Rapid-Cycling Bipolar Disorder: Emerging Treatments and Enduring Controversies: Treatment Options for Rapid Cycling

Treatment Options for Rapid Cycling

Mood stabilizers. These are the cornerstone of treatment for all types of bipolar disorder, and the current APA practice guidelines recommend lithium, valproate, or lamotrigine as first-line agents for patients who meet criteria for rapid cycling. The inclusion of lithium may be surprising, since a significant percentage of rapid-cycling patients have been noted to be lithium-unresponsive.^[2] However, a recent meta-analysis of treatment studies suggests that lithium may be no less effective than other mood stabilizers.^[12] The survey of 16 studies comprising 905 rapid-cycling patients treated with carbamazepine, lamotrigine, lithium, topiramate, or valproate demonstrated no superiority for any particular treatment. More recently, a 20-month trial of rapid-cycling patients randomized to receive lithium or valproate demonstrated equivalent efficacy for both agents.^[13]

Lamotrigine has demonstrated effectiveness for acute bipolar depression and was recently studied as maintenance treatment in rapid-cycling patients. A double-blind, placebo-controlled trial by Calabrese and colleagues^[14] involving 182 patients demonstrated that 46% of rapid-cycling bipolar II patients receiving lamotrigine were stable for 6 months without relapse, compared with 18% of those receiving placebo. For rapid-cycling bipolar I patients, however, the difference between the placebo and lamotrigine arms was not significant, apparently due to a high placebo response. No controlled data exist to support the value of any other anticonvulsants in the treatment of rapid cycling.

Atypical antipsychotics. These agents have begun to receive growing attention for treating varied subtypes of bipolar illness beyond acute mania, including rapid cycling. Efficacy data are at present strongest for olanzapine. These data include a secondary analysis of a 3-week placebo-controlled trial of olanzapine as acute treatment of bipolar I disorder, which demonstrated clinical improvement in 58% of rapid-cycling patients taking olanzapine vs 28% of those on placebo.^[15] The combination of olanzapine and fluoxetine has also been studied. An 8-week, placebo-controlled trial in which depressed bipolar I patients were randomized to receive olanzapine monotherapy, olanzapine/fluoxetine combination, or placebo demonstrated that depressed rapid cyclers randomized to olanzapine/fluoxetine, but not to olanzapine, monotherapy had significant improvement in depressive symptoms compared with placebo.^[16]

Among studies of quetiapine, the strongest evidence of efficacy in rapid cycling was demonstrated by the so-called BOLDER trial, an 8-week, double-blind, placebo-controlled trial that randomized depressed bipolar patients to placebo or quetiapine. A subgroup analysis^[17] of 108 rapid-cycling patients showed significant improvement in depressive symptoms among the quetiapine-treated patients, with minimal changes in mania ratings.

Other atypical antidepressants, including ziprasidone, aripiprazole, and risperidone, have demonstrated effectiveness in treating acute mania but lack data for use in patients with rapid cycling. However, in a clozapine add-on trial involving 15 patients with rapid cycling, more than 80% showed some improvement over a 12-month study period, although it was not as robust as that seen in non-rapid-cycling patients.^[18]

Other treatments. Electroconvulsive therapy is often used in refractory mood disorders, and limited evidence suggests its efficacy in rapid cycling as well.^[19] Suprametabolic doses of thyroid hormone are advocated by some authors even in the absence of biochemical hypothyroidism, although data to support this intervention are not extensive. The anticonvulsant calcium channel blocker nimodipine also has received attention based on preliminary observations.^[20] Omega-3 fatty acids have gained growing interest for the treatment of bipolar disorder, although an 8-week placebo-controlled study failed to demonstrate efficacy in rapid cycling.^[21] Finally, although somatic therapies remain a cornerstone of treatment for bipolar illness, adjunctive cognitive-behavioral therapy and interpersonal/social rhythm therapies have demonstrated value, particularly with regard to normalizing sleep hygiene patterns and minimizing the impact of interpersonal and environmental stressors that can destabilize mood.^[22]