Robert P. Kustra

Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label study☆

This open-label study was designed to evaluate lamotrigine monotherapy as a possible alternative in patients with juvenile myoclonic epilepsy who previously failed treatment with valproate. Patients (n=63) were transitioned from valproate to lamotrigine during an 8-week escalation phase followed by 24 weeks of lamotrigine monotherapy. On Week 24 of the treatment phase, investigators judged that 50 and 67% of patients completing the study had shown mild, moderate, or marked improvement in adverse events and global clinical status, respectively, and 76% of patients rated lamotrigine as somewhat better (13%) or much better (63%) than valproate. The majority of patients completing the study experienced no deterioration of seizure control when switching from valproate to lamotrigine. These results support additional research on lamotrigine in juvenile myoclonic epilepsy.

Effect of lamotrigine on depressive symptoms in adult patients with epilepsy

In this investigation, the effects of lamotrigine versus placebo on depressive symptoms in patients with epilepsy were prospectively assessed. This investigation was a secondary analysis of a randomized, double-blind, placebo-controlled, parallel-group study in which adult patients received adjunctive lamotrigine (n=32) or placebo (n=38) for a 7-week dose escalation phase, followed by a 12-week maintenance phase, for primary generalized tonic-clonic (PGTC) seizures. Mood symptoms were assessed with the Beck Depression Inventory, second edition (BDI-II), the Profile of Mood States (POMS), and the Cornell Dysthymia Rating Scale-Self-Report (CDRS). Mean (SD) BDI-II scores at screening reflected mild depressive symptoms and were similar between groups (lamotrigine 18.3 (12.1), placebo 16.8 (12.0)). At the end of the maintenance phase, mean (SD) improvement from baseline was greater with lamotrigine than placebo with respect to BDI-II score (lamotrigine 8.9 (7.6), placebo 1.7 (8.5), P=0.01) and POMS total score (lamotrigine 32.0 (30.4), placebo 6.5 (32.3), P=0.03) and numerically greater with lamotrigine than placebo for CDRS score (lamotrigine 7.3 (7.8), placebo 4.1 (13.9), P=0.50). Among the subset of patients with at least mild depression (BDI-II score10), mean improvement from baseline was numerically, but not statistically significantly, greater with lamotrigine (11.5, n=13) than placebo (3.1, n=18) (P=0.054). Median percentage reductions in seizure frequency were significantly greater with lamotrigine than placebo during the escalation phase, the maintenance phase, and the escalation and maintenance phases combined for PGTC seizures and all generalized seizures. However, improvement in seizure frequency was not correlated with improvement in mood (r=0.1, P=ns). Compared with placebo, lamotrigine improved mood symptoms independently of seizure reduction in patients with generalized seizures. Lamotrigine may be useful in treating patients with epilepsy and comorbid depressive symptoms.

Improved mood states with lamotrigine in patients with epilepsy

Lamotrigine (LTG) was added to other antiepileptic drugs (AEDs) in a study of adjunctive therapy. In addition to seizure control and adverse effects, patients were evaluated for changes in mood states and quality of life. The Profile of Mood States (POMS) and 31-item Quality of Life in Epilepsy (QOLIE-31) instruments were administered at baseline (N=196), after addition of LTG as adjunctive treatment (N=155), and after withdrawal of other drugs to LTG monotherapy (N=51). POMS scores correlated highly with the QOLIE-31 Emotional Well-Being subscale, a known measure of mood. All POMS subscales were significantly improved (all P<0.0001) at the end of the adjunctive therapy phase. POMS scores remained significantly better than baseline among patients completing the conversion to monotherapy (all P<0.003). Minimal clinically important changes were determined for POMS scores. These data indicate that LTG improves mood states to a clinically important degree, even in the presence of other AEDs. The improvement likely was not a synergy but attributable only to LTG because it remained stable after withdrawal of the other AEDs.

Epilepsy and women's health issues: unmet needs--survey results from women with epilepsy.

The impact of epilepsy on women involves unique issues related to hormone effects on seizure control, seizure and drug effects on reproductive health, birth control options, and bone mineral density. Patient-physician communication on these critical issues may not be adequate. This survey evaluated womens perceptions and misconceptions of the issues they face with the diagnosis of epilepsy and the use of antiepileptic drugs (AEDs). The goals of the survey were to identify the level of current patient-physician dialogue on these issues and to determine whether women perceived a need for more information from their physicians. Across the responders, the greatest concerns related to AED therapy were weight gain (63%) and bone health (64%). Among women less than 35 years old, 69% were concerned about pregnancy. Women with epilepsy who access online health information are not adequately educated by their physicians about the impact of epilepsy and AED therapy.

