Lamotrigine for the Treatment of Bipolar Disorder

Lamotrigine for the Treatment of Bipolar Disorder Patricia M Engle and Amy M Heck

OBJECTIVE:

To describe the available data regarding the clinical efficacy of lamotrigine for the treatment of bipolar disorder.

SUMMARY:

Anticonvulsants have emerged as alternative mood-stabilizing agents for patients with bipolar disorder who do not respond to lithium. Data regarding the efficacy of lamotrigine have been generated primarily from case reports, small open trials, and one large, randomized, placebo-controlled trial. These reports suggest that lamotrigine may be effective for the management of bipolar disorder. CONCLUSIONS:

Although current data are limited, treatment-refractory patients with bipolar disorder may benefit from lamotrigine therapy. Several studies are currently underway to determine the appropriate role of lamotrigine in the treatment of bipolar disorder. KEY WORDS: lamotrigine, anticonvulsant, bipolar disorder.

Ann Pharmacother 2000;34:258-62.

REQUEST

What is the role of lamotrigine for the treatment of bipolar disorder? RESPONSE

BACKGROUND

Bipolar disorder is a mental illness characterized by fluctuating manic and depressive episodes that affects more than 2.3 million adults in the US.1,2 Patients with bipolar disorder tend to have a high rate of morbidity and mortality by suicide.2,3 In fact, up to 20% of people with this disease commit suicide.2 Although lithium has been the mainstay of therapy for many years, it is effective as a mood stabilizer in only 20 –30% of patients with bipolar illness.4,5 A considerable number of patients are unable to tolerate lithium’s adverse effects, while others do not achieve blood concentrations necessary to fully suppress symptoms.6 For example, one study7 reported that approximately 40% of patients discontinued lithium therapy due to undesirable weight gain and decreased coordination and cognition. Managing depression in bipolar patients presents another challenge because currently available mood-stabilizing medications may be ineffective in treating the depressive component of the bipolar mood cycle. The concern for induction of mania and rapid cycling following the use of tricyclic antidepressants, selective serotonin-reuptake inhibitors, and monoamine oxidase inhibitors often precludes the use of antidepressants in this patient population.8,9 The natural development of manic-depressive illness is proposed to be similar to the underlying pathophysiology of epilepsy, a disorder characterized by chronic low-grade Author information provided at the end of the text.

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electrical stimulation that lowers the seizure threshold and eventually leads to spontaneous seizures. Anticonvulsants have therefore emerged as alternative mood-stabilizing agents for the therapy of bipolar illness. Valproate and carbamazepine have been extensively evaluated and are generally considered effective for the management of acute mania.10 Although limited data exist, the efficacy of gabapentin for the treatment of bipolar disorder has also been assessed.11 Data collected from these reports suggest that although these agents may prevent manic episodes in patients refractory to lithium, they may not be effective for the management of depressive episodes. Additional therapeutic regimens are needed to comprehensively treat the manifestations of bipolar illness. Lamotrigine, initially approved for add-on therapy, is now approved for monotherapy in the management of partial seizures in adults who are receiving treatment with a single enzyme-inducing antiepileptic drug, and for the adjunctive treatment of Lennox-Gastaut syndrome.12 Lamotrigine is postulated to act at voltage-gated sodium channels, thus stabilizing neuronal membranes by inhibiting the release of the excitatory neurotransmitters glutamate and aspartate. Early clinical trials evaluating lamotrigine for the treatment of epilepsy reported improvement in patients’ mood and general well-being. Forty-one of 62 patients receiving lamotrigine as add-on therapy for seizure management chose to continue lamotrigine therapy for its moodelevating effects, yet only 11 of these patients had a significant reduction in seizure frequency.13,14 More recent reports have attempted to evaluate the efficacy of lamotrigine in the treatment of bipolar disorder. CLINICAL EFFICACY

