Cognitive Adverse Events Research Articles

Statin withdrawal in people with dementia

There are approximately 24 million people worldwide with dementia; this is likely to increase to 81 million by 2040. Dementia is a progressive condition, and usually leads to death eight to ten years after first symptoms. End-of-life care should emphasise treatments that optimise quality of life and physicians should minimise unnecessary or non-beneficial interventions. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors; they have become the cornerstone of pharmacotherapy for the management of hypercholesterolaemia but their ability to provide benefit is unclear in the last weeks or months of life. Withdrawal of statins may improve quality of life in people with advanced dementia, as they will not be subjected to unnecessary polypharmacy or side effects. However, they may help to prevent further vascular events in people of advanced age who are at high risk of such events. To evaluate the effects of withdrawal or continuation of statins in people with dementia on: cognitive outcomes, adverse events, behavioural and functional outcomes, mortality, quality of life, vascular morbidity, and healthcare costs. We searched ALOIS (medicine.ox.ac.uk/alois/), the Cochrane Dementia and Cognitive Improvement Group Specialised Register on 11 February 2016. We also ran additional searches in MEDLINE, EMBASE, PsycINFO, CINAHL, Clinical.Trials.gov and the WHO Portal/ICTRP on 11 February 2016, to ensure that the searches were as comprehensive and as up-to-date as possible. We included all randomised, controlled clinical trials with either a placebo or 'no treatment' control group. We applied no language restrictions. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, using standard methodological procedures expected by Cochrane. We found no studies suitable for inclusion therefore analysed no data. The search strategy identified 28 unique references, all of which were excluded. We found no evidence to enable us to make an informed decision about statin withdrawal in dementia. Randomised controlled studies need to be conducted to assess cognitive and other effects of statins in participants with dementia, especially when the disease is advanced.

Reports of Perceived Adverse Events of Stimulant Medication on Cognition, Motivation, and Mood: Qualitative Investigation and the Generation of Items for the Medication and Cognition Rating Scale.

Objective: There is no questionnaire to specifically monitor perceived adverse events of methylphenidate (MPH) on cognition, motivation, and mood. The current study therefore had two goals. First, to harvest accounts of such putative events from transcripts of interviews in samples enriched for such potential experiences. Second, to use the derived data to generate items for a new questionnaire that can be used for monitoring such events in medication trials or routine clinical care.Methods: Following a literature search aimed at identifying associations between MPH and cognition and/or motivation, a qualitative semistructured interview was designed to focus specifically on the domains of cognition (i.e., reasoning, depth/breadth of thinking, intellectual capacity, and creativity) and motivation (i.e., drive, effort, and attitudes toward rewards/incentives). Interviews were conducted with 45 participants drawn from the following four groups: (a) clinicians, child and adolescent psychiatrists, and pediatricians specializing in attention-deficit/hyperactivity disorder (ADHD) (n = 15); (2) teachers, with experience of teaching at least 10 medicated children with ADHD (n = 10); (3) parents of children with ADHD (n = 8) treated with MPH; and (4) adolescents/adults with ADHD (n = 12). Purposeful sampling was used to selectively recruit ADHD participants whose histories suggested a degree of vulnerability to MPH adverse events. Data were analyzed using a deductive approach to content analysis.Results: While we probed purposefully for cognitive and motivational adverse events, a third domain, related to mood, emerged from the reports. Therefore, three domains, each with a number of subdomains, were identified from the interview accounts: (i) Cognition (six subdomains; attention/concentration, changes in thinking, reduced creativity, sensory overload, memory, slower processing speed); (ii) motivation (four subdomains; loss of intrinsic motivation for goal-directed activities, external locus of control, lack of effort/engagement in daily tasks, increased focus on incentives); and (iii) mood (three subdomains; dampening of spontaneity/flat affect, mood dysregulation, increased anxiety/edginess). On the basis of these reports, 34 items were specified and incorporated into a prototype questionnaire, which was piloted and refined on the basis of field-testing.Conclusions: Items were identified that capture potential/perceived cognitive, motivational, and mood-related adverse events of MPH. The items generated will allow us to further develop and psychometrically examine their prevalence, and the extent to which they are associated with medication adherence, treatment outcome, impairment, and other reported adverse events (e.g., loss of appetite/cardiovascular effects).

