Newer antiepileptic drugs in bipolar disorder: rationale for use and role in therapy

Antiepileptic drugs (AEDS) are used regularly in the treatment of patients with bipolar disorders. Carbamazepine and valproic acid (sodium valproate) are effective as antimanic treatments, and the success of these medications has prompted investigation of other AEDs as possible treatments in patients with mood disorders. Lamotrigine appears to be the most promising of the newer AEDs with respect to effects in mood disorders. Current evidence suggests efficacy of this drug both as monotherapy and as an adjunctive agent in bipolar depression, and studies are underway to clarify its efficacy in mood stabilisation and rapid cycling, as currently available data are equivocal. Use of gabapentin is not as well supported in the literature, although data from open trials using it as an adjunctive agent suggest that it may be helpful in patients with bipolar depression. There have been some open trials and case reports supporting the use of topiramate as an adjunctive agent for the treatment of mania; however, data from controlled trials are not yet available. Further controlled trials of lamotrigine, gabapentin or topiramate as monotherapy and adjunctive treatment are needed to clarify their potential roles in the treatment of patients with mood disorders.     

Selection criteria for the clinical use of the newer antiepileptic drugs

In recent years, several new antiepileptic drugs (AEDs) have been licensed: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. These drugs have proven efficacy as add-on therapy in patients with difficult-to-treat partial epilepsy, as 20-50% of patients treated in add-on trials experienced a seizure reduction of >or=50%. Relatively few trials have been conducted to evaluate these drugs as monotherapy for patients with newly diagnosed epilepsy. In the monotherapy trials that have been conducted, the newer drugs were often as efficacious as conventional drugs, and their tolerability was often better. However, the methodology of these trials can be criticised. Because of the relative lack of robust data for the newer agents, the conventional drugs have thus far maintained their status as first-line monotherapy. However, when first-line monotherapy fails, an alternative drug has to be chosen from the available conventional and newer drugs. This article aims to give detailed background information on the newer AEDs in order to enable physicians to make a rational choice from the available drugs for individual patients. Data are provided for the different newer AEDs on mechanisms of action; efficacy in refractory partial epilepsy, newly diagnosed epilepsy in adults and generalised seizure types; adverse effects; pharmacokinetics; and use in special patient categories.     

Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta‐analyses

Several newer antiepileptic drugs (AEDs) have been introduced into clinical practice, offering choices for individualizing the treatment of epilepsy since AEDs have different efficacy and tolerability profiles. In particular, questions exist regarding which AEDs are the best options for the monotherapy of focal epilepsy. Is carbamazepine (CBZ), which is considered the standard treatment for focal epilepsy, still the best option for monotherapy of focal epilepsy, despite the emergence of new AEDs? In this systematic review, we compared the relative tolerability of all available AEDs for monotherapy of all types of epilepsy as well as their efficacy in the monotherapy of focal epilepsy. In addition, we compared CBZ with other AEDs for the monotherapy of focal epilepsy. We performed a search of the MEDLINE/PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for randomized controlled clinical trials. To compare the relative efficacy and tolerability of the AEDs, we performed network meta‐analyses using a Bayesian random‐effects model. Sensitivity analyses were conducted to determine the robustness of the results. A total of 65 studies were included in this review, composing 16,025 patients. Clobazam, levetiracetam, lamotrigine, oxcarbazepine, sulthiame, topiramate, and valproate had the best efficacy profiles and demonstrated no evidence of superiority or inferiority compared with CBZ. However, CBZ showed the greatest risk of patient discontinuation due to intolerable adverse reactions, whereas lamotrigine had the best safety profile and an 81% probability of being the best for the tolerability outcome of patient withdrawals from the study due to intolerable adverse reactions, followed by sulthiame (60%) and clobazam (51%). The newer AEDs—levetiracetam, lamotrigine, oxcarbazepine, sulthiame, and topiramate—should be considered for monotherapy of focal epilepsy because they were demonstrated to be as effective as the older ones (CBZ, clobazam, and valproate) for the treatment of focal epilepsy and were more tolerable. Lamotrigine was the AED with the best tolerability profile, suggesting that it may be the best option for the treatment of focal epilepsy in children and adults.     

Anticonvulsants in the treatment of mood disorders: assessing current and future roles

Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.     

Anticonvulsants in the treatment of mood disorders: assessing current and future roles

Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.     

