Adverse Cognitive Effects Research Articles

Reconsideration of the Benefits of Pharmacological Interventions for the Attenuation of the Cognitive Adverse Effects of Electroconvulsive Therapy.

The cognitive adverse effects (AEs) of electroconvulsive therapy (ECT) limit the wider use of the treatment. These AEs can be attenuated by changing the way ECT is administered; however, such changes may reduce the response rate, the speed of response, or both. A recent systematic review and meta-analysis identified more than a dozen pharmacologic interventions in 26 randomized controlled trials (RCTs) that sought to reduce ECT-induced cognitive AEs. Because of large differences across RCTs, only a few outcomes for a few interventions could be pooled in meta-analysis, and most pooled analyses included only 2-3 RCTs. Important findings were that acetylcholinesterase inhibitors, ketamine, memantine, and liothyronine were associated with improved global cognitive functioning at 1-14 days post-ECT. Anti-inflammatory treatments and opioid receptor antagonists were not associated with improvement in general cognitive outcome at 1-14 days post-ECT. Meta-analysis was not possible for the remaining interventions, including piracetam, melatonin, pemoline, nortriptyline, herbal agents, drugs acting on the cortisol pathway, opioid receptor antagonists, l-tryptophan, vasopressin analogs, calcium channel blockers, and others; in individual RCTs, some of these interventions attenuated some cognitive measures as some time points after ECT. Regrettably, none of the RCTs examined clinically meaningful outcomes such as subjective cognitive impairment, impairments in daily life, and persistent autobiographical memory deficits. Future research should study such clinically meaningful outcomes (rather than laboratory tests), using pharmacologic interventions, perhaps in combination, for ECT procedures that are associated with higher cognitive AE burden. A risk is that whatever attenuates ECT-induced cognitive AEs may also attenuate ECT-related therapeutic benefits.

Aconitum Alkaloid Songorine Exerts Potent Gamma-Aminobutyric Acid-A Receptor Agonist Action In Vivo and Effectively Decreases Anxiety without Adverse Sedative or Psychomotor Effects in the Rat.

Songorine (SON) is a diterpenoid alkaloid from Aconitum plants. Preparations of Aconitum roots have been employed in traditional oriental herbal medicine, however, their mechanisms of action are still unclear. Since GABA-receptors are possible brain targets of SON, we investigated which subtypes of GABA-receptors contribute to the effects of SON, and how SON affects anxiety-like trait behavior and psychomotor cognitive performance of rats. First, we investigated the effects of microiontophoretically applied SON alone and combined with GABA-receptor agents picrotoxin and saclofen on neuronal firing activity in various brain areas. Next, putative anxiolytic effects of SON (1.0–3.0 mg/kg) were tested against the GABA-receptor positive allosteric modulator reference compound diazepam (1.0–5.0 mg/kg) in the elevated zero maze (EOM). Furthermore, basic cognitive effects were assessed in a rodent version of the psychomotor vigilance task (PVT). Local application of SON predominantly inhibited the firing activity of neurons. This inhibitory effect of SON was successfully blocked by GABA(A)-receptor antagonist picrotoxin but not by GABA(B)-receptor antagonist saclofen. Similar to GABA(A)-receptor positive allosteric modulator diazepam, SON increased the time spent by animals in the open quadrants of the EOM without any signs of adverse psychomotor and cognitive effects observed in the PVT. We showed that, under in vivo conditions, SON acts as a potent GABA(A)-receptor agonist and effectively decreases anxiety without observable side effects. The present findings facilitate the deeper understanding of the mechanism of action and the widespread pharmacological use of diterpene alkaloids in various CNS indications.

Microdosing psilocybin for chronic pain: a case series.

Psychedelic serotonergic agonists such as psilocybin have recently been shown to produce sustained benefit in refractory depression, end of life anxiety, and addiction when administered in hallucinogenic doses and coupled with psychotherapy. Although it has been suggested that similar high-dose protocols may help chronic pain conditions, there are few published clinical trials of psychedelics for pain. The use of these agents in subpsychedelic doses for chronic pain management has received even less attention. This case series details the experiences of 3 individuals who have used low-dose psilocybin to manage chronic neuropathic pain. Although the nature and etiology of each patient's pain vary, they share a common experience, including inefficacy of current therapeutics and decreased quality of life. Through self-administration of psilocybin, these patients have achieved robust pain relief with decreased reliance on traditional analgesic medications. Despite varying preparations and uncertain potencies, the analgesic effects for all 3 patients occurred at doses without a psychedelic experience and with minimal cognitive or somatic adverse effects. Furthermore, the efficacy of pain relief and, in some cases, the duration of the effect were magnified when coupled with functional exercise. In addition, in 1 case, repeated dosing seemed to produce increased relief, suggesting a possible long-term plasticity-mediated effect. These commonalities highlight psilocybin's therapeutic potential in the treatment of chronic pain that warrants further investigation.