Concise Review: Stem Cell Interventions for People With Cerebral Palsy: Systematic Review With Meta-Analysis.

: Evidence for stem cells as a potential intervention for cerebral palsy is emerging. Our objective was to determine the efficacy and safety of stem cells for improving motor and cognitive function of people with cerebral palsy. Searches were conducted in October 2015 in CENTRAL, EMBASE, MEDLINE, and Cochrane Libraries. Randomized controlled trials and controlled clinical trials of stem cells for cerebral palsy were included. Two authors independently decided upon included trials, extracted data, quality, and risk of bias. The primary outcome was gross motor function. Secondary outcomes were cognitive function and adverse events (AEs). Effects were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI), using a random-effects model. Five trials comprising 328 participants met inclusion criteria. Four cell types were studied: olfactory ensheathing, neural, neural progenitors, and allogeneic umbilical cord blood (UCBs). Transplantation procedures differed from central nervous system neurosurgical transplantation to intravenous/arterial infusion. Participants were followed short-term for only 6 months. Evidence of variable quality indicated a small statistically significant intervention effect from stem cells on gross motor skills (SMD 1.27; 95% CI 0.22, 2.33), with UCBs most effective. There were insufficient and heterogeneous data to compare cognitive effects. Serious AEs were rare (n = 4/135 [3%] stem cells; n = 3/139 [2%] controls). Stem cells appeared to induce short-term improvements in motor skills. Different types of stem cell interventions were compared, meaning the data were heterogeneous and are a study limitation. Further randomized controlled trials are warranted, using rigorous methodologies. Stem cells are emerging as a scientifically plausible treatment and possible cure for cerebral palsy, but are not yet proven. The lack of valid animal models has significantly hampered the scope of clinical trials. Despite the state of current treatment evidence, parents remain optimistic about the potential improvements from stem cell intervention and feel compelled to exhaust all therapeutic options, including stem cell tourism. Receiving unproven therapies from unvalidated sources is potentially dangerous. Thus it is essential that researchers and clinicians stay up to date. A systematic review and meta-analysis summarizing and aggregating current research data may provide more conclusive evidence to inform treatment decision making and help direct future research.

Transcranial direct current stimulation (tDCS) for improving activities of daily living, and physical and cognitive functioning, in people after stroke.

Transcranial direct current stimulation (tDCS) for improving activities of daily living, and physical and cognitive functioning, in people after stroke.

Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers.

The pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg(-1) alcohol using 40% vodka). In a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. Alcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. SMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed.

Exercise improves cognition in Parkinson's disease: The PRET-PD randomized, clinical trial.

This article reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes that were gathered as part of the Progressive Resistance Exercise Training in Parkinson's disease (PD) randomized, controlled trial. This study was a prospective, parallel-group, single-center trial. Fifty-one nondemented patients with mild-to-moderate PD were randomly assigned either to modified Fitness Counts (mFC) or to Progressive Resistance Exercise Training (PRET) and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention (BTA). Eighteen patients in mFC and 20 patients in PRET completed the trial. At 12 and at 24 months, no differences between groups were observed. At 12 months, relative to baseline, mFC improved on the Digit Span (estimated change: 0.3; interquartile range: 0, 0.7; P = 0.04) and Stroop (0.3; 0, 0.6; P = 0.04), and PRET improved only on the Digit Span (0.7; 0.3, 1; P < 0.01). At 24 months, relative to baseline, mFC improved on the Digit Span (0.7; 0.3, 1.7; P < 0.01) and Stroop (0.3; 0.1, 0.5; P = 0.03), whereas PRET improved on the Digit Span (0.5; 0.2, 0.8; P < 0.01), Stroop (0.2; -0.1, 0.6; P = 0.048), and BTA (0.3; 0, 0.8; P = 0.048). No neurological or cognitive adverse events were observed. This study provides class IV level of evidence that 24 months of PRET or mFC may improve attention and working memory in nondemented patients with mild-to-moderate Parkinson's disease.