左乙拉西坦与丙戊酸钠用于颞叶癫痫添加治疗的疗效对比

目的：对比左乙拉西坦和丙戊酸钠对6个月单药治疗无效的颞叶癫痫（temporal lobe epilepsy,TLE）患者进行添加治疗的疗效。方法：对使用卡马西平、奥卡西平、拉莫三嗪单药治疗6个月无效的180例TLE患者分别添加丙戊酸钠、左乙拉西坦进行联合治疗,对比两者疗效。结果：卡马西平、奥卡西平、拉莫三嗪单药治疗6个月无效的TLE患者添加左乙拉西坦或丙戊酸钠联合治疗后发作频率有明显降低,其中左乙拉西坦较丙戊酸钠疗效更好,结果有显著性差异（P<0.05）。结论：对使用卡马西平、奥卡西平、拉莫三嗪单药治疗6个月无效的TLE患者,添加左乙拉西坦疗效优于丙戊酸钠。     

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.     

Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and the puerperium

The treatment of epilepsy in pregnancy is particularly challenging in that the fetal and maternal risks associated with maternal seizures need to be balanced against the potential teratogenic effects of antiepileptic drugs (AEDs). Pregnancy is known to affect the pharmacokinetics of older-generation AEDs. Understanding such alterations is important in the effort to optimise drug therapy since they may affect seizure control as well as fetal drug exposure. Therapeutic drug monitoring has therefore been recommended to control for changes in the disposition of the older-generation AEDs during pregnancy. Much less is known about gestation-induced alterations in the pharmacokinetics of the newer AEDs that have been introduced in the last 15 years. Lamotrigine is by far the most extensively studied of the newer AEDs. Pronounced alterations have been reported in the apparent clearance of lamotrigine, with an increase of >300% from baseline in late pregnancy in some patients on monotherapy, most likely due to enhanced metabolism. The available data suggest that the corresponding decline in plasma concentrations can be associated with loss of seizure control. More limited data indicate that a similar decline in plasma concentrations of the active monohydroxy derivative of oxcarbazepine may occur in late pregnancy. Preliminary experience also suggests that a significant fall in plasma concentrations of levetiracetam may occur during pregnancy. No systematic information is available on the pharmacokinetics during pregnancy of other newer AEDs (e.g. gabapentin, pregabalin, tiagabine, topiramate or zonisamide). Given the importance of maintaining optimal treatment of epilepsy during pregnancy, therapeutic drug monitoring appears to be justified for lamotrigine and oxcarbazepine in particular. Systematic studies of the effects of pregnancy on the pharmacokinetics of the other newer-generation AEDs are urgently needed.     

Suicidality and antiepileptic drugs: is there a link?

The main purpose of the present article is to review the possible risk factors for suicidal behaviour in epilepsy with a special emphasis on the different antiepileptic drugs (AEDs). Epidemiological data show that, in general, the suicide rate among patients with epilepsy is 5-fold higher than that in the general population, while in temporal lobe epilepsy and complex partial seizures it is approximately 25-fold higher. A certain psychiatric comorbidity may provoke suicidality in patients with epilepsy, and depression and cognitive impairment seem to be the main risk factors for suicidality in epilepsy. In addition, depression and cognitive deterioration in epilepsy may share common neuropsychological mechanisms in terms of hypofrontality. This may cause similar psychopathological signs in both diagnostic categories, including suicidality. Analysis of the literature has shown that serotonin metabolism disturbances are involved in the pathogenesis of suicidal behaviour irrespective of primary diagnosis. Serotonin disturbances also seem to be a common link between depression, suicidality and even epilepsy itself.The various AEDs differ not only in their mechanisms of action, but also in influences on cognition and mood in epileptic patients and suicidality, respectively. Until now, only Ketter's hypothesis has been proposed to explain the psychotropic effects of different AEDs, although it does not explain the positive psychotropic effects of some AEDs, such as carbamazepine and oxcarbazepine. According to this model, all psychotropic effects of AEDs may be the result of effects on the function of two types of receptor functions: gamma-aminobutyric acid (GABA) ergic and antiglutamatergic; other possible mechanisms have not been incorporated. Presumably, other neurochemical mechanisms, and a serotonergic mechanism in particular, should also be taken into account when explaining the psychotropic effects of different AEDs. Based on these data, it has been suggested that AEDs with certain serotonergic properties should reduce the suicidality risk because they exert effects similar to antidepressants (i.e. selective serotonin reuptake inhibitors), whereas AEDs that lack serotonergic mechanisms would not be effective in suicidality prevention. In line with this paradigm, phenobarbital and phenytoin seem to be the only drugs with proven suicidality risk. On the other hand, carbamazepine, oxcarbazepine, valproate and lamotrigine could be regarded as drugs with antisuicidal properties because they all improve cognitive functions and mood in epileptic patients, and possess serotonergic mechanisms of action. The other AEDs, including topiramate, tiagabine, vigabatrin, levetiracetam and zonisamide, all exert negative effects on mood and cognition, although their influence on suicidality has not been proven in evidence-based studies yet. Although zonizamide has serotonergic properties, it exerts negative psychotropic effects, whereas gabapentin is devoid of serotonergic properties but has positive psychotropic effects on mood and cognition. To more fully explain the positive and negative psychotropic effects and influence on suicidality of AEDs, Ketter's paradigm should be supplemented by an understanding of the serotonergic mechanisms of different AEDs. Further trials are required to prove or refute this model.     

