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Purpose: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation., Methods: Hormone profiles in men and women taking VPA (n = 40) or LTG (n = 36) monotherapy for epilepsy were compared. None of the women were receiving hormonal contraception or replacement. Patients gave details of seizure type and frequency, menstrual cycle, and medical and drug history. Body mass index was calculated, and fasting insulin, glucose, cholesterol, triglycerides (TG), high- and low-density lipoproteins, testosterone, dihydroepiandosterone (DHEA), androstenedione, sex hormone-binding globulin (SHBG), free androgen index (FAI), luteinising hormone (LH), follicle-stimulating hormone (FSH), and antiepileptic drug (AED) concentrations were measured., Results: There were no differences between treatment groups for both sexes in age and seizure control. Only four obese VPA-treated women were hyperinsulinaemic (p = 0.05); three with abnormal menstrual cycles; one with raised testosterone. Testosterone (p = 0.02), FAI (p = 0.03), and TG (p = 0.02) levels were higher, however, in women taking the drug. Obese patients of both sexes (p = 0.01) and VPA-treated men (p = 0.03) had higher insulin concentrations., Conclusions: VPA therapy may be associated with subclinical elevation in fasting insulin levels. Testosterone and TG levels were higher in VPA-treated women compared with the levels in those taking LTG. However, only a minority of obese females exhibited biochemical characteristics suggestive of PCOS. Biochemical screening may allow women at risk of developing PCOS to avoid VPA.

The aim of this study was to compare the effect of treatment with lamotrigine (LTG) or carbamazepine (CBZ) on health-related quality of life (HRQOL) and to demonstrate the use of the SEALS Inventory as a comparative tool in clinical trials. Two hundred and sixty patients with newly diagnosed epilepsy were randomized to 48 weeks of treatment with LTG (n = 131) or CBZ (n = 129). HRQOL was measured at baseline and weeks 4, 12, 24, and 48 using the modified Side Effect and Life Satisfaction (SEALS) Inventory-a 38-item questionnaire divided into five subscales: Worry, Temper, Cognition, Dysphoria, and Tiredness. Overall, SEALS scores in the LTG group decreased (improved) significantly from baseline (P = 0.001). The LTG group had improvement in all five subscales over the 48 weeks of the study. CBZ patients had significantly worse SEALS scores than LTG patients at week 4 (P < 0.038). There was no significant change (positive or negative) in subsequent SEALS assessments. Analysis of SEALS data by subscale showed that the the CBZ group experienced more cognitive side-effects in general and more general changes in energy levels and affect during the first 4 weeks of treatment. These changes may help explain the difference in study completion rate: LTG 65%, CBZ 51% (P = 0.018). LTG offers the patient with newly diagnosed epilepsy significant benefits of greater tolerability and better health-related quality of life compared with CBZ. The SEALS Inventory is an effective tool for use in clinical trials of AEDs; it was a better predictor of trial completion than seizure counts, and used as a covariate enabled better detection of treatment effects. In general practice, the use of the SEALS Inventory to assess HRQOL has the potential to improve quality of care for people with epilepsy., (Copyright 2000 BEA Trading Ltd.)

In a multicentre, double-blind trial 150 elderly patients (mean age 77 years) with newly diagnosed epilepsy were randomised in a 2:1 ratio to treatment with lamotrigine (LTG) or carbamazepine (CBZ). Following a short titration period, the dosage was individualised for each patient while maintaining the blind over the next 24 weeks. The main difference between the groups was the rate of drop-out due to adverse events (LTG 18% versus CBZ 42%). This was in part a consequence of the lower rash rate with LTG (LTG 3%, CBZ 19%; 95% CI 7-25%). LTG-treated patients also complained less frequently of somnolence (LTG 12%, CBZ 29%; 95% CI 4-30%). Although there was no difference between the drugs in time to first seizure, a greater percentage of LTG-treated patients remained seizure-free during the last 16 weeks of treatment (LTG 39%, CBZ 21%; P = 0.027). Overall, more patients continued on treatment with LTG than CBZ (LTG 71%, CBZ 42%; P < 0.001) for the duration of the study. The hazard ratio for withdrawal was 2.4 (95% CI 1.4-4.0) indicating that a patient treated with CBZ was more than twice as likely to come off medication than one taking LTG. In conclusion, LTG can be regarded as an acceptable choice as initial treatment for elderly patients with newly diagnosed epilepsy.

Purpose: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add-on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice., Methods: The panel of experts reviewed all published and unpublished data related to the incidence and risk factors for serious rash with LTG., Results: An allergic skin reaction occurs in approximately 10% of patients, usually in the first 8 weeks. Rashes leading to hospitalization, including Stevens-Johnson syndrome and hypersensitivity syndrome, occurred in approximately one of 300 adults and one of 100 children in clinical trials and appeared to be increased with overrapid titration when starting therapy and with concurrent valproate (VPA)., Conclusions: Recommendations are made for both minimizing the likelihood of serious rash and for management of rash in patients taking LTG. Risk of serious rash may possibly be lessened by strict adherence to manufacturer's dosing guidelines, particularly in patients who are at higher risk: those on concurrent VPA and in the pediatric population.

