Abstract: Bipolar depression is difficult to treat because most antidepressants, although effective in relieving depressive symptoms, have a propensity to induce a manic switch and rapid cycling. Lamotrigine offers new hope to treat depressive symptoms without inducing a manic switch or rapid cycling in bipolar patients. As well, lamotrigine has efficacy in preventing recurrence of depressive episodes but its efficacy in preventing manic episodes has not been proven.

Résumé : Lamotrigine : une percée importante du traitement de la dépression bipolaire
La dépression bipolaire est difficile à traiter parce que la plupart des antidépresseurs, malgré leur efficacité à soulager les symptômes dépressifs, ont une propension à induire un déclenchement de la manie et des cycles rapides. La lamotrigine présente un nouvel espoir de traiter les symptômes dépressifs sans déclencher la manie ou les cycles rapides chez les patients bipolaires. En outre, la lamotrigine est efficace pour prévenir la récurrence des épisodes dépressifs, mais son efficacité à prévenir les épisodes maniaques n’a pas été prouvée.

Key words: bipolar depression, lamotrigine, manic switch, rapid cycling

Treating bipolar depression is complex and often challenging for clinicians (1). This challenge is related to some extent to the fact that almost all antidepressants induce manic and hypomanic switch and cycle accleration in bipolar patients. Furthermore, although mood stabilizers such as lithium have been shown to have efficacy in bipolar depression in smaller placebo-controlled cross-over trials, clinicians are not impressed with the efficacy of mood stabilizer monotherapy in relieving depressive symptoms in bipolar patients. Thus, treatment of bipolar depression is clearly an unmet clinical need.

An ideal treatment for bipolar depression should do the following:

1. treat acute depressive episode
   
2. prevent relapse/recurrence of depressive symptoms
   
3. not induce manic and hypomanic episodes
   
4. not induce rapid cycling
   
5. prevent recurrence of manic and hypomanic episodes

This paper will briefly review lamotrigine to determine if it fulfils criteria for an ideal treatment for bipolar depression.

Is lamotrigine effective in treating acute bipolar depression?

Calabrese and others conducted the most comprehensive double-blind placebo-controlled study for bipolar depression to date (2). In that study, 195 patients with bipolar depression were randomized to lamotrigine monotherapy with 50 mg/day (n = 66), lamotrigine monothearpy 200 mg/day (n = 63) or placebo (n = 66) for 7 weeks. Results indicated that patients randomized to lamotrigine 200 mg/day showed significantly greater improvement compared with those randomized to placebo on Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression-Improvement (CGI-I) scale. About 51% of patients in the 200 mg/day group met criteria for response on CGI-I compared with 41% in 50 mg/day group and 26% of patients in the placebo group. Thus, the results of this study clearly indicate that lamotrigine is effective in treating acute bipolar depression (2).

Does lamotrigine prevent relapse or recurrence of depressive symptoms or episodes?

Two recent double-blind studies examined the efficacy of lamotrigine in preventing depressive relapses in bipolar 1 patients. In the first study, bipolar 1 depressed patients were treated with lamotrigine monotherapy or add-on therapy in an open-label design and those meeting the stabilization criteria were randomized to double-blind treatment with lamotrigine monotherapy (n = 221), lithium monotherapy (n = 121) or placebo monotherapy (n = 121) for 18 months. Results indicated that lamotrigine was more effective than placebo in delaying time to intervention for any mood episode or a depressive episode (3). In a second study, patients with bipolar 1 disorder were recruited in a manic or hypomanic phase and were stabilized with lamotrigine monotherapy or add-on therapy to psychotropic medications and those stabilized were randomized to double-blind treatment with either lamotrigine monotherapy (n = 59), lithium monothearpy (n = 46) or placebo monotherapy (n=70) for 18 months. Lamotrigine was significantly superior to placebo in time to any mood episode or depressive episode (4).

Thus, the results of two double-blind trials clearly indicate that lamotrigine is effective in delaying depressive relapses and recurrences in bipolar 1 patients.

Does lamotrigine induce manic and hypomanic episodes in bipolar patients?

The nature of the bipolar disorder is such that patients with this disorder experience both manic and depressive episodes as part of the natural course of the disorder. Hence, if a bipolar 1 depressed patient experiences a manic or hypomanic episode while on a given medication, the episode might have been triggered by the medication or the episode might have been the natural expression of the course of the disorder and the medication played no role. The best way to ascertain whether a medication has a tendency to induce manic and hypomanic episodes in bipolar disorder patients is to examine the incidence of manic and hypomanic episodes in patients on the active medication in comparison to those on placebo.

The incidence of manic and hypomanic episodes was examined in bipolar 1 depressed patients on lamotrigine monotherapy, compared with those treated with placebo monotherapy for 7 weeks (2). About 5% of patients on placebo and 5.5% of patients on lamotrigine therapy experienced a switch and the difference was not statistically significant. In recently stabilized bipolar 1 depressed patients, double-blind treatment with lamotrigine monotherapy did not lead to higher incidence of manic and hypomanic switch, regardless of the definition used to determine the switch into mania and hypomania (3).

Therefore, there is clear evidence from short- and long- term placebo-controlled trials that lamotrigine does not induce a manic or hypomanic switch in patients with bipolar 1 disorder.

Does lamotrigine induce rapid cycling?

