Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy

It is well known that epilepsy, antiepileptic drugs (AEDs), and the reproductive system have complex interactions. Fertility is lower in both men and women with epilepsy than in the general population. Moreover, reproductive endocrine disorders are more common among patients with epilepsy than among the population in general. These disorders have been attributed both to epilepsy itself and to use of AEDs. The use of the liver enzyme-inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone-binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time, the increase in serum SHBG levels leads to diminished bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, and thus to reduced fertility. Liver enzyme-inducing AEDs also reduce the efficacy of oral contraceptives. Valproic acid medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of valproic acid-related reproductive endocrine changes in men is unknown. On the other hand, in women, use of valproic acid appears to be associated with a frequent occurrence of reproductive endocrine disorders characterised by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. These disorders are especially common among women who have gained weight during valproic acid treatment. There are some discrepancies regarding the reported occurrence of reproductive endocrine disorders in women taking valproic acid for epilepsy. However, most studies also including patients receiving valproic acid for other reasons than epilepsy, and studies in different non-epileptic animal models, have shown an association between valproic acid medication and hyperandrogenism and related reproductive endocrine disorders. From a practical point of view, the length of the menstrual cycles and bodyweight should be monitored in women with epilepsy after commencement of treatment with valproic acid. A serum testosterone assay is helpful in following the possible biochemical endocrine changes. Ultrasonography of the ovaries (preferably transvaginal) is indicated if clinical assessment and serum testosterone measurement imply that there is a clinically significant valproic acid-related reproductive endocrine problem. That would be the case if the menstrual cycles were irregular or prolonged (usually >35 days) and serum testosterone levels elevated, especially with associated weight gain. The endocrine effects of the new AEDs have not been widely studied. However, it seems they may offer an alternative if reproductive endocrine problems emerge during treatment with the older AEDs.     

抗癫痫药物对认知功的影响

认知功能是指接受、加工、储存和应用信息的能力.它是人们成功地完成各种活动最重要的心理条件.理解力、记忆力、注意力、学习能力、警觉和想象能力等均被认为是重要的认知能力[1].癫痫患儿的认知能力受癫痫发作、社会心理因素、抗癫痫药物(AEDs)等多种因素的影响.儿童较成人而言,由于大脑兴奋性和抑制性尚未达到平衡,更易罹患癫痫,且更易发生认知功能障碍.AEDs在减低致痫神经元兴奋性的同时亦降低了正常神经元的兴奋性,从而损伤认知功能.     

抗癫痫药物对认知功能的影响

认知功能是指接受、加工、储存和应用信息的能力。它是人们成功地完成各种活动最重要的心理条件。理解力、记忆力、注意力、学习能力、警觉和想象能力等均被认为是重要的认知能力。癫痫患儿的认知能力受癫痫发作、社会心理因素、抗癫痫药物（AEDs）等多种因素的影响。儿童较成人而言，由于大脑兴奋性和抑制性尚未达到平衡，更易罹患癫痫，且更易发生认知功能障碍。     

新抗癫癎药影响认知功能的研究进展

近10年来,对癫癎的研究迅速发展,临床上出现了一批新的抗癫癎药物(AEDs),如奥卡西平、氨己烯酸、拉莫三嗪、唑尼沙胺、加巴喷丁、硫加宾、托吡酯和左乙拉西坦.与传统的抗癫癎药物相比,疗效相似,而耐受性更好.另外几个新抗癫癎药物的疗效相近,治疗谱相似.癫癎患者需要长年用药,甚至终身服药,因此,选择抗癫癎药物主要是基于药物的耐受性、避免对身体和精神的不良反应、防止对患者认知功能的损害.认知功能损害是影响癫癎患者生活质量的主要因素之一.     

Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents.