Statins and their effect on cognition: Let's clear up the confusion.

Lipid-lowering drugs, such as statins, rank in the top 5 most frequently used prescription drugs in Canada. In fact, between 2007 and 2011, more than 2.9 million Canadians were taking a lipid-lowering drug.1 With a plethora of robust evidence for secondary prevention of cardiovascular disease, coupled with a well-tolerated adverse effect profile, it is no wonder that statins are prescribed quite often. In the past decade, however, some case reports have suggested a possible increase in the risk of cognitive adverse events, such as memory loss, forgetfulness or feeling “fuzzy,” associated with their use.2 In 2005, Health Canada released a statement in the Canadian Adverse Reaction Newsletter suggesting a possible association between statins and memory loss.3 The onset of these adverse events described in the case reports varied, but most occurred within 1 year of statin initiation. Most of the cases (11/19) reported an improvement in cognitive symptoms once the statin was stopped or the dose reduced. In 2012, the Food and Drug Administration (FDA) issued a safety announcement to health care professionals, warning them about the potential risk of cognitive impairment (memory loss, forgetfulness, amnesia, memory impairment, confusion) with the use of statins for a period of 1 day to years.2 Review of these cases did not reveal an association between cognitive impairment and a specific statin, dose or age of patient. These cases were generally reversible, with symptoms disappearing approximately 3 weeks after statin discontinuation. The FDA also enforced a change in the monograph of statin products to warn health care professionals about this rare, but possible, adverse event. This change in monograph has not been mandated in Canada. On the opposite end of the spectrum, some research evaluated the potential use of statins in the prevention and treatment of Alzheimer disease (AD).4 This article focuses on the effects of statins on cognition and the use of statins for the prevention and treatment of AD.

Cognitive adverse events of topiramate in patients with epilepsy and intellectual disability

Topiramate (TPM) is an effective antiepileptic drug (AED). A high proportion of patients, however, experiences cognitive adverse events (CAEs), especially in verbal fluency, memory spans, and working memory. To our knowledge, CAEs of TPM have not been studied systematically in patients with intellectual disability (ID). This may be due to the fact that many of those patients are not able to follow test instructions properly and that neuropsychological instruments are not validated for that group. Cognitive deterioration in patients with ID may thus easily be overlooked. Topiramate is in frequent use in persons with ID. We included 26 consecutive patients with epilepsy and ID in this observational study who had undergone neuropsychological examinations as part of clinical routine before and after the introduction of TPM into the therapeutic regimen (n=4) or before and after the withdrawal of TPM (n=22). Examinations under TPM showed reduced cognitive speed, reduced verbal memory, reduced verbal fluency, and reduced flexibility compared to examinations without TPM. Despite some limitations (especially small sample size, high interindividual variation of the results dependent on the degree of ID, effects of other – limited – changes in the therapeutic regimen), our study indicates that TPM in persons with epilepsy and ID may lead to CAEs comparable to those in persons with normal intelligence. Neuropsychological testing is mandatory in order not to miss CAEs that might severely impair quality of life.

Online vs offline effects of anodal transcranial direct current stimulation on response speed

s / Brain Stimulation 8 (2015) 360e377 362 55% for attention in patients; 37% for executive function to 66% for memory in caregivers). Patient/caregiver agreement was moderate in 3 domains (kappa > 0.40). Objective deficit identification was poor among patients (8% to 45%) and caregivers (12% to 40%). Memory, visuospatial and executive problem report by caregivers was adequately verified (75% to 86%), but patient report only for memory (83%). Discussion: Findings suggests that patient report lacks sensitivity to objectively verified cognitive deficits, though specificity is good for memory. Patient report may be adequate to confirm a general cognitive problem, but should not be relied upon in DBS candidates to identify specific cognitive impairments. Neuropsychological evaluation is preferable to patient report to identify cognitive adverse events (e.g., frontal syndrome) in regulatory filings.