Deep brain stimulation in the ALIC-BNST region targeting the bed nucleus of stria terminalis in patients with obsessive–compulsive disorder: effects on cognition after 12 months

PurposeThe aim of this study was to evaluate cognitive effects 12 months after Deep Brain Stimulation (DBS) of the Bed Nucleus of Stria Terminalis (BNST) in patients with refractory Obsessive–Compulsive Disorder (OCD).MethodsEight patients (5 female; mean ± SD age 36 ± 15) with OCD were included. A neuropsychological test battery covering verbal and spatial episodic memory, executive function, and attention was administered preoperatively and 12 months after surgery. Medical records were used as a source for descriptive data to probe for any changes not covered by standardized checklists and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the primary outcome measure.ResultsAt 12 months, seven patients showed response to DBS: three were full responders (i.e., Y-BOCS ≥ 35% improvement), and four were partial responders (Y-BOCS 25–34% improvement). Relative to baseline, there was a slight decline on visuo-spatial learning (p = 0.027), and improved performance on the Color-Word Interference inhibition/switching subtest (p = 0.041), suggesting improvement in cognitive flexibility.ConclusionsDBS in the BNST for treatment refractory OCD generates very few adverse cognitive effects and improves cognitive flexibility after 12 months of stimulation. The improvement in Y-BOCS and the absence of major cognitive side effects support the BNST as a potential target for DBS in severe OCD.

Use of High-Dose Androgens Is Associated with Reduced Brain-Derived Neurotrophic Factor in Male Weightlifters

Introduction: Use of high-dose androgens causes drastic changes in hormonal milieu and is associated with adverse medical, psychological, and cognitive effects. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors plays a critical role in neuroplasticity, with implications for cognitive function and mental health. The impact of long-term, high-dose androgen use on BDNF in a natural setting has not been investigated. This study examined the association between long-term androgen exposure and BDNF levels, and the links between BDNF, heavy resistance exercise, hormones, androgens, and mental health. Methods: We measured serum levels of BDNF and sex steroid hormones in male weightlifters (N = 141) with a history of current (n = 59), past (n = 29), or no (n = 52) androgen use. All participants completed questionnaires assessing maximum strength and measures of anxiety and depression. Group differences in BDNF were tested using general linear models adjusting for age and associations between BDNF and strength, anxiety, and depression using Pearson’s or Kendall’s correlations. Results: Both current (mean: 44.1 ng/mL [SD: 12.7]) and past (39.5 ng/mL [SD: 13.9]) androgen users showed lower serum BDNF levels compared to nonusing controls (51.5 [SD: 15.3], p < 0.001, ηp² = 0.10). BDNF levels were negatively related to maximal strength, and with hormonal status in past androgen users, but no significant associations were found with measures of depression and anxiety. Conclusion: Lower circulating BDNF concentrations in current and past androgen users suggest that high-dose androgen exposure triggers persistent changes in BDNF expression. Further studies are needed to verify the relationship and its potential clinical implications.

Rivastigmine for ECT-induced cognitive adverse effects in late life depression (RECALL study): A multicenter, randomized, double blind, placebo-controlled, cross-over trial in patients with depression aged 55 years or older: Rationale, objectives and methods.

