- Email: [email protected]
Lamotrigine therapy in patients requiring a change in antiepileptic drug regimen
Seizure (2005) 14, 254—261
www.elsevier.com/locate/yseiz
Lamotrigine therapy in patients requiring a change in antiepileptic drug regimen§ Robert P. Kustra a,*, Kimford J. Meador b, Bradley K. Evans c, Lisa M. Leschek-Gelman d, Dawn A. Groenke a, Anne E. Hammer a, Kevin P. Nanry a, John A. Messenheimer a The TARGET Study Group1 a
Epilepsy Clinical Development, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, NC 27709, USA University of Florida, Gainsville, FL, USA c Northern Michigan Neurology, Traverse City, MI, USA d Neurology Associates, Wilmington, DE, USA b
KEYWORDS Lamotrigine; Epilepsy; Adjunctive therapy; Monotherapy; Quality of life
Summary 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.
§
Presented in part at the American Epilepsy Society Annual Meeting 2002, Seattle, WA. * Corresponding author. Tel.: +1 919 483 6925. E-mail address: [email protected] (R.P. Kustra). 1 See acknowledgments.
1059-1311/$ — see front matter # 2005 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2005.02.003
Lamotrigine adjunctive and monotherapy
255
Conclusion: Lamotrigine as adjunctive treatment and monotherapy may improve side effect burden and quality of life in patients requiring a change in AED therapy. # 2005 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.
Introduction
Methods
This study was a large, multicenter, open-label investigation of adults with partial seizures who required a change in their current AED regimen because of inadequate seizure control, unacceptable side effects, or both. 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. Because of restrictive inclusion and exclusion criteria, treatment groups in clinical trials for regulatory approval may not be representative of the population treated once a drug comes into general use. These trials, for various reasons, often do not accurately reflect the effectiveness of AEDs when used in the clinic setting. Despite their shortcomings, the value of large, open-label clinical studies includes an opportunity to document aspects of clinical response, including quality of life and safety issues that may be evident in the more routine use of the AED yet not apparent in more rigorous registration-based trials. Results from similarly designed studies with gabapentin and levetiracetam have been recently published.1,2 Lamotrigine [Lamictal1; 6-(2,3—dichlorophenyl)—1,2,4 triazine—3,5 diamine] is chemically unrelated to other currently marketed AEDs. The anticonvulsant effects of lamotrigine may result from its ability to block presynaptic voltage sensitive sodium channels, thereby stabilizing neuronal membranes and inhibiting the release of excitatory amino acid neurotransmitters (e.g. glutamate and aspartate) that play a role in the generation and spread of epileptic seizures.3 An additional recently described mechanism involves regulation of the inward hyperpolarization current (Ih).4,5 Eleven double-blind, placebo-controlled studies have demonstrated that lamotrigine is effective and well-tolerated when added to current antiepileptic therapy.6 Lamotrigine has been shown to be safe and effective in double-blind trials for conversion to monotherapy7 and for initial monotherapy.8,9 However, the benefits of converting to lamotrigine monotherapy in terms of side effect reduction and quality of life improvement in a general clinical practice setting have not been reported.
Investigator selection Investigators were predominantly community neurologists with active epilepsy practices in the United States.
Patient selection Patients aged 16 years and above were considered for entry into the study if they had a confident diagnosis of epilepsy with partial seizures (simple or complex, with or without secondary generalization) and were taking one or two AEDs of any type. These patients required a change in therapy because of inadequate seizure control, unacceptable side effects, or both. Patients were required to be capable of completing seizure diaries and selfrated questionnaires. Patients were not eligible to participate in the study if they had received lamotrigine within 30 days prior to enrollment; had a history of known or suspected hypersensitivity to lamotrigine or a history of nonepileptic seizures; were currently undergoing vagal nerve stimulation or planning surgery to control seizures during the study; were currently participating in another clinical trial or planning to enroll in another trial while participating in this trial; were pregnant or lactating; had a presence of severe hepatic or renal insufficiency, severe hematologic disease, or a clinically significant comorbidity of an unstable or progressive nature that could interfere with the objectives of this study. The study was approved by an Institutional Review Board at each investigational site, and written, informed consent was obtained from each patient.
Study objectives and endpoint measures The primary objective of the study was to evaluate the tolerability of lamotrigine when added to current AED regimen and as conversion to monotherapy. Tolerability was assessed by the change in frequency and severity of adverse events measured by the Liverpool Adverse Experience Profile (AEP).10 Patients rated each of the 19 items on a 4-point scale: 1 (never a problem), 2 (rarely a problem), 3
256
R.P. Kustra et al.
(sometimes a problem), 4 (always or often a problem). Clinical consideration of adverse event burden measured with the AEP has been shown to improve quality of life in patients with epilepsy in a randomized trial.11 Tolerability was also assessed by the number of patients reporting serious adverse events and the number of patients discontinuing the study due to adverse events related to lamotrigine. A secondary objective was to evaluate change in quality of life in patients taking adjunctive and monotherapy lamotrigine as measured by Quality of Life in Epilepsy-31 (QOLIE-31). Quality of life is defined as patients’ perception of their current level of functioning and satisfaction when compared to what they perceive to be ideal. The QOLIE-31 is a subset from Quality of Life in Epilepsy-89, a selfadministered questionnaire designed to specifically assess quality of life in patients with epilepsy across nine domains: seizure worry, overall quality of life, emotional well being, energy/fatigue, cognitive functioning, medication effects, social functioning, health status, and an overall score.12 The reliability and validity of QOLIE-31 have been established.13 An investigator global assessment and patients’ self-rated satisfaction with their treatment were also assessed. Investigators rated patients’ overall status on a Likert scale ranging from 1 (marked deterioration) to 7 (marked improvement) from baseline to the end of each treatment phase. Patients rated their satisfaction with their current epilepsy medication(s) on a Likert scale ranging from 1 (highly dissatisfied) to 6 (highly satisfied) from baseline to the end of each phase. Depressive symptoms may affect quality of life in patients with epilepsy.14 Therefore, as a supplement to the protocol, the Profile of Mood States (POMS) was added to assess patients’ mood at baseline and after the adjunctive and monotherapy phases. The POMS is a self-rated checklist of 65
Figure 1
items evaluating self-perception of mood with 6 states: fatigue-inertia, vigor-activity, depressiondejection, anger-hostility, tension-anxiety, and confusion-bewilderment.15 In addition to the objectives stated above, the proportion of patients who completed each phase with at least 50% reduction in seizures from baseline and proportion of patients who became seizure free were determined. Because some patients entered the trial well controlled on their current AED regimen, the percent of patients remaining seizure free throughout each phase was also measured.
