Adverse Cognitive Effects Research Articles

Clinical Improvement in Depression and Cognitive Deficit Following Electroconvulsive Therapy.

Electroconvulsive therapy (ECT) is a long-standing treatment choice for disorders such as depression when pharmacological treatments have failed. However, a major drawback of ECT is its cognitive side effects. While numerous studies have investigated the therapeutic effects of ECT and its mechanism, much less research has been conducted regarding the mechanism behind the cognitive side effects of ECT. As both clinical remission and cognitive deficits occur after ECT, it is possible that both may share a common mechanism. This review highlights studies related to ECT as well as those investigating the mechanism of its outcomes. The process underlying these effects may lie within BDNF and NMDA signaling. Edema in the astrocytes may also be responsible for the adverse cognitive effects and is mediated by metabotropic glutamate receptor 5 and the protein Homer1a.

Non-invasive brain stimulation and cognitive function in patients with major depressive disorder or bipolar depression: systematic review and meta-analysis

IntroductionNon-invasive brain stimulation protocols are effective treatments for depressive episodes. Although the cognitive adverse effects of electroconvulsive therapy (ECT) are well documented, evidence regarding the cognitive effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) is mixed.ObjectivesThe aim of this study was to synthesize research on the cognitive effects of non-invasive brain stimulation protocols and to differentiate between studies of major depressive disorder (MDD), bipolar depression and mixed populations.MethodsFollowing a systematic literature search of multiple electronic databases, a series of meta-analyses were conducted to estimate standardized mean differences (SMD) between pre- and post-treatment cognitive functioning across nine cognitive domains. Where possible, SMDs were estimated separately for MDD, bipolar depression and mixed populations. In studies that included both patients with MDD and bipolar depression, the percentage of patients with a diagnosis of bipolar depression was tested as a potential moderator.ResultsMore than 150 treatment arms were included in the analyses. For ECT, we observed a small decline in language functioning and a decrease in autobiographical memory scores. There was no evidence of pre-post differences across other cognitive domains. For rTMS and tDCS, small to moderate cognitive improvements were observed for several cognitive domains, for example for executive functioning. Across most analyses, between-study heterogeneity was high and could not be accounted for by differences between MDD, bipolar depression or mixed populations.ConclusionsThere was limited evidence that differentiation between studies of MDD, bipolar depression and mixed populations accounted for between-study heterogeneity in analyses of pre-post differences in cognitive functioning. Given that most studies included both patients with MDD and bipolar depression, this finding should be treated as preliminary. Across all the treatment protocols examined, more data are needed to investigate the cognitive effects of non-invasive brain stimulation in patients with bipolar depression.Disclosure of InterestNone Declared

Effects of tamoxifen and exemestane on cognitive function in postmenopausal patients with breast cancer.

Cognitive effects of tamoxifen have been described. We augment data from a previous short-term (ST) follow-up study with long-term (LT) data to evaluate ST and LT cognitive effects of tamoxifen followed by exemestane and exemestane in breast cancer patients. Patients from the Tamoxifen and Exemestane Adjuvant Multinational trial received 5 years exemestane (exemestane group, n = 114) or 2.5 years tamoxifen followed by 2.5 years exemestane (sequential group, n = 92). Neuropsychological performance was assessed pre-endocrine therapy, after 1 year (ST follow-up) and at 5 years (LT follow-up). A control group of healthy participants (n = 120) were assessed with parallel intervals. With random effects modeling we evaluated cognitive changes from baseline to ST and LT follow-up. Statistical tests were 2-sided. After controlling for age, intelligence quotient, attrition, menopausal symptoms, anxiety and/or depression, and/or fatigue, the sequential group showed ST and LT decline compared with control participants on verbal memory (effect size [ES] = 0.26, P = .01; ES = 0.34, P = .003) and executive function (ES = 0.27, P = .007; ES = 0.38, P = .002). Compared with the exemestane group, the sequential group demonstrated ST decline on information processing speed (ES = 0.33, P = .01) and executive function (ES = 0.32, P = .01) and LT decline on verbal memory (ES = 0.33, P = .02). The exemestane group showed no cognitive decline compared with control participants. Cognitive adverse effects of tamoxifen alone and after switching to exemestane were observed, suggestive of a carryover effect of tamoxifen. Our results underline the need for well-controlled, prospective trials studying cognitive effects of endocrine therapy.

Comparison of Efficacy and Safety of Magnetic Seizure Therapy and Electroconvulsive Therapy for Depression: A Systematic Review.