BackgroundCognitive side-effects are an important reason for the limited use of electroconvulsive therapy (ECT). Cognitive side-effects are heterogeneous and occur frequently in older persons. To date, insight into these side-effects is hampered due to inconsistencies in study designs and small sample sizes. Among all cognitive side-effects, confusion and delirious states are especially troublesome for patients, relatives and clinicians. In particular inter-ictal delirium-like states are worrisome, since they may lead to premature treatment discontinuation. Besides a need for further insight into determinants of cognitive side-effects of ECT, there is a great need for treatment options.Methods and designThe Rivastigmine for ECT-induced Cognitive Adverse effects in Late Life depression (RECALL) study combines a multicenter, prospective cohort study on older patients with depression, treated with ECT, with an embedded randomized, placebo-controlled cross-over trial to examine the effect of rivastigmine on inter-ictal delirium. Patients are recruited in four centers across the Netherlands and Belgium. We aim to include 150 patients into the cohort study, in order to be able to subsequently include 30 patients into the trial. Patients are included in the trial when inter-ictal delirium, assessed by the Confusion Assessment method (CAM), or a drop in Mini Mental State Examination (MMSE) score of ≥4 during ECT, develops. In the cohort study, comprehensive measurements of ECT-related cognitive side-effects—and their putative determinants—are done at baseline and during the ECT-course. The primary outcome of the clinical trial is the effectiveness of rivastigmine on inter-ictal delirium-severity, assessed with a change in the Delirium Rating Scale-Revised-98. Secondary outcomes of the clinical trial are several ECT-characteristics and side-effects of rivastigmine.DiscussionThis study is the first clinical trial with a focus on ECT-induced, inter-ictal delirium. The cohort provides the basis for recruitment of patients for the cross-over trial and additionally provides an excellent opportunity to unravel cognitive side-effects of ECT and identify putative determinants. This paper describes the rationale and study protocol.Clinical trial registrationEudraCT 2014-003385-24.

CO122 Patient Versus Caregiver and Clinician Reports of Cognitive Difficulties in Patients with Schizophrenia Switching to Long-Acting Injectable Antipsychotic Aripiprazole Lauroxil: A Post Hoc Analysis

Discrepancies between patient- and clinician-perceived cognitive functioning in people with schizophrenia have been associated with functional impairment, which can be further confounded by side effects of treatment. Perceived cognitive impairment and level of agreement between patient, clinician, and caregiver responses on the New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) were assessed for patients with schizophrenia switching to the long-acting injectable antipsychotic aripiprazole lauroxil (AL).

Electroconvulsive Therapy in Children and Adolescents in Germany-A Case Series From 3 University Hospitals.

Electroconvulsive therapy (ECT) is a well-established, safe, and efficacious treatment for severe psychiatric disorders. In children and adolescents, it is used much less frequently than in adults, likely because of a lack of knowledge. We retrospectively analyzed all patients aged 12 to 17 years who completed a course of ECT at 3 psychiatric university hospitals in Germany between 2010 and 2020. Clinical Global Impression Severity (CGI-S) scores were assessed based on electronic medical records. Changes in CGI-S scores were assessed using a paired samples t test. Predictors for response and remission were assessed using binomial logistic regression. We included 32 patients. The CGI-S scores improved significantly from before to after ECT treatment (6.9 vs 3.9, t = 10.0, P < 0.01). A total of 40.6% of patients responded (CGI ≤ 3) and 21.9% remitted (CGI ≤ 2). The number of ineffective medication trials in the 6 months before ECT treatment was significantly associated with response (odds ratio, 0.54; P = 0.028) and remission (odds ratio, 0.31; P = 0.048). Five patients reported subjective cognitive adverse effects, 2 patients exhibited a prolonged seizure, 1 patient reported headaches, and 1 patient experienced a mild allergic reaction after anesthesia with etomidate. A total of 65.6% of patients experienced no adverse effects at all. This retrospective analysis found ECT to be effective and safe in children and adolescents irrespective of their main diagnosis. The reported data point to the importance of an early use of ECT for severe psychiatric diseases in child and adolescent psychiatry.

Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker: A Pilot Study.

