Neuropsychiatric Adverse Events Research Articles

Defining Causality in Neurological & Neuropsychiatric COVID-19 Vaccine Complications: What Have We Learnt from Current and Previous Vaccination Campaigns?

Worldwide SARS-CoV-2 vaccination campaigns for prevention of COVID-19 are currently underway. In clinical trials and in open-label monitoring the vaccines have shown efficacy against COVID-19 and there have been limited and transient side effects. Previous vaccination campaigns have taught us that neurological adverse events to vaccinations can occur. In this review, we summarise what is already known about neurological and neuropsychiatric adverse events of COVID-19 vaccinations, and place this in the context of historical vaccination campaigns. There have been a number of neurological and neuropsychiatric adverse events following immunisation (AEFI) in association with SARS-CoV-2 vaccinations, however in each case there is either no definitive evidence currently to support causality or recognised adverse events are extremely rare. Causality assessment aids such as the Causality Assessment of an Adverse Event Following Immunization from the World Health Organisation and the Bradford Hill criteria may help us better understand potential neurological and neuropsychiatric adverse events to COVID-19 vaccinations. Functional neurological disorder (FND) can be precipitated by the process of vaccination and has previously been noted to potentially spread between individuals, particularly in younger communities. Importantly FND does not implicate the vaccine constituents and therefore should not hamper ongoing vaccination campaigns. Although neurological and neuropsychiatric AEFI may occur after SARS-CoV-2 vaccinations, at present there are no common causally associated neurological adverse events. It is likely that some patients will develop FND in response to vaccination, although this does not implicate vaccine constituents. In cases of future serious neurological or neuropsychiatric AEFIs, judicious and rapid assessment of causality must occur. In general, the benefits of ARS-CoV-2 vaccination at present outweigh the risks from a neurological standpoint, although in specific situations the risk-benefit ratio will vary depending on geographic and demographic factors as well as population risk factors. Ensuring as minimal disruption as possible to ongoing swift worldwide vaccination campaigns is essential to establish the herd immunity required to end the COVID-19 pandemic.

Chapter 26 - Neuropsychiatric effects of subthalamic deep brain stimulation

The subthalamic nucleus (STN) is a subcortical, glutamatergic, excitatory, relay nucleus that increases the inhibitory drive of the basal ganglia and suppresses action. It is of central relevance to the neuropsychological construct of inhibition, as well as the pathophysiology of Parkinson's disease (PD). Deep brain stimulation (DBS) of the STN (STN-DBS) is an established surgical treatment for PD that can be complicated by adverse neuropsychiatric side effects, most commonly characterized by impulsivity and mood elevation, although depression, anxiety, apathy, and cognitive changes have also been reported. Notwithstanding these adverse neuropsychiatric effects in PD, STN-DBS may also have a role in the treatment of refractory psychiatric disorders, as more is understood about the physiology of this nucleus and techniques in neuromodulation are refined. In this chapter, we link neuropsychiatric symptoms after STN-DBS for PD to the biological effects of electrode implantation, neurostimulation, and adjustments to dopaminergic medication, in the setting of neurodegeneration affecting cortico-striatal connectivity. We then provide an overview of clinical trials that have employed STN-DBS to treat obsessive-compulsive disorder and discuss future directions for subthalamic neuromodulation in psychiatry.

Adverse Neuropsychiatric Events Associated with Varenicline: A Case Series

Varenicline is an orally administered α4β2 nicotinic acetylcholine (Ach) receptor, partial agonist. This drug has been known to be more effective in the treatment of nicotine withdrawal than bupropion and nicotine replacement therapies. Besides this effectiveness, it has some systemic and neuropsychiatric side effects that physicians have been experienced often. Here, we aimed to draw attention to the possible neuropsychiatric risks of varenicline use by discussing the symptoms, clinical course, and treatment methods of four patients who admitted to psychiatry and neurology outpatient clinics, had a history of the therapeutic dose of varenicline use, and developed neuropsychiatric side effects. The first case was about a panic attack, and the second case had headaches, sleepiness, and tremors. In the third case, a psychotic attack due to varenicline was observed while and in the last case, myoclonic seizure symptoms were seen. Little is known about neuropsychiatric side effects due to varenicline. Neurological and psychiatric side effects should be closely monitored, and patients should be evaluated in a multidisciplinary way. The patients in this study will help to better define the neuropsychiatric side effects due to varenicline.

Overnight switch from levetiracetam to brivaracetam. Safety and tolerability.