As a new physical therapeutic technique, magnetic seizure therapy (MST) has established efficacy in the treatment of depression with few cognitive side effects, and thus appears to be a potential alternative to electroconvulsive therapy (ECT). The findings of randomized controlled trials (RCTs) examining the efficacy and safety of MST versus ECT for depression are inconsistent. This systematic review of RCTs was designed with the aim of assessing the safety and efficacy of MST versus ECT for patients with depression. The WanFang, Chinese Journal Net (CNKI), EMBASE, PubMed, Cochrane Library, and PsycINFO databases were systematically searched by three independent investigators, from their inceptions to July 24, 2021. In total, four RCTs (n = 86) were included and analyzed. Meta-analyses of study-defined response (risk ratio (RR) = 1.36; 95% CI = 0.78 to 2.36; p = 0.28; I2 = 0%), study-defined remission (RR = 1.17; 95% CI = 0.61 to 2.23; p = 0.64; I2 = 0%), and the improvement in depressive symptoms (standardized mean difference (SMD) = 0.21; 95% CI = -0.29 to 0.71; p = 0.42; I2 = 0%) did not present significant differences between MST and ECT. Three RCTs evaluated the cognitive effects of MST compared with ECT using different cognitive measuring tools, but with mixed findings. Only two RCTs reported adverse drug reactions (ADRs), but these lacked specific data. Only one RCT reported discontinuation due to any reason. This preliminary study suggests that MST appears to have a similar antidepressant effect as ECT for depression, but mixed findings on adverse cognitive effects were reported.

Prenatal and current phthalate exposure and cognitive development in 7-year-old children from the Odense child cohort

BackgroundPhthalates are endocrine disrupters used in a variety of consumer products. Human studies suggest an association between phthalate exposure and cognitive development but adverse effects of the recently introduced phthalate substitutes have only been sparsely studied. ObjectivesTo investigate associations between prenatal and concurrent exposure to phthalates and IQ in 7-year-old children from the Odense Child Cohort. MethodsPregnant women from the Odense Child Cohort had phthalate metabolites measured in urine samples during 3rd trimester in 2010 to 2012. In addition, phthalates were also measured in urine samples from their offspring at age 7 years. IQ was assessed at age 7 years using four subtests from Wechsler Intelligence Scale for Children. The total study population consisted of 585 mother-child pairs with available prenatal urinary phthalate metabolites concentrations and IQ data at age 7 years. A subset of those (N = 274) had urinary phthalate metabolites measured in child urine at age 7 years. Phthalate concentrations were grouped into tertiles and associations with IQ were investigated using multiple linear regression adjusting for sex, maternal education and maternal/child BMI. ResultsUrinary phthalate metabolite concentrations both in pregnant women and children were generally lower compared to previous cohorts. Children with high prenatal urinary concentrations of MEP and metabolites of DEHP (∑DEHPm)(3rd tertile) had −3.1 (95% CI: −5.5, −0.6) (MEP) and − 3.0 (−5.5, −0.6) (∑DEHPm) IQ points at age 7 years compared to children with low concentrations (1st tertile). High concurrent urinary phthalate concentrations of MCPP, ∑DnHxPm, ∑DiDPm and ∑DiNPm in the 3rd tertile was associated with −3.7 (−7.2, −0.2), −4.4 (−7.9, −0.9), −3.7 (−7.2, −0.2) and − 5.6 (−9.1, −2.2) IQ points, respectively, compared to those with the lowest concentrations (1st tertile). ConclusionWe found significant inverse associations between some prenatal and concurrent urinary phthalate concentrations and IQ at age 7 years in this low exposed population. This suggests that exposure to phthalates both prenatally and during early childhood could be hazardous to child neurodevelopment, however, large-scale prospective studies assessing phthalate exposure through multiple urine samples, and possibly investigating cocktail effects of the chemicals as well as long term follow-up are warranted.