Lack of effect of cimetidine on the pharmacokinetics of sustained-release bupropion.

The objective of this study was to assess whether cimetidine affects the pharmacokinetics of sustained‐release (SR) bupropion hydrochloride and the active metabolite, hydroxybupropion. This randomized, open‐label, two‐period crossover study was conducted in 24 healthy volunteers 18 to 45 years of age. ANOVA showed that administration of two 150 mg bupropion SR tablets with one 800 mg cimetidine tablet following an overnight fast did not change values for AUC∞, Cmax, tmax, t1/2, and CL/F (CL/F calculated for bupropion only) for either bupropion or hydroxybupropion as compared with two 150 mg bupropion SR tablets alone. In this study, it appears that there is no effect of cimetidine on the pharmacokinetics of bupropion SR.

Relative influences of adjunctive topiramate and adjunctive lamotrigine on scanning and the effective field of view.

A subsample of 67 adult patients with partial seizures participating in a randomized, double-blind study comparing the cognitive effects of adjunctive lamotrigine (LTG) and adjunctive topiramate (TPM) was administered Performance On-Line (POL) in addition to a battery of neuropsychological tests at baseline, week 8 and week 16 of treatment. The POL is a self-administered computer task that measures scanning, divided-attention, and the effective field of view. Although the POL does not measure driving performance, POL scores are correlated with driving performance. The results show that adjunctive TPM, but not adjunctive LTG, negatively impacted cognition. Both simple target identification and divided-attention performance on POL were compromised in the TPM group but not in the LTG group. The relative POL impairment associated with chronic TPM treatment was similar to that observed with the acute effects of alcohol with a breath level of .045% or a low dose of alprazolam (0.5mg). Thus, driving-related visual and cognitive skills were compromised by adjunctive TPM treatment. Therapeutic doses of adjunctive TPM pose a potential risk of impaired scanning and divided-attention skills.

Lamotrigine therapy in patients requiring a change in antiepileptic drug regimen

INTRODUCTION The tolerability of lamotrigine as adjunctive and monotherapy in patients requiring a change in antiepileptic drug (AED) therapy was assessed in this multicenter, open-label study. Open-label studies conducted in the clinic setting may provide additional drug tolerability and effectiveness information that may not be evident in pre-approval clinical trials. METHODS Adult patients with partial seizures received adjunctive lamotrigine for 16 weeks. Patients taking a single enzyme-inducing AED could convert to lamotrigine monotherapy for an additional 12 weeks. Patients were assessed at baseline, end of adjunctive therapy, and end of monotherapy using the Liverpool Adverse Experience Profile (AEP), Quality of Life in Epilepsy-31, a patient satisfaction rating, and a subjective investigator global assessment. RESULTS Of the 547 patients enrolled (mean age 42.7 years, 58% female), 421 (77%) completed adjunctive therapy. Upon completion of the adjunctive phase, mean improvement from baseline was 4.3 points on the AEP, and investigators rated 71% of patients as improved in global status. Overall score on the QOLIE 31 improved by 10 points from baseline. One hundred and seventy-eight patients entered and 143 (80%) patients completed the monotherapy phase. In patients completing lamotrigine monotherapy, mean improvement from baseline was 5.9 points on the AEP, and investigators rated 92% as improved in global status. Overall score on the QOLIE 31 score improved by 15 points from baseline. CONCLUSION Lamotrigine as adjunctive treatment and monotherapy may improve side effect burden and quality of life in patients requiring a change in AED therapy.

Conversion to lamotrigine monotherapy from valproate monotherapy in older adolescent patients with epilepsy