Study design The study (Fig. 1) included a 16-week adjunctive phase followed by the option to convert to lamotrigine monotherapy for an additional 12 weeks for patients taking a single enzyme-inducing antiepileptic drug (EIAED). Patients who met the enrollment criteria prior to initiating study drug completed the AEP, QOLIE-31, and the patient global rating of satisfaction with their current epilepsy treatment. Baseline (historical) seizure frequency was determined retrospectively for the 3 months prior to initiating the study by patient self-report. For those patients taking valproate (VPA) or other non-EIAEDs, lamotrigine was initiated at 25 mg every other day for 2 weeks, 25 mg every day for 2 weeks, and then 25 mg twice daily for 1 week. Patients taking an EIAED initiated lamotrigine at 50 mg every day for 2 weeks, 50 mg twice daily for 2 weeks, and then 100 mg twice daily for 1 week. Subsequent dose adjustments were made as clinically indicated to a target maintenance dose of 100—500 mg per day. During the adjunctive phase, adjustment to background AEDs was allowed in keeping with usual clinical practice. Patients
Study design.
Lamotrigine adjunctive and monotherapy
were asked to complete seizure diaries during the final 8 weeks of each phase. Upon completion of 16 weeks of adjunctive therapy, investigators performed the global assessment and patients completed the AEP, QOLIE-31, and the rating of satisfaction with their current epilepsy treatment. At this time, patients on a single EIAED were given the option to convert to lamotrigine monotherapy and continue in the study for an additional 12 weeks if deemed appropriate by the investigator. Those patients who did not enter the monotherapy phase were discontinued from the study and treated according to the investigator’s usual clinical practice. Background concurrent EIAED was gradually withdrawn (25% reduction in daily dose per week) over a period of 4 weeks and lamotrigine monotherapy was continued for an additional 8 weeks. At the end of the monotherapy phase, investigators conducted a global assessment and patients completed the AEP, QOLIE-31, and the rating of satisfaction with their current epilepsy treatment. Investigators also reported all serious adverse events and reasons leading to premature discontinuation from the study.
257
Table 1
547
Age
42.7 14.8 years Range: 16—93 years
Gender
58% female 42% male
Seizure typea
Complex partial with generalization 69% Complex partial without generalization 58% Simple partial 19% Generalized tonic clonic 19%
Mean seizures/month Median seizures/month Seizure-free at baseline
7.6 24.2 2 14%
Baseline AEDb
Carbamazepine 38% Phenytoin 35% Valproic acid 25% Gabapentin 11% Phenobarbital 10% Topiramate 10% other 10%
a b
Data analysis Mean overall change scores from baseline to the end of adjunctive and monotherapy for the AEP, QOLIE31 and POMS were analyzed using paired t-tests. For all statistical tests, p < 0.05 was considered significant. Investigator’s global assessment scores, patient satisfaction with AEDs, and change in seizure frequency were summarized using descriptive statistics only.
Baseline demographics.
Number of patients
Patients could report more than one seizure type. Patients could be taking one or two AEDs at baseline.
and 300 119 mg/day in patients not on concurrent VPA. One hundred and seventy-eight (178) patients were eligible for and attempted conversion to lamotrigine monotherapy. Eighty percent (n = 143) completed the monotherapy phase (Fig. 2). Mean monotherapy maintenance lamotrigine dose was 412 115 mg/day.
Tolerability
Results Demography Upon completion of screening, 547 adult patients, mean age 42.7 years, 58% female, entered the adjunctive phase of the study at 116 sites across the United States. Demographic information is summarized in Table 1. Reasons for study entry were inadequate seizure control (45%), unacceptable side effects (25%), or both (30%). Fourteen percent of patients reported no seizures during the historical baseline period. Before enrollment, only 5% of patients were highly satisfied with their current AED treatment. Of the 547 patients who entered the adjunctive phase, 77% (n = 421) completed it (Fig. 2). Mean adjunctive lamotrigine maintenance dose was 201 106 mg/day in patients on concurrent VPA
Mean improvement from baseline in AEP score was 4.3 at end of the adjunctive phase ( p < 0.0001) and 5.9 by the end of monotherapy ( p < 0.0001). In patients discontinuing prematurely, mean improvement in AEP total score from baseline was 3.3 ( p = 0.0019). A total of 32 (6%) patients reported serious adverse events, including two cases of rash (neither was Stevens Johnson Syndrome). Sixty-eight patients discontinued the study because of lamotrigine related adverse events, although the specific event leading to discontinuation was not collected.
Quality of life Patients who completed the QOLIE-31 at the end of each phase were included in the analyses (n = 396 adjunctive and n = 130 monotherapy). Results are
258
R.P. Kustra et al.
Figure 2
Patient accountability.
reported as improvement from baseline to the end of adjunctive therapy and monotherapy (Fig. 3). All domains showed improvement and reached statistical significance ( p < 0.0001) versus baseline. A change of approximately 11 total points or more on QOLIE-31 scales is considered be clinically significant.16 QOLIE-31 domains that showed this degree of improvement included: seizure worry, energy/fatigue, cognitive functioning and medication effects.
Global assessments Based on the investigator’s assessment, 71% of patients improved in global status at the completion of lamotrigine adjunctive therapy. This increased to 92% of patients completing the monotherapy phase. During monotherapy, investigators reported that some patients experienced mild (1%) or moderate (1%) deterioration in their overall status, and 5% experienced no change. In the self-rated global assessment of satisfaction with AED regimen, 33% of patients reported being highly satisfied upon completion of lamotrigine adjunctive therapy compared with 5% at baseline. At the end of monotherapy, 56% of patients reported being highly satisfied with lamotrigine treatment.
