Emerging Therapies for Bipolar Disorder: A Clinical Update

With the number of approved agents for the treatment of mania and depression nearly tripling, appropriate management of bipolar disorder has become increasingly complex over the last decade. Until relatively recently, the mainstay treatment of bipolar disorder included lithium, divalproex, and, to a lesser extent, carbamazepine. However, with the approval of all of the atypical antipsychotics, as well as the approval of the novel antiepileptic agent lamotrigine as a maintenance therapy, our armamentarium for managing bipolar disorder has increased significantly.

The prevalence of the disease, treatment outcomes, and key side effects of lamotrigine and the atypical antipsychotics, olanzapine and quetiapine, were featured topics at this year's APA meeting. In addition, 2 novel approaches to treatment for bipolar depression -- repetitive transcranial magnetic stimulation and vagus nerve stimulation -- were discussed, as well as the importance of psychoeducation as a component of a comprehensive treatment plan for bipolar disorder.

Lamotrigine

Lamotrigine received approval from the US Food and Drug Administration (FDA) for the maintenance treatment of bipolar I disorder in 2003, but appears to have better efficacy for prevention of relapse into depression than for the treatment of mania.^[1] Several large, randomized, placebo-controlled trials have supported the use of lamotrigine in the treatment of bipolar disorder.^[2-7] A recent open-label study of lamotrigine suggests that it improves clinical severity in patients with bipolar disorder either as a monotherapy or in combination with valproate, with similar results.^[8] In this same open-label trial, self-reported quality of life enjoyment and cognitive function scores improved over 12 weeks when lamotrigine was added to ongoing bipolar therapy.^[9] However, the data supporting the use of lamotrigine for treatment of bipolar depression are mixed: Some studies showed that the agent produced significant improvement over placebo,^[2] but in at least 1 study, no significant improvement for bipolar I disorder was shown, and in another, improvement for bipolar I disorder, but not bipolar II, was observed.^[10]

Lamotrigine-Associated Rash

One of the most severe and troubling potential side effects associated with the use of lamotrigine is a rash, which, in severe cases, can lead to toxic epidermal necrolysis or Stevens-Johnson syndrome. Dr. Joseph R. Calabrese, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, described the appropriate clinical management of lamotrigine-associated rash in his presentation at the APA meeting.^[11] Although the percentage of patients experiencing a benign rash in lamotrigine studies was roughly equivalent in the active treatment placebo groups, there was a higher rate of dropout because of the side effect (6.3% dropout rate in the lamotrigine 200-mg group and 4.7% in the 50-mg group vs 3% dropout rate in the placebo group).^[12] To reduce the potential for rash, Dr. Calabrese suggests gradual uptitration of the dosing, starting with 25 mg for the first 2 weeks, 50 mg for Weeks 3 and 4, and increasing to 100 mg and 200 mg in Weeks 5 and 6. Drug interactions are particularly important to consider; in particular, the dose of lamotrigine should be halved when used in conjunction with divalproex and doubled when used with carbamazepine.