Although most studies do report poor response to lithium therapy in RCBD, Wehr and colleagues7 suggest that in some patients with rapid cycling, the discontinuation of antidepressant drugs may allow lithium to act as a more effective anticycling mood-stabilizing agent.
Divalproex: effective in manic phase
In contrast to lithium, an open trial of a homogenous cohort of patients with RCBD by Calabrese and colleagues3,8 found divalproex to possess moderate to marked acute and prophylactic antimanic properties with only modest antidepressant effects (Table 1). Data from 6 open studies involving 147 patients with rapid cycling suggest that divalproex possesses moderate to marked efficacy in the manic phase, but poor to moderate efficacy in the depressed phase. Positive outcome predictors were bipolar II and mixed states, no prior lithium therapy, and a positive family history of affective disorder. Predictors of negative response included increase in frequency and severity of mania, and borderline personality disorder.
Divalproex therapy in combination with lithium may improve response rates.9 Calabrese and colleagues, however, have examined large cohorts of patients, including those comorbid with alcohol, cocaine, and/or cannabis abuse, treated with a lithium-divalproex combination over 6-month study periods. The researchers found that only 25% to 50% of patients stabilized, and that of those not exhibiting a response, the majority (75%) did not respond because of treatment-refractory depression in the context of RCBD.3
Although experts believe divalproex to be more effective than lithium in preventing episodes associated with RCBD, such a conclusion awaits confirmation with the near completion of a double-blind, 20-month maintenance trial sponsored by the National Institute of Mental Health (NIMH).
Carbamazepine’s role in combination therapy
Early reports by Post and colleagues in 1987 suggested that rapid cycling predicted positive response to carbamazepine, but later findings by Okuma in 1993 refuted this. Other collective open and controlled studies suggest that this anticonvulsant possesses moderate to marked efficacy in the manic phase, and poor to moderate efficacy in the depressed phase of RCBD. Again, combination therapy with lithium may offer greater efficacy. Of significance, carbamazepine treatment outcomes have not been prospectively evaluated in a homogeneous cohort of rapid cyclers.
The limitations of carbamazepine therapy are well known and available evidence also does not seem to support monotherapy with this agent as being useful in RCBD, especially in the treatment and prophylaxis of depressive or mixed phases of the disorder. Thus, further controlled studies are needed to examine the agent’s potential role and safety in combination therapies for RCBD.
Table 1
SPECTRUM OF ACUTE AND PROPHYLACTIC EFFICACY OF DIVALPROEX IN RAPID-CYCLING BIPOLAR DISORDER
| Spectrum of marked responses to divalproex in bipolar rapid cycling | ||
|---|---|---|
| Acute | Prophylactic | |
| Dysphoric hypomania/mania | 87% | 89% |
| Elated hypomania/mania | 64% | 77% |
| Depression (n = 101, mean follow-up 15 months) | 21% | 38% |
| Adapted from Calabrese and Delucchi. Am J Psychiatry. 1990;147:431-434 and Calabrese et al. J Clin Psychopharmacol. 1993;13:280-283. | ||
Lamotrigine: best hope for monotherapy
Lamotrigine monotherapy has been reported to be effective in some RCBD cases. The data suggest that it possesses both antidepressant and mood-stabilizing properties.10
An open, naturalistic study of 5 women with treatment-refractory rapid cycling by Fatemi et al11 demonstrated both mood-stabilizing and antidepressant effects from lamotrigine monotherapy or augmentation at a mean dose of 185 ±33.5 mg/d. In 14 clinical reports involving 207 patients with bipolar disorder, 66 of whom had rapid cycling, lamotrigine was observed to possess moderate to marked efficacy in depression and hypomania, but only moderate efficacy in mania.
An open, prospective study compared the efficacy of lamotrigine add-on or monotherapy in 41 rapid cyclers to 34 nonrapid cyclers across 48 weeks. Improvement from baseline to last visit was significant between both subgroups for depressive and hypomanic symptoms. Patients presenting with more severe manic symptoms did less well.13
In the first double-blind, placebo-controlled study of lamotrigine in RCBD,12 182 of 324 patients with rapid cycling responded to treatment with open-label lamotrigine and were then randomized to the study’s double-blind phase. Forty-one percent of lamotrigine-treated vs. 26% of placebo-treated patients were stable without relapse during 6 months of monotherapy. Patients with rapid-cycling bipolar II disorder consistently experienced more improvement than their bipolar I counterparts (Figure 1). The results of this only prospective, placebo-controlled, acute-treatment study of rapid-cycling bipolar patients to date indicate that lamotrigine monotherapy is useful for some patients with RCBD, particularly those with bipolar II.
Frye et al14 conducted a double-blind, placebo-controlled study of 23 patients with rapid cycling utilizing a crossover series of three 6-week monotherapy evaluations of lamotrigine, gabapentin, and placebo. Marked antidepressant response on lamotrigine was seen in 45% of the participants compared with 19% of patients on placebo and a similar response rate among those on gabapentin.