AIM: The relative gastrointestinal toxicity of NSAIDs in normal clinical practice is unknown. The aim of this study was to estimate the risk of upper gastrointestinal bleeding associated with NSAIDs and analgesics, with special emphasis on those agents that have been introduced in recent years. DESIGN: Multicentre case-control study. PATIENTS: All incident community cases of upper gastrointestinal bleeding from a gastric or duodenal lesion in patients aged >18 years of age (4309 cases). After secondary exclusions, 2813 cases and 7193 matched controls were included in the analysis. SETTING: Eighteen hospitals in Spain and Italy with a total study experience of 10,734,897 person-years. MAIN OUTCOME MEASURE: Odds ratios of upper gastrointestinal bleeding for each drug, with adjustment for potential confounders. For each individual drug the reference category was defined as those not exposed to the drug. RESULTS: The incidence of upper gastrointestinal bleeding was 401.4 per million inhabitants aged >18 years. Thirty-eight percent of cases were attributable to NSAIDs. Individual risks for each NSAID were dose dependent. Ketorolac was associated with the highest risk estimate (24.7; 95% CI 8.0, 77.0). For newer NSAIDs, the risks were as follows: aceclofenac 1.4 (95% CI 0.6, 3.3), celecoxib 0.3 (95% CI 0.03, 4.1), dexketoprofen 4.9 (95% CI 1.7, 13.9), meloxicam 5.7 (95% CI 2.2, 15.0), nimesulide 3.2 (95% CI 1.9, 5.6) and rofecoxib 7.2 (95% CI 2.3, 23.0). The risk was significantly increased in patients with a history of peptic ulcer and/or upper gastrointestinal bleeding, and in those taking antiplatelet drugs. CONCLUSIONS: NSAID-induced upper gastrointestinal bleeding is a common cause of hospital admission. Apart from the patient's history of peptic ulcer, its risk depends on the particular drug and its dose, and on concomitant treatments. Our results do not confirm that greater selectivity for COX-2 confers less risk of upper gastrointestinal bleeding.     

Behavioural effects of the newer antiepileptic drugs: an update

The negative and positive effects of the nine newer antiepileptic drugs that have received a product licence in the UK or in the US are reviewed. The importance of avoiding misinterpretation of the data because of confounding factors such as alternative psychosis, the release phenomenon or drug interactions is emphasised. Vigabatrin has been associated with both psychosis and depression. Due to the concentric visual field defects that may occur with vigabatrin, its use is now limited, although it remains the drug of choice for infantile spasms. Lamotrigine seems to be largely associated with improvement rather than deterioration of mood and behaviour. It may have a role in treating affective disorder. Gabapentin probably has relatively little effect on behaviour but may exacerbate behavioural problems in some children with pre-existing difficulties. Topiramate may precipitate both psychosis and depression, but these are less likely to occur if the currently recommended lower starting doses, escalation rates and target doses are used. The data for tiagabine are limited, but there is no clear evidence for psychosis or depression being caused by this drug. Oxcarbazepine may be of value in treating mood disorder, but the information is very limited. There are few reports of behavioural disturbances with levetiracetam, but the data suggest that there is no significant increase in psychosis or depression. There are some reports of psychosis and other behavioural disturbances with felbamate, but the use of this drug is limited by the serious adverse effects of hepatotoxicity and aplastic anaemia. There is some evidence for psychosis with zonisamide, but there is also a suggestion that this drug may be of benefit in treating psychiatric disorders. Careful individual assessment of each patient should enable the clinician to determine whether the medication or some other factor is responsible for any behavioural disturbance.     

Metabolic drug interactions with newer antipsychotics: a comparative review

Newer antipsychotics introduced in clinical practice in recent years include clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and amisulpride. These agents are subject to drug-drug interactions with other psychotropic agents or with medications used in the treatment of concomitant physical illnesses. Most pharmacokinetic interactions with newer antipsychotics occur at the metabolic level and usually involve changes in the activity of the major drug-metabolizing enzymes involved in their biotransformation, i.e. the cytochrome P450 (CYP) monooxygenases and/or uridine diphosphate-glucuronosyltransferases (UGT). Clozapine is metabolized primarily by CYP1A2, with additional contribution by other CYP isoforms. Risperidone is metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4. Olanzapine undergoes both direct conjugation and CYP1A2-mediated oxidation. Quetiapine is metabolized by CYP3A4, while sertindole and aripiprazole are metabolized by CYP2D6 and CYP3A4. Ziprasidone pathways include aldehyde oxidase-mediated reduction and CYP3A4-mediated oxidation. Amisulpride is primarily excreted in the urine and undergoes relatively little metabolism. While novel antipsychotics are unlikely to interfere with the elimination of other drugs, co-administration of inhibitors or inducers of the major enzymes responsible for their metabolism may modify their plasma concentrations, leading to potentially significant effects. Most documented metabolic interactions involve antidepressant and anti-epileptic drugs. Of a particular clinical significance is the interaction between fluvoxamine, a potent CYP1A2 inhibitor, and clozapine. Differences in the interaction potential among the novel antipsychotics currently available may be predicted based on their metabolic pathways. The clinical relevance of these interactions should be interpreted in relation to the relative width of their therapeutic index. Avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and, possibly, plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving newer antipsychotics.     