Brivaracetam is a newer antiseizure medication than levetiracetam. It has a more selective action on the synaptic vesicle glycoprotein 2A binding site, and it seems to provide a more favorable neuropsychiatric profile. The aim of this study was to assess the safety and tolerability of an overnight switch from levetiracetam to brivaracetam. This was a retrospective descriptive study including patients with epilepsy treated with levetiracetam, who switched due to inefficacy or previous adverse events (AEs). In total, forty-one patients were included (mean age 40.9±17.8years, women 48.8%). Focal epilepsy represented 75.6% (n=31) of patients (structural cause [n=25], unknown cause [n=6]). Four patients had idiopathic generalized epilepsy, two had developmental and epileptic encephalopathy and four patients were unclassified. The reason to start brivaracetam was inefficacy in 53.7% (n=22), AEs in 65.9% (25/27 neuropsychiatric) and both in 19.5% (n=8). Brivaracetam-related AEs were reported in 24.4%. Neuropsychological AEs associated with the previous use of levetiracetam improved in 76% of patients. Treatment was discontinued in 19.5% patients. Patients' reported seizure frequency improved, worsened and remained stable in 26.8%, 12.2%, and 61.0% of the cases, respectively. An overnight switching to brivaracetam is safe and well tolerated. This treatment can improve levetiracetam-related neuropsychiatric AEs.

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.

1033. One year of Bictegravir in Mexico City: Differences in the Neuropsychiatric Adverse Events vs. Efavirenz

BackgroundIn Mexico, Efavirenz (EFV) was considered as first-line regimen for several years. However, the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) had a history neuropsychiatric effects such as depression, suicidal thoughts, insomnia, hypersomnia, impairment cognition, impairment in quality of life, these adverse events cause poor adherence and abandon EFV regimens. Since June 2019, bictegravir (BIC) in a single tablet regimen was introduced in Mexico as a first-line treatment. Therefore, the objective of the study was to compare the presence of depressive and cognitive symptoms, suicidality, sleep disturbances, quality of life between BIC and EFV regimens.MethodsProspective cross-sectional study, non-probability sample, both groups BIC and EFV were matched according to age. Patients were recruited from June 2019 to May 2020 in Condesa Specialized Clinic in Mexico City. All the patients had 1 to 4 months from starting treatment. The evaluation test used were Medical Outcomes Study Short Form-36 (SF-36), Beck Depression Inventory (IDB-IA), Center for Epidemiologic Studies-Depression Suicidal Ideation subscale (CES-D IS), State Impulsivity Scale (SIS) and Pittsburgh Sleep Quality Index (PSQI).ResultsOne thousand six hundred patients, 800 in BIC group and 800 in EFV group. The mean age 37 years. Non-statistical difference was found in sociodemographic and HIV-related variables. Statistically significant differences were found between BIC and EFV groups (t = 1.91 - 15.28, p < 0.03). The largest differences were seen in cognitive symptoms such as impulsivity, quality of life mental score and suicidal ideation (t > 10.61). No differences were found in physical role and sleep disorders.BIC & EFV groups comparison ConclusionIn this study we found BIC group have fewer neuropsychiatric events than EFV group. The principal differences were in cognitive symptoms, suicidality, functionality associated with central nervous system symptoms. We suggest having a long-term follow-up of the sleep quality variables, to observe patient’s adaptation to treatment for a period over to 12 months.Disclosures All Authors: No reported disclosures

Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice

IntroductionIntegrase inhibitors (INI) 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. MethodsRetrospective descriptive study of patients starting DTG from 2015 to 2017. Discontinuation of treatment, adverse effects and previous psychiatric pathology were recorded. Follow-up is carried out since the beginning of the treatment and hospitalizations, emergency room (ER) visits and primary care (PC) were registered. The study was authorizedby the Ethics Committee for Clinical Research of Aragon. Results283 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 was detected in 5%. This group of patients had a more frequent previous psychiatric history (62 vs 41%; p=0.002) than the ongoing treatment group and they needed more visits to PC (18.8 vs 8.4% p=0.016), ER (8,7 vs 3.3% p=0.061) and in one case even hospitalization due to AE. ConclusionPatients 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 INI. Symptoms such as anxiety, insomnia, depression can be DTG AEs more frequently than expected. Being identified by PC and emergency physicians could avoid the unnecessary prescription of other medications.

Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case-cross-over study.

