Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy

doi:10.1016/j.yebeh.2003.08.033

Epilepsy & Behavior

Volume 4, Issue 6, December 2003, Pages 659-666

https://doi.org/10.1016/j.yebeh.2003.08.033 Get rights and content

Abstract

Objective. This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects.

Methods. This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician’s choice). Patients were converted during an ⩽8-week Escalation/Taper Phase from their prestudy antiepileptic drug (carbamazepine, phenytoin, or valproate) to lamotrigine via a protocol-specified dosing algorithm or to conventional therapy via standard dosing guidelines. After monotherapy was achieved, patients continued in the study for a 24-week Maintenance Phase.

Results. More lamotrigine patients (65%) than conventional therapy patients (57%) completed the 24-week Maintenance Phase (primary efficacy endpoint). The mean time to withdrawal from the study was 175 days (SD=83.1) for lamotrigine patients compared with 156 days (SD=80.7) for conventional therapy patients. Adverse events, the most common reason for discontinuing the Maintenance Phase, accounted for 16% of withdrawals among lamotrigine patients compared with 26% of withdrawals among conventional therapy patients. The mean reduction in seizure frequency was 53% (SD=55.1) for patients using lamotrigine compared with 32% (SD=149.9) for patients using conventional therapy. Humanistic measures including investigator global assessment, the patient self-assessment, and QOLIE-31 scores show that lamotrigine monotherapy was perceived by both physicians and patients to have benefits over monotherapy with conventional antiepileptic drugs.

Conclusions. Converting from monotherapy with a less effective or poorly tolerated conventional antiepileptic drug to monotherapy with lamotrigine is associated with better clinical and humanistic outcomes than converting to an alternative conventional antiepileptic drug.

Introduction

Choice of antiepileptic drug therapy is guided by the goals of maximizing seizure control and minimizing side effects. Provided that seizure control is maintained, monotherapy is preferred to polytherapy because polytherapy heightens the risk of side effects and drug interactions, increases the cost of therapy, and reduces patient compliance. Physicians may treat patients with several monotherapy alternatives in an attempt to identify the treatment providing the optimum ratio of efficacy to tolerability.

The broad spectrum of efficacy and documented tolerability of the antiepileptic drug lamotrigine [1], introduced in the United States in 1994, render it a good candidate for monotherapy for patients inadequately controlled or experiencing unacceptable side effects with other antiepileptic drugs. In patients with newly diagnosed epilepsy, lamotrigine monotherapy is as effective against partial and generalized tonic–clonic seizures as carbamazepine [2] or phenytoin monotherapy [3]. Moreover, while it controls seizures as well as these conventional agents, lamotrigine is better tolerated [1], [2], [3], and it improves patients’ health-related quality of life [4]. Compared with carbamazepine and phenytoin, lamotrigine is associated with a lower incidence of neurologic adverse events such as asthenia, dizziness, and somnolence; and it does not negatively impact cognitive function [2], [3], [5], [6]. Unlike valproate, lamotrigine does not cause weight gain [7]. This randomized, open-label study compared the efficacy and tolerability of lamotrigine monotherapy with those of monotherapy with the conventional antiepileptic drugs carbamazepine, phenytoin, or valproate in patients who required a change in therapy because of inadequate seizure control or unacceptable side effects.

Section snippets

Patients

Patients ⩾16 years of age diagnosed with epilepsy and experiencing any seizure type classifiable by the International Classification of Seizures [8] were eligible for the study. Females were eligible only if they had a negative urine or serum pregnancy test at screening and agreed to use acceptable contraceptive methods during the study or were incapable of bearing children. Eligible patients were currently being treated with one of the conventional antiepileptic drugs carbamazepine, phenytoin,

Patients

One hundred twenty-two (122) patients were enrolled in the study, and 115 were randomized (Fig. 2). Fifty-seven (57) patients were randomized to receive lamotrigine, and 58 patients were randomized to receive a conventional antiepileptic drug. The numbers of patients completing the study were 37 in the lamotrigine group and 33 in the conventional therapy group. The most common reason for discontinuation from either the Escalation/Taper Phase or the Maintenance Phase in both groups was adverse

Discussion

These data suggest that when monotherapy with a conventional antiepileptic drug is unsuccessful because of inadequate seizure control or poor tolerability, converting to monotherapy with lamotrigine may be more beneficial than converting to an alternative conventional antiepileptic drug. In this study, conversion from unsuccessful monotherapy with carbamazepine, phenytoin, or valproate to lamotrigine monotherapy was associated with a higher incidence of treatment success (primary endpoint,

Acknowledgements

The authors thank Jane Saiers, Ph.D., for assistance with writing the manuscript. The following investigators participated in this study: George Adam (Minneapolis, MN); Ricardo Ayala (Tallahassee, FL); Andrew Bragdon (Syracuse, NY); D Combs Cantrell (Irving, TX); Walter Carlini (Medford, OR); Jose E. Cavazos (Denver, CO); Joan Christine Dean (Winston-Salem, NC); James DeMatteis (Erie, PA); Maroun Dick (Memphis, TN); Lewis Eberly (Alexandria, VA); Michael Englert (South Bend, IN); Irl Extein