Data supporting the clinical efficacy of lamotrigine in the treatment of bipolar disorder are generated primarily 2000 February, Volume 34

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from case reports and small open trials.3,15-22 Investigators and clinicians agree that large-scale, multicenter, prospective trials are necessary to confirm effectiveness and to evaluate the appropriate use of lamotrigine for the treatment of bipolar disorder. Lamotrigine is an ideal candidate for clinical trials evaluating the treatment of bipolar disorder because of its high therapeutic index, moderate protein binding, and failure to induce hepatic enzymes. In addition, sedation and impaired psychomotor function are minimal with lamotrigine when compared with other agents.23-25 Calabrese et al.16 reported a 49-year-old man who presented medication-free in the depressed phase of rapid-cycling bipolar I disorder. Severe depression followed an episode of classic mania, characterized by engagement in foolish business ventures that left him hundreds of thousands of dollars in debt. The depressive episode was accompanied by crying spells, decreased physical and sexual energy, irritability, and suicidal thoughts. He had previously failed a three-year trial of lithium, a four-year trial of fluoxetine monotherapy, and a three-week trial of carbamazepine. Intolerable nausea prompted discontinuation of carbamazepine. In the previous year, the patient had experienced eight episodes (4 manic, 4 depressive) without symptom-free euthymic periods. Lamotrigine monotherapy was initiated at 25 mg/d and titrated over seven weeks to 200 mg/d. Baseline ratings for depression and mania were assessed using the 31-item Hamilton Depression Scale (HAM-D) and the Global Assessment Scale (GAS). Ratings were recorded at 1, 2, 4, 6, 8, 12, 16, and 20 weeks after initiation of therapy. The patient’s HAM-D rating improved from a baseline value of 46 to a value of 9 after 20 weeks of therapy. The GAS score also improved from 32 to 69 over the same time period. After 11 months of therapy, the patient continued taking lamotrigine and remained euthymic. A similar case report published by Labbate and Rubey17 describes a 48-year-old man with treatment-refractory bipolar disorder who demonstrated remarkable improvement after lamotrigine was added to his medication regimen. The patient experienced depression that alternated with episodes of hypomania, characterized by excessive energy, spending sprees, and ability to work without sleep. Fifty hospitalizations and 12 full courses of electroconvulsive therapy characterized his illness during the previous 10 years. Hospitalizations were most often due to the more numerous depressive episodes. The patient received adequate trials of desipramine, nortriptyline, sertraline, fluoxetine, paroxetine, and bupropion with thyroid augmentation, always in combination with regimens of lithium, carbamazepine, or valproic acid. Trials with neuroleptics were implemented as well, and he frequently took four to six psychotropic medications at one time. Although electroconvulsive therapy improved symptoms, maintenance treatments were needed, sometimes weekly. Lamotrigine therapy was initiated at 25 mg/d and titrated over a period of six weeks to 500 mg/d. Two months later, most of the patient’s other medications were gradually discontinued. Implementation of lamotrigine therapy correlated with consistent imwww.theannals.com