Electroconvulsive therapy (ECT) remains the benchmark for treatment resistant depression, yet its cognitive adverse effects have a negative impact on treatment. A predictive safety biomarker early in ECT treatment is needed to identify patients at cognitive risk to maximize therapeutic outcomes and minimize adverse effects. We used ictal electroencephalography frequency analysis from suprathreshold treatments to assess the relationships between ECT dose, ictal power across different frequency domains, and cognitive outcomes. Seventeen subjects with treatment resistant depression received right unilateral ECT. Structural magnetic resonance imaging was obtained pre-ECT for electric field modeling to assess ECT dose. Serial assessments with 24-lead electroencephalography captured ictal activity. Clinical and cognitive assessments were performed before and after ECT. The primary cognitive outcome was the change in Delis Kaplan Executive Function Verbal Fluency Letter Fluency. Ictal theta (4-8 Hz) power in the Fp1/Fp2 channels was associated with both whole-brain electric field strength (t(2,12) = 19.5, P = 0.007)/(t(2,10) = 21.85, P = 0.02) and Delis Kaplan Executive Function Verbal Fluency Letter Fluency scores (t(2,12) = -2.05, P = 0.05)/(t(2,10) = -2.20, P = 0.01). Other frequency bands (beta, alpha, delta, and gamma) did not demonstrate this relationship. This pilot data identify ictal theta power as a potential safety biomarker in ECT and is related to the strength of the ECT dose. Ictal theta power could prove to be a convenient and powerful tool for clinicians to identify those patients most susceptible to cognitive impairment early in the treatment series. Additional studies are needed to assess the role of longitudinal changes in ictal theta power throughout the ECT series.

Ketamine and Electroconvulsive Therapy: Better Together?

IntroductionMajor depressive disorder (MDD) is a highly prevalent clinical condition with a leading cause of disability worldwide. The currently available therapeutic agents have important limitations regarding side effects, partial or non-responsiveness. Patients are considered to have treatment-resistant depression (TRD) if there is no effect or minimal effectiveness after receiving adequate dose-duration use of antidepressants from two different categories. For this patients, electroconvulsive therapy (ECT) can be a treatment option and new therapies appear to tackle TRD like ketamine, a dissociative anesthetic and analgesic.ObjectivesThe authors elaborate a narrative literature review to understand if ketamine might enhance the antidepressant efficacy of ECT.MethodsPubMed database searched using the terms “Electroconvulsive therapy”, “ketamine” and “treatment-resistant depression”.ResultsECT is currently recommended as an end-line therapy for TRD. Memory impairment after ECT could be a consequence of indiscriminate activation or saturation of glutamate receptors during the treatment, disrupting hippocampal plasticity involved in memory. Ketamine inhibits N-methyl-d-aspartate (NMDA) receptors, while stimulating glutamate release and was proposed as an ECT adjuvant, might reduce cognitive adverse effects, time until response/ remission and inclusively improve response rates to ECT. However, response and remission rates of ketamine in ECT showed no significant difference from the comparator groups and was associated with higher rates of psychiatric and cardiovascular adverse events.ConclusionsThe results did not support the use the combination of ketamine and propofol as anesthetic agents for ECT in patients with MDD. However, further studies are needed to investigate the beneficial clinical and cognitive effects of ketamine alone in ECT settings.DisclosureNo significant relationships.

Drug therapy problems and predicting factors among ambulatory epileptic patients in Jimma Medical Center, Southwest Ethiopia.

BackgroundThe care of epileptic patients is complicated by the cognitive adverse effect of the drug, disease, pharmacokinetics, and pharmacodynamics properties of antiepileptic drugs which in turn intensify the risk of drug therapy problems among epileptic patients.ObjectiveTo assess drug therapy problems and predicting factors among ambulatory epileptic patients at Jimma University Medical Center, Southwest Ethiopia, from September 2020 to May 2021.MethodologyA hospital-based prospective observational study was conducted. A semi-structured questionnaire was used to collect data from patients as well as from charts. Drug therapy problems were identified using Cipolle’s, Morley, and Strand drug therapy problem identification and classification method. Data were entered into Epi data manager version 4.6 and exported to statistical software package for social science version 23.0 for analysis. Multiplestepwise backward logistic regression analysis was carried out to identify predictors of drug therapy problems. The 95% CI was used to show an association between the dependent and independent variables. P-value < 0.05 was considered as statistically significant.ResultsOf the total 320 epileptic patients 224(70.0%) patients had at least one drug therapy problem. A total of 395 drug therapy problems were identified among two hundred twenty-four patients with an average of 1.2 drug therapy problems per patient. The frequently identified drug therapy problems were non-compliance 115(29.11), adverse drug reaction 110(27.84%), and dose too low 103(26%). Getting of a drug by purchasing [AOR = 4.6,95%CI:(2.05–10.7)], poorly involvement of the patients in therapeutic decision making [AOR = 3.02,95%CI:(1.5–6.06)], the number of medications ≥ two [AOR = 5.3,95%CI:(1.2–22.9)] and having had uncontrolled seizure [AOR = 10.9,95%CI:(4.9–24.2)] were independent predictors of drug therapy problems.ConclusionsDrug therapy problems were common among epileptic patients in the study area. Patients who were getting their drugs by purchasing, poorly involved in therapeutic decision making, having had an uncontrolled seizure, and taking two and above drugs were more likely to experience drug therapy problems. Therefore, due attention should be given to patients with the aforementioned problems to decrease the occurrence of drug therapy problems and improve overall outcomes among epileptic patients.