Mood
Figure 3 Quality of Life in Epilepsy (QOLIE-31): In patients completing each phase, the mean QOLIE-31 change from baseline scores after adjunctive and monotherapy were statistically significant across all domains (p < 0.01).
In the subset of patients completing the Profile of Mood States, mean total mood disturbance score improved from 54 at baseline (n = 198) to 33 at the end of adjunctive therapy (n = 158), p < 0.001. Further improvements were noted at the end of monotherapy (n = 52), to a mean total mood disturbance of 31, p < 0.001. Improvements were noted across all 6 domains of the POMS.
Lamotrigine adjunctive and monotherapy
Seizure reduction All data reported below include only patients who provided acceptable seizure diaries after completing each phase (i.e., approximately half of the patients enrolled). Therefore, improvements in seizure control in the group of patients who were compliant with study procedures may not be representative of the entire study population. After completing the adjunctive therapy phase, 144 of 206 (70%) experienced at least a 50% reduction in seizure frequency from baseline and 75 (36%) became seizure free. Of the 28 patients seizure free at baseline, 25 (89%) remained seizure free. Seven patients discontinued for lack of efficacy during the adjunctive phase. Among the patients that completed the monotherapy phase 51 of 63 (81%) experienced at least a 50% reduction in partial seizure frequency from baseline and 31 (49%) became seizure free. Of the 18 patients seizure free at baseline 12 (67%) remained seizure free. Eleven patients discontinued for lack of efficacy during the monotherapy phase.
Discussion The results of this study suggest that lamotrigine improved AED regimen tolerability. Patients who completed the adjunctive and monotherapy phases also experienced an improvement in quality of life, satisfaction with drug regimen, and mood during lamotrigine adjunctive therapy. These parameters improved even further upon conversion to monotherapy. During adjunctive therapy, patients showed an improvement in all domains of the AEP. When patients were converted to monotherapy, tolerability improved even further. These results suggest that the adverse events experienced initially during adjunctive therapy may have been attributable to the concurrent baseline AED or related to additive or pharmacodynamic effects of the AEDs combined. It has been shown previously that lamotrigine monotherapy has a lower incidence of adverse events than lamotrigine adjunctive therapy.7 Gilliam recently reported results from a randomized clinical trial in which use of the AEP was compared with usual care.11 Patients whose physicians were aware of AEP score showed greater improvement on AEP score: 25% versus 5% for usual care, p < 0.01. Improvement in quality of life was noted in overall score on the QOLIE-31. Patients improved most markedly on the domains of medication effects, seizure worry and cognitive functioning. While it
259
is known that epilepsy can impair quality of life, it is also known that epilepsy can adversely affect patient’s mood. Based on the POMS, patients reported improvement in total mood disturbance during both the adjunctive and monotherapy phases. This observation is consistent with previous findings that showed lamotrigine improved mood in patients with complex partial seizures17 and in patients with epilepsy treated with lamotrigine monotherapy in a double-blind trial.18 Along with improved tolerability, the majority of patients completing the study also experienced an increase in levels of satisfaction with their current AED therapy. Satisfaction improved over baseline during lamotrigine adjunctive therapy and improved further with monotherapy. Improved satisfaction may result in improved adherence to AED regimens resulting in better clinical effectiveness. Investigators reported a significant improvement in the majority of patients during adjunctive therapy and a significant improvement in almost all patients once converted to monotherapy. This study has several limitations. First, the openlabel design makes it difficult to associate any improvements with the drug under study. Patient adherence with study procedures was not optimal, as indicated by the number of patients that did not complete seizure diaries. When patients discontinued the study prematurely for adverse events, the specific event was not captured, a practice that makes it impossible to determine the types of events that led to discontinuation. Finally, analysis of endpoints included only patients who completed each phase of the study as opposed to a more rigorous intent-to-treat approach. The importance of these data lies in the fact that large, community-based studies can provide tolerability and effectiveness information that add to or amplify data obtained from pre-approval, double-blind clinical trials. Differing clinical practice settings and practitioner approaches to treatment of epilepsy make generalizability of safety and efficacy from rigorous, well-controlled, clinical trials difficult. Despite the shortcomings of the open-label design, the results of this study are consistent with those reported in controlled clinical trials. Therefore, this study supports the utility of lamotrigine adjunctive therapy and monotherapy in patients requiring a change in their AED regimen.
Acknowledgements We acknowledge the following investigators who entered patients for the successful completion of
260