Potential of levetiracetam in mood disorders: a preliminary review

Levetiracetam is a newer antiepileptic agent that was first approved by the US FDA in 1999 as an adjunctive therapy for the treatment of refractory partial epilepsy in adults. Since then, it has been approved for a wider patient population, i.e. as adjunctive therapy for partial seizures in patients >4 years of age (worldwide) and as first-line monotherapy for partial seizures in patients >16 years of age (in Europe); and as adjunctive therapy for juvenile myoclonic seizures (in Europe and the US). It has a favourable pharmacokinetic profile and appears to act at a specific site in the CNS. Pharmacodynamic evidence indicates that levetiracetam indirectly facilitates GABAergic function, and an increasing body of evidence suggests an important role for GABA in the pathophysiology of mood disorders. Preclinical studies using animal models of depression, anxiety and mania provide evidence for levetiracetam as a mood stabiliser. Preliminary clinical evidence from case reports and open-label pilot studies indicates that the drug, both as add-on therapy and as monotherapy, has efficacy in a wide range of bipolar spectrum disorders. Most recently, a 31% remission rate was reported in patients with bipolar disorder who were in the depressed phase at baseline and who received levetiracetam as add-on therapy for 8 weeks in an open-label trial. While these results are encouraging, placebo-controlled data are needed to further clarify the role of levetiracetam in the treatment of mood disorders.     

A comparison of clinical practice guidelines in the initial pharmacological management of new-onset epilepsy in adults

OBJECTIVE: Clinical practice guidelines (CPGs) are intended not only to provide supportive information for health care providers but also to act as a guide for health care policy decisions. However, extant CPGs do not always reach the same conclusions. The objective of this study was to compare recommendations for initial pharmacological treatment of new-onset epilepsy in adults as stated within published CPGs. METHODS: We performed a systematic review of CPGs, which were published by prominent national organizations between January 2000 and June 2005, regarding the initial pharmacological treatment of epilepsy in adults. RESULTS: Five CPGs and 1 evidence report were identified that focus on pharmaceutical management in epilepsy. The 3 guidelines most relevant to the question of new-onset epilepsy treatment in adults were developed by the American Academy of Neurology (AAN), Scottish Intercollegiate Guidelines Network (SIGN), and National Institute for Health and Clinical Excellence (NICE). AAN recommends the use of both recently introduced antiepileptic drugs (AEDs: gabapentin, lamotrigine, topiramate, and oxcarbazepine) and standard agents (carbamazepine, phenytoin, valproic acid/divalproex, and phenobarbital) in newly diagnosed epilepsy, i.e., a nontiered approach. Alternatively, NICE recommends using newer AEDs (lamotrigine, topiramate, and oxcarbazepine) only in patients who derive no benefit from older agents--a tiered approach. SIGN notes that all AEDs licensed for monotherapy have similar efficacy in newly diagnosed epilepsy--a recommendation for a nontiered approach. The newer AEDs (lamotrigine and oxcarbazepine) are recommended as first-line initial treatment as are standard agents (carbamazepine and valproic acid/divalproex). The NICE guideline includes economic and quality-of-life evidence in their recommendations while AAN and SIGN do not. In these regards, current data fails to show superiority for newer agents. CONCLUSION: In the past 5 years, several CPGs have been published in epilepsy management. Only 3 guidelines have explicit recommendations for initial pharmacological treatment of adults with epilepsy. With some variation regarding which medications are recommended from each group, all CPGs promote standard and newer AEDs as having similar clinical efficacy. Until efficacy, quality of life, or cost data for the newer agents demonstrates a superior outcome, older AEDs remain viable options as first-line for monotherapy in newly diagnosed patients and may provide cost benefits over newer agents.     

Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy

Antiepileptic drugs (AEDs) are used extensively to treat multiple non-epilepsy disorders, both in neurology and psychiatry. This article provides a review of the clinical efficacy of AEDs in non-epilepsy disorders based on recently published preclinical and clinical studies, and attempts to relate this efficacy to the mechanism of action of AEDs and pathophysiological processes associated with the disorders. Some newer indications for AEDs have been established, while others are under investigation. The disorders where AEDs have been demonstrated to be of clinical importance include neurological disorders, such as essential tremor, neuropathic pain and migraine, and psychiatric disorders, including anxiety, schizophrenia and bipolar disorder. Many of the AEDs have various targets of action in the synapse and have several proposed relevant mechanisms of action in epilepsy and in other disorders. Pathophysiological processes disturb neuronal excitability by modulating ion channels, receptors and intracellular signalling pathways, and these are targets for the pharmacological action of various AEDs. Attention is focused on the glutamatergic and GABAergic synapses. In psychiatric conditions such as schizophrenia and bipolar disorder, AEDs such as valproate, carbamazepine and lamotrigine appear to have clear roles based on their effect on intracellular pathways. On the other hand, some AEDs, e.g. topiramate, have efficacy for nonpsychiatric disorders including migraine, possibly by enhancing GABAergic and reducing glutamatergic neurotransmission. AEDs that seem to enhance GABAergic neurotransmission, e.g. tiagabine, valproate, gabapentin and possibly levetiracetam, may have a role in treating neurological disorders such as essential tremor, or anxiety disorders. AEDs with effects on voltage-gated sodium or calcium channels may be advantageous in treating neuropathic pain, e.g. gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine and valproate. Co-morbid conditions associated with epilepsy, such as mood disorders and migraine, may often respond to treatment with AEDs. Other possible disorders where AEDs may be of clinical importance include cancer, HIV infection, drug and alcohol abuse, and also in neuroprotection. A future challenge is to evaluate the second-generation AEDs in non-epilepsy disorders and to design clinical trials to study their effects in such disorders in paediatric patients. Differentiation between the main mechanisms of action of the AEDs needs more consideration in drug selection for tailored treatment of the various non-epilepsy disorders.     

新型抗癫痫药物治疗复杂部分性发作癫痫的保留率比较

目的:分别给予新诊断的复杂部分性发作癫痫患者不同的新型抗癫痫药单药治疗,比较4种抗癫痫新药的总有效率和一年保留率。方法:对253例新诊断的复杂部分性发作及复杂部分性发作继发全面性发作癫痫患者随机给予奥卡西平、托吡酯、左乙拉西坦、拉莫三嗪单药治疗,比较其总有效率和一年保留率,并分析停药原因。结果:4种抗癫痫新药控制癫痫的疗效基本一致,总有效率为75.4%～87.1%,无统计学差异。拉莫三嗪的保留率最高(88.6%),其次为左乙拉西坦(85.3%),托吡酯为68.5%,奥卡西平最低(61.4%)。拉莫三嗪与其他3种抗癫痫新药的保留率有统计学差异(P<0.05),其他3种药物之间无统计学差异。停药或换药的主要原因是癫痫控制无效或加重(28例,42.4%);其次是不良反应(13例,19.7%)及药物价格(10例,15.2%)。结论:4种抗癫痫新药的有效性无明显优劣差异,拉莫三嗪的一年保留率最高,停药原因主要为药物疗效不佳和不良反应。     

儿童抗癫痫药物治疗药物监测

抗癫痫药物（AEDs）是治疗癫痫的主要药物,现有27种抗癫痫药物,这使得治疗药物监测（TDM）的应用越来越广泛,同时,抗癫痫药物也是进行TDM最常见的药物。第一代抗癫痫药物卡马西平、苯巴比妥、苯妥英钠、乙琥胺、扑米酮、丙戊酸在TDM方面积累了很多经验,现在TDM将更多地应用于新的抗癫痫药物如醋酸艾司利卡西平、非氨酯、加巴喷丁、拉科酰胺、拉莫三嗪、左乙拉西坦、奥卡西平、吡仑帕奈、哌拉西坦、普瑞巴林、瑞替加滨、卢非酰胺、司替戊醇、噻加宾、托吡酯、氨己烯酸和唑尼沙胺。本文通过对样本类型、样本的采集和处理、参考范围的概念进行综述,旨在为儿童抗癫痫用药的药物监测提供依据。     

Pharmacologic management of epilepsy in the elderly

OBJECTIVE: To review the epidemiology and pharmacologic management of epilepsy in elderly patients. DATA SOURCES: Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted. DATA SYNTHESIS: Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures. CONCLUSION: The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.     

Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations

Antiepileptic drugs (AEDs) can have both beneficial and adverse psychotropic effects. They act on neurotransmitter systems, neuronal ion permeability and other targets, although the exact mechanisms are not generally fully elucidated. A systematic review of the literature reveals evidence for both positive and negative effects on depression, anxiety, aggression, psychosis and sleep in patients with epilepsy. Topiramate, vigabatrin, levetiracetam, tiagabine and zonisamide have been associated primarily with adverse psychotropic effects, whilst gabapentin, pregabalin, lacosamide and lamotrigine, in particular, have demonstrated a more beneficial psychotropic profile, especially with regard to affective symptoms. This review, however, identifies specific methodological issues with studies that have reported on the psychotropic effects of AEDs, suggesting that some of the findings might be inconclusive or unreliable because of confounding factors, particularly the presence of psychiatric history. More rigorous double-blind, randomized, placebo-controlled trials on larger numbers of patients with epilepsy, with clear inclusion/exclusion criteria, that are specifically designed to investigate psychotropic changes are more likely to produce results that inform clinical practice and direct future research.     

Mood disorders in patients with epilepsy: epidemiology and management

Patients with epilepsy are at high risk for depression because of an incompletely understood combination of factors that may be both psychosocial and neurological. Interictal depression in patients with epilepsy is an undertreated condition, in part because of concern regarding drug interactions and the risk of exacerbating seizures with antidepressant treatment. Bipolar disorder is not described as occurring with a higher than expected frequency in the population with epilepsy, but high rates of depression and suicide are well recognised, highlighting the need for more emphasis on antidepressive treatment in this group of at-risk patients. Neurological factors, including site and lateralisation of seizure focus, may be important for the development of depression, with left-sided seizure foci having a higher association with depressive symptoms. Forced normalisation may be a factor in the paradoxical onset of depression in patients with epilepsy whose seizures suddenly become well controlled by anti-seizure treatment. Lowering of folic acid levels by some antiepileptic drugs (AEDs) may also influence the expression of depression in patients with epilepsy. New AEDs continue to emerge as beneficial treatments themselves for mood disorders, with lamotrigine, gabapentin and, to a lesser extent, topiramate having clinical trials data to support their use in patients with bipolar disease. Similar positive data are available for vagal nerve stimulation. Mood effects of AEDs can be complicated, however, as many of these drugs (e.g. tiagabine) have also been reported to cause depression as an adverse effect. Electroconvulsive therapy in depressed patients with epilepsy requires special consideration. The selective serotonin reuptake inhibitors (SSRIs) and antidepressants that act at multiple receptors (e.g. nefazodone, venlafaxine) are the most appropriate treatments for depressed patients with epilepsy. Among these agents, citalopram has a low risk of interactions with AEDs. Bupropion, clomipramine and maprotiline are associated with a greater risk of seizures compared with other antidepressants and consequently should be used with caution in the treatment of depression in patients with epilepsy.     

Use of second-generation antiepileptic drugs in the pediatric population

Epilepsy is common in the pediatric population. Nine second-generation antiepileptic drugs have been approved in the US for use in epilepsy over the past 15 years: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Their use in pediatric patients is fairly widespread, despite most of these agents not having US FDA indications for use.Felbamate and gabapentin were the first two second-generation antiepileptic drugs to be approved in the US. Felbamate use has been limited because of the occurrence of hepatotoxicity and aplastic anemia. Although gabapentin is a fairly well tolerated antiepileptic drug, its use has also been limited as a result of inconsistent efficacy and concern about seizure exacerbation. Lamotrigine and topiramate are broad-spectrum antiepileptic drugs with efficacy in a wide variety of seizure types. Both agents have some tolerability concerns: rash with lamotrigine and neuropsychiatric events with topiramate. There are very little data on tiagabine use in children, but this agent appears to be effective and to have a good tolerability profile. Levetiracetam is a second-generation antiepileptic agent that is available intravenously. Considering its good efficacy, fast onset of action, and low incidence of serious adverse effects, its use in the acute setting could potentially increase. Oxcarbazepine and zonisamide have been relatively well studied in pediatric seizure patients, including use as monotherapy. Both agents have demonstrated good efficacy and tolerability for patients as young as 1 month old. Vigabatrin and rufinamide are currently not available in the US, but have been shown to have some success in other countries. Pregabalin is the newest antiepileptic agent, but lacks pediatric data currently.     

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.     

Therapeutic drug monitoring of the newer antiepileptic drugs

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.