Altered default mode network associated with pesticide exposure in Latinx children from rural farmworker families

Pesticide exposure has been associated with adverse cognitive and neurological effects. However, neuroimaging studies aimed at examining the impacts of pesticide exposure on brain networks underlying abnormal neurodevelopment in children remain limited. It has been demonstrated that pesticide exposure in children is associated with disrupted brain anatomy in regions that make up the default mode network (DMN), a subnetwork engaged across a diverse set of cognitive processes, particularly higher-order cognitive tasks. This study tested the hypothesis that functional brain network connectivity/topology in Latinx children from rural farmworker families (FW children) would differ from urban Latinx children from non-farmworker families (NFW children). We also tested the hypothesis that probable historic childhood exposure to pesticides among FW children would be associated with network connectivity/topology in a manner that parallels differences between FW and NFW children. We used brain networks from functional magnetic resonance imaging (fMRI) data from 78 children and a mixed-effects regression framework to test our hypotheses. We found that network topology was differently associated with the connection probability between FW and NFW children in the DMN. Our results also indicated that, among 48 FW children, historic reports of exposure to pesticides from prenatal to 96 months old were significantly associated with DMN topology, as hypothesized. Although the cause of the differences in brain networks between FW and NFW children cannot be determined using a cross-sectional study design, the observed associations between network connectivity/topology and historic exposure reports in FW children provide compelling evidence for a contribution of pesticide exposure on altering the DMN network organization in this vulnerable population. Although longitudinal follow-up of the children is necessary to further elucidate the cause and reveal the ultimate neurological implications, these findings raise serious concerns about the potential adverse health consequences from developmental neurotoxicity associated with pesticide exposure in this vulnerable population.

A new cognitive safety monitoring plan for interventional studies involving patients with advanced dementia: Insights from the ECT-AD Study