Tolerability and safety of the new anti-obesity medications.

Worldwide obesity prevalence has nearly doubled since 1980. Due to numerous co-morbidities, obesity represents a serious health and socioeconomic problem worldwide. Pharmacotherapy should be an integral part of comprehensive obesity management. Drug therapy can assist in weight loss and its maintenance in those individuals who do not achieve appropriate weight loss through lifestyle interventions alone. After the withdrawal of sibutramine from the market in 2010, orlistat, a lipase inhibitor, was the only remaining prescription drug approved for the long-term treatment of obesity. In 2012, phentermine/topiramate extended-release (PHEN/TPMER) combination and lorcaserin were approved by the US FDA as novel medications for long-term weight management. Three major phaseIII trials conducted with each drug confirmed their efficacy in terms of weight loss/maintenance and improvement of cardiometabolic risks. No head-to-head studies between the two new anti-obesity drugs have been carried out. However, in the existing studies PHEN/TPMER had a superior weight loss profile to lorcaserin but the incidence of adverse effects was lower with lorcaserin. Both drugs were well-tolerated, and adverse events were modest in intensity, dose dependent, rather rare, and tended to decrease with the duration of treatment. Major safety concerns regarding PHEN/TPMER include elevations in resting pulse rate, teratogenicity, mild metabolic acidosis, and psychiatric and cognitive adverse events. Valvulopathy, cognitive impairment, psychiatric disorders, and hypoglycemia represent major safety concerns for lorcaserin. Although existing trials have not demonstrated any significant issues with PHEN/TPMER-induced heart rate elevation and lorcaserin-induced valvulopathy, all safety concerns should be seriously taken into account in patients treated with either of these novel anti-obesity medications.

Comparison of the Risk of Psychological and Cognitive Disorders Between Persistent and Nonpersistent Statin Users

Despite their cardiovascular benefits, statin use has been associated with a wide array of actual or perceived psychological and cognitive adverse events. The objective of this study was to compare baseline characteristics and the risk of developing psychological and cognitive disorders between persistent and nonpersistent statin users. We performed a retrospective cohort study (October 1, 2003, to March 1, 2010) of 13,626 statin users in a regional US military health-care system. The persistence of statin use was defined by cumulative pharmacy fill data. Outcomes were the occurrence of psychological diseases during follow-up using prespecified groups based on International Classification of Diseases, Ninth Revision, codes: (1) schizophrenia and psychosis, (2) major depression and bipolar disorders, (3) all psychological diseases, and (4) dementia and cognitive disorders. Statin users who were nonpersistent at 2years were younger, less likely to be men, and had fewer co-morbidities than persistent users. They were also more likely to be diagnosed with schizophrenia or psychosis (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.20 to 2.10) and cognitive disorders (OR 1.56, 95% CI 1.19 to 2.03) during follow-up compared with persistent users. There was not an association between nonpersistence at 2years and the development of depression and bipolar disorders (OR 0.99, 95% CI 0.85 to 1.15) or combined psychological diseases (OR 0.97, 95% CI 0.86 to 1.09). Cumulative persistence with statin therapy as a continuous measure was associated with less risk of all outcomes. In conclusion, persistent statin users did not demonstrate an increase in the diagnosis of psychological disorders compared with nonpersistent users. Nonpersistent statin use was associated with a greater likelihood of being diagnosed with psychotic or cognitive disorders.

Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain

N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.