Background and aimsVarenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.DesignCase–cross‐over study.SettingUK‐based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.ParticipantsAdult smokers (n =282,429) observed during periods when exposed and not exposed to either varenicline or NRT.MeasurementsMain outcomes included suicide, self‐harm, myocardial infarction (MI), all‐cause death and cause‐specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91–180 days prior to the event) or multiple 90‐day reference periods to increase statistical power.FindingsIn the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18–1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self‐harm (OR = 1.32, 95% CI = 1.12–1.56) and suicide (OR = 3.56, 95% CI = 1.32–9.60) but a reduction in all‐cause death (OR = 0.75, 95% CI = 0.61–0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36–1.74), self‐harm (OR = 1.30, 95% CI = 1.18–1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11–2.10), COPD (OR = 1.33, 95% CI = 1.14–1.56) and all causes (OR = 1.28, 95% CI = 1.18–1.40) when using multiple reference periods.ConclusionsThere appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self‐harm and (2) varenicline and increased risk of self‐harm and suicide, as well as a negative association between varenicline and all‐cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self‐harm).

Approccio integrato per la gestione di pazienti con disturbi psichiatrici-tabagisti tra U.O. CSM Catanzaro e Centro Antifumo - S.S. Ser.D. Soverato

The use of tobacco is one of the major social and health problems of our times, the leading cause of preventable death.The steady reduction in the prevalence of smoking in the general population in recent decades has not been observed in populations with psychiatric disorders.Hence a pilot project that aims to promote a territorial network between the Mental Health Services and the Anti-Smoking Centers for a global intervention strategy to combat smoking in patients with psychiatric disorders trying to create conditions of "Tobacco Services-Free", including employees, at any point inside and outside the structure.The experience made with a Protocol is particularly significant in the first place to dispel the clich&amp;eacute;s on the problem of smoking and mental illness in accordance with the scientific data present in the literature.The treatment of these patients can be successful if psychiatric services in addressing the problem offer behavioral motivational support to their patients.Collaboration with specialist Centers is essential for the treatment of addiction.Varenicline was effective in helping patients achieve abstinence or reduce the number of cigarettes smoked, and did not show a significant increase in neuropsychiatric adverse events.It is desirable that all Mental Health Services be able to carry out informational-motivational counseling onsmoking-related risks, favoring access for motivated patients to specific cessation programs in collaboration with specialized services (Anti-Smoking Centers).

13711 Isotretinoin use in acne is associated with a higher odds of the adverse effect of insomnia: Results from the US FDA Adverse Events Reporting System

Background: Isotretinoin has been associated with a higher risk for potentially serious neuropsychiatric adverse events (AE), eg, suicide. Insomnia can be the initial presenting symptom of many neuropsychiatric reactions.

“Emotional Chemobrain”: A new concept for chemotherapy adverse drug effect?

“Emotional chemobrain” is a new paradigm that relates the occurrence of alterations in the psychological wellbeing of patients to the adverse drug effects of chemotherapy on the neurobiological level. The concept of “emotional chemobrain” is the analogue concept of the classical concept of “chemobrain” but that concerns emotional disturbances related to chemotherapy. Disgust is a negative emotion that might accompany any stressful life event such as having cancer. Increased disgust may lead to the development of mental disorders such as mood and anxiety disorders. Patients with cancer may develop negative emotions such as self-disgust because of their affected autonomy and life style on the one hand and because of chemotherapy's effect on their brain on the other. Self-disgust might be considered as a factor contributing to psychological distress exacerbation in this category of physically ill individuals. In addition to lifestyle modifications and body changes, self-disgust might be exacerbated by chemotherapy in the same way other negative emotions might be exacerbated by this kind of treatment. It might be speculated that the emotional side effects of chemotherapy concern activation modifications in brain regions relevant to emotional elaboration and regulation such as the insular lobe and the amygdala. “Emotional chemobrain” should be considered whenever neuropsychiatric adverse effects of chemotherapy are manifested in patients with cancer. Future studies might be interested in studying the effect of chemotherapy on brain regions that can affect regulation of emotions such as self-disgust.