<h3>Introduction</h3> Many pharmacological and some non-pharmacological treatments (e.g., electroconvulsive therapy, ECT) are associated with adverse cognitive effects in older adults, and this is particularly true for those with advanced dementia. Thus, it is imperative that studies investigating new treatments with potential cognitive side effects include a robust cognitive safety monitoring plan when the target population includes older adults with advanced dementia. However, detecting adverse cognitive events (ACEs) in this population poses unique challenges for two reasons: (1) the extant literature offers no recommendations or guidelines for defining what level of decline constitutes an ACE in this population, and (2) these patients are more likely to show floor effects on baseline cognitive testing, making it difficult to measure treatment-related adverse cognitive effects. To address these challenges, we created a new, empirically derived, and individually tailored cognitive safety monitoring plan that accounts for potential floor effects on pre-treatment cognitive testing. This plan was developed in the context of an ongoing, randomized controlled trial (the NIA supported "ECT-AD" study) to investigate the safety and efficacy of ECT for refractory agitation and aggression in patients with severe Alzheimer's disease (AD) <h3>Methods</h3> An extensive literature review was conducted to identify cognitive measures that have been found to be psychometrically sound for use in patients with advanced dementia, as well as psychometric data from those scales that could be used to define floor effects. Additionally, we inquired informant-rated scales of daily functioning that could serve as a proxy measure of cognitive status when patients exhibit baseline floor effects on cognitive testing. The team specifically focused on daily functioning scales for this purpose, given the robust association between cognition and activities of daily living in AD – an association that becomes stronger with disease progression (Liu-Seifert et al., 2016). Lastly, we reviewed the literature on statistical approaches to measuring reliable change on these kinds of cognitive/functional scales to define what constitutes statistically meaningful decline. <h3>Results</h3> The Severe Impairment Battery-8 (SIB-8) was chosen as the primary cognitive measure. The SIB-8 is a brief, clinician-administered test that has strong psychometric properties in patients with advanced dementia (Schmitt et al., 2009; Schmitt et al., 2013). Baseline floor effects on the SIB-8 were defined as a total score of ≤ 5/16. This value was chosen because it is approximately two standard deviations below the modal SIB-8 score in a large sample (N > 1300) of patients with moderate-to-severe dementia (Schmitt et al., 2013). For patients who <i>do not</i> exhibit baseline floor effects on the SIB-8, a post-treatment decline of ≥ 6 points would be considered an ACE. This threshold was empirically derived from the review of evidence-based approaches to measuring reliable change. Specifically, we used the Standard Deviation Index (SDI) method that uses the normative psychometric properties of a given test, along with an individual's test scores at two time points to derive a reliable change score. Using normative SIB-8 data from a large sample of comparable patients with AD (Schmitt et al., 2013), the SDI indicates that a decline of ≥ 5.6 points from baseline represents a statistically meaningful change. For patients who <i>do</i> exhibit baseline floor effects on the SIB-8, we will use the Barthel Index (BI) as a proxy measure of cognitive function (Mahoney & Barthel, 1965). The BI is an informant-rated scale (score range: 0-100) that assesses performance in basic activities of daily living (e.g., feeding, bathing). An ACE will be defined as a decline of ≥ 30 points on the BI from baseline, which was derived from the SDI method using normative BI data from a large sample (N=341) of comparable patients with AD (Kamiya et al., 2014). If an ACE is detected (using either the SIB-8 or BI) on the morning of, but prior to, a patient's next scheduled ECT treatment, then treatment will be held until the next treatment day. If a patient exhibits persistent decline prior to treatment on three consecutive days, then ECT will be discontinued. <h3>Conclusions</h3> By accounting for practical and statistical challenges in assessing cognitive function in patients with advanced dementia, we have designed a new, empirically derived, and conditional approach to monitoring for ACEs in real-time in clinical trials targeting this patient population. While the proposed cognitive safety monitoring plan was developed in the context of an inpatient ECT study, the procedures are agnostic to the specific type of treatment and can be readily adapted to a variety of interventional research contexts involving patients with severe dementia. <h3>This research was funded by</h3> National Institute of Health/National Institute on Aging (R01AG061100-01, NCT03926520)

Breathing-Focused Yoga Intervention on Respiratory Decline in Chronically Pesticide-Exposed Farmers: A Randomized Controlled Trial.

BackgroundOccupational exposure to pesticides has been associated with lung and cognitive function exacerbations. In the present study, we tested the effectiveness of breathing focused yoga intervention on alleviation of adverse respiratory and cognitive effects associated with chronic pesticide exposure in farmers.MethodsWe undertook a parallel, two-armed randomized controlled trial with blinded outcome assessors on a chronically pesticide-exposed farming population. The study was conducted at district Panipat, State Haryana located in the Northern part of India from November 2019 to August 2020. A total of 634 farmers were screened, and 140 farmers were randomized to breathing-focused yoga intervention (BFY, n = 70) and waitlist control arms (n = 65). BFY was delivered weekly in 45-min group sessions over 12 weeks followed by home-based practice. The primary outcome was the change in spirometry-based markers of pulmonary function from baseline expressed as raw values, Global Lung Initiative (GLI) percent predicted (pp), and GLI z-scores after 24 weeks of intervention. Secondary variables were Trail making tests (TMT A and B), Digit symbol substitution (DSST), and WHO Quality of life-BREF (WHOQOL-Bref). Analysis was by intention-to-treat. Mediation analysis was done considering oxidative stress markers as potential mediators.ResultsAt the end of 6 months of intervention, the overall follow-up in the participants was 87.85% (n = 123); 90% (n = 63) in the control group, and 85.71% in the yoga group (n = 60). The mean age of the study cohort (n = 140) was 38.75 (SD = 7.50) years. Compared with the control group, at 24 weeks post-intervention, the BFY group had significantly improved status of the raw sand z scores markers of airway obstruction, after adjusting for confounders, FEV1, FVC, FEF25-75 [z score-adjusted mean differences (95% CI); 1.66 (1.10–2.21) 1.88 (1.21–2.55), and 6.85 (5.12–8.57), respectively. A fraction of FEF25-75 change (mediation percentage 23.95%) was explained by glutathione augmentation. There were also significant improvements in cognitive scores of DSST, TMT-A and TMT-B, and WHOQOL-Bref.ConclusionIn conclusion, regular practice of BFY could improve the exacerbations in the markers of airway obstruction in chronically pesticide-exposed farmers and cognitive variables. A significant mediating effect of glutathione augmentation was also observed concerning the effect of the intervention on FEF25-75. These findings provide an important piece of beneficial evidence of the breathing-based yoga intervention that needs validation across different farming ethnicities.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: CTRI/2019/11/021989.

