Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

375 Investigational strategiesWhat are the lessons from clinical trials for rapid cycling?Perhaps the most striking lesson from trials that have focused on rapid cycling ishow difficult it is to study this condition. To date the only published parallelgroupdouble-blind controlled trial reporting results for rapid cycling found asignificant advantage for lamotrigine over placebo. This trial is remarkable notonly because it represents the best available evidence pertaining to the treatment ofrapid cycling, but also because the results document a clearly consistent pattern ofdifferential response across multiple outcome measures in which BP-II rapidcycling appears robustly responsive to lamotrigine and BP-I patients appearminimally, if at all, responsive to lamotrigine (Calabrese et al., 2000).Published reports of lithium treatment for rapid cycling suffer from the limitationsof mirror design, but do suggest lithium can be a beneficial treatment forsome rapid-cycling patients (Dunner et al., 1977; Maj et al., 1989). One smallsingle-blind trial described benefit for thyroid hormone at hypermetabolic doses(Bauer and Whybrow, 1990). There are, however, no published studies thatexamine the use of valproate, carbamazepine, gabapentin, oxcarbazepine, conventionalantipsychotics, or atypical antipsychotics under double-blind conditions.Some recent clinical trials may create confusion when reporting results for rapidcyclingpatients for outcomes other than rapid cycling. For example, post hoc analyseshave been conducted to examine results for rapid-cycling patients enrolled in doubleblindtrials testing the efficacy of potential treatments for acute episodes of mania ordepression. Such results, with appropriate caveats, can be perfectly acceptable, butconfusion may arise for several reasons. First, the reported outcome measure foracute episodes is easily misinterpreted as an outcome for rapid cycling per se.Changein rating scale scores over a brief (usually 3–4-week) phase of blinded treatment doesnot speak to the issue most pertinent for rapid cycling – change in cycle frequencyover time. Second, even interpretation of acute response rates should take intoconsideration whether the process of randomization balances treatment groups forthe presence of rapid cycling. Third, published reports often fail to clarify whetherresults presented for rapid-cycling patients refer to current or lifetime rapid cycling,and fail to make clear that the diagnosis of rapid cycling relied on a single questionasked during the baseline assessment of an acutely ill patient. Consistent with theDSM-IV classification, rapid cycling concurrent with study entry might represent avalid state designation. Bipolar individuals who are not currently cycling rapidly, butwho have experienced a period of rapid cycling in the remote past, might define aclinically important trait. Bipolar patients shown to be prone to periods of cycleacceleration or affective switch may represent a distinct subgroup, perhaps at highrisk of becoming manic during treatment with standard antidepressant medications.Consistent use of operationalized definitions and validated procedures for assessment