拉莫三嗪与丙戊酸钠对癫痫患者认知功能影响对比研究

目的:评价拉莫三嗪与丙戊酸钠对癫痫患者认知功能的影响。方法:将82例癫痫患者随机均分为拉莫三嗪组(治疗组)与丙戊酸钠组(对照组),利用简易精神状态检查量表(MMSE),分别于治疗前、用药3个月及用药6个月后对患者认知功能进行神经心理学评估。结果:治疗组在用药3个月及用药6个月时与用药前比较,MMSE分值无明显差异;对照组在用药3个月及6个月时与用药前比较,MMSE分值明显下降。结论:丙戊酸钠对患者认知功能有影响,而拉莫三嗪在治疗前后对患者认知功能无明显影响。     

526例癫痫患儿用药情况调查

目的 了解我院癫痫患儿抗癫痫药物的使用情况,为临床用药及个体化给药提供参考。方法 对我院门诊526例癫痫患儿的抗癫痫药物的药品品种、血药浓度、症状控制情况进行统计、归纳和讨论。结果 我院抗癫痫药物以丙戊酸钠和卡马西平使用最多,两药对血药浓度控制较好,86%患儿的症状得到控制。结论 我院抗癫痫药物的使用基本合理,在用药过程中还应该加强药学服务和个体化给药。     

Hyponatremia induced by antiepileptic drugs in patients with epilepsy

Introduction: Hyponatremia induced by antiepileptic drugs (AEDs) has not received sufficient attention in patients with epilepsy.

Areas covered: We reviewed articles between 1966 and 2015 about hyponatremia as an adverse effect of AEDs in patients with epilepsy. The incidence, clinical symptoms, onset times of AEDs-induced hyponatremia are discussed in detail, as are the risk factors associated with AEDs-induced hyponatremia and mechanisms underlying its development. We also briefly describe strategies for treating AED-induced hyponatremia.

Expert opinion: Carbamazepine and oxcarbazepine are the most common AEDs which induce hyponatremia in patients with epilepsy. Recently, other AEDs, such as eslicarbazepine, sodium valproate, lamotrigine, levetiracetam and gabapentin have also been reported to cause hyponatremia. Understanding the risk associated with AED-induced hyponatremia and taking effective measures to combat serum sodium imbalance induced by AED therapy are necessary.     

Efficacy and safety of innovator versus generic drugs in patients with epilepsy: a systematic review

Generic antiepileptic drugs achieve blood concentrations similar to those of innovator drugs in healthy volunteers, but their comparative effectiveness has not been well evaluated. Thus, we assessed the efficacy, tolerability, and safety of innovator versus generic antiepileptic drugs. We searched the MEDLINE database, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science for studies that evaluated innovator and generic antiepileptic drugs in patients with epilepsy and reported data on prespecified outcomes. We extracted data on study design, interventions, quality criteria, study population, baseline characteristics, and outcomes. Compared with initiation of innovator antiepileptic drugs, initiation of generic antiepileptic drugs did not significantly alter seizure occurrence (relative risk [RR] 0.87, 95% confidence interval [CI] 0.64-1.18; strength of evidence: low) or frequency (standardized mean difference 0.03, 95% CI -0.08-0.14; strength of evidence: low), withdrawals due to lack of efficacy (RR 1.02, 95% CI 0.41-2.54; strength of evidence: low) or adverse events (RR 0.79, 95% CI 0.28-2.20; strength of evidence: low), pharmacokinetic concentrations (maximum, minimum, or area under the curve [strength of evidence: low]), or a myriad of adverse events (strength of evidence: low or insufficient) in clinical trials. In qualitatively evaluated observational studies, switching between forms of antiepileptic drug (innovator to generic, generic to generic) may increase the risk of hospitalization (strength of evidence: low), hospital stay duration (strength of evidence: low), and a composite end point of medical service utilization (strength of evidence: insufficient) but may not increase outpatient service utilization (strength of evidence: low). Data are limited predominantly to carbamazepine, phenytoin, and valproic acid. Clinical trials are limited by small sample size, short-term nature, and lack of specification of A-rated generic products (generics that the United States Food and Drug Administration has deemed bioequivalent to the innovator drug). Observational trials lack full accounting for confounders and have inherent limitations. With a low strength of evidence, it appears that initiating an innovator or generic antiepileptic drug will provide similar efficacy, tolerability, and safety but that switching from one form to the other may be associated with more hospitalizations and longer hospital stays.     