There is no evidence to indicate that lamotrigine induces rapid cycling in bipolar patients. On the contrary, lamotrigine has been tested for its efficacy in stabilizing mood in rapid-cycling bipolar 1 and 2 patients. Patients with rapid-cycling bipolar disorder (n = 324) were treated with lamotrigine open-label therapy, and concomitant psychotropic medications were gradually discontinued. Those meeting stabilization criteria (n = 182) were randomized to 6 months double-blind treatment with lamotrigine monotherapy or placebo monotherapy. The overall survival in the study was significantly greater for bipolar 2 patients on lamotrigine compared with those randomized to placebo, although the difference was not significant for bipolar 1 rapid-cycling patients. A significantly greater number (46%) of bipolar 2 patients on lamotrigine had no mood relapses, compared with only 18% of those treated with placebo (3).

The results of this study provide evidence that lamotigine may be useful in stabilizing mood in bipolar 2 rapid-cycling patients.

Is lamotrigine effective in preventing manic or hypomanic relapses and recurrences in bipolar 1 patients?

The efficacy of lamotrigine in preventing and delaying manic and hypomanic episodes was examined in two double-blind studies reviewed above (3,4). Although lithium was superior to placebo in delaying manic episodes in both studies, lamotrigine was not more effective than placebo. However, when the data from the two studies were combined, the results indicated that lamotrigine was statistically significantly superior to placebo in delaying manic episodes.

The studies suggest that if lamotrigine has any efficacy in preventing manic episodes, it is likely such effect is only modest and further studies are needed to verify this.

Should lamotrigine be used to treat depression in bipolar 1 patients?

Based on the studies reviewed above, it is reasonable to conclude that lamotrigine meets at least 4 of the 5 criteria proposed above.

There is no treatment to date approved by the Federal Drug Administration in the USA or Therapeutics Products Program in Canada to treat bipolar depression. Given the lack of safer and approved treatments for bipolar 1 depression, the evidence reviewed above suggests lamotrigine is clearly a significant advance for treatment of bipolar 1 depression. It is likely that this medication will be approved by the regulatory authorities within the near future for acute and maintenance treatment of bipolar 1 depression.

When and how do you use lamotrigine?

Lamotrigine should be the first-line treatment for bipolar 1 depressed patients with a previous history of severe manic episodes. It is recommended to combine it with lithium or valproate in such patients, as the efficacy of lamotrigine in preventing manic episodes has not been proven. It can be used as a monotherapy in bipolar 2 depressed patients or rapid-cycling bipolar 2 patients.

Lamotrigine is well tolerated by most patients. However, skin rash occurs in 10% of patients treated with lamotrigine and the risk of rash is related to rapid dose escalation and concomitant use of valproate. In approximately 1% of those that develop rash, it can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis, both of which can be life threatening. Although there are some signs to help differentiate serious rash from benign rash, it is recommended to discontinue lamotrigine if physicians are unsure about the nature of the rash.

Patients taking lamotrigine must monitor for the occurrence of rash on a daily basis. The rash is more likely to occur within the first 6 weeks of commencing lamotrigine therapy. Physicians should advise their patients to consult them right away in the event of skin rash.

Lamotrigine can be started at 12.5 mg to 25 mg daily and can be increased by 25 mg every 2 weeks during the first 6 weeks. The starting dosage and dosage escalation should be halved for patients taking valproate and doubled for patients on carbamazepine. Most patients respond to an average dosage of about 150 to 200 mg but the dosage could be increased up to 400 mg if necessary.

In conclusion, lamotrigine is an excellent treatment for acute and maintenance treatment of bipolar depression, and it is in general well tolerated, with the exception of skin rash.

1. Yatham LN, Kusumakar V, Parikh SV, Haslam DRS, Matte R, Sharma V, and others. Bipolar depression: treatment options. Can J Psychiatry 1997;42 Suppl 2:87S–91S.
2. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd ED. A double-blind placebo-controlled study of lamontrigine monotherapy in outpatients with bipolar 1 depression. Lamictal 602 Study Group. J Clin Psychiatry 1999;60:79–88.
3. Calabrese JR, Bowden CL, Sachs GS, Yatham LN, and others. A placebo-controlled 18-month trial of lamontrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. In preparation for submission to JAMA.
4. Bowden CL, Calabrese JR, Sachs GS, Yatham LN, Asghar SA, Hompland M, and others. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. [submitted].
5. Calabrese JR, Suppes T, Bowden CL, and others. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group [In Process Citation]. J Clin Psychiatry 2000;61 841–850.

http://www.cpa-apc.org/Publications/Archives/Bulletin/2002/april/yatham.asp

SMHAI Home | About Suicide | About Mental Health | Suicide Prevention | Suicide Survivors
Suicide Attempters | Self-Injury - Cutters | Crisis | Donate | SMHAI Library | Online Support & Resources
Speakers & Presentations | Memorials, Remebrances & Celebrations Of Life | Healing Music
Suggested Reading - Survivors | Suggested Reading - Attempters & Self-Injurers | Mental Health Pros.
Upcoming Events | Dr. Roerich's Welcome | Ann Gay's Welcome | Legal & About SMHAI
Privacy Policy | Copyright Notice | Awards Honoring SMHAI | SMHAI Awards Program | Contact

© SMHAI 2004 - 2006 All Rights Reserved.
No copying or redistribution without expressed written permission of SMHAI.
Logo Design by Allen R. Jacobson.
Site launched July 01, 2004.