ABSTRACT Background: Pharmacokinetic interactions can make necessary anti-epileptic medication (AED) changes hazardous for children with epilepsy. We report the utility of a dosing algorithm designed to maintain stable trough lamotrigine (LTG) concentrations during conversion from valproate (VPA) to LTG monotherapy in adolescents aged 16–20 years. Methods: Patients were enrolled into the study if they required a change in their AED regimen due to lack of efficacy or intolerable side effects. Conversion to LTG monotherapy took place in a four part treatment algorithm. Lamotrigine was escalated according to a target dose of 200 mg/day over 8‐weeks. Valproate was withdrawn over a period of 2–6 weeks, depending on the initial dose. Lamotrigine dose was further escalated to 500 mg/day and continued for four weeks as monotherapy. Trough serum concentrations of LTG were measured during each phase of the trial. Results: Twelve of 16 patients completed the study. After the LTG escalation to 200 mg/day, mean trough serum concentrations of 8.0 μg/mL did not differ significantly from the 9.5 μg/mL after VPA withdrawal or the 9.2 μg/mL after 4 weeks of monotherapy at 500 mg/day. Adverse events led to premature discontinuation for one subject. Two subjects withdrew due to worsening seizures during LTG monotherapy possibly due to non-compliance. Limitations of the trial include the open label design and small sample size of the sub-analysis. Conclusion: In adolescent patients, this algorithm produces stable LTG serum concentrations with favorable tolerability during a transition from VPA to LTG monotherapy.

Cognitive effects of lamotrigine versus topiramate as adjunctive therapy in older adults with epilepsy

Older individuals may be more susceptible to cognitive side effects of antiepileptic drugs than are younger adults. This randomized, double-blind study compared the cognitive effects of lamotrigine (median maintenance dosage, 500.0 mg/d) and topiramate (median maintenance dosage, 300.0 mg/d) as adjunctive therapy for 16 weeks in patients ≥50 years of age. Fifty-one patients (lamotrigine, n=25; topiramate, n=26) were enrolled, and 28 patients (lamotrigine, n=15; topiramate, n=13) completed the study. In a combined analysis of all cognitive tests performed, no significant differences between treatment groups were noted. However, analyses of individual cognitive test results revealed that lamotrigine-treated patients had significantly better results on the Controlled Oral Word Association Test and the Symbol-Digit Modalities Test, whereas topiramate-treated patients had significantly more favorable results on the Digit Cancellation Test and the Rey Auditory-Verbal Learning Test. Larger studies are needed to further clarify the differences in the cognitive effects of lamotrigine and topiramate in older patients.

Effects of lamotrigine monotherapy in patients with newly diagnosed juvenile myoclonic epilepsy: An open-label study

BACKGROUND It is important that drug therapy for juvenile myoclonic epilepsy(JME), a lifelong disorder requiring long-term therapy, is effective and well tolerated with long-term use. Lamotrigine as monotherapy or adjunctive therapy has been demonstrated to be effective in reducing the frequency of partial and generalized seizures in short- and long-term studies in children, adolescents, adults, and elderly patients with epilepsy, including those with JME. With its tolerability profile and spectrum of efficacy, lamotrigine might be an appropriate option for newly diagnosed patients with JME, a possibility that has not been empirically assessed. OBJECTIVE The aim of this study was to assess the efficacy and tolerability of lamotrigine monotherapy in patients with newly diagnosed JME. METHODS This open-label study was conducted at 18 clinical sites across the United States. Patients aged ≥12 years with newly diagnosed JME and who had experienced at least 1 generalized motor seizure since diagnosis but were antiepileptic treatment-naive or had received inappropriate treatment due to misdiagnosis were enrolled. During the first 8 weeks of the study, lamotrigine (25-mg or 100-mg tablets) was introduced (to a maximum dosage of 100-500 mg/d, based on instructions in the package insert and clinical response). This dose escalation was followed by a 24-week treatment phase during which lamotrigine dose could be adjusted as needed to achieve optimal clinical benefit. Efficacy end points included the rates of patients with a decrease from baseline of at least 50% in the frequency of myoclonic, tonic-clonic, and absence seizures; and the rate of patients with mild, moderate, or marked improvement from baseline in global clinical status as perceived by the investigators. Adverse events were recorded in patient diaries, and diary information was reviewed by study personnel at clinic visits. Results were analyzed using descriptive statistics. RESULTS Twenty-nine patients (17 females, 12 males; mean [SD] age, 24.0 [11.3] years [range, 12-50 years]) were included in the efficacy analysis. During the lamotrigine monotherapy treatment period, 58% of patients experienced a reduction from baseline of at least 50% in days with myoclonic seizures, and 56% and 38% of patients experienced a reduction of at least 50% in the frequency of generalized tonic-clonic seizures and absence seizures, respectively. At week 24 of the monotherapy phase, investigators perceived that 72% of patients had shown mild, moderate, or marked improvement in global clinical status relative to the start of the study. CONCLUSIONS In this study, lamotrigine monotherapy given to patients with newly diagnosed JME was associated with a reduction in the frequency of seizures and improvement in global clinical status as rated by the investigators. Lamotrigine was generally well tolerated.