Lamotrigine in Bipolar Depression

By | January 19, 2015

Bipolar Depression

Lamotrigine is an anticonvulsant with demonstrated efficacy in treating generalized and partial seizures (). It has been available for over 12 years but has only recently been investigated in bipolar illness. Nonetheless, because of its apparent efficacy in difficult-to-treat bipolar states (depression in both type I and type II patients and rapid cycling) its use has increased rapidly since its approval by the U.S. Food and Drug Administration (FDA). In a recent survey of participants in the large, National Institute of Mental Health (NIMH)-sponsored bipolar study (known as STEP-BD), 15% of bipolar patients were receiving lamotrigine (). Patients receiving lamotrigine were more likely to be rapid cycling or have had a history of an antidepressant-induced mania or hypomania (). Two published trials have demonstrated the efficacy of lamotrigine monotherapy in depressed bipolar patients. The first of these, sponsored by the drug’s manufacturer, was a double-blind, placebo-controlled, randomized, monotherapy trial of 195 depressed, type I, bipolar patients (). Two active arms administered lamotrigine at either 50 mg or 200 mg daily after a slow taper (50 mg was reached after 2 weeks, 200 mg was reached after 5 weeks). The study was designed with the primary outcome measure being improvement on the Hamilton Rating Scale for Depression (Ham-D). However, improvement did not reach statistical significance because of the high placebo response rate (37%) (). Nevertheless, participants’ results on both the Clinical Global Impression (CGI) and the Montgomery-Asberg Depression Rating Scale (MADRS) showed significant improvement at both 50-mg and 200-mg doses. For the MADRS the response rates were 54%, 48%, and 29% for lamotrigine 200 mg, lamotrigine 50 mg, and placebo, respectively. This effect size is similar to that seen for antidepressants in the treatment of unipolar depression (). Despite the slow titration schedule, the lamotrigine groups separated from placebo at 3 weeks (1 week after reaching the 50-mg dose), and remained superior for the remaining 4 weeks of the study ().

Similar results were obtained in the second randomized, placebo-controlled trial when Frye et al. (2000) examined 31 severely ill, bipolar I subjects in a triple cross-over design (examining lamotrigine, gabapentin, and placebo). The response rate of 52% in the lamotrigine group was statistically superior to both gabapentin (26%), and placebo (23%) ().

Prophylaxis of Episodes

Lamotrigine has been studied in two large, placebo-controlled, long-term (18-months), maintenance trials. These studies were designed to examine patients who had recently been manic () and those who had recently been depressed (). In both studies, lamotrigine was more effective at preventing or delaying future depressions than mania or hypomania. A combined analysis of 638 patients, who were randomized to one of three groups (lithium, lamotrigine, or placebo), found that both lithium and lamotrigine were superior to placebo at delaying intervention for depression and that lamotrigine was numerically superior to lithium (). These studies have led to the approval of lamotrigine by the FDA for maintenance treatment in bipolar disorder.

Type II bipolar patients experienced a similar outcome in an open study in which lamotrigine was administered for 6 months to 17 patients (). Twelve patients completed the study (70%) and experienced a significant reduction in the Ham-D score and a significant improvement in the CGI score ().

Adjunctive Use

Lamotrigine may also be useful as an adjunct. In an open add-on, naturalistic study of 22 nonresponsive (to either divalproex plus and antidepressant or divalproex plus a mood stabilizer), depressed, bipolar subjects, lamotrigine was very effecitve (). Sixteen of the 22 subjects (72%) were responsive by the end of week 4. Suppes et al. (1999) reported a similar study with a similar outcome in which nine type I bipolar subjects and eight type II bipolar subjects who had not done well with other medications had lamotrigine added to their regimen. Eleven (65%) improved significantly over the 5-month observation period. Calabrese et al. (1999a) openly treated 15 patients with lamotrigine monotherapy and 60 patients with add-on lamotrigine for 48 weeks. Patients had type I or type II bipolar disorder, but only 40 were depressed when they entered the study. Forty-eight percent experienced marked improvement and an additional 20% had moderate improvement. In another study, lamotrigine or placebo were added to fluoxetine in eight type II bipolar patients who did not improve while receiving fluoxetine monotherapy (). Although there was not a significant change in the Ham-D scores for this small study, the CGI scores improved in 84% of lamotrigine plus fluoxetine subjects, compared with 30% of fluoxetine-only subjects ().