LIN28 expression and function in medulloblastoma.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatment modalities are not completely effective and can lead to severe neurological and cognitive adverse effects. In addition to urgently needing better treatment approaches, new diagnostic and prognostic biomarkers are required to improve the therapy outcomes of MB patients. The RNA-binding proteins, LIN28A and LIN28B, are known to regulate invasive phenotypes in many different cancer types. However, the expression and function of these proteins in MB had not been studied to date. This study identified the expression of LIN28A and LIN28B in MB patient samples and cell lines and assessed the effect of LIN28 inhibition on MB cell growth, metabolism and stemness. LIN28B expression was significantly upregulated in MB tissues compared to normal brain tissues. This upregulation, which was not observed in other brain tumors, was specific for the aggressive MB subgroups and correlated with patient survival and metastasis rates. Functionally, pharmacological inhibition of LIN28 activity concentration-dependently reduced LIN28B expression, as well as the growth of D283 MB cells. WhileLIN28 inhibition did not affect the levels of intracellular ATP, it reduced the expression of the stemness marker CD133 in D283 cellsand the sphere formation of CHLA-01R cells. LIN28B, which is highly expressed in the human cerebellum during the first few months after birth, subsequently decreased with age. The results of this study highlight the potential of LIN28B as a diagnostic and prognostic marker for MB and openthe possibility to utilize LIN28 as a pharmacological target to suppress MB cell growth and stemness.

High‐stakes examinations and educational inequality: Evidence from transitory exposure to air pollution

AbstractWe study the impact of transitory random disturbances to cognitive performance and a minimum‐passing‐score policy on access to graduate education among students who took a series of high‐stakes exams. Exploiting thermal inversions and individual fixed effects, we document significant adverse cognitive effects of transitory exposure to air pollution during the exam. The harmful cognitive effects permanently reduce students' chances of getting into graduate school, especially for marginal students who scored just below the cutoff score. Marginal students would be less affected by random disturbances and have more equal access to graduate education had such an exam policy not been adopted.

Safety and efficacy of etomidate in combination with oxycodone in painless gastroscopic procedures in the elderly: A prospective randomized controlled trial study

Etomidate is often combined in rapid succession during induction of anesthesia. However, the effect of pretreatment with oxycodone on recovery of cognitive function and adverse effects has rarely been studied. We conducted a prospective randomized controlled trial to compare etomidate alone with etomidate combined with oxycodone in elderly patients undergoing painless gastroscopy. Hundred elderly patients undergoing painless gastroscopy were divided into a control and an observation group, with 50 cases in each group. The age, gender, height, weight, body mass index and American Society of Anesthesiologists physical status (I/II) of patients in both groups were recorded. The recovery of cognitive function was compared in both groups using the Neurobehavioral Cognitive Status Examination. Adverse events, including somatic motor reactions, hypotension, bradycardia, myocardial tremor, nausea and vomiting, and injection pain, were also recorded in both groups. Moreover, heart rate, peripheral capillary oxygen saturation, systolic blood pressure, and diastolic blood pressure were evaluated in the 2 groups at different time points. A total of 100 patients were enrolled in this study. The demographic characteristics in the 2 groups were not significantly different (P > .05). Regarding the recovery of cognitive functions, more subjects in the observation group passed the memory, arithmetic and orientation test than in the control group (P < .05). Fewer adverse events such as dynamic body reactions, cardiac tremor, nausea and vomiting, and injection pain occurred in the observation group than in the control group (P < .05). During anesthesia and after awakening, the results of peripheral capillary oxygen saturation, systolic blood pressure and diastolic blood pressure were better in the observation group than in the control group (P < .05). Etomidate in combination with oxycodone for painless gastroscopic operation in the elderly is a safe and effective anesthetic strategy.

Modulation of GABAB receptors in the insula bidirectionally affects associative memory of epilectic rats in both spatial and non-spatial operant tasks.

Stimulation of gamma-aminobutyric acid (GABA) activity through GABA receptor agonists is the basic mechanism of many anticonvulsant drugs. Nevertheless, many of these GABergic drugs have adverse cognitive effects. We previously found that GABAB receptors (GABABRs) in the insula regulate operant associative memory in healthy rats. The present study aimed at investigating the effects of GABABR modulation in the insula on operant associative memory in epileptic rats, along with the underlying mechanisms. The lithium-pilocarpine model of temporal lobe epilepsy (TLE) was established in male Sprague-Dawley rats. A 22-gauge stainless-steel guide cannula was surgically implanted into the granular insula cortex of the epileptic rats. Baclofen (125 ng/μl, 1 μl), CGP35348 (12.5 μg/μl, 1 μl), or saline (1 μl) was slowly infused through the guide cannula. The Intellicage automated behavioral testing system was used to evaluate operant associative memory of the epileptic rats, including non-spatial operant tasks (basic nosepoke learning and skilled nosepoke learning) and spatial operant tasks (chamber position learning). The expression of the GABABR subunits GB1 and GB2 in the insula was examined by immunofluorescence and Western blotting. The Intellicage tests demonstrated that baclofen significantly impaired basic nosepoke learning, skilled nosepoke learning and chamber position learning of the epileptic rats, while CGP35348 boosted these functions. Immunofluorescence staining revealed that GB1 and GB2 were expressed in the insula of the epileptic rats, and Western blotting analysis showed that baclofen enhanced while CGP35348 inhibited the expression of these subunits. GABABRs in the insula bidirectionally regulate both spatial and non-spatial operant associative memory of epileptic rats. Effects of GABABRs on cognition should be taken into account when evaluating new possible treatments for people with epilepsy.