provement in symptoms. The patient reported feeling better than he had felt in 15 years and described only mild mood fluctuations without hypomania. He did not report significant adverse effects from lamotrigine and remained euthymic while taking lamotrigine 500 mg/d, paroxetine 40 mg/d, and levothyroxine 125 µg/d. Fatemi et al.3 reported experience with lamotrigine in five patients with rapid-cycling bipolar disorder. The patients were women ranging in age from 27 to 48 years who had bipolar I or II disorder with rapid cycling for a period of three to 20 years. All subjects were nonresponders or partial responders to traditional mood stabilizers. Each patient received lamotrigine titrated to a minimum dose of 150 mg/d (mean 185) in combination with various psychotropic medications. The other medications included fluoxetine, methylphenidate, triiodothyronine, tetraiiodothyronine, valproate, and lithium. Duration of treatment ranged from 189 to 265 days, and four patients were able to discontinue all other psychotropic medications while receiving lamotrigine therapy. Patients were assessed for evidence of cycling mood using the GAS, Beck Depression Inventory (BDI), and Young Mania Rating Scale (YMRS) before and after treatment with lamotrigine. All patients exhibited mood-stabilizing effects and significant antidepressant activity. Comparison of behavioral scores before and after treatment with lamotrigine showed a statistically significant improvement in BDI scores (p < 0.006). Evaluation of change in symptoms over time revealed a significant decline in BDI symptoms (p < 0.001) and a significant improvement in GAS scores (p < 0.031). A dose-dependent relationship was established between GAS scores and lamotrigine. Evaluation with the YMRS did not reveal any significant therapeutic effects of lamotrigine. No significant adverse effects were reported with lamotrigine therapy. The small number of female subjects limits extrapolation of results to larger populations. The authors also failed to report the exact dosing titration schedule, which makes duplication of this particular regimen difficult. In addition, concurrent use of psychotropic medications may have had synergistic effects with lamotrigine that could not be determined from this report. Kusumakar and Yatham19 administered lamotrigine to seven patients with rapid-cycling bipolar disorder. Six of the patients, with a mean age of 30 years and a mean number of nine affective episodes during the previous year, were newly diagnosed. The seventh patient was an elderly woman with an eight-year history of rapid-cycling bipolar disorder, which had previously been treated with lithium, carbamazepine, valproate, and various antidepressant medications. Lamotrigine therapy was initiated in all seven patients at 25 mg twice daily and titrated over four weeks to a maximum dose of 75 mg twice daily. Four of the six newly diagnosed patients responded to lamotrigine therapy. One patient became euthymic by the end of the second week, and the other three by the end of the fourth week. All four patients remained in remission at the conclusion of the observation period. The two patients who did not respond continued to experience mixed episodes of mania and de-


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pression. With regard to the elderly woman, depressive symptoms remitted within one week; however, development of a rash prompted discontinuation of lamotrigine four weeks after initiation of therapy. Lamotrigine therapy was restarted four days later, and the patient subsequently remained well. The authors did not cite their methods for assessing baseline severity of illness and response to lamotrigine therapy. Therefore, conclusions from this report are limited. Kusumakar and Yatham20 conducted a separate open-label, prospective study of 22 patients who were refractory to treatment with a combination of valproate and another mood stabilizer or an antidepressant for six weeks. Baseline HAMD scores of ≥18 of 21 items were required for enrollment. Patients were treated with valproate 1000–2250 mg/d for two weeks prior to initiation of lamotrigine therapy. Lamotrigine was then added at an initial dose of 25 mg twice daily and increased to 50 mg twice daily at week 2 if the HAM-D 21-item score was >15. HAM-D scores were measured weekly for six weeks. Paired t-tests comparing baseline HAM-D scores with scores after one and six weeks of therapy showed significant improvement in depression. Sixteen of the 22 patients had a ≥50% reduction in HAM-D score by week 4 compared with baseline. Fourteen of the patients entered remission (score ≤6) by week 6, and none of the patients experienced hypomania or mania. However, three of the five patients with rapid-cycling disease were considered nonresponders. Lamotrigine was well tolerated by all patients and none developed a rash. Although lamotrigine demonstrated short-term efficacy in combination with other mood-stabilizing agents in this trial, the long-term efficacy of lamotrigine in the treatment of bipolar disorder is unknown. Calabrese et al.26 conducted the first randomized, double-blind, multicenter study evaluating lamotrigine monotherapy in the treatment of the depressive phase of bipolar disorder. The study compared two target doses of lamotrigine (50 and 200 mg/d) with placebo in 195 patients with bipolar I disorder over a seven-week period. Subjects were required to have a minimum score of 18 on the 17-item HAM-D scale and be experiencing a major depressive episode for more than two weeks’ but less than one year’s duration to be eligible for the study. All other psychoactive medications were discontinued at least five elimination half-lives prior to randomization. To balance the effects of recent lithium use, randomization was stratified according to the intensity of lithium treatment during the five months prior to study entry. The lamotrigine dose was escalated to reach the target dose by week 3 in the 50-mg/d group and by week 5 in the 200-mg/d group. Weekly psychiatric evaluations assessed the observed and last observation carried forward (LOCF) responses through the HAM-D scale, the Montgomery-Asberg Depression Rating Scale (MADRS), the Mania Rating Scale, and the Clinical Global Impressions scales for Severity (CGI-S) and Improvement (CGII). A response was defined as ≥50% score reduction on the 17-item HAM-D or MADRS scales or a rating of very much improved or much improved on the CGI-I scale. 260