this study: Bassel Abou-Khalil, MD (Nashville, TN); Sami Aboumatar, MD (Kingston, NY); Aaron Allen, MD (Lumberton, NC); Avraham Almozlino, MD (Newton, MA); Gregory Anderson, MD (Lexington, KY); Clara Applegate, MD (West Plains, MO); Jan Baxt, MD (Snellville, GA); Beverly Beadle, MD (Little Rock, AR); Peter Bellafiore, MD (Wakefield, RI); Rukmaiah Bhupalam, MD (Louisville, KY); Harvinder Birk, MD (Redding, CA); Susan Blue, MD (Fort Worth, TX); Alphonse Bobowick, MD (Waterbury, CT); Bruce Bogdanoff, MD (Chester, PA); Charles Brondos, MD (Spokane, WA); Richard Brooks, MD (Schenectady, NY); Jose Canedo, MD (Columbus, GA); Ira Casson, MD (Forest Hills, NY); Niranjan Chandragiri, MD (Goodyear, AZ); John Chawluk, MD (Pottsville, PA); Shahid Choudhary, MD (Poplar Bluff, MO); Nelson Cooke, MD (Spokane, W); Lizbeth Cravens, MD (Kansas City, MO); Michael Daras, MD (New York, NY); Lloyd Davis, MD (Des Plaines, IL); Konstantin Dzamashvili, MD (Lombard, IL); Roy Elterman, MD (Dallas, TX); Philip Ente, MD (Lompoc, CA); Raina Ernstoff, MD (Royal Oak, MI); Toufic Fakhoury, MD (Lexington, KY); Jose Ferreira, MD (Tampa, FL); Robert Frere, MD (Saint Louis, MO); Steven Gable, MD (South Bend, IN); Bruno Gallo, MD (Sarasota, FL); John Gambin, MD (Eureka, CA); Peter Gannon, MD (Stockton, CA); Daniel Garber, MD (Asheville, NC); Bogdan Gheorghiu, MD (Spartanburg, SC); John Gilroy, MD (Southfield, MI); Paul Ginsberg, MD (Hollywood, FL); Stanley Ginsburg, MD (Denver, CO); Justin Graff, MD (Tupelo, MS); Joel Greenberg, MD (Savannah, GA); Scott Hall, MD (Bedford, TX); Mark Harris, MD (Atlanta, GA); Rizwan Hassan, MD (Wichita, KS); Nancy Hausman, MD (Marshfield, WI); Barry Hendin, MD (Phoenix, AZ); Andrew Hilburger, MD (Batavia, NY); Sandra Horowitz, MD (Framingham, MA); Phillip Hsu, MD (Springfield, MA); Charles Imbus, MD (Arcadia, CA); Riaz Janjua, MD (Cumberland, MD); Linda Johnson, MD (Overland Park, KS); Jeffrey Jones, MD (Battle Creek, MI); Raymond Kandt, MD (Highpoint, NC); Avery Katz, MD (Clifton, NJ); Stephen Kirzinger, MD (Louisville, KY); Daniel Lee, MD (Greenville, NC); Richard Leschek, MD (Frederick, MD); Thomas Lin, MD (Lima, OH); Jan Mashman, MD (Danbury, CT); Paul Mazzeo, MD (Beaufort, SC); Paul Mccabe, MD (Hershey, PA); James Mcdowell, MD (Olympia, WA); David Mclaren, MD (Columbia, MO); Laszlo Mechtler, MD (Buffalo, NY); Elliot Michel, MD (Natrona Heights, PA); Marshall Nash, MD (Decatur, GA); Steven Norris, MD (Sarasota, FL); Steven Novom, MD (Sherman Oaks, CA); Burtram Odenheimer, MD (Wichita, KS); Victor Owusu-Yaw, MD (Danville, VA); Luis Pagani, MD (Cincinnati, OH); Carol Pappas, MD (St Petersburg, FL); Steven Park, MD (Milwaukee, WI); Mrugendra Patel, MD (Richlands, VA); Jordan Popper, MD (Honolulu, HI); Arun Rajan, MD (New Bedford, MA); David Rankine, MD (Chattanooga, TN); Sumant Rawat, MD (Pueblo,
R.P. Kustra et al.
CO); Mary River, MD (Visalia, CA); David Roby, MD (Philadelphia, PA); David Rosenbaum, MD (New York, NY); Jonathan Ross, MD (Methuen, MA); Harmeet Sachdev, MD (San Jose, CA); Michael Sauter, MD (Greensburg, PA); Jack Scariano, MD (Knoxville, TN); Arthur Schiff, MD (Lawrenceville, GA); Peter Schilder, MD (Annapolis, MD); Kenneth Siegel, MD (Fairfield, CT); Susan Snodgrass, MD (Tampa, FL); Sowbhagya Sonthineni, MD (Binghamton, NY); Todd Swick, MD (Houston, TX); David Tabby, MD (Philadelphia, PA); Timothy Thoits, MD (Grand Rapids, MI); Alexandre Todorov, MD (Northport, AL); Paula TothRussell, MD (South Bend, IN); Brad Volpi, MD (Walnut Creek, CA); Lee Voulters, MD (Vicksburg, MS); William Wagner, MD (Westminster, CO); Stephen Waldman, MD (Fullerton, CA); Braxton Wannamaker, MD (Orangeburg, SC); Richard Warren, MD (Marrero, LA); Terry Watkin, MD (Reston, VA); John Wulff, MD (Muncie, IN); Colin Zadikoff, MD (Cincinnati, OH); Wladimir Zyznewsky, MD (Wheeling, WV). We also acknowledge Alison Hartigan for her assistance with the manuscript.
References 1. Morrell MJ, Mclean MJ, Willmore LJ, et al. Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. Seizure 2000;9:241—8. 2. Morrell MJ, Leppick I, French J, et al. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res 2003;54:153—61. 3. Wang SJ, Sihra TS, Gean PW. Lamotrigine inhibition of glutamate release from isolated cerebrocortical nerve terminals by suppression of voltage-activated calcium channel activity. NeuroReport 2001;12:2255—8. 4. Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 2002;5:767—74 [abstract]. 5. Zona C, Tancredi V, Longone P, et al. Neocortical potassium currents are enhanced by the antiepileptic drug lamotrigine. Epilepsia 2002;43:685—90. 6. Leach JP, Brodie MJ. In: Levy RH, Mattson RH, Meldrum BS, editors. Lamotrigine clinical use in antiepileptic drugs. 4th ed., NY: Raven Press; 1995. 7. Gilliam F, Vazquez B, Sackellares J, et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51:1018—25. 8. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345(8948):476—9. 9. Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: A double-blind comparison with phenytoin. Epilepsia 1999;40: 601—7. 10. Baker GA, Jacoby A, Buck D, et al. Quality of life of people with epilepsy: a European study. Epilepsia 1997;38:353—62. 11. Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows for reduction of adverse antiepileptic drug effects. A randomized trial. Neurology 2004;62:23—7.
Lamotrigine adjunctive and monotherapy
12. Cramer J, Perrine K, Devinsky O, et al. Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. Epilepsia 1998;39:81—8. 13. Devinsky O, Vickrey B, Cramer J, et al. Development of the quality of life in epilepsy inventory. Epilepsia 1995;36:1089— 104. 14. Kanner A, Balabanov A. Depression and epilepsy: how closely are they related? Neurology 2002;58(Suppl. 5):S27—39. 15. McNair DM, Lorr M, Droppleman LF. EITS manual for the profile of mood states. San Diego, CA: Educational and Industrial Testing Service; 1971.