Simulated Electroconvulsive Therapy: A Novel Approach to a Control Group in Clinical Trials.

Agitation is the most common behavioral symptom of Alzheimer disease (AD) affecting approximately 40% to 60% of the AD population, yet there are no Food and Drug Administration-approved therapies for the myriad of behavioral or psychological symptoms of dementia. There is growing evidence from naturalistic studies that electroconvulsive therapy (ECT) is a safe and effective treatment for agitation in AD patients who are refractory to pharmacotherapy and behavioral interventions. Despite the existing evidence, ECT remains underused because of stigma, lack of education, and concerns regarding adverse cognitive effects. Randomized controlled clinical trials of ECT are an opportunity to provide high-quality evidence of ECT as a safe and efficacious treatment for agitation in the AD population. We describe the methods for the Electroconvulsive Therapy in Alzheimer's Dementia study, which uses a novel, simulated ECT (S-ECT) control group to conduct a single-blind efficacy study of ECT for the treatment of agitation and aggression in individuals with moderate to severe AD. We discuss the rationale, study design, methodology, ethical and practical challenges, and management strategies in using an S-ECT group as the comparator arm in this randomized controlled trial of ECT in AD-related treatment refractory agitation and aggression. Validation of the safety and efficacy of ECT in patients with advanced AD with refractory agitation and aggression is necessary. This can be accomplished through creative formulation of S-ECT groups that effectively maintain the blind while providing scientific integrity.

Calcium Channel Antagonists for Mood Disorders.

Development of new thymoleptic medications has primarily centered on anticonvulsants and antipsychotic drugs. Based on our studies of intracellular calcium ion signaling in mood disorders, we were interested in the use of novel medications that act on this mechanism of neuronal activation as potential mood stabilizers. We reviewed the dynamics of the calcium second messenger system and the international body of data demonstrating increased baseline and stimulated intracellular calcium levels in peripheral cells of patients with bipolar mood disorders. We then examined studies of the effect of established mood stabilizers on intracellular calcium ion levels and on mechanisms of mobilization of this second messenger. After summarizing studies of calcium channel blocking agents, whose primary action is to attenuate hyperactive intracellular calcium signaling, we considered clinical experience with this class of medications and the potential for further research. Established mood stabilizers normalize increased intracellular calcium ion levels in bipolar disorder patients. Most case series and controlled studies suggest an antimanic and possibly mood stabilizing effect of the calcium channel blocking medications verapamil and nimodipine, with fewer data on isradipine. A relatively low risk of teratogenicity and lack of cognitive adverse effects or weight gain suggest possible applications in pregnancy and in patients for whom these are considerations. Medications that antagonize hyperactive intracellular signaling warrant more interest than they have received in psychiatry. Further experience will clarify the applications of these medications alone and in combination with more established mood stabilizers.

Cognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach?

One in three people will be diagnosed with cancer during their lifetime. The community of cancer patients is growing, and several common cancers are becoming increasingly chronic; thus, cancer survivorship is an important part of health care. A large body of research indicates that cancer and cancer therapies are associated with cognitive impairment. This research has mainly concentrated on chemotherapy-associated cognitive impairment but, with the arrival of immunotherapies, the focus is expected to widen and the number of studies investigating the potential cognitive effects of these new therapies is rising. Meanwhile, patients with cognitive impairment and their healthcare providers are eagerly awaiting effective approaches to intervene against the cognitive effects of cancer treatment. In this Review, we take stock of the progress that has been made and discuss the steps that need to be taken to accelerate research into the biology underlying cognitive decline following chemotherapy and immunotherapy and to develop restorative and preventive interventions. We also provide recommendations to clinicians on how to best help patients who are currently experiencing cognitive impairment.

Association between blood metals mixtures concentrations and cognitive performance, and effect modification by diet in older US adults.

