Adults with Epilepsy: Is Monotherapy the Only Answer?

Summary: Monotherapy with antiepileptic drugs (AEDs) should be the aim in most patients with epilepsy and is achievable in most newly diagnosed cases. "Rational po-lytherapy" is a valuable new concept that can be usefully applied to a minority of patients. Assessment of new AEDs as monotherapy is a challenging problem, and appropriate clinical trial methodology is currently evolving. Although tiagabine (TGB) is established as an effective add-on agent in refractory partial epilepsy, its role in monotherapy is not yet clear. Preliminary studies suggest that TGB is effective and well tolerated as monotherapy. Ongoing large monotherapy studies should establish the comparative efficacy and tolerability of TGB vs. conventional AEDs.     

Drug selection for the newly diagnosed patient: When is a new generation antiepileptic drug indicated?

Abstract. Treatment options in epilepsy have increased dramatically since the early 1990s with the introduction of nine new generation antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). This makes drug selection much more complicated and challenging. This review discusses drug selection in patients with newly diagnosed epilepsy and in particular the role of new AEDs in this population. The choice of treatment should always be based on a careful comparison of the risk-benefit ratio for the different treatment options and the outcome of such evaluation may be different in patients with new onset compared with chronic epilepsy. Efficacy, tolerability and safety are the main criteria for selection of AEDs and any first line drug for patients with newly diagnosed epilepsy must have demonstrated satisfactory efficacy as monotherapy in that patient population. So far, of the new AEDs only lamotrigine, oxcarbazepine and topiramate have documentation sufficient to be granted licence for use as monotherapy in most European countries. Because the new generation AEDs have failed to demonstrate improved effectiveness as monotherapy, old generation AEDs such as carbamazepine and valproate remain drugs of first choice for partial and generalised seizures, respectively. However, there are special situations and populations where a new AED may be a reasonable first line drug. These include vigabatrin in West syndrome associated with tuberous sclerosis, lamotrigine as alternative to valproate in idiopathic generalised seizures in women of childbearing potential and lamotrigine for the treatment of epilepsy in the elderly population. The role of the new generation AEDs is likely to become more prominent as more experience is gained.     

Innovative Designs of Controlled Clinical Trials in Epilepsy

Summary: Uncontrolled noncomparative clinical observations of investigational antiepileptic drugs (AEDs) often lead to overoptimistic efficacy results and are therefore of very limited value for clinical AED development. The classic add-on trial with placebo as control treatment, in contrast, has provided unequivocal evidence of the efficacy of classic and new AEDs and has also identified less useful AEDs. Drug interactions, carryover effects, difficulty in analyzing individual drug action, and the recognition that monotherapy is by far the more common way of prescribing AEDs have led to the development of classic active control monotherapy trials. A major problem of these trials is a no-difference outcome, which allows no useful interpretation. Recently, two alternative monotherapy designs have been developed to avoid the deadlock of a no-difference outcome. In these designs the active control drug is administered in an attenuated form (low dosage or low concentration) or a placebo control is used when standard treatment is discontinued during presurgical evaluation. Both designs have produced unequivocal evidence of the efficacy of the investigational AED during monotherapy. Ethical concerns are minimized by the introduction of preset escape criteria for patient protection. These designs are valuable new supplements for the clinical development of investigational AEDs for monotherapy in epilepsy. In our opinion, alternative monotherapy designs should be preceded by more than one pivotal add-on, placebo-controlled trial.     