261
16. Cramer J, Hammer AE, Kustra RP. Improvement in quality of life with conversion to lamotrigine monotherapy. Epilepsy Behav 2004;5:224—30. 17. Sackellares DK, Sackellares JC. Improvement in depression associated with partial epilepsy in patients treated with lamotrigine. Epilepsy Behav 2002;3:510—6. 18. Edwards K, Sackellares J, Vuong A, et al. Lamotrigine monotherapy improves depressive symptoms in epilepsy: a doubleblind comparison with valproate. Epilepsy Behav 2001;2:28— 36.
www.elsevier.com/locate/yseiz
Lamotrigine therapy in patients requiring a change in antiepileptic drug regimen§ Robert P. Kustra a,*, Kimford J. Meador b, Bradley K. Evans c, Lisa M. Leschek-Gelman d, Dawn A. Groenke a, Anne E. Hammer a, Kevin P. Nanry a, John A. Messenheimer a The TARGET Study Group1 a
Epilepsy Clinical Development, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, NC 27709, USA University of Florida, Gainsville, FL, USA c Northern Michigan Neurology, Traverse City, MI, USA d Neurology Associates, Wilmington, DE, USA b
KEYWORDS Lamotrigine; Epilepsy; Adjunctive therapy; Monotherapy; Quality of life
Summary 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.
§
Presented in part at the American Epilepsy Society Annual Meeting 2002, Seattle, WA. * Corresponding author. Tel.: +1 919 483 6925. E-mail address: [email protected] (R.P. Kustra). 1 See acknowledgments.
1059-1311/$ — see front matter # 2005 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2005.02.003
Lamotrigine adjunctive and monotherapy
255
Conclusion: Lamotrigine as adjunctive treatment and monotherapy may improve side effect burden and quality of life in patients requiring a change in AED therapy. # 2005 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.
Introduction
Methods
This study was a large, multicenter, open-label investigation of adults with partial seizures who required a change in their current AED regimen because of inadequate seizure control, unacceptable side effects, or both. 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. Because of restrictive inclusion and exclusion criteria, treatment groups in clinical trials for regulatory approval may not be representative of the population treated once a drug comes into general use. These trials, for various reasons, often do not accurately reflect the effectiveness of AEDs when used in the clinic setting. Despite their shortcomings, the value of large, open-label clinical studies includes an opportunity to document aspects of clinical response, including quality of life and safety issues that may be evident in the more routine use of the AED yet not apparent in more rigorous registration-based trials. Results from similarly designed studies with gabapentin and levetiracetam have been recently published.1,2 Lamotrigine [Lamictal1; 6-(2,3—dichlorophenyl)—1,2,4 triazine—3,5 diamine] is chemically unrelated to other currently marketed AEDs. The anticonvulsant effects of lamotrigine may result from its ability to block presynaptic voltage sensitive sodium channels, thereby stabilizing neuronal membranes and inhibiting the release of excitatory amino acid neurotransmitters (e.g. glutamate and aspartate) that play a role in the generation and spread of epileptic seizures.3 An additional recently described mechanism involves regulation of the inward hyperpolarization current (Ih).4,5 Eleven double-blind, placebo-controlled studies have demonstrated that lamotrigine is effective and well-tolerated when added to current antiepileptic therapy.6 Lamotrigine has been shown to be safe and effective in double-blind trials for conversion to monotherapy7 and for initial monotherapy.8,9 However, the benefits of converting to lamotrigine monotherapy in terms of side effect reduction and quality of life improvement in a general clinical practice setting have not been reported.
Investigator selection Investigators were predominantly community neurologists with active epilepsy practices in the United States.
Patient selection Patients aged 16 years and above were considered for entry into the study if they had a confident diagnosis of epilepsy with partial seizures (simple or complex, with or without secondary generalization) and were taking one or two AEDs of any type. These patients required a change in therapy because of inadequate seizure control, unacceptable side effects, or both. Patients were required to be capable of completing seizure diaries and selfrated questionnaires. Patients were not eligible to participate in the study if they had received lamotrigine within 30 days prior to enrollment; had a history of known or suspected hypersensitivity to lamotrigine or a history of nonepileptic seizures; were currently undergoing vagal nerve stimulation or planning surgery to control seizures during the study; were currently participating in another clinical trial or planning to enroll in another trial while participating in this trial; were pregnant or lactating; had a presence of severe hepatic or renal insufficiency, severe hematologic disease, or a clinically significant comorbidity of an unstable or progressive nature that could interfere with the objectives of this study. The study was approved by an Institutional Review Board at each investigational site, and written, informed consent was obtained from each patient.
Study objectives and endpoint measures The primary objective of the study was to evaluate the tolerability of lamotrigine when added to current AED regimen and as conversion to monotherapy. Tolerability was assessed by the change in frequency and severity of adverse events measured by the Liverpool Adverse Experience Profile (AEP).10 Patients rated each of the 19 items on a 4-point scale: 1 (never a problem), 2 (rarely a problem), 3
256
R.P. Kustra et al.
(sometimes a problem), 4 (always or often a problem). Clinical consideration of adverse event burden measured with the AEP has been shown to improve quality of life in patients with epilepsy in a randomized trial.11 Tolerability was also assessed by the number of patients reporting serious adverse events and the number of patients discontinuing the study due to adverse events related to lamotrigine. A secondary objective was to evaluate change in quality of life in patients taking adjunctive and monotherapy lamotrigine as measured by Quality of Life in Epilepsy-31 (QOLIE-31). Quality of life is defined as patients’ perception of their current level of functioning and satisfaction when compared to what they perceive to be ideal. The QOLIE-31 is a subset from Quality of Life in Epilepsy-89, a selfadministered questionnaire designed to specifically assess quality of life in patients with epilepsy across nine domains: seizure worry, overall quality of life, emotional well being, energy/fatigue, cognitive functioning, medication effects, social functioning, health status, and an overall score.12 The reliability and validity of QOLIE-31 have been established.13 An investigator global assessment and patients’ self-rated satisfaction with their treatment were also assessed. Investigators rated patients’ overall status on a Likert scale ranging from 1 (marked deterioration) to 7 (marked improvement) from baseline to the end of each treatment phase. Patients rated their satisfaction with their current epilepsy medication(s) on a Likert scale ranging from 1 (highly dissatisfied) to 6 (highly satisfied) from baseline to the end of each phase. Depressive symptoms may affect quality of life in patients with epilepsy.14 Therefore, as a supplement to the protocol, the Profile of Mood States (POMS) was added to assess patients’ mood at baseline and after the adjunctive and monotherapy phases. The POMS is a self-rated checklist of 65
Figure 1
items evaluating self-perception of mood with 6 states: fatigue-inertia, vigor-activity, depressiondejection, anger-hostility, tension-anxiety, and confusion-bewilderment.15 In addition to the objectives stated above, the proportion of patients who completed each phase with at least 50% reduction in seizures from baseline and proportion of patients who became seizure free were determined. Because some patients entered the trial well controlled on their current AED regimen, the percent of patients remaining seizure free throughout each phase was also measured.
