A study evaluating the safety and efficacy of 2 dosages of lamotrigine (50 mg/d or 200 mg/d) compared with placebo in the treatment of a major depressive episode in patients with bipolar I disorder over 7 weeks demonstrated significant antidepressant efficacy.15 These bipolar outpatients displayed clinical improvement as early as the third week of treatment, and switch rates for both dosages did not exceed that of placebo. Patients with RCBD, however, were excluded from this initial trial. Subsequent studies have demonstrated similar magnitudes of efficacy in patients with RCBD, primarily in the prevention of depressive episodes, including the 6-month RCBD maintenance study10 and 2 recently completed 18-month maintenance studies of patients with bipolar I disorder, either recently manic or recently depressed.
Lamotrigine thus may have a special role in RCBD treatment. Its most significant side effect in bipolar disorder is benign rash, which has occurred in 9.0% (108 of 1,198) of patients randomized to lamotrigine vs. 7.6% (80 of 1,056) of those randomized to placebo in pivotal multicenter, double-blind, placebo-controlled bipolar trials.
In mood disorder trials conducted to date, the rate of serious rash, defined as requiring both drug discontinuation and hospitalization, has been 0.06% (2 of 3,153) on lamotrigine and 0.09% (1 out of 1,053) on placebo. No cases of Steven’s Johnson syndrome or toxic epidermal necrolysis were observed.16 A low starting dose and gradual titration of lamotrigine (Table 2) appear to minimize the risk of serious rash.
Levothyroxine: possible add-on therapy
Levothyroxine should be considered as add-on therapy in patients with known hypothyroidism, borderline hypothyroidism, or otherwise treatment-refractory cases.
The strategy of thyroid supplementation is derived from Gjessing’s 1936 report of success in administering hypermetabolic doses of thyroid hormone to patients with periodic catatonia. Stancer and Persad17 initially reported the potential efficacy of this therapeutic maneuver in rapid cyclers; remissions were induced by hypermetabolic thyroid doses in 5 of 7 patients with treatment-refractory bipolar disorder. No data currently support any prophylactic efficacy of thyroid supplementation monotherapy for RCBD treatment.
Bauer and Whybrow18 suggest that thyroid supplementation with T4 added to mood stabilizers augments efficacy independent of pre-existing thyroid function. The potential side effects of long-term levothryoxine administration, namely osteoporosis and cardiac arrhythmias, limit the usefulness of thyroid augmentation in RCBD.
Atypical antipsychotics: perhaps in combination
Coadministering atypical antipsychotics in other mood stabilizers may help rapid cyclers with current or past psychotic symptoms during their mood episodes, but further study is clearly needed.
Atypical antipsychotic medications may have specific mood-stabilizing properties, particularly in the management of mixed and manic states. In the first prospective trial of clozapine monotherapy in bipolar disorder, Calabrese and colleagues in 1994 reported that rapid cycling did not appear to predict nonresponse to treatment.
In the first randomized, controlled trial involving clozapine in bipolar disorder, Suppes et al19 noted significant improvement for symptoms of mania, psychosis, and global improvement. Subjects with nonpsychotic bipolar disorder showed a degree of improvement similar to that seen in the entire clozapine-treated group. These results support a mood-stabilizing role for clozapine.
Preliminary studies of risperidone and olanzapine further suggest therapeutic utility for atypical antipsychotics.
Figure 1 LAMOTRIGINE VS. PLACEBO IN RAPID-CYCLING BIPOLAR DISORDER
Table 2
DOSAGE PLAN FOR LAMOTRIGINE IN MONOTHERAPY AND COMBINATION
| Treatment period | Type of therapy | Daily dosage |
|---|---|---|
| Weeks 1-2 | Monotherapy With divalproex With carbamazepine | 25 mg 12.5 mg 50 mg |
| Weeks 3-4 | Monotherapy With divalproex With carbamazepine | 50 mg 25 mg 100 mg |
| Week 5 | Monotherapy With divalproex With carbamazepine | 100 mg 50 mg 200 mg |
| Thereafter | Monotherapy With divalproex With carbamazepine | 200 mg 100 mg 400 mg |
Topiramate: in patients with weight problems
Evidence from 12 open studies of 223 patients with bipolar disorder suggest that this anticonvulsant may possess mood-stabilizing properties while sparing patients the weight gain commonly seen with other pharmacotherapies.
Two studies of topiramate as an add-on therapy come to mind. Marcotte in 1998 retrospectively studied 44 patients with RCBD, 23 (52%) of whom demonstrated moderate or marked improvement on a mean topiramate dosage of 200 mg/d.
Sachs also reported that symptoms for some patients with a treatment-refractory bipolar disorder could be improved when topiramate was added to their medication regimen. Available data encourage further controlled studies of topiramate add-on therapy for RCBD, especially in obese patients.
Gabapentin: contradictory reports
Preliminary data from 14 open-label studies of gabapentin in 302 bipolar patients reported a response rate of around 67% when used as an add-on therapy, usually in mania or mixed states. A moderate antimanic effect was observed among a total of 23 rapid cyclers in 9 of the studies.
The reports are contradictory, however, and available data do not firmly support the agent’s efficacy in RCBD treatment.