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Seventy-seven men and 118 women with a mean age of 40 years were enrolled in the study. There were no significant differences in patient characteristics between treatment groups at baseline. Patients receiving lamotrigine 200 mg/d (100 mg bid) demonstrated significant improvement in all efficacy endpoints using both LOCF and observed case analyses, except the LOCF assessment of the 17-item HAM-D and both observed and LOCF analyses of the 31item HAM-D total score. More than 50% of patients receiving lamotrigine 200 mg/d met response criteria on the 17-item HAM-D, MADRS, and CGI-I scales. This rate of improvement was significantly greater for the MADRS and CGI-I scales than the improvement rate observed for patients receiving placebo (p < 0.05). A greater number of patients receiving lamotrigine 200 mg/d experienced improvement in depression scores compared with patients receiving 50 mg/d. However, the lamotrigine 200-mg/d group reached the target dose two weeks after the 50-mg/d group. Therefore, the 200-mg/d group received the target dose for only three weeks of the seven-week study, whereas the 50-mg/d group received the target dose for five weeks.26 Manic, hypomanic, or mixed episodes occurred in three patients receiving placebo, two patients receiving lamotrigine 50 mg/d, and five patients receiving lamotrigine 200 mg/d (no statistical significance between groups). Approximately 30% of patients withdrew from the study for various reasons, including adverse events, inadequate response, protocol violation, and loss to follow-up. Although 32 patients withdrew from the study due to adverse events (10 placebo, 12 lamotrigine 50 mg/d, 10 lamotrigine 200 mg/d), headache was the only adverse event to occur more frequently in the lamotrigine treatment groups than the placebo group. The investigators concluded that lamotrigine monotherapy has significant antidepressant efficacy in bipolar depression.26 This finding confirms earlier reports, although the results are limited to therapy of seven weeks’ duration. Further studies are needed to evaluate the efficacy of lamotrigine for suppression of mania. CONSIDERATIONS

Although the previously presented reports indicate that lamotrigine may be an effective treatment for the management of bipolar illness, certain factors should be considered prior to initiation of therapy. Five to 10% of patients develop a rash during lamotrigine therapy.21,27 This rarely leads to Stevens-Johnson syndrome or toxic epidermal necrolysis. Patients at increased risk for the development of rash include those of advanced age and those undergoing rapid dose escalation. 27 Thus, lamotrigine should be titrated slowly and withdrawn at the first sign of a rash. Furthermore, patients receiving valproate may be at an increased risk for developing rash because valproate competes for hepatic glucuronidation, thus doubling lamotrigine serum concentrations. As a result, when lamotrigine is administered in combination with valproate, it should be started at a low dose and increased slowly.12 During clini-


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cal trials,12 lamotrigine was safely initiated at doses of 25 mg every other day in epileptic patients receiving valproate. Although Kusumakar and Yatham 20 safely initiated lamotrigine therapy at 25 mg twice daily in bipolar patients receiving valproate, a very small sample size was studied. Therefore, a conservative approach for initiating lamotrigine therapy in conjunction with valproate would include adhering to the manufacturer’s recommended titration schedule until further safety information becomes available. According to lamotrigine product labeling,12 patients receiving valproate therapy should receive an initial lamotrigine dose of 25 mg every other day for two weeks, followed by 25 mg/d for an additional two weeks, with titration in increments of 25–50 mg every one to two weeks thereafter. SUMMARY