Study design The study (Fig. 1) included a 16-week adjunctive phase followed by the option to convert to lamotrigine monotherapy for an additional 12 weeks for patients taking a single enzyme-inducing antiepileptic drug (EIAED). Patients who met the enrollment criteria prior to initiating study drug completed the AEP, QOLIE-31, and the patient global rating of satisfaction with their current epilepsy treatment. Baseline (historical) seizure frequency was determined retrospectively for the 3 months prior to initiating the study by patient self-report. For those patients taking valproate (VPA) or other non-EIAEDs, lamotrigine was initiated at 25 mg every other day for 2 weeks, 25 mg every day for 2 weeks, and then 25 mg twice daily for 1 week. Patients taking an EIAED initiated lamotrigine at 50 mg every day for 2 weeks, 50 mg twice daily for 2 weeks, and then 100 mg twice daily for 1 week. Subsequent dose adjustments were made as clinically indicated to a target maintenance dose of 100—500 mg per day. During the adjunctive phase, adjustment to background AEDs was allowed in keeping with usual clinical practice. Patients
Study design.
Lamotrigine adjunctive and monotherapy
were asked to complete seizure diaries during the final 8 weeks of each phase. Upon completion of 16 weeks of adjunctive therapy, investigators performed the global assessment and patients completed the AEP, QOLIE-31, and the rating of satisfaction with their current epilepsy treatment. At this time, patients on a single EIAED were given the option to convert to lamotrigine monotherapy and continue in the study for an additional 12 weeks if deemed appropriate by the investigator. Those patients who did not enter the monotherapy phase were discontinued from the study and treated according to the investigator’s usual clinical practice. Background concurrent EIAED was gradually withdrawn (25% reduction in daily dose per week) over a period of 4 weeks and lamotrigine monotherapy was continued for an additional 8 weeks. At the end of the monotherapy phase, investigators conducted a global assessment and patients completed the AEP, QOLIE-31, and the rating of satisfaction with their current epilepsy treatment. Investigators also reported all serious adverse events and reasons leading to premature discontinuation from the study.
257
Table 1
547
Age
42.7 14.8 years Range: 16—93 years
Gender
58% female 42% male
Seizure typea
Complex partial with generalization 69% Complex partial without generalization 58% Simple partial 19% Generalized tonic clonic 19%
Mean seizures/month Median seizures/month Seizure-free at baseline
7.6 24.2 2 14%
Baseline AEDb
Carbamazepine 38% Phenytoin 35% Valproic acid 25% Gabapentin 11% Phenobarbital 10% Topiramate 10% other 10%
a b
Data analysis Mean overall change scores from baseline to the end of adjunctive and monotherapy for the AEP, QOLIE31 and POMS were analyzed using paired t-tests. For all statistical tests, p < 0.05 was considered significant. Investigator’s global assessment scores, patient satisfaction with AEDs, and change in seizure frequency were summarized using descriptive statistics only.
Baseline demographics.
Number of patients
Patients could report more than one seizure type. Patients could be taking one or two AEDs at baseline.
and 300 119 mg/day in patients not on concurrent VPA. One hundred and seventy-eight (178) patients were eligible for and attempted conversion to lamotrigine monotherapy. Eighty percent (n = 143) completed the monotherapy phase (Fig. 2). Mean monotherapy maintenance lamotrigine dose was 412 115 mg/day.
Tolerability
Results Demography Upon completion of screening, 547 adult patients, mean age 42.7 years, 58% female, entered the adjunctive phase of the study at 116 sites across the United States. Demographic information is summarized in Table 1. Reasons for study entry were inadequate seizure control (45%), unacceptable side effects (25%), or both (30%). Fourteen percent of patients reported no seizures during the historical baseline period. Before enrollment, only 5% of patients were highly satisfied with their current AED treatment. Of the 547 patients who entered the adjunctive phase, 77% (n = 421) completed it (Fig. 2). Mean adjunctive lamotrigine maintenance dose was 201 106 mg/day in patients on concurrent VPA
Mean improvement from baseline in AEP score was 4.3 at end of the adjunctive phase ( p < 0.0001) and 5.9 by the end of monotherapy ( p < 0.0001). In patients discontinuing prematurely, mean improvement in AEP total score from baseline was 3.3 ( p = 0.0019). A total of 32 (6%) patients reported serious adverse events, including two cases of rash (neither was Stevens Johnson Syndrome). Sixty-eight patients discontinued the study because of lamotrigine related adverse events, although the specific event leading to discontinuation was not collected.
Quality of life Patients who completed the QOLIE-31 at the end of each phase were included in the analyses (n = 396 adjunctive and n = 130 monotherapy). Results are
258
R.P. Kustra et al.
Figure 2
Patient accountability.
reported as improvement from baseline to the end of adjunctive therapy and monotherapy (Fig. 3). All domains showed improvement and reached statistical significance ( p < 0.0001) versus baseline. A change of approximately 11 total points or more on QOLIE-31 scales is considered be clinically significant.16 QOLIE-31 domains that showed this degree of improvement included: seizure worry, energy/fatigue, cognitive functioning and medication effects.
Global assessments Based on the investigator’s assessment, 71% of patients improved in global status at the completion of lamotrigine adjunctive therapy. This increased to 92% of patients completing the monotherapy phase. During monotherapy, investigators reported that some patients experienced mild (1%) or moderate (1%) deterioration in their overall status, and 5% experienced no change. In the self-rated global assessment of satisfaction with AED regimen, 33% of patients reported being highly satisfied upon completion of lamotrigine adjunctive therapy compared with 5% at baseline. At the end of monotherapy, 56% of patients reported being highly satisfied with lamotrigine treatment.
Mood
Figure 3 Quality of Life in Epilepsy (QOLIE-31): In patients completing each phase, the mean QOLIE-31 change from baseline scores after adjunctive and monotherapy were statistically significant across all domains (p < 0.01).