Monotherapy Trials of New Antiepileptic Drugs

Summary: A number of clinical trials that test the efficacy and safety of the newer antiepileptic drugs (AEDs) have recently been concluded. Two dose-response trials in inpatients with refractory partial seizures and outpatients with newly diagnosed partial epilepsy established the efficacy of gabapentin as monotherapy. Lamotrigine was found to have efficacy similar to that of phenytoin and carbamazepine (CBZ) and to be better tolerated than CBZ in patients with newly diagnosed epilepsy. It was also shown to have efficacy as monotherapy in partial seizures, based on the results of an active controlled trial, and in the treatment of absence seizures, based on the results of a responder-enriched study. Topiramate as monotherapy was found to be efficacious for treatment of partial-onset seizures, based on the results of a single-center dose-response trial. A dose-response trial that tested the efficacy of tiagabine monotherapy in patients with refractory partial epilepsy was uninformative. Oxcarbazepine was found to be safe and efficacious in four comparative trials in patients with newly diagnosed epilepsy as well as in one placebo-controlled inpatient trial in patients with refractory partial seizures.     

A review of the antiepileptic drug tiagabine

Tiagabine (TGB), a recently approved antiepileptic drug (AED), has a specific mechanism of action that is unique among AEDs. A potent AED with linear, predictable pharmacokineties, it inhibits gamma-aminobutyric acid (GABA) reuptake into neurons and glia. Tiagabine does not have any clinically relevant effects on hepatic metabolism or on serum concentrations of other AEDs, nor does it interact with commonly used non-AEDs. The most common side effects of TGB in controlled studies are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These events are usually mild to moderate in severity and generally do not require medical intervention. At dosages of 30-56 mg daily, TGB is an effective add-on treatment for partial seizures. Although patients who have medically refractory epilepsy can be converted to TGB monotherapy, more controlled studies are necessary to confirm the efficacy of TGB as monotherapy and to determine the effective dosage range.     

Tiagabine Monotherapy in the Treatment of Partial Epilepsy

Summary: Three studies were conducted to assess tiagabine (TGB) hydrochloride monotherapy in patients with partial seizures. The first was a double-blind, placebo-controlled trial of 11 patients (seven TGB, four placebo) undergoing evaluation for epilepsy surgery. Baseline antiepileptic drug (AED) therapy was discontinued abruptly before monotherapy. Although 24-h seizure rates increased during monotherapy in both groups, patients receiving TGB experienced fewer seizures than placebo patients. Subsequent studies (an open-label, dose-ranging study; n = 31 and a double-blind, randomized comparison of 6 and 36 mg/day TGB; n = 102 and 96, respectively) involved discontinuation of baseline AEDs. In the dose-ranging study, 19 of 31 patients (61%) converted to TGB monotherapy, with a mean final dose of 38.4 mg/day (range 24–54 mg/day) in those who completed the study ( n = 12). In the low- vs. high-dosage study, median 4-week complex partial seizure rates decreased significantly in patients from both dose groups who completed the monotherapy period ( p <0.05 compared with baseline). In the intent-to-treat analysis, significantly more patients in the high-dose group experienced a reduction in seizures of at least 50% compared with the low-dose group ( p = 0.038). Overall, the types of adverse events with TGB monotherapy were similar to those observed in add-on trials. These initial trials in difficult-to-treat epilepsy patients indicate that TGB monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other AEDs.     

Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy

Few comparative clinical trials of newer antiepileptic drugs (AEDs) in patients with refractory partial epilepsy are available. Therefore, meta-analysis is a widely used and useful method for comparing them. Despite the limitations of indirect comparisons, and recognizing that these drugs were tested at different doses, such comparisons can be helpful to physicians making practical treatment decisions. The purposes of this study were to present newer meta-analysis results for add-on levetiracetam compared with placebo and to estimate its efficacy and tolerability compared with other new AEDs (gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide) in a meta-analysis using methods for making indirect comparisons. Randomized placebo-controlled clinical trials of add-on therapy with levetiracetam, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide in patients with refractory partial epilepsy were identified in the Cochrane Library 2002. A fixed-effects model was used to estimate Mantel-Haenszel odds ratios for the responder rate (efficacy measure) and withdrawal rate (mainly tolerability measure) of levetiracetam and other new AEDs versus placebo. Because no head-to-head clinical trials comparing these new AEDs exist, adjusted indirect comparisons were then made between levetiracetam and each other AED using the meta-analysis results. At the doses tested, levetiracetam was more effective in terms of responder rate than gabapentin (odds ratio 2.64 with 95% CI 1.51-4.63) and lamotrigine (odds ratio 1.86 with 95% CI 1.04-3.34) and equally well tolerated. Levetiracetam had a significantly lower withdrawal rate than topiramate (odds ratio 0.52 with 95% CI 0.29-0.93) and oxcarbazepine (odds ratio 0.55 with 95% CI 0.33-0.92), with comparable efficacy. Although levetiracetam did not differ significantly from the other AEDs, numerical trends favoring levetiracetam were obtained in response rate and in withdrawal rate (tiagabine, zonisamide). Indirect comparisons based on meta-analysis suggest that add-on therapy with levetiracetam has a favorable responder and/or withdrawal rate relative to several AEDs in patients with partial epilepsy with doses used in clinical trials. These meta-analyses give only short-term efficacy and safety data. Comparative clinical trials and long-term studies of these agents are needed to confirm these findings.     

Antikonvulsive Pharmakotherapie Jugendlicher und Erwachsener

In spite of the introduction and improvement especially of epilepsy surgery and also of other treatment options, such as ketogenic diet or neurostimulation, anticonvulsant chronic drug treatment has clearly remained the standard for the vast majority of epilepsy patients. Since 1992 when the first antiepileptic drug (AED) of the newer generation was introduced, a marked increase of seizure freedom among epilepsy patients, which is still the primary goal of treatment, has, however, not been reached. However, some of the new AEDs potentially allow better tolerable long-term treatment due to superior pharmacological characteristics. This might help to address the aspect of chronic AED treatment or comorbidities more efficiently. Hence, tolerability reasons led to a ranking according to the guidelines of the German Neurological Society that recommend lamotrigine and levetiracetam as first-line AEDs in cases of focal epileptogenesis. Special individual needs and considerations may allow and justify other AEDs in certain patients who are labelled for monotherapy. In cases of generalized epileptogenesis in adults valproic acid remains the first-line AED but lamotrigine may be preferred in special circumstances which include aspects such as teratogenicity. Ethosuximide is a first-line AED together with valproic acid followed by lamotrigine. If bilateral convulsive seizures occur primidone and phenobarbital may be considered as third-line AEDs. Several experts prefer levetiracetam although it is labelled only for off-label treatment in juvenile myoclonic epilepsy and not as monotherapy. The latter, however, should remain state of the art, as it more practicable and the easiest to assess concerning effectiveness. If treatment fails in spite of a correct diagnosis and classification an alternative monotherapy should be considered although a variety of publications have indicated that in the era of new AEDs combinations may be necessary to achieve sustained freedom of seizures. Thus the necessity to obtain alternative monotherapies should probably be expressed less dogmatically than currently published in the guidelines. Combinations should be as simple as possible and be comprehensible concerning the individual impact of the combination partners. High efficacy, lack of interactions and good tolerability have made levetiracetam to the most important add-on drug beyond the well-established and supra-additive combination of valproic acid and lamotrigine. Further investigations must be carried out on whether the latest new AEDs lacosamide, retigabine and perampanel all offer new modes of action with benefits for patients and opening the door to a more rational polytherapy in epilepsy treatment. Currently similar efficacy suggests that the risk of clinically relevant interactions and tolerability is the most important factor when choosing the appropriate add-on drug. Discontinuation may be considered only after freedom of seizures for many years and the prognosis is most favorable when the major causative factor no longer exists or has been eliminated.     

Long-Term Experience with Topiramate as Adjunctive Therapy and as Monotherapy in Patients with Partial Onset Seizures: Retrospective Survey of Open-Label Treatment

Summary: Because initial studies of new antiepileptic drugs (AEDs) are add-on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One-third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure-free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add-on therapy in partial onset epilepsy.     

Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit—possible relationship to AED tolerance

Purpose: A drug holiday seems to produce seizure interval prolongation (SIP) after reinstitution of antiepileptic drugs (AEDs). This effect was demonstrated mainly with carbamazepine. We evaluated SIP with newer AEDs and tested the relationship of SIP to history of AED tolerance. Methods: We prospectively studied patients with refractory epilepsy admitted to the Vanderbilt epilepsy monitoring unit (EMU) over a period of 12 months. We included only patients on levetiracetam, lamotrigine, or oxcarbazepine who had their AEDs withdrawn on admission and reinstituted without change upon discharge. We defined SIP as the interval from EMU discharge to first seizure minus the interval between the last two seizures before EMU admission. Results: A total of 43 patients completed the study; 15 were on monotherapy. SIP was greater than zero in this patient group (p < 0.0001), with a mean prolongation of 19.4 ± 28.0 days. The average SIP was higher (p = 0.01) in patients on monotherapy (29.7 ± 23.8 days) than patients on polytherapy (13.9 ± 29.0 days). SIP tended to be greater in patients with a prior history of AED tolerance (25.7 ± 36.8 days) compared to patient with no prior history of AED tolerance (14.0 ± 16.3 days). Discussion: SIP does occur after brief AED withdrawal. This effect is greater in patients on monotherapy and tends to be larger in patients with a history of AED tolerance. The SIP effect may be related to the phenomenon of tolerance, clinically seen as resistance to AED therapeutic effect.     

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta‐analysis

Second and third generation AEDs have been directly compared to controlled‐release carbamazepine (CBZ‐CR) as initial monotherapy for new‐onset focal epilepsy. Conversely, no head‐to‐head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta‐analysis (NMA). Randomized, double‐blinded, parallel group, monotherapy studies comparing any AED to CBZ‐CR in adults with newly diagnosed untreated epilepsy with focal‐onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment‐emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ‐CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR‐CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6‐ and 12‐month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ‐CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ‐CR (OR 0.659, 95% CrI 0.428‐0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ‐CR     

Monotherapy Clinical Trials of New Antiepileptie Drugs: Design, Indications, and Controversies

Summary: The focus in assessing new antiepileptie drugs (AEDs) varies with the needs of the assessor. Patients and doctors seek evidence-based clinical information, regulatory agencies look for efficacy and safety, and the health-care industry demands data on the risk-benefit ratio attached to a product. The pharmaceutical companies attempt to satisfy the interests of all parties involved. Most new AEDs obtain a first license based on placebo-controlled, randomized clinical trials as add-on therapy in patients with chronic refractory partial epilepsy, a method which, in fact, explores the efficacy of different drug combinations rather than measuring the efficacy of the new drug itself. Although that methodology satisfies the requirements of the licensing authorities, it fails to provide the clinical community with the information necessary to make rational treatment decisions, as would be derived from monotherapy studies. This article reviews controversies surrounding monotherapy studies and the design of comparative monotherapy clinical trials. A persuasive argument can be made that the goal of clinical trial design should be ethically acceptable, clinically meaningful studies in which new AEDs are compared with optimal doses of standard AEDs to inform clinical practice, meet licensing requirements, guide reasonable marketing efforts, and allow appropriate reimbursement.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

Measuring the efficacy of antiepileptic drugs.