Negative effects of antiepileptic drugs on mood in patients with epilepsy.

With the introduction of several new antiepileptic drugs into clinical practice, renewed attention has been focussed on treatment-emergent adverse effects, including mood disorders. There are several possible causes of psychiatric disorders in patients with epilepsy, including antiepileptic drugs, and it is often difficult to determine whether psychopathological manifestations, especially depressive symptoms, are due to drug therapy or to multiple other factors. Assessment of the negative effects of antiepileptic drugs on mood should always consider all potential factors. Case series, audits and open observational studies can identify psychopathological features, case-control studies are useful for identifying the endophenotypes of patients at risk of adverse effects on mood, and controlled clinical trials give good estimates of incidence of such effects, adjusted for the spontaneous occurrence of symptoms. The barbiturates, vigabatrin and topiramate show greater associations with the occurrence of depressive symptoms than other antiepileptic drugs, presenting in up to 10% of all patients, but even more so in susceptible patients. Data on zonisamide are scarce but it seems that mood disorders may occur in approximately 7% of patients who are receiving high dosages of this drug. In most cases, the use of monotherapy, with slow titration schedules, can significantly reduce the incidence of mood disorders. Tiagabine, levetiracetam and felbamate present an intermediate risk, with prevalence of depression of about 4% or lower. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin and lamotrigine are all associated with low risks for depression (<1%), and several of these antiepileptic drugs seem to have a positive effect on mood. Antiepileptic drugs can negatively affect mood and behaviour by different mechanisms: potentiation of GABA neurotransmission, folate deficiency, pharmacodynamic interactions with other antiepileptic drugs in polytherapy regimens, forced normalisation. Individuals with a personal or family history of depression should be carefully followed after initiation of therapy with a new antiepileptic drug, especially if structural brain abnormalities such as hippocampal sclerosis are present.     

Sexual dysfunction related to antiepileptic drugs in patients with epilepsy

Introduction: Epilepsy is a common disease that is mostly treated with antiepileptic drugs (AEDs). However, the sexual dysfunction (SD) side effects related to the use of AEDs have not received sufficient attention.

Areas covered: The purpose of this review is to examine the current evidence on SD-related side effects of AEDs. The incidence, clinical features and major types of SD are summarized. Furthermore, various AEDs that may cause SDs are addressed in detail. Finally, we briefly summarize the treatments for SD related to AEDs.

Expert opinion: SD related to AEDs is common. Symptoms include erectile dysfunction (ED), hyposexuality, hypersexuality and ejaculatory dysfunction. Traditional AEDs such as valproate and enzyme-inducing AEDs (EIAEDs) may produce high incidences of decreased libido. Recently, sexual function changes related to new AEDs have been reported. Topiramate, pregabalin and gabapentin may cause SD, whereas oxcarbazepine, lamotrigine and levetiracetam may improve sexual function. Although the treatment for SD related to AEDs remains unclear, switching to another AED may be an option. Further studies are necessary to better understand and treat SD related to AEDs.     

Behavioral adverse effects of antiepileptic drugs in epilepsy

Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs.     