In the subset of patients completing the Profile of Mood States, mean total mood disturbance score improved from 54 at baseline (n = 198) to 33 at the end of adjunctive therapy (n = 158), p < 0.001. Further improvements were noted at the end of monotherapy (n = 52), to a mean total mood disturbance of 31, p < 0.001. Improvements were noted across all 6 domains of the POMS.
Lamotrigine adjunctive and monotherapy
Seizure reduction All data reported below include only patients who provided acceptable seizure diaries after completing each phase (i.e., approximately half of the patients enrolled). Therefore, improvements in seizure control in the group of patients who were compliant with study procedures may not be representative of the entire study population. After completing the adjunctive therapy phase, 144 of 206 (70%) experienced at least a 50% reduction in seizure frequency from baseline and 75 (36%) became seizure free. Of the 28 patients seizure free at baseline, 25 (89%) remained seizure free. Seven patients discontinued for lack of efficacy during the adjunctive phase. Among the patients that completed the monotherapy phase 51 of 63 (81%) experienced at least a 50% reduction in partial seizure frequency from baseline and 31 (49%) became seizure free. Of the 18 patients seizure free at baseline 12 (67%) remained seizure free. Eleven patients discontinued for lack of efficacy during the monotherapy phase.
Discussion The results of this study suggest that lamotrigine improved AED regimen tolerability. Patients who completed the adjunctive and monotherapy phases also experienced an improvement in quality of life, satisfaction with drug regimen, and mood during lamotrigine adjunctive therapy. These parameters improved even further upon conversion to monotherapy. During adjunctive therapy, patients showed an improvement in all domains of the AEP. When patients were converted to monotherapy, tolerability improved even further. These results suggest that the adverse events experienced initially during adjunctive therapy may have been attributable to the concurrent baseline AED or related to additive or pharmacodynamic effects of the AEDs combined. It has been shown previously that lamotrigine monotherapy has a lower incidence of adverse events than lamotrigine adjunctive therapy.7 Gilliam recently reported results from a randomized clinical trial in which use of the AEP was compared with usual care.11 Patients whose physicians were aware of AEP score showed greater improvement on AEP score: 25% versus 5% for usual care, p < 0.01. Improvement in quality of life was noted in overall score on the QOLIE-31. Patients improved most markedly on the domains of medication effects, seizure worry and cognitive functioning. While it
259
is known that epilepsy can impair quality of life, it is also known that epilepsy can adversely affect patient’s mood. Based on the POMS, patients reported improvement in total mood disturbance during both the adjunctive and monotherapy phases. This observation is consistent with previous findings that showed lamotrigine improved mood in patients with complex partial seizures17 and in patients with epilepsy treated with lamotrigine monotherapy in a double-blind trial.18 Along with improved tolerability, the majority of patients completing the study also experienced an increase in levels of satisfaction with their current AED therapy. Satisfaction improved over baseline during lamotrigine adjunctive therapy and improved further with monotherapy. Improved satisfaction may result in improved adherence to AED regimens resulting in better clinical effectiveness. Investigators reported a significant improvement in the majority of patients during adjunctive therapy and a significant improvement in almost all patients once converted to monotherapy. This study has several limitations. First, the openlabel design makes it difficult to associate any improvements with the drug under study. Patient adherence with study procedures was not optimal, as indicated by the number of patients that did not complete seizure diaries. When patients discontinued the study prematurely for adverse events, the specific event was not captured, a practice that makes it impossible to determine the types of events that led to discontinuation. Finally, analysis of endpoints included only patients who completed each phase of the study as opposed to a more rigorous intent-to-treat approach. The importance of these data lies in the fact that large, community-based studies can provide tolerability and effectiveness information that add to or amplify data obtained from pre-approval, double-blind clinical trials. Differing clinical practice settings and practitioner approaches to treatment of epilepsy make generalizability of safety and efficacy from rigorous, well-controlled, clinical trials difficult. Despite the shortcomings of the open-label design, the results of this study are consistent with those reported in controlled clinical trials. Therefore, this study supports the utility of lamotrigine adjunctive therapy and monotherapy in patients requiring a change in their AED regimen.
Acknowledgements We acknowledge the following investigators who entered patients for the successful completion of
260