Clinical trials of new antiepileptic drugs (AEDs) include regulatory studies aimed at demonstrating efficacy and reasonable safety, post-marketing open-open label studies and longer term outcome studies. Regulatory trials involve a carefully selected population of patients and are conducted under rigorously standardised conditions. Data from such studies cannot often be translated into clinical practice. Pragmatic post-marketing studies using flexible dosing schedules allow clinicians to better judge the utility of the new drug in a wider population of patients with epilepsy and decide the most appropriate dosing schedules. This paper discusses some of the issues surrounding the measurement of efficacy of new AEDs in both pre- and post-marketing phases of their development. All of the newer AEDs are initially used in patients with refractory partial seizures as adjunctive treatment. These trials are generally parallel-group studies although cross-over designs have been employed. The use of placebo-control is uncontroversial in this type of study. Efficacy endpoints are generally manipulations of seizure frequency on study drug compared to control. Global outcome measures and health related quality of life scores can also be used to measure efficacy. As the standard AEDs are associated with a high rate of seizure remission in patients who receive them as monotherapy, demonstration of superior efficacy of a new agent in a comparative trial will require large numbers of patients in a design that takes into account the natural history of treated epilepsy. Comparing investigational agents to a standard AED in an 'active-control' study with demonstration of equivalent efficacy would seem to be an acceptable way of assessing efficacy of new AEDs in this population. Some regulators, however, do not accept equivalence as proof of efficacy and insist on demonstration of superiority compared to a control. The use of placebo alone in the control group is ethically dubious. Several innovative study designs have, therefore, been used to satisfy regulatory requirements, while maintaining patient safety including withdrawal to monotherapy using high versus low dose comparators. Observational outcome studies provide the best opportunity of exploring the long-term utility of individual AEDs. Such studies largely follow standard clinical practice and need considerable time and resources. They can, however, yield valuable information about the effectiveness of AEDs in everyday clinical practice. Data from regulatory trials should be complemented by postmarketing studies and longer term studies of outcome to help clinicians decide the best way of utilising new AEDs and establishing their role in the therapeutic armamentarium.     

Lamotrigine: A Review of Antiepileptic Efficacy

Summary: Lamotrigine (LTG) is a chemically novel anti-epileptic drug (AED) that blocks voltage-sensitive sodium channels, leading to inhibition of neurotransmitter release, principally glutamate. LTG is active in a wide range of pharmacologic models of epilepsy, demonstrating a potency and duration of action generally superior to currently available AEDs. Preliminary evidence of efficacy was provided by single-dose studies showing effects on reducing interictal spike activity and photoconvulsive response. A total of eight randomized, double-blind, placebo-controlled, crossover trials have established the efficacy of LTG in patients with refractory partial epilepsy. Literature reports suggest LTG also is effective in patients with idiopathic generalized epilepsy, including absence seizures, and in patients with Lennox-Gastaut syndrome. Other reports suggest that LTG is useful in the pediatric population, and an interim report of an open monotherapy trial suggests that the efficacy of LTG was comparable to that of carbamazepine (CBZ) but the adverse experiences leading to discontinuation were less frequent.     

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17 years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.     

Epilepsy: from consensus to daily practice

Most clinicians would accept that epilepsy treatment should begin with monotherapy, and in the majority of cases this is the preferred drug maintenance option. The clinical choice of one antiepileptic drug (AED) over another should be based on firm evidence of efficacy and tolerability as evaluated in comparative monotherapy studies and pharmacokinetics. This paper presents the findings of evidence-based reviews of AED monotherapy in patients newly diagnosed with epilepsy. The main study was conducted in the United Kingdom and investigated the clinical evidence supporting AEDs used as first-line monotherapy. In this paper the general treatment recommendations will focus on valproate, one of the mainstay drugs used in the fight against epilepsy. Finally, with these recommendations in mind, the principles behind AED drug selection in clinical practice will be discussed. Factors for consideration that impact on AED decision-making include: seizure and syndrome diagnosis, AED tolerability profiles, patient characteristics and pharmacokinetic/pharmacodynamic AED interactions.     