Classical neurotransmitters and neuropeptides involved in generalized epilepsy: a focus on antiepileptic drugs

We describe the alterations of classical neurotransmitters and neuropeptides in generalized epilepsy. A neuronal network in this disease is developed. Gamma aminobutyric acid (GABA) hypoactivity induces dopamine hyperactivity because dopaminergic neurons are affected by the inhibitory influence of the GABAergic system through GABA(A) receptors. Glutamate hyperactivity is exerted via presynaptic N-methyl-D-aspartate (NMDA) receptors, which strongly inhibit serotoninergic neurons, and via postsynaptic ionotropic glutaminergic receptors, which can induce epileptic seizures. A collection of specific subreceptors of classical neurotransmitters and neuropeptides involved in epileptogenesis is reported. The question arises whether agonists/antagonists of neuropeptides (neuropeptide Y, galanin…) could have additional antiepileptic properties. The effect of conventional and newer antiepileptic drugs interfering with these subreceptors is discussed on the basis of the neuronal network suggested. From these data, it is concluded that new antiepileptic drugs interfering with other specific subreceptors (GABA(B) antagonists, metabotropic glutaminergic receptors subtype 5 (mGlu5R) antagonists, mGlu2/3R agonists, 5-serotonin (5-HT(7)) agonists) could further stabilize the neuronal network in generalized epilepsy.     

Levetiracetam therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new anti-epileptic drug (AED) levetiracetam in a cohort of 100 adult patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two groups, otherwise comparable for age, gender, weight-adjusted daily dose of levetiracetam, and dosing frequency: group A (n = 65), receiving levetiracetam plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin; group B (n = 35), receiving levetiracetam plus AEDs without inducing properties of CYP metabolism, namely valproic acid and lamotrigine. Plasma levetiracetam concentrations were measured by HPLC with spectrophotometric detection. Median morning trough levetiracetam plasma concentrations were significantly lower in patients of group A than in patients of group B (10.4 microg/mL versus 14.7 microg/mL, P < 0.001). Median weight-normalized levetiracetam apparent oral clearance (CL/F) was 1.3-fold in patients receiving AED inducers compared with patients on AED noninducers (1.93 versus 1.45 mL x min(-1) x kg, P < 0.001). No gender-related difference was observed in CL/F values. Levetiracetam plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 500 to 5000 mg/d, although at a given daily dose an appreciable interpatient variability was observed in matched plasma drug concentrations. Concomitant AED inducers can contribute to variability in levetiracetam disposition in patients with epilepsy. The observed differences were moderate and possibly of minor clinical significance.     

Topiramate therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.     

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

Rationale

Antiepileptic drugs (AEDs) have been available for many years; yet, new members of this class continue to be identified and developed due to the limitations of existing drugs, which include a propensity for cognitive impairment. However, there is little preclinical information about the cognitive effects they produce, which clinically include deficits in attention and slowing of reaction time.

Objectives

The purpose of this study was to profile two first-generation AEDs, phenytoin and valproate, and three second-generation AEDs, levetiracetam, pregabalin and lacosamide. Initially, each drug was examined across a range of well characterised preclinical seizure tests, and then each drug was evaluated in the five-choice serial reaction time test (5-CSRTT) based on efficacious doses from the seizure tests.

Materials and methods

Each AED was tested for anti-seizure efficacy in either (1) the maximal electroshock seizure test, (2) s.c. PTZ seizure test, (3) amygdala-kindled seizures and (4) the genetic absence epilepsy rat of Strasbourg model of absence seizures. On completion of these studies, each drug was tested in rats trained to asymptotic performance in the 5-CSRTT (0.5 s SD, 5 s ITI, 100 trials). Male rats were used in all studies.

Results

Each AED was active in at least one of the seizure tests, although only valproate was active in each test. In the 5-CSRT test, all drugs with the exception of levetiracetam, significantly slowed reaction time and increased omissions. Variable effects were seen on accuracy. The effect on omissions was reversed by increasing stimulus duration from 0.5 to 5 s, supporting a drug-induced attention deficit. Levetiracetam had no negative effect on performance; indeed, reaction time was slightly increased (i.e. faster).

Conclusions

These results highlight somewhat similar effects of phenytoin, valproate, pregabalin and lacosamide on attention and reaction time, and comparison to efficacious doses from the seizure tests support the view that there may be a better separation with the newer AEDs. Levetiracetam had no detrimental effect in the 5-CSRTT, which may be consistent with clinical experience where the drug is considered to be well tolerated amongst the AED class.