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Health-related quality of life (HRQoL) instruments are useful for better understanding the overall difficulties faced by patients with epilepsy. Furthermore, those instruments may help discriminate between patients treated with different antiseizure medications [4]. There may be a relationship between adverse effects of antiseizure medication treatment (AST) and HRQoL.
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Causative factors and phenomenology of depression in EPILEPSY—A review
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Citation Excerpt :
From a pharmaco-therapeutic perspective, this presumed similarity has resulted in the widespread belief in the efficacy of antidepressants in epilepsy patients. Mood stabilizers such as lamotrigine (LTG) has significant effect on moods in epileptic patients in at least 11 studies, including 3 randomized control investigations.134–143 Interestingly, Labiner et al. (2009) recently revealed that the effects of LTG on mood primarily affect anger or hostility rather than depression itself.142
It is a known fact that depression is the one of the leading causes of years lived with disability and the fourth leading cause of disability-adjusted life-years worldwide. Depression is often under-recognized among patients of epilepsy due to lack of awareness of depressive symptoms. Due to improper management of depression in epileptic patients, it can interfere with treatment outcomes and hence can impair the quality of life. Undermanaged depression in epilepsy is generally associated with work absenteeism and direct medical costs. Electronic bibliographic databases like PubMed and Google Scholar were searched using the format “(depression, epilepsy and symptoms)”. Cross-linked searches were made taking the lead from key articles. Recent articles and those exploring the etiological factors & symptomatic presentation of depression were focused upon. The main purpose of this review was to study the causative association between epilepsy and depression and to discuss the varied symptomatic presentation.
The biopsychosocial model and quality of life in persons with active epilepsy
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Despite a long recognized need in the field of the importance of the psychological and social factors in persons with epilepsy (PWE), the medical community has continued to focus primarily on seizures and their treatment (the biological–biomedical model). From the biopsychosocial perspective, a person's lived experience needs to be incorporated into the understanding of quality of life. While the biopsychosocial model has gained prominence over the years, it has not been studied much in epilepsy.
The study sample included 1720 PWE from the 2003 and the 2005 Canadian Community Health Survey (CCHS). Data were analyzed using set correlation, as it allows for the examination of the relative contribution of sets of independent variables (biological, psychological, and social domains) and a set of dependent variables (quality of life) of interest, defined as self-rated health status, self-rated mental health status, and life satisfaction.
Results provide strong evidence that the full biopsychosocial model explained a significantly larger amount of variance in quality of life (R² = 55.0%) compared with the biological–biomedical model alone (R² = 24.8%). When the individual domains of the biopsychosocial model were controlled for, the psychological (R² = 24.6%) and social (R² = 18.5%) domains still explained a greater amount of the variance in quality of life compared with the biological–biomedical model (R² = 14.3%).
While seizure freedom will continue to be an important treatment goal in epilepsy, the psychological and social domains are an important consideration for both interventional programs and clinical research designed to improve quality of life in PWE. Better integration of social workers and psychologists into routine care may help address these disparities.
Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: A pilot study
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About 25% of patients with epilepsy are refractory to treatment, so that new, more effective antiepileptic drugs (AEDs) are urgently needed. Animal models that simulate the clinical situation with individuals responding and not responding to treatment are important to determine mechanisms of AED resistance and develop novel more effective treatments. We have previously developed and characterized such a model in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. In this model, prolonged treatment of epileptic rats with phenobarbital (PB) results in two subgroups, PB responders and PB nonresponders. When PB nonresponders were treated in previous experiments with phenytoin (PHT), 83% of the PB-resistant rats were also resistant to PHT. In the present study we examined if rats with PB resistant seizures are also resistant to lamotrigine (LTG), using continuous EEG/video recording of spontaneous seizures over 10 consecutive weeks. For this purpose, a new group of epileptic rats was produced and selected by treatment with PB into responders and nonresponders. As in previous studies, PB nonresponders had a significantly higher seizure frequency before onset of treatment. During subsequent treatment with LTG, all PB nonresponders and 60% of the PB responders exhibited >75% reduction of seizure frequency and were therefore considered as LTG responders. Plasma levels of LTG did not differ significantly between responders and nonresponders. The data of this pilot study indicate that LTG is more effective than PHT to suppress seizures in PB nonresponders in this model, but that not all PB responders also respond to LTG. Overall, our data provide further evidence that AED studies in post-SE TLE models are useful in determining and comparing AED efficacy and investigating predictors and mechanisms of pharmacoresistance.
Anger with murderous impulse induced by lamotrigine
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Citation Excerpt :
Lamotrigine (LTG) is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. Other than life-threatening skin reactions, LTG has fewer side effects than other anticonvulsants and has excellent tolerability [1–3]. We present here two cases of major depressive disorder with bipolarity in which LTG induced anger with murderous impulse.
To report two cases of major depressive disorder in which lamotrigine (LTG) induced anger with murderous impulse.
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Case 1 manifested with anger and murderous impulse when taking 125 mg/day of LTG. A reduction to 75 mg/day calmed this anger. Case 2 manifested with the same symptom when taking 25 mg/day of LTG, and the symptom immediately disappeared upon stopping LTG.
Use of LTG for epilepsy in intellectually disabled patients was reported to be associated with onset or exacerbation of aggressive or violent behavior. The two cases would suggest that LTG may cause anger so severe as to be accompanied with murderous impulse when administered to patients with mood disorders. Physicians should be cognizant of this possible, albeit infrequent, adverse effect even in use of LTG for mood disorders.
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^☆: GlaxoSmithKline, the maker of lamotrigine, sponsored the research described in this article.

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Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy☆

Abstract

Introduction

Section snippets

Patients

Patients

Discussion

Acknowledgements

Lancet

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

J. Clin. Epidemiol.

Lamotrigine

Epilepsia

Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin

Epilepsia

Outcomes of add-on treatment with lamotrigine in partial epilepsy

Epilepsia

Safety review of adult clinical trial experience with lamotrigine

Drug Saf.

Intractable epilepsy in children: the efficacy of lamotrigine treatment, including non-seizure-related benefits

Neuropediatrics