Patients with rapid-cycling bipolar disorder (RCBD) can be frustrating to treat. Despite growing research and data, knowledge and effective therapies remain limited. How do you manage patients with rapid cycling who do not respond robustly to lithium, divalproex, or carbamazepine monotherapy? Are combination therapies likely to be more effective? Where does lamotrigine fit in? Is there a role for conventional antidepressants?
We’ll explore these and related questions—but the final answers are not yet in. Recognition of RCBD is important because it presents such difficult treatment challenges. Available evidence does suggest that rapid cycling as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (Box 1), describes a clinically specific course of illness that may require treatments different from currently used traditional drug therapies for nonrapid cycling bipolar disorder, particularly as no one agent appears to provide ideal bimodal treatment and prophylaxis of this bipolar disorder variant.
THE CHARACTERISTICS OF RAPID CYCLING
Rapid cycling is a specifier of the longitudinal course of illness presentation that is seen almost exclusively in bipolar disorder and is associated with a greater morbidity. Dunner and Fieve1 originally coined the term when evaluating clinical factors associated with lithium prophylaxis failure. Since that time the validity of rapid cycling as a distinct course modifier for bipolar disorder has been supported by multiple studies, leading to its inclusion in the fourth edition of