Patient-Reported Outcomes at Time of CAR-T Cell Therapy

Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with hematological malignancies. Currently three FDA approved products are available for treatment of relapsed/refractory lymphoid malignancies, and several products are in different stages of clinical investigations for treatment of multiple myeloma and other hematological malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We previously reported neuropsychiatric patient-reported outcomes (PROs) of long-term survivors after CAR-T cell therapy (Ruark at al. BBMT 2020; 26: 34-43), but without baseline PROs before treatment for comparison. In this study we have utilized PROs, including PROMIS® measures, to assess symptoms and quality of life (QOL) of patients with relapse/refractory non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) at time of arrival to our cellular immunotherapy clinic for CAR-T cell therapy. Between February 2019 and March 2020, patients received a PRO questionnaire at time of their arrival to our immunotherapy clinic. The questionnaire included the PROMIS Scale v1.2-Global Health, PROMIS-29 Profile v2.1, PROMIS Cognitive Function Short-Form v2.0, as well as 30 additional questions, including questions pertaining to cognitive function. As of March 30, 2020, 58 questionnaires were returned (59% response rate for online questionnaire versus 80% for paper questionnaire) and included in the analysis. Patients' characteristics are summarized in Table 1. PROMISmeasures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). Cognitive function was assessed for all patients by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems; answering "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). The PROMIS Cognitive Function Short-Form was added later to the PRO questionnaire and data are available for 28 patients. The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T score of PROMIS Global Physical Health was clinically meaningfully different from the mean in the general US population (43.7), while the mean T scores of all the other domains, including Global Mental Health, Social Function, Anxiety, Depression, Fatigue, Pain Interference, Sleep Disturbance and Cognitive Function were not clinically meaningfully different from the mean in the general US population. 23 of the 56 participants for whom complete data were available (41%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1). On univariate risk factor analysis, older age was found to be associated with worse Global Physical Health (p=0.04) but with a trend for less depression (p=0.07). Diagnosis of ALL was found to be a risk factor for depression (p&amp;lt;0.01). Time from diagnosis or number of prior lines of treatment were not found to be risk factors for neuropsychiatric status at time of CAR-T cell therapy. Our study demonstrates overall worse physical function in our cohort of 58 patients with hematological malignancies at time of CAR-T cell therapy, compared to the general population, but no clinically meaningful difference was found in neuropsychiatric status. 41% of the participants reported depression, anxiety or cognitive difficulties at time of CAR-T cell therapy, compared to 47.5% of participants 1-5 years after CAR-T cell therapy in our prior published work (Ruark at al. BBMT 2020; 26: 34-43). Ten participants (17.2%) reported 1-4 cognitive difficulties at time of CAR-T cell therapy compared to 37.5% of participants 1-5 years after CAR-T cell therapy. However, conclusions cannot be drawn from these two independent cohorts, and longitudinal data are needed to compare patients' neuropsychiatric status before and after CAR-T cell therapy in order to determine the treatment effect. Such study is currently ongoing in our institution. Disclosures Maloney: Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents &amp; Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Bioline Rx: Consultancy, Honoraria.

Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES.

This study aimed to evaluate the efficacy and safety of varenicline, bupropion, and nicotine replacement therapy (NRT) among smokers with schizophrenia spectrum disorders in post hoc analyses of Evaluating Adverse Events in a Global Smoking Cessation Study data. Smokers with schizophrenia spectrum disorder (N=390) and without a psychiatric illness (control group, N=4,028) were randomly assigned to receive varenicline, bupropion, NRT patch, or placebo for 12 weeks. Outcomes included abstinence rates during treatment and follow-up, number needed to treat (NNT) for abstinence, incidence of neuropsychiatric adverse events (NPSAEs), and temporal relationship between NPSAEs and abstinence status. Smokers with schizophrenia smoked more and had greater dependence and fewer prior trials of cessation pharmacotherapy at baseline. At each time point, smokers with schizophrenia assigned to varenicline had significantly greater odds of abstinence compared with their matched placebo group, with NNT comparable to the control group. Bupropion and NRT increased odds of abstinence; confidence intervals (CIs) included 1 for some comparisons, and NNT for smokers with schizophrenia was greater than for the control group. No treatment was associated with significantly more NPSAEs, compared with placebo, in either cohort. The estimated NPSAE rate was 5% (95% CI=3.0-7.7) for smokers with schizophrenia and 1% (95% CI=0.6-2.1) for the control group. Over one-third of NPSAEs occurred during partial or full abstinence, suggesting a multifactorial nature. For smokers with schizophrenia, varenicline led to significantly higher abstinence rates, and NNT was comparable to the control group. A significant proportion of NPSAEs occurred during early abstinence. No treatment significantly increased NPSAE prevalence.

CB1 and GLP-1 Receptors Cross Talk Provides New Therapies for Obesity.

Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists.

Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions.

Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

BackgroundTo inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.MethodsWe searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework.FindingsWe identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92).InterpretationThe evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable.FundingWHO.

Discontinuation due to neuropsychiatric adverse events with efavirenz- and dolutegravir-based antiretroviral therapy: a comparative real-life study

ObjectivesDespite the high efficacy of antiretroviral treatment, no drug is free from adverse events (AEs). Efavirenz (EFV) and dolutegravir (DTG) are antiretroviral drugs for which neuropsychiatric adverse events (NPAEs) have...