Clinical Practice Guidelines for the Use of Electroconvulsive Therapy.

Clinical Practice Guidelines for the Use of Electroconvulsive Therapy.

Prevalence and Associated Risk Factors of Anemia Among Hospitalized Children in a Tertiary Level Hospital in Botswana.

Anemia is a global health concern and has been associated with long term cognitive and behavioral adverse effects. A cross sectional study was conducted to determine the prevalence of and risk factors for anemia in infants and children between 6 months to 5 years of age admitted to a tertiary hospital in Botswana. Baseline full blood count of every patient admitted during the study period was assessed to determine if anemia was present. Data were collected from patient's medical inpatient chart, electronic medical record (Integrated Patient Management System (IPMS)), and through interviewing parents and caregivers. Multivariate logistic regression model was used to identify risk factors of anemia. A total of 250 patients were included in the study. Prevalence of anemia in this cohort was 42.8%. There were 145 (58%) males. Of the patients with anemia, 56.1%, 39.2%, and 4.7% had mild, moderate, and severe anemia, respectively. Microcytic anemia consistent with iron deficiency was identified in 61 (57%) patients. Age was the only independent predictor of anemia. Children aged 24 months and more had a 50% lower risk of having anemia than their younger counterparts (odds ratio (OR) 0.52; 95% Confidence Interval (95% CI) 0.30 to 0.89). The findings of this study demonstrate anemia as a serious health concern in the pediatric population in Botswana.

Cognitive adverse effects of epilepsy and its predictors attending outpatient department of South Gondar zone hospitals, Amhara Region, Ethiopia 2020 /2021.

Epilepsy is the most common neurologic disorder which is further complicated by neurobehavioral co-morbidities, cognitive impairment, psychiatric disorders, and social problems. However, assessments of cognitive status of epileptic patients are far too low during clinical visits. This calls for early neuropsychological assessment soon after the diagnosis of epilepsy for a better treatment plan and outcome for epileptic patients. This study aimed to assess the cognitive adverse effects of epilepsy and its predictors attending outpatient departments of South Gondar Zone hospitals Amhara region Ethiopia 2020/2021. A multi-center institutional-based cross-sectional study was conducted. A total of 509 respondents were included with a response rate of 93.9%. Previously adapted pretested structured questionnaire was used containing, socio-demographic, clinical, and seizure related factors. Mini-Mental State Examination (MMSE) was used to measure cognitive impairment. A systematic random sampling technique was applied. Data were entered into Epi data version 4.4.2 then exported to SPSS version 24 for analysis. Descriptive statistics, bivariable and multivariable binary logistic regressions with odds ratios and 95% confidence interval were employed. The level of significance of association was determined at a p-value < 0.05. Prevalence of cognitive impairment in this study was 69.2% (95%CI; 65.4, 73.1). Rural residents (AOR = 4.16,95%CI, 1.99,8.67), respondents who couldn't read and write (AOR = 2.62, 95%CI; 1.24, 5.5,) longer duration of seizure disorder (AOR = 4.59,95%CI; 2.01,10.52), taking combined Phenobarbital and Phenytoin (AOR = 4.69,95%CI; 1.88,11.69), having history of head injury (AOR = 3.29,95%CI;1.30,8.32), having depression (AOR = 4.76,95%CI;2.83,7.98), and anxiety (AOR = 3.11,95%CI; 1.58,6.12) were significantly associated with cognitive impairment. Prevalence of cognitive impairment in this study was high. Regular neuropsychiatric assessment of patients with epilepsy should be encouraged especially for those participants with longer durations of illness, who are rural residents, who take combined Phenobarbital and Phenytoin, participants who had a history of head injury, depression, and anxiety.