The methodology of the various case reports and trials limits the clinical implications for lamotrigine in the treatment of bipolar disorder. To date, few large-scale, wellcontrolled trials have been reported in the literature. In addition, long-term efficacy studies evaluating suppression of mania and depression are necessary. Dosing regimens and titration schedules vary between the reported trials and case reports. However, doses of 200 mg/d demonstrated greatest efficacy compared with placebo. Several multicenter, double-blind, placebo-controlled trials are currently underway to determine an appropriate dosing schedule for lamotrigine in the treatment of bipolar disorder.28 In addition, these studies are evaluating the efficacy of lamotrigine in the various cycles of bipolar disease, in maintenance treatment of bipolar disorder, and in treatment of bipolar I versus bipolar II disorder. The available information to date presents lamotrigine as a promising option for controlling both manic and depressive episodes in treatment-refractory bipolar patients. Lamotrigine has demonstrated mood-elevating effects without induction of mania or hypomania. Compliance issues that exist with conventional lithium, valproate, and carbamazepine treatment may present less of a problem with lamotrigine because of its relative safety and tolerability. Treatment-refractory patients with bipolar disorder may find hope in the addition of lamotrigine to the reserve of treatments for this debilitating illness. Patricia M Engle PharmD, at time of writing, PharmD Student, Purdue University, West Lafayette, IN; now, Medical Student, School of Medicine, Indiana University, Indianapolis, IN Amy M Heck PharmD, Assistant Professor of Pharmacy Practice, Purdue University; Drug Information Specialist, Clarian Health Partners, Indianapolis, IN Reprints: Amy M Heck PharmD, D711 Myers Bldg., Wishard Health Services, 1001 W. 10th St., Indianapolis, IN 46202, FAX 317/6132316, E-mail [email protected]

EXTRACTO

REFERENCES 1. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994:317-91. 2. National Institute of Mental Health. US Department of Health and Human Services, 1999, NIH publication no. 99-4584.