High-dose and low-dose varenicline for smoking cessation in adolescents: a randomised, placebo-controlled trial

Although cigarette smoking typically begins in adolescence, evidence for successful pharmacological smoking cessation interventions for this population is scarce. In adult smokers, varenicline is the most effective single pharmacotherapy. The aim of this study was to assess the efficacy and tolerability of varenicline for smoking cessation in adolescents. We did a randomised, placebo-controlled trial with adolescent smokers aged 12-19 years who were seeking treatment to quit at 57 outpatient centres (in the USA, Russia, South Korea, Taiwan, Canada, and Georgia). Participants were randomly assigned (1:1:1) to receive 12 weeks of high-dose varenicline (1 mg twice daily; 0·5 mg twice daily if bodyweight ≤55 kg), low-dose varenicline (0·5 mg twice daily; 0·5 mg once daily if bodyweight ≤55 kg), or placebo, then followed up for 40 additional weeks. At all visits, participants received brief, developmentally tailored smoking cessation counselling (<10 min per session) delivered by a trained counsellor. The primary efficacy outcome was continuous abstinence from weeks 9 to 12, measured via a Nicotine Use Inventory and confirmed by urine cotinine testing. The primary tolerability outcome was frequency of treatment-emergent adverse events, including neuropsychiatric adverse events, occurring after the first dose and within 30 days of the last dose of study medication. This trial is registered with ClinicalTrials.gov, NCT01312909. Between April 26, 2011, and Jan 18, 2018, 312 participants were enrolled and completed participation in the study: 109 in the high-dose varenicline group, 103 in the low-dose varenicline group, and 100 in the placebo group. The continuous abstinence rates from week 9 to 12 were 20% (22 of 109) in the high-dose varenicline group, 27% (28 of 103) in the low-dose varenicline group, and 18% (18 of 100) in the placebo group. Abstinence rates between high-dose varenicline and placebo groups (odds ratio [OR] 1·18 [95% CI 0·59-2·37]; p=0·63) and between low-dose varenicline and placebo groups (1·73 [0·88-3·39]; p=0·11) did not differ significantly. Treatment-emergent adverse events occurred in 65 (60%) of 108 participants in the high-dose group, 53 (53%) of 100 in the low-dose group, and 52 (53%) of 99 in the placebo group, and most were rated as mild. Neuropsychiatric treatment-emergent adverse events occurred in 18 (17%) of 108 participants in the high-dose group, 11 (11%) of 100 in the low-dose group, and 12 (12%) of 99 in the placebo group, and none was rated as severe. This trial did not show an advantage in abstinence with varenicline compared with placebo among adolescent smokers. The rates of treatment-emergent adverse events were similar to those in previous trials of adult smokers, raising no new tolerability signals. These findings do not support the use of varenicline as a first-line pharmacotherapy for smoking cessation in adolescents. Pfizer.

Psychosis as an adverse effect of antibiotics

Adverse neuropsychiatric effects of antibiotic medications have been well documented. There is evidence suggesting a direct relationship between acute psychosis and antibiotic exposure. Conversely, the tetracycline antibiotic minocycline has been associated with improvements in psychopathology in patients with psychotic disorders. The purpose of the present study was to investigate the prevalence of spontaneously reported adverse drug reactions (ADRs) of psychotic symptoms in adults for antibiotics and the odds of psychosis compared to minocycline for individual antibiotics and antibiotic classes. We searched the publicly available U.S. F.D.A. Adverse Event Reporting System (FAERS) from inception through March 2020 for which an antibiotic was the suspected agent of an adverse drug reaction (ADR). We investigated 23 different antibiotics, comprising 183,265 adverse event reports and 2955 psychosis ADRs. For individual antibiotics, the prevalence of psychosis ADRs ranged from 0.3 to 3.8%. Fifteen antibiotics were associated with a significantly increased odds of psychosis (OR ​= ​1.67–9.48), including penicillins, fluoroquinolones, macrolides, cephalosporins, and doxycycline. Our results suggest that psychosis is a potential adverse effect of antibiotic treatment, but risks vary by specific agents. Future studies in this area are needed to identify specific underlying biological mechanisms that contribute to these associations. Findings may also inform on clinical decisions regarding the selection of antibiotic therapy in vulnerable patient populations.

Covid-19 treatment-induced neuropsychiatric adverse effects

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) was first notified in Wuhan, China, in December 2019, and has rapidly spread worldwide, due to its high transmission rate. It has been identified as the causative agent of the now termed coronavirus disease (COVID-19), which can range from mild condition to potentially fatal respiratory distress syndrome