Three hundred and forty seven patients with epilepsy from 54 centres across Europe not fully controlled with sodium valproate (VPA, n = 117), carbamazepine (CBZ, n = 129), phenytoin (PHT, n = 92) or phenobarbital (PB, n = 9) monotherapy were recruited into a lamotrigine (LTG) substitution study. If 50% or more seizure reduction occurred (responders) on addition of LTG, an attempt was made to withdraw the original antiepileptic drug (AED). If successful, this was followed by a 12 week period of LTG monotherapy. Overall, 73% patients completed the add-on phase (47% responders), 41% attempted AED withdrawal and 23% achieved LTG monotherapy. In the 60 patients (17%) completing the trial by remaining on LTG monotherapy, median monthly seizure frequency was reduced from 6 during baseline to 1.7. Sixteen percent of patients were withdrawn due to adverse effects, mostly during the add-on phase. Dizziness and diplopia occurred most frequently in the CBZ group, nervousness and ataxia in the PHT group, and rash and tremor in the VPA group. Slower LTG dose escalation resulted in fewer withdrawals due to rash in the VPA-treated patients (38% to 8%, P < 0.01). The responder rate was higher (P < 0.01) in patients with idiopathic tonic-clonic seizures (61%) than in those with partial seizures (43%). The addition of LTG to VPA (64% responders) produced a significantly better response (P < 0.001) than adding it to CBZ (41% responders) or PHT (38% responders). This effect was seen for partial (VPA, 57%; CBZ, 39%; PHT, 39%; P < 0.02) as well as tonic-clonic seizures (VPA, 70%; CBZ, 53%; PHT, 50%; NS). These data lend credence to the suggestion of therapeutic synergy between LTG and VPA.

Lamotrigine (LTG) inhibits repetitive high frequency firing in depolarised neurones by selectively prolonging slow inactivation of the sodium channel, thereby suppressing the release of excitatory amino acids. It has been shown to be effective in 11 pivotal double-blind add-on trials in patients with refractory partial seizures with or without secondary generalisation. Subsequent anecdotal data support its efficacy for typical and atypical absences, myoclonic jerks, tonic or clonic seizures, Lennox-Gastaut syndrome and infantile spasms. Most recently LTG has been compared with carbamazepine and phenytoin in double-blind trials in patients with newly diagnosed partial and primary and secondary generalised tonic-clonic seizures. At the doses used, its efficacy was similar to the older agents for all seizure types, but LTG was better tolerated than both of the older agents. The commonest side-effects with LTG include headache, nausea, diplopia, dizziness, ataxia and tremor. Rash occurs in fewer than 5% patients. Its incidence can be reduced by starting treatment with a low dose, particularly in patients receiving concomitant sodium valproate which inhibits LTG metabolism. Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but LTG itself has no effect on hepatic metabolic processes. A pharmacodynamic interaction with carbamazepine necessitates a dosage reduction in some patients when LTG is introduced. LTG is a new antiepileptic agent with a long elimination half-life, a broad spectrum of activity, and a wide therapeutic ratio.

This prospective study was designed to ascertain whether measurement of lamotrigine (LTG) concentrations in the epilepsy clinic could be used to predict the onset of complete seizure control or the emergence of adverse effects. LTG was initiated in doses of 25 or 50 mg daily in 69 patients with newly diagnosed or poorly controlled epilepsy and was increased monthly in 50-mg increments until the patient became seizure-free for at least 6 months or developed adverse effects that abated after a reduction in dosage. LTG and other antiepileptic drug (AED) concentrations were measured at each clinic visit but were not supplied to the investigator examining the patients. Overall, 19 patients either withdrew due to lack of efficacy or defaulted from the clinic. Of the remaining 50 patients, 32 (19 monotherapy, 13 polytherapy) became seizure-free at widely varying daily LTG doses (median 200 mg, range 25-850 mg) and concentrations (median 3.8 mg/L, range 1.4-18.7 mg/L). Likewise, the 18 patients (5 monotherapy, 13 polytherapy) who experienced intolerable side effects showed substantial variations in daily LTG doses (median 300 mg, range 100-900 mg) and concentrations (median 4.0 mg/L, range 0.4-18.5 mg/L). No useful concentration-effect or concentration-toxicity relation with LTG could be demonstrated in this study; therefore, we believe that routine therapeutic drug monitoring with this new AED is not currently indicated.

Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated.

Epilepsy arises from an imbalance of inhibitory and excitatory influences in the brain. Vigabatrin (VIG) decreases the breakdown of the inhibitory neurotransmitter gamma-aminobutyric acid, whereas lamotrigine (LTG) reduces presynaptic excitatory amino acid release. 22 patients with refractory epilepsy, treated with an anticonvulsant regimen containing VIG, entered a balanced, double blind, placebo controlled, crossover trial of additional LTG. Treatment periods of 12 weeks (25 mg, 50 mg, 100 mg LTG twice daily for four weeks at each dose, and matched placebo) were followed by wash out intervals of four weeks. 14 of the 20 patients completing the study improved, resulting in a significant fall in seizure days and numbers. Analysis of seizure type confirmed a beneficial effect on partial and secondary generalised tonic-clonic seizures. At the highest LTG dose (200 mg daily) there was a median fall of 37% in seizure count with nine (45%) patients reporting > 50% reduction. Three of these patients were seizure free during this month of treatment. Side effects were minimal throughout the study. Concentrations of other antiepileptic drugs, including those of carbamazepine 10,11-epoxide, were not modified by LTG. This study suggests a substantial efficacy for a regimen containing VIG and LTG. Combinations of drugs with complementary modes of action may provide a rational pharmacological approach to the management of refractory epilepsy.

With the launching worldwide of a range of new antiepileptic drugs (AEDs), the prescriber has a much wider choice than ever before. Comparative studies between new and established AEDs are few, and those between new AEDs are rarely performed. This report considers the strengths and weaknesses of nine new and established AEDs. Scores ranging from -2 to +2 are given under six headings: mechanism of action, pharmacokinetics, efficacy, side effects, drug interactions, and a comfort factor. Perceived advantages and disadvantages in their clinical use are summarized and a final "star rating" produced for each. This process is illustrated by a detailed critique of lamotrigine (LTG). The star system is intended to stimulate dialogue among epileptologists in reaching a consensus in the pharmacologic management of the epileptic patient.