Sex Differences in the Effects of High Fat Diet on Neuroinflammation in a Mouse Model of VCID

AbstractBackgroundNeuroinflammation plays a central role in the progression of vascular contributions to cognitive impairment and dementia (VCID). Unfortunately, anti‐inflammatory therapeutics have proven insufficient so far at ameliorating the progression of VCID. This may be because broadly suppressing inflammation prohibits its beneficial functions. Instead, supporting endogenous inflammation resolving programs may prove more effective. Mid‐life metabolic disease is a major risk factor for VCID, particularly in women. Therefore, we examined neuroinflammation at middle‐age in both males and females with VCID. We modeled metabolic disease via long‐term administration of a high fat (HF) diet, and VCID via unilateral carotid artery occlusion surgery which results in chronic cerebral hypoperfusion. We hypothesized that metabolic disease would lead to more adverse cognitive and neuroinflammatory effects in middle‐aged females compared to males in a mouse model of VCID.Method8.5 month old male and female C57BL/6J mice were placed on a HF or control diet for 7 months. At month 3, they received VCID or sham surgery. At month 6, cognitive function was assessed. Half of the brains were collected for histology while the other half were flash frozen for qPCR analysis of pro‐inflammatory and pro‐resolving mediators.ResultHippocampal‐dependent spatial memory was impaired in VCID males, regardless of diet; however, in females, both HF diet and VCID (or a combination of the two) impaired spatial memory. In males, HF diet increased microglial activity in the hippocampus. Additionally, HF diet in combination with VCID surgery increased expression of pro‐inflammatory markers as well as pro‐resolving mediators in males. However, females on a HF diet experienced a suppression of microglia activity in the hippocampus. HF‐fed females, regardless of surgery, had decreased expression of both pro‐inflammatory markers as well as pro‐resolving mediators.ConclusionIn line with clinical findings, these data suggest that metabolic disease increases cognitive deficits to a greater extent in middle‐aged females than males. Further, our data suggest VCID with metabolic disease increases neuroinflammation and its resolution in males, while metabolic disease suppresses neuroinflammation and its resolution in females. This highlights the need for a better understanding of the sex differences in neuroinflammation following vascular injury.

Neuropathology of a patient with AD treated with low doses of verubecestat

AbstractBackgroundBACE‐1 inhibition in humans is limited by the existence of cognitive adverse effects. Understanding the specific effects of these compounds on brain histopathology is key to refining this drug target.Methodsneuropathological examination of a patient with Alzheimer’s disease (AD) treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat.Resultsbrain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated AD cases.Conclusionalthough the overall findings were mild, our findinds suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation. We will discuss the implications for future trials.

Differences in Cognitive Adverse Effects and Seizure Parameters Between Thiopental and Propofol Anesthesia for Electroconvulsive Therapy.

Electroconvulsive therapy (ECT) is a well-established treatment option in case of severe and treatment-resistant psychiatric conditions. In this retrospective study, we compared the 2 anesthetics propofol and thiopental in terms of seizure quality, cognitive adverse effects, and clinical outcome. Data collection was performed retrospectively by a chart review, including patient files and medical records. A total of 64 patients (female = 60.9%) treated with ECT within the period of February 2019 to March 2020 were included. Of these, 35 (54.7%) received thiopental for ECT narcosis and 29 (45.3%) were treated with propofol. Six hundred sixteen ECT treatments (mean number per case, 9.6) were performed in total. The mean electroencephalogram seizure duration (38.3 vs 28.1 seconds, t = 3.534, degrees of freedom [ df ] = 62, P < 0.001) and motor seizure duration (21.5 vs 12.0, t = 4.336, df = 62, P < 0.001) as well as postictal suppression index and heart rate increase were significantly higher in the thiopental group. Mean stimulation energy needed per session was higher in the propofol group (88.6% vs 73.0%, Mann-Whitney U test, P = 0.042). The ECT series was more likely to be interrupted due to cognitive adverse effects in the thiopental group ( P = 0.001, Pearson χ 2 = 10.514, df = 1). Number of patients achieving remission was significantly higher in the thiopental group (31.4% vs 6.9%, P = 0.015, χ 2 = 5.897, df = 1). Thiopental led to better seizure duration and quality and was associated with a higher rate of remission. As a downside, thiopental was also associated with a greater risk of cognitive adverse effects.

Evaluation of a Rapid Topiramate Titration Scheme for the Early Detection of Cognitive Side Effects.