this study: Bassel Abou-Khalil, MD (Nashville, TN); Sami Aboumatar, MD (Kingston, NY); Aaron Allen, MD (Lumberton, NC); Avraham Almozlino, MD (Newton, MA); Gregory Anderson, MD (Lexington, KY); Clara Applegate, MD (West Plains, MO); Jan Baxt, MD (Snellville, GA); Beverly Beadle, MD (Little Rock, AR); Peter Bellafiore, MD (Wakefield, RI); Rukmaiah Bhupalam, MD (Louisville, KY); Harvinder Birk, MD (Redding, CA); Susan Blue, MD (Fort Worth, TX); Alphonse Bobowick, MD (Waterbury, CT); Bruce Bogdanoff, MD (Chester, PA); Charles Brondos, MD (Spokane, WA); Richard Brooks, MD (Schenectady, NY); Jose Canedo, MD (Columbus, GA); Ira Casson, MD (Forest Hills, NY); Niranjan Chandragiri, MD (Goodyear, AZ); John Chawluk, MD (Pottsville, PA); Shahid Choudhary, MD (Poplar Bluff, MO); Nelson Cooke, MD (Spokane, W); Lizbeth Cravens, MD (Kansas City, MO); Michael Daras, MD (New York, NY); Lloyd Davis, MD (Des Plaines, IL); Konstantin Dzamashvili, MD (Lombard, IL); Roy Elterman, MD (Dallas, TX); Philip Ente, MD (Lompoc, CA); Raina Ernstoff, MD (Royal Oak, MI); Toufic Fakhoury, MD (Lexington, KY); Jose Ferreira, MD (Tampa, FL); Robert Frere, MD (Saint Louis, MO); Steven Gable, MD (South Bend, IN); Bruno Gallo, MD (Sarasota, FL); John Gambin, MD (Eureka, CA); Peter Gannon, MD (Stockton, CA); Daniel Garber, MD (Asheville, NC); Bogdan Gheorghiu, MD (Spartanburg, SC); John Gilroy, MD (Southfield, MI); Paul Ginsberg, MD (Hollywood, FL); Stanley Ginsburg, MD (Denver, CO); Justin Graff, MD (Tupelo, MS); Joel Greenberg, MD (Savannah, GA); Scott Hall, MD (Bedford, TX); Mark Harris, MD (Atlanta, GA); Rizwan Hassan, MD (Wichita, KS); Nancy Hausman, MD (Marshfield, WI); Barry Hendin, MD (Phoenix, AZ); Andrew Hilburger, MD (Batavia, NY); Sandra Horowitz, MD (Framingham, MA); Phillip Hsu, MD (Springfield, MA); Charles Imbus, MD (Arcadia, CA); Riaz Janjua, MD (Cumberland, MD); Linda Johnson, MD (Overland Park, KS); Jeffrey Jones, MD (Battle Creek, MI); Raymond Kandt, MD (Highpoint, NC); Avery Katz, MD (Clifton, NJ); Stephen Kirzinger, MD (Louisville, KY); Daniel Lee, MD (Greenville, NC); Richard Leschek, MD (Frederick, MD); Thomas Lin, MD (Lima, OH); Jan Mashman, MD (Danbury, CT); Paul Mazzeo, MD (Beaufort, SC); Paul Mccabe, MD (Hershey, PA); James Mcdowell, MD (Olympia, WA); David Mclaren, MD (Columbia, MO); Laszlo Mechtler, MD (Buffalo, NY); Elliot Michel, MD (Natrona Heights, PA); Marshall Nash, MD (Decatur, GA); Steven Norris, MD (Sarasota, FL); Steven Novom, MD (Sherman Oaks, CA); Burtram Odenheimer, MD (Wichita, KS); Victor Owusu-Yaw, MD (Danville, VA); Luis Pagani, MD (Cincinnati, OH); Carol Pappas, MD (St Petersburg, FL); Steven Park, MD (Milwaukee, WI); Mrugendra Patel, MD (Richlands, VA); Jordan Popper, MD (Honolulu, HI); Arun Rajan, MD (New Bedford, MA); David Rankine, MD (Chattanooga, TN); Sumant Rawat, MD (Pueblo,
R.P. Kustra et al.
CO); Mary River, MD (Visalia, CA); David Roby, MD (Philadelphia, PA); David Rosenbaum, MD (New York, NY); Jonathan Ross, MD (Methuen, MA); Harmeet Sachdev, MD (San Jose, CA); Michael Sauter, MD (Greensburg, PA); Jack Scariano, MD (Knoxville, TN); Arthur Schiff, MD (Lawrenceville, GA); Peter Schilder, MD (Annapolis, MD); Kenneth Siegel, MD (Fairfield, CT); Susan Snodgrass, MD (Tampa, FL); Sowbhagya Sonthineni, MD (Binghamton, NY); Todd Swick, MD (Houston, TX); David Tabby, MD (Philadelphia, PA); Timothy Thoits, MD (Grand Rapids, MI); Alexandre Todorov, MD (Northport, AL); Paula TothRussell, MD (South Bend, IN); Brad Volpi, MD (Walnut Creek, CA); Lee Voulters, MD (Vicksburg, MS); William Wagner, MD (Westminster, CO); Stephen Waldman, MD (Fullerton, CA); Braxton Wannamaker, MD (Orangeburg, SC); Richard Warren, MD (Marrero, LA); Terry Watkin, MD (Reston, VA); John Wulff, MD (Muncie, IN); Colin Zadikoff, MD (Cincinnati, OH); Wladimir Zyznewsky, MD (Wheeling, WV). We also acknowledge Alison Hartigan for her assistance with the manuscript.
References 1. Morrell MJ, Mclean MJ, Willmore LJ, et al. Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. Seizure 2000;9:241—8. 2. Morrell MJ, Leppick I, French J, et al. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res 2003;54:153—61. 3. Wang SJ, Sihra TS, Gean PW. Lamotrigine inhibition of glutamate release from isolated cerebrocortical nerve terminals by suppression of voltage-activated calcium channel activity. NeuroReport 2001;12:2255—8. 4. Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 2002;5:767—74 [abstract]. 5. Zona C, Tancredi V, Longone P, et al. Neocortical potassium currents are enhanced by the antiepileptic drug lamotrigine. Epilepsia 2002;43:685—90. 6. Leach JP, Brodie MJ. In: Levy RH, Mattson RH, Meldrum BS, editors. Lamotrigine clinical use in antiepileptic drugs. 4th ed., NY: Raven Press; 1995. 7. Gilliam F, Vazquez B, Sackellares J, et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51:1018—25. 8. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345(8948):476—9. 9. Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: A double-blind comparison with phenytoin. Epilepsia 1999;40: 601—7. 10. Baker GA, Jacoby A, Buck D, et al. Quality of life of people with epilepsy: a European study. Epilepsia 1997;38:353—62. 11. Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows for reduction of adverse antiepileptic drug effects. A randomized trial. Neurology 2004;62:23—7.
Lamotrigine adjunctive and monotherapy
12. Cramer J, Perrine K, Devinsky O, et al. Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. Epilepsia 1998;39:81—8. 13. Devinsky O, Vickrey B, Cramer J, et al. Development of the quality of life in epilepsy inventory. Epilepsia 1995;36:1089— 104. 14. Kanner A, Balabanov A. Depression and epilepsy: how closely are they related? Neurology 2002;58(Suppl. 5):S27—39. 15. McNair DM, Lorr M, Droppleman LF. EITS manual for the profile of mood states. San Diego, CA: Educational and Industrial Testing Service; 1971.
261
16. Cramer J, Hammer AE, Kustra RP. Improvement in quality of life with conversion to lamotrigine monotherapy. Epilepsy Behav 2004;5:224—30. 17. Sackellares DK, Sackellares JC. Improvement in depression associated with partial epilepsy in patients treated with lamotrigine. Epilepsy Behav 2002;3:510—6. 18. Edwards K, Sackellares J, Vuong A, et al. Lamotrigine monotherapy improves depressive symptoms in epilepsy: a doubleblind comparison with valproate. Epilepsy Behav 2001;2:28— 36.