The medical and surgical treatment of tumoral seizures: Current and future perspectives

Epilepsy surgery represents the main treatment option for epileptogenic brain tumors. Scalp video-electroencephalography (EEG) and magnetic resonance imaging (MRI) may suffice for defining lesional area and seizure-onset zone in discrete, surgically resectable lesions. The choice of timing for surgery requires a multidisciplinary evaluation, especially in children, when a "wait and see" approach is chosen. Discordant electroclinical and neuroimaging data and an ill-defined epileptogenic lesion require invasive investigations. A multimodal integrated approach may maximize the extent of resection while preserving cerebral function in the eloquent cortex. Radical removal of the tumor is the most important predictor of seizure freedom. Additional predictors include histopathology, age at surgery, duration of epilepsy, and seizure type. Patients with brain tumors are highly vulnerable in relation to the frequent drug-resistance of seizures, the potential interactions between antiepileptic drugs (AEDs) and chemotherapeutic agents (CMTs), and the risk of AED-related cognitive adverse events (24% higher than in the rest of the epilepsy population), in addition to brain damage resulting from tumor itself, surgery, and radiotherapy. No robust, randomized, controlled evidence supports the choice of AEDs for the treatment of seizures in patients with brain tumors. Newer AEDs have limited or no enzyme-inducing profile, prevalent renal excretion, lower plasma protein binding and, consequently, fewer interactions with CMTs. Enzyme-inducing AEDs can lower serum levels of concomitantly administered CMTs. Class I evidence suggests that in patients with brain tumors who do not have a history of seizures, prophylactic use of AEDs is neutral or ineffective.

SAT2 * SODIUM OXYBATE, A BREAKTHROUGH TREATMENT OF ALCOHOL WITHDRAWAL SYNDROME AND MAINTENANCE OF ALCOHOL ABSTINENCE (D&amp;A)

SAT2 * SODIUM OXYBATE, A BREAKTHROUGH TREATMENT OF ALCOHOL WITHDRAWAL SYNDROME AND MAINTENANCE OF ALCOHOL ABSTINENCE (D&amp;A)

Intravenous topiramate: Comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers

Although oral topiramate (TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long-term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration (FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation. This study was an open-label, two-way crossover of oral and intravenous TPM in 12 healthy adult volunteers. Initially two subjects received 50 mg, intravenously and orally. Following evidence of safety in the first two subjects, 10 individuals received 100 mg doses of intravenous and oral TPM randomly sequenced 2 weeks apart. Blood samples were taken just prior to drug administration and at intervals up to 120 h afterwards. TPM was measured using a validated liquid chromatography-mass spectrometry method. Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2. All subjects completed the study. The mean (±standard deviation) absolute oral bioavailability was 109% (±10.8%). For intravenous and oral TPM the mean distribution volumes were 1.06 L/kg (±0.29) and 0.94 L/kg (±0.24). Clearances were 1.33 L/h (±0.26) and 1.22 L/h (±0.26). The half-life values were 42.3 h (±6.2) and 41.2 h (±7.5). No changes in heart rate, blood pressure, electrocardiography, or infusion site reactions were observed. Mild central nervous system cognitive adverse events and ataxia occurred between dosing and 2 h post dose with both intravenous and oral administration. With intravenous TPM, these adverse effects occurred as early as during the 15-min intravenous infusion. In healthy adults, oral TPM is bioequivalent to intravenous TPM, and infusion of 50-100 mg over 15 min is safe. Neurologic effects occurred during the infusion, demonstrating that TPM rapidly diffuses into the brain, which supports its evaluation for neonatal seizures. Results from this pilot study will inform the design of subsequent studies in children and newborns, including controlled clinical trials intended to assess the efficacy and safety of intravenous TPM for neonatal seizures. In addition, our results provide support for the further development of intravenous TPM as bridge therapy for older children and adults in whom oral TPM therapy is interrupted.

Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial

Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. Forest Research Institute.

Recent FDA statin alerts: Evaluating the evidence

The labels for statins have undergone numerous changes in recent months, with FDA adding new warnings about the potential for increased fasting plasma glucose and glycosylated hemoglobin (A1C) levels and the potential for generally nonserious and reversible cognitive adverse effects with use of statin therapy. In addition, the drug interaction section of various statins has been modified to include new contraindications and dosing restrictions when used with certain medications.

