Rapid Cycling in Bipolar Disorder: Diagnostic Issues and Treatment Options

These findings are in line with those reported in 5 other large studies of rapid cycling summarized in Table 2.^2-4,6,7 In fact, a significantly higher proportion of patients with BP II among rapid cyclers was found in 2 of the 3 studies that waived duration criteria for affective episodes,^2,3 whereas the third study⁴ did not report any data in this respect. The studies that did not waive duration criteria did not find a greater proportion of patients with BP II among rapid cyclers.^6,7 On the other hand, the 2 studies in which circularity of course was a prerequisite found rapid cycling to be a relatively stable pattern on follow-up,^3,4 whereas the 3 studies that did not require circularity of course found rapid cycling to be a very unstable pattern.^2,6,7

The difference is particularly striking if we compare the studies by Wehr and colleagues⁴ and Coryell and colleagues.² The former study (waiving duration criteria for affective episodes and requiring circularity of course) found that 41% of patients continued to be rapid cyclers through an average follow-up duration of about 5 years, whereas the latter (waiving duration criteria but not requiring circularity of course) found that only 2.6% of patients remained rapid cyclers through a follow-up period of 4 years.

These results suggest that the DSM-IV definition of rapid cycling, although very reliable, may not be sufficiently inclusive (ie, it may exclude patients with very short episodes of very high frequency, who are typical in terms of external validators and are currently regarded as rapid cyclers by many researchers and clinicians). Moreover, the addition of the requirement of pole switching (ie, at least 1 direct transition from 1 polarity of mood to the other) during the previous year may increase the prognostic and therapeutic implications of the diagnosis of rapid cycling.

TREATMENT OF RAPID CYCLING
Lithium

A statement that is commonly made in the literature on bipolar disorder is that rapid cyclers are refractory to lithium(Drug information on lithium) prophylaxis. This notion dates back to the classic paper by Dunner and Fieve⁸ in which the concept of rapid cycling was introduced. These investigators reported a failure of lithium prophylaxis in 82% of rapid cyclers and 41% of non–rapid-cycling bipolar patients, a statistically significant difference (P < .05). However, their comparison was actually flawed. In fact, failure of lithium prophylaxis was defined as the occurrence of at least 1 new episode during an observation period of at least 6 months, not considering that rapid cyclers are by definition more likely than non–rapid cyclers to have a new episode during any observation period, whether or not they are treated.

Dunner and Fieve⁹ certainly realized the tautology intrinsic in their observation, since 3 years later they published a study of 29 rapid cyclers treated with lithium for at least 1 year, in which they correctly compared the lithium-treatment period with a period of the same duration preceding the start of treatment, and found that the percentage of time spent in euthymia was significantly increased and the percentage of time spent in mania and depression was significantly reduced during the treatment period. Their conclusion was that lithium does have an impact on rapid cycling. The 1974 paper by Dunner and Fieve is always quoted in publications concerning treatment of rapid cyclers, whereas the 1977 paper is almost never mentioned. Dunner, commonly quoted as the investigator who first demonstrated that rapid cyclers are refractory to treatment with lithium, actually stated that, “lithium alone should be the first pharmacological treatment of rapid cycling.”¹⁰

In that same article, Dunner points out that it may take a long time before the mood-stabilizing effect of lithium becomes apparent in rapid cyclers. This observation calls our attention to a potential bias of those studies in which an experimental drug is added to the mood stabilizer that the patient is already receiving (often lithium), a protocol that has become very fashionable. The improvement that is sometimes observed in these studies, and ascribed to the drug that has been added, may actually be caused by the delayed effect of lithium.

Most studies that add an experimental drug to the mood stabilizer do not actually explore the prophylactic effect of the experimental drug (ie, its capacity to prevent new episodes) but rather its acute antimanic and antidepressant effect. This acute antimanic and antidepressant effect of the experimental drug is often compared in rapid cyclers versus non–rapid cyclers. This comparison, however, may be biased by the fact that the natural course of affective episodes is different in the 2 groups of patients. The average duration of both manic and depressive episodes may be shorter in rapid cyclers than in non–rapid cyclers, so that the likelihood of a spontaneous remission during the treatment period may be higher in rapid cyclers.

Lamotrigine

The only drug for which a statistically significant superiority over placebo has been reported in the prevention of recurrences of rapid-cycling patients with bipolar disorder is lamotrigine(Drug information on lamotrigine). In a double-blind study of 182 rapid cyclers who received lamotrigine or placebo for 6 months, 41% of the patients in the lamotrigine group were stable without relapse for 6 months compared with 26% of those in the placebo group (P = .03)¹¹; however, the difference was significant with BP II but not BP I.

In a meta-analysis based on 16 reports involving 1856 patients with BP, it was found that rapid cycling was associated with lower effectiveness of all treatments evaluated. No evidence of superiority of any treatment was found.¹² In a doubleblind parallel-group trial of 254 subjects who were rapid cyclers, no significant difference was found between lithium and valproate(Drug information on valproate) regarding the rate of relapse into any mood episode and the time to relapse.¹³

In a double-blind crossover study, Denicoff and colleagues14 randomly assigned a sample of patients with BP, including a subsample of rapid cyclers, to 1 year of treatment with lithium, 1 year with carbamazepine(Drug information on carbamazepine), and 1 year with the combination. A marked or moderate improvement on the Clinical Global Impression Scale was found in 28% of the rapid cyclers during the year of treatment with lithium, in 19% of them during the year of treatment with carbamazepine, and in 56.3% of them during the year of treatment with the combination, a statistically significant difference (P < .05).

Combination therapy

These last results support the clinical impression that the combination of at least 2 mood stabilizers is needed for most rapid cyclers. According to Dunner, “if the patient does not respond to lithium monotherapy, we suggest adding a second mood stabilizer, either carbamazepine or valproate. Our general approach is to add either carbamazepine or valproate (with no particular preference for either) to lithium rather than switching, because we have found better results clinically by adding rather than switching.”¹⁰

Further double-blind studies comparing the various available mood stabilizers (and atypical antipsychotics) and their combinations in patients fulfilling the different definitions of rapid cycling are clearly warranted.

Dr Maj is professor of psychiatry and chairman of the department of psychiatry of the University of Naples SUN. He is presidentelect of the World Psychiatric Association. He was president of the European Psychiatric Association (2003-2004) and of the Italian Psychiatric Association (2000-2002).

He reports that he has no conflicts of interest concerning the subject matter of this article.

Drugs Mentioned in This Article

Carbamazepine (Carbatrol, Tegretol, others)
Lamotrigine (Lamictal)
Lithium (Eskalith)
Valproate/Valproic acid (Depakote, others)

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