Topiramate (TPM) is effective for treating epilepsy, but executive dysfunction is a common side effect that could significantly affect everyday life. Additionally, previous studies have suggested that patients might be unaware of these changes. To evaluate a rapid TPM titration scheme for the early detection of adverse cognitive side effects. In this retrospective study, we assessed changes in objective cognitive performance (EpiTrack®) after rapidly titrating TPM (50 mg per day during an inpatient stay) in 49 epilepsy patients and compared those results with an outpatient control group that underwent the recommended standard titration (n = 23 with 25-50 mg per week). Using Bayesian statistics, analyses revealed decisive evidence of a negative effect on cognitive performance when TPM was introduced (BF 31480000000) independent of the titration speed (BF 0.739). When using a fast titration rate, deficits in executive function increased from a baseline of 53.1to73.5% at follow-up, and 55.1% experienced a statistically significant intraindividual decline. When using the standard titration scheme, impairments increased from 52.2 to 65.2%, with an intraindividual deterioration found in 52.2% of the patients. Physicians might be able to detect adverse cognitive side effects sooner in epilepsy patients if TPM is administered using a faster titration rate while applying repeated cognitive assessments within days. This approach might help prevent any unnoticed intolerance and eventual negative consequences for the patient. Therefore, we recommend monitoring early on foradverse changes instead of withholding a potentially effective treatment option because of anticipated side effects.

High-definition transcranial direct current stimulation (HD-tDCS) as augmentation therapy in late-life depression (LLD) with suboptimal response to treatment—a study protocol for a double-blinded randomized sham-controlled trial

BackgroundLate-life depression (LLD) has a poorer prognosis and higher relapse rate than younger adults, with up to one third of patients with LLD showing suboptimal response to antidepressant therapy. LLD has been associated with significant impairment in cognition and daily functioning. Few studies have evaluated the therapeutic effects of high-definition transcranial direct current stimulation (HD-tDCS) on depressive and cognitive symptoms of LLD. The current randomized controlled trial assesses the efficacy of HD-tDCS as an augmentation therapy with antidepressants compared to sham-control in subjects with LLD.MethodsFifty-eight patients with LLD will be recruited and randomly assigned to the active HD-tDCS or sham HD-tDCS group. In both groups, patients will receive the active or sham intervention in addition to their pre-existing antidepressant therapy, for 2 weeks with 5 sessions per week, each lasting 30 min. The primary outcome measures will be the change of depressive symptoms, clinical response and the remission rate as measured with the Hamilton Depression Rating scale (HAMD-17) before and after the intervention, and at the 4th and 12th week after the completed intervention. Secondary outcome measures include cognitive symptoms, anxiety symptoms, daily functioning and adverse effects. DiscussionOlder adults with depression are associated with poorer outcomes or unsatisfactory responses to antidepressant therapy, and significant cognitive decline. Therefore, a new effective treatment option is needed. This randomized control trial aims at assessing the efficacy of HD-tDCS on ameliorating the depressive, cognitive and anxiety symptoms, and improving the daily functioning of subjects with LLD.Trial registrationClinicalTrials.gov NCT05322863. Registered on 11 April 2022.

Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote

Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood–brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.

Effects of cenobamate on cognitive performance of epilepsy patients

PurposeCenobamate (CNB) is a new antiseizure medication (ASM) for the treatment of focal epilepsy in adults. While efficacy of CNB was confirmed in controlled clinical trials, its effects on cognition are unclear. Cognitive adverse effects of ASM affect quality of life and retention rate. Therefore, we investigated whether the adjunctive treatment with CNB is associated with changes in cognitive performance. MethodEfficacy and tolerability of CNB were investigated in an observational study. Fifty patients with pharmacoresistant focal epilepsy aged 18 to 71 years (Mdn = 37.5 years) were tested before (T0) and after reaching the first target dose of CNB, usually after three months (T1). Cognitive performance was assessed using the EpiTrack©, a change-sensitive screening tool for attention and executive functions. ResultsThe median CNB dose at T1 was 125 mg/day (range: 50 – 250 mg/day). Most patients received 2–3 concomitant ASMs. Individual test scores remained stable in 72%, significantly improved in 16%, and significantly deteriorated in 12% of the patients from T0 to T1. The total group showed a significant improvement in EpiTrack scores (p < .01). Changes in EpiTrack performance from T0 to T1 occurred independently of CNB dose, changes in the total drug load or reduction in seizure frequency. ConclusionMost of the patients showed stable or improved cognitive performance. Thus, there is preliminary evidence that adjunctive CNB is not associated with an increased risk of cognitive side effects for the majority of patients. These findings need to be confirmed in controlled trials encompassing higher doses.

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.