Levetiracetam is as effective as carbamazepine in newly diagnosed epilepsy

Evaluation of: Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 6, 402-408 (2007). Despite the emergence of multiple antiepileptic drugs (AEDs) in the past decade, the task of choosing the right drug for monotherapy in patients with newly diagnosed epilepsy remains a precarious task. This is especially true when trying to choose a new AED over a more traditional agent. Much of this uncertainty stems from the fact that there are only a handful of studies that are able to demonstrate efficacy of a new drug over an older AED. While the newer drugs appear more favorable because of better tolerability, safety profiles and simple pharmacokinetics, many do not have an indication for monotherapy. Of course, this is further contingent upon the stringent limitations placed by regulatory bodies, such as the US FDA, who govern approval of AEDs for monotherapy. The current randomized study attempts to evaluate the efficacy of levetiracetam in monotherapy compared with controlled-release carbamazepine, a gold standard in patients with newly diagnosed epilepsy.     

Comparative bioethics in bipolar and epilepsy research.

RATIONALE: AEDs are increasingly evaluated for efficacy in bipolar disorders utilizing double-blind, placebo-controlled, randomized clinical trials (RCTs) as required by the FDA. However, the risk to patients is under-estimated in trial design. Bipolar depression has a significant risk for suicide; bipolar episodes can lead to kindling with increased long-term morbidity; rapid regression may occur during the placebo phase or during dose ranging trials with resultant active suicide status. The associated risks mandate that the ethics of FDA-required protocols are addressed. METHOD: Comparative analysis and literature review of bipolar and epilepsy research designs. RESULTS: In psychiatry, all INDs require RCTs for approval. In epilepsy, AEDs are initially approved as add-on agents only. Once AEDs have demonstrated add-on efficacy, cross-over studies comparing active AEDs, sub-optimal dosing paradigms, new-onset, and pre-surgical inpatient placebo trials are utilized to prove efficacy of the new AED in monotherapy. Ethical considerations to avoid seizures and to minimize risks to subjects have led to newer clinical trial designs. CONCLUSIONS: The FDA initially requires add-on studies with new AEDs due to the risk of seizures during the placebo phase. The author argues that bipolar research warrants similar add-on studies to prove efficacy because the risk of suicide and increased long-term morbidity in the bipolar population is as significant as the risk of seizures in the epilepsy population. Although the number of patients needed to prove statistical efficacy would increase, the safety of such research would also markedly increase. The author further concludes that with the risk of suicide during bipolar research, ethical considerations require increased frequency of patient contact with a significant other co-signing the informed consent for research and serving as a contact for the coordinator.     

Strategies to prevent overtreatment with antiepileptic drugs in patients with epilepsy

Overtreatment is defined here as an unnecessary and excessive drug load in the management of epilepsy leading to a suboptimal risk-to-benefit balance. Pharmacological overtreatment can often be prevented by deciding and counselling carefully about the need for antiepileptic drugs (AEDs) given the limitations of current AEDs. Although AEDs will reduce the incidence of seizures, they have no demonstrated ability to prevent epilepsy in patients at risk or to modify the course of epilepsy in patients following the first seizure. In addition, starting AEDs may not be necessary for control of epileptic seizures induced by precipitation or predisposing factors or for benign epilepsies with rare or mild seizures. Start monotherapy with the chosen first-line AED, initially at low doses titrating up to the low maintenance dose. Avoid drug loading (except for emergency treatment). If seizures continue, titrate to the limit of tolerability which will however, achieve additional seizure control in approximately 20% of patients. If, as in many patients, dosing to the limit of tolerability is not beneficial, the dose should be reduced. Switching to an average dose of another first line AED is another option to prevent overtreatment. Avoid drug overload during add-on therapy by slowly reducing the dose of the first drug in patients having adverse effects, ideally by an amount that the patient does not experience any further adverse effects, if possible, before adding another drug. If the patient does not benefit unequivocally from two-drug therapy within 3 months (and approximately 75% will not benefit), slowly transfer to monotherapy of the second drug and start with a newly chosen AED for add-on. To counteract the propensity to overmedication in chronic epilepsy is not easy. Great benefits, without loss of seizure control, are often gained by slowly reducing the overall drug load.