh sleep quality index (PSQI).ResultsEighteen males and two females whose median age was 26 (interquartile range [IQR]: 23–32) years completed 48 weeks of follow-up. The median EFV concentrations were 1.88 (IQR: 1.54–2.42), 1.74 (IQR: 1.36–1.93), 1.93 (IQR: 1.66–2.22), and 1.85 (IQR: 1.54–2.14) mg/L at weeks 4, 12, 24, and 48, respectively. The viral load was 4.59 (IQR: 4.10–5.19) log10 copies/mL at baseline, and it decreased by 4.6 (IQR: 3.98–5.18) log10 copies/mL from baseline to week 48. Three of 20 (15%), 10 of 20 (50.0%), 17 of 20 (85%), and 18 of 19 (95%) participants had a plasma viral load less than 50 copies/mL at weeks 4, 12, 24, and 48, respectively. The median CD4 cell count was 330 (IQR: 237–410) cells/μL at baseline, and it increased to 473 (IQR: 344–574) cells/μL at 48 weeks. The HAMD score was 5 (IQR: 3–9.8) and 3 (IQR: 2.25–4) at baseline and 48 weeks, respectively. The PSQI score was 4 (IQR: 2–5.8) and 3 (IQR: 2–4) at baseline and 48 weeks, respectively. Dizziness was the most common event, occurring in 70% of patients within the first 2 weeks of treatment.ConclusionPatients prescribed with EFV 400 mg-containing agents demonstrated favourable virological and immunological responses. And the plasma EFV concentration was within the recommended therapeutic range, with fewer adverse reactions than with EFV 600 mg. EFV 400 mg was effective and safe in Chinese HIV-infected patients.Trial registrationNCT04596488; Registered 21 October, 2020; Retrospectively registered.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease

Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. ClinicalTrials.gov Identifier: NCT02569398.