Background:Chronic exposure to heavy metals has been associated with adverse neurological outcomes in older adults. Inflammatory processes are suspected as an underlying pathway by which metals exert their neurotoxicity. In parallel, a diet rich in antioxidant and anti-inflammatory components may protect against chronic inflammation.Objectives:We examined the associations of blood concentrations of lead, cadmium, and manganese as a mixture with cognitive performance in older US adults and potential modification of these associations by diet as measured by the Healthy Eating Index 2015 (HEI-2015) and the Adapted Dietary Inflammatory Index (ADII).Methods:We used data on 1,777 adults ≥60 years old from the US National Health and Nutrition Examination Survey (NHANES; 2011–2014). We derived the ADII and the HEI-2015 from two nonconsecutive 24-hour diet recalls. Cognitive performance was measured by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning subtest, the animal fluency test, and the Digit Symbol Substitution Test (DSST). We also constructed a composite z-score reflecting overall cognitive performance. We used quantile g-computation to evaluate the joint associations of a mixture of metals with cognitive performance test scores. We also evaluated effect modification by sex and diet quality indices using Cochran Q tests.Results:The median (interquartile range) of blood metals were 0.38 μg/L (0.35), 14.70 μg/L (11.70), and 8.74 μg/L (4.06) for cadmium, lead, and manganese, respectively. Increasing blood concentrations of all metals by one quartile was associated with a decrease in overall cognitive performance (–0.04; 95% confidence interval [CI] = –0.09, 0.02), CERAD (–0.04; 95% CI = –0.12, 0.03), animal fluency (–0.02; 95% CI, –0.11, 0.06), and DSST (–0.05; 95% CI = –0.11, 0.02) test scores. These associations were more pronounced in adults with high pro-inflammatory or low-diet quality and null or positive though imprecise associations in participants with a high anti-inflammatory. These associations also varied by sex with inverse associations in men and positive associations in women.Conclusions:Our findings suggest that adherence to an antioxidant and anti-inflammatory diet may prevent blood metals adverse cognitive effects among older adults. If confirmed, strategies based on diet could provide a potential complementary and efficient approach to counteract effects of environmental pollutants.

Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression

Ornithine transcarbamylase deficiency is a rare X-linked genetic urea cycle disorder leading to episodes of acute hyperammonemia, adverse cognitive and neurological effects, hospitalizations, and in some cases death. DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency; however, the impact of sex and prophylactic immunosuppression on ornithine transcarbamylase gene therapy outcomes is not well characterized. This study sought to describe the impact of sex and immunosuppression in adult, sexually mature female and male cynomolgus macaques through day 140 after DTX301 administration. Four study groups (n = 3/group) were included: male non-immunosuppressed; male immunosuppressed; female non-immunosuppressed; and female immunosuppressed. DTX301 was well tolerated with and without immunosuppression; no notable differences were observed between female and male groups across outcome measures. Prednisolone-treated animals exhibited a trend toward greater vector genome and transgene expression, although the differences were not statistically significant. The hepatic interferon gene signature was significantly decreased in prednisolone-treated animals, and a significant inverse relationship was observed between interferon gene signature levels and hepatic vector DNA and transgene RNA. These observations were not sustained upon immunosuppression withdrawal. Further studies may determine whether the observed effect can be prolonged.

Experience and Management of the Adverse Effects of Analgesics After Surgery: A Pediatric Patient Perspective.

After surgery, the adverse effects (AEs) of analgesics are common and critical factors influencing the postoperative experience of pediatric patients. Inadequate management of AEs has been found to prolong hospital stay, increase readmission rates and decrease satisfaction with care. The aim of this qualitative descriptive study was to better understand the AEs of analgesics from the perspective of adolescent patients with idiopathic scoliosis after spinal surgery. A total of 7 patients participated in the study. Semistructured interviews were conducted at discharge and 1 week after discharge. Transcribed data were analyzed using qualitative content analysis and themes were identified. Overall, participants most frequently reported gastrointestinal and cognitive AEs, with constipation being the most persistent and bothersome. The pediatric participants used a combination of 3 strategies to mitigate analgesic AEs, namely pharmacologic, nonpharmacologic, and reduction of analgesic intake. Participants demonstrated a lack of understanding of AEs and involvement in their own care. Future studies should be conducted to evaluate the efficacy of nonpharmacological strategies in managing analgesic AEs for pediatric patients after surgery.