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3. Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapidcycling bipolar disorder. J Clin Psychiatry 1997;58:522-7. 4. Prien R, Gelenberg A. Alternatives to lithium for the preventative treatment of bipolar disorder. Am J Psychiatry 1989;146:840-8. 5. Calabrese JR, Fatemi SH, Kujawa MJ, Woyshville MJ. Predictors of response to mood stabilizers. J Clin Psychopharmacol 1996;16(suppl):2431. 6. Blinder BJ, Bhat S, Sanathara VA. Advances in mood stabilizing medications. West J Med 1998;169:39-40. 7. Gitlin MJ, Cochran S, Jamison KR. Maintenance lithium treatment: side effects and compliance. J Clin Psychiatry 1989;50:127-31. 8. Post RM, Denicoff KD, Leverich GS, Frye MA. Drug-induced switching in bipolar disorder: epidemiology and therapeutic implications. CNS Drugs 1997;8:352-65. 9. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995;152:1130-8. 10. Keck PE, McElroy SL, Strakowski SM. Anticonvulsants and antipsychotics in the treatment of bipolar disorder. J Clin Psychiatry 1998;59 (suppl 6):72-81. 11. Schaffer CB, Schaffer LC. Gabapentin in the treatment of bipolar disorder. Am J Psychiatry 1997;154:291-2. 12. Product labeling. Lamictal (lamotrigine). Research Triangle Park, NC: Glaxo Wellcome, February 1999. 13. Smith D, Chadwick D, Baker G, Davis G, Dewey M. Seizure severity and the quality of life. Epilepsia 1993;34(suppl):31-5. 14. Smith D, Baker G, Davies G. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993;34:312-22. 15. Sporn J, Sachs G. The anticonvulsant lamotrigine in treatment-resistant manic-depressive illness. J Clin Psychopharmacol 1997;17:185-9. 16. Calabrese JR, Fatemi SH, Woyshville MJ. Antidepressant effects of lamotrigine in rapid cycling bipolar disorder (letter). Am J Psychiatry 1996;153:1236. 17. Labbate LA, Rubey RN. Lamotrigine for treatment-refractive bipolar disorder (letter). Am J Psychiatry 1997;154:1317. 18. Walden J, Hesslinger B, van Calker D, Berger M. Addition of lamotrigine to valproate may enhance efficacy in the treatment of bipolar affective disorder. Pharmacopsychiatry 1996;29:193-5. 19. Kusumakar V, Yatham LN. Lamotrigine treatment of rapid cycling bipolar disorder. Am J Psychiatry 1997;154:1171-2. 20. Kusumakar V, Yatham LN. An open study of lamotrigine in refractory bipolar depression. Psychiatry Res 1997;72:145-8. 21. Kotler M, Matar MA. Lamotrigine in the treatment of resistant bipolar disorder. Clinical Neuropharmacol 1998;21:65-7. 22. Erfurth A, Walden J, Grunze H. Lamotrigine in the treatment of schizoaffective disorder. Neuropsychobiol 1998;38:204-5. 23. Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321-7. 24. Hamilton MJ, Cohen AF, Yuen AW, Harkin N, Land G, Weatherley BC, et al. Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia 1993;34:166-73. 25. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345: 476-9. 26. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 1999;60:7988. 27. Ferrier IN. Lamotrigine and gabapentin. Alternatives in the treatment of bipolar disorder. Neuropsychobiol 1998;38:192-7. 28. Calabrese JR, Rapport DJ, Shelton MD, Kujawa M, Kimmel SE. Clinical studies on the use of lamotrigine in bipolar disorder. Neuropsychobiol 1998;38:185-91.

OBJETIVO: Señalar

los datos disponibles respecto a la eficacia clínica de lamotrigina para el tratamiento del trastorno de tipo bipolar. RESUMEN DEL CASO: Los anticonvulsivantes han aparecido como una alternativa para la normalización del estado emocional en pacientes que


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no responden adecuadamente al litio. Los datos respecto a la eficacia de lamotrigina se han obtenido principalmente del estudio de casos, ensayos abiertos reducidos y de uno grande, aleatorizado, placebo–control. Estos estudios sugieren que lamotrigina puede ser eficaz en el tratamiento del trastorno de tipo bipolar. CONCLUSIONES: Aunque los datos disponibles son limitados, los pacientes afectos de trastorno de tipo bipolar refractarios al tratamiento pueden beneficarse del efecto terapéutico de lamotrigina. Actualmente están en curso varios estudios para determinar el papel de lamotrigina en el tratamiento del trastorno de tipo bipolar. JUAN ROCA-ACIN

RÉSUMÉ: Certains

anticonvulsivants sont devenus des normothymiques alternatifs pour des patients atteints de troubles bipolaires en cas d’échec ou de contre-indication du lithium. Les données concernant l’efficacité de la lamotrigine proviennent de descriptions de cas, de petits essais ouverts et d’un seul essai randomisé contrôlé contre placebo ayant inclus 195 patients. Ces données suggèrent que la lamotrigine pourrait être efficace dans le traitement des troubles bipolaires. CONCLUSIONS: Bien que les données soient limitées, les patients atteints de troubles bipolaires réfractaires sont susceptibles de bénéficier d’un traitement par la lamotrigine. Plusieurs études sont en cours pour préciser les conditions d’emploi de la lamotrigine dans le traitement des troubles bipolaires. BRUNO EDOUARD

RÉSUMÉ OBJECTIF: Décrire

les données disponibles à propos de l’efficacité clinique de la lamotrigine dans le traitement des troubles bipolaires.

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