Topiramate and cognitive impairment: evidence and clinical implications

Topiramate is an antiepileptic drug (AED) with multiple mechanisms of action that has been shown to be effective in a number of neuropsychiatric disorders. However, cognitive dysfunction is frequently observed in such patients, often representing a relevant challenge in their management. Moreover, there is a long-held recognition that AEDs may profoundly affect cognitive functions. This paper reviews available data on cognitive adverse events in patients with neurological disorders treated with topiramate, discussing the role of different contributing factors such as the pharmacological properties of the drug, the specific features of the brain disorder, and other variables pertinent to the discussion. All studies agree that up to 10% of patients may complain of treatment-emergent adverse events on cognition. Such problems occur early during treatment (i.e. within 6 weeks) and emerge in a dose-dependent fashion, suggesting that such prevalence may be significantly reduced using the drug in monotherapy and adopting individualized doses and titration schedules. The magnitude of the problem is generally mild to moderate and the subjective perception of the patient needs to be taken into account. In fact, apart from language problems, data are not conclusive. Comparisons with new AEDs are limited to levetiracetam and lamotrigine, in both cases generally disfavoring topiramate, while data regarding first-generation AEDs show clear differences only for verbal fluency.

Adaptive Behavior Outcomes in Infants Treated With Adjunctive Topiramate

Data from two global studies (6-week open-label, phase 1 study; 20-day double-blind, phase 3 study) and their 1-year open-label extensions were pooled to assess long-term effects of adjunctive topiramate on adaptive behavior in infants with clinical or video-electroencephalographic evidence of refractory, partial-onset seizures. The primary safety and efficacy results of adjunctive topiramate treatment were reported previously. We report the changes in adaptive behavior of infants, based on Vineland Scales of Adaptive Behavior. Of 284 infants (mean [S.D.] age, 12 [6.3] months) enrolled, 89% (n = 252) manifested partial-onset seizures, and 41% (n = 116) manifested clinically relevant, symptomatic etiologies at pretreatment baseline. Overall, Vineland scores were below average at pretreatment baseline. The most frequently used concomitant antiepileptic drugs included valproic acid (59%), phenobarbital (31%), and carbamazepine (19%). The most common treatment-emergent cognitive and neuropsychiatric adverse events included anorexia (35%) and somnolence (27%). A clinically significant decline (approximately 15 points, or 1 S.D.) occurred in both Vineland Scales composite (mean change, -14.0) and domain standard scores from pretreatment baseline to open-label extension endpoint. However, individual domain raw scores increased, indicating that infants progressed in acquisitions of adaptive skill, but at a slower rate than the normative population.

The Incidence of Cognitive Adverse Events Related to Eslicarbazepine Acetate: An Integrated Analysis (P06.116)

Objective: Eslicarbazepine acetate (ESL) is a novel AED currently in development in the US as adjunct treatment for partial-onset seizures. Background Cognitive dysfunction is frequently observed in patients with epilepsy and represents an important challenge in the management of patients with this disorder. 1 In this respect, the contribution of antiepileptic drugs (AEDs) is of relevance, and studies in healthy volunteers have shown that AEDs produce cognitive effects. 1,2 Design/Methods: 797 subjects in the safety population were studied. Investigators recorded adverse events at each visit from Visit 1 and throughout the study (including at early discontinuation and at the post study visit). A Treatment Emergent Adverse Events (TEAE) was defined as an event that occurred on or after the date of first dose, or the date of randomization if the dates of the first dose or the onset of the event were missing or incomplete. All TEAEs affecting any aspect of cognition were tabulated. Results: TEAEs identified as related to cognition were disturbance in attention, memory impairment, amnesia, aphasia, bradyphrenia, and psychomotor retardation. The incidence of these TEAEs was ≤ 2% in all ESL dose groups. The highest incidence occurred in the ESL 1200 mg group, with bradyphrenia and aphasia only observed in this dose group. Conclusions: In this analysis, treatment with eslicarbazepine acetate as adjunct therapy to 1 to 3 concomitant AEDs was associated with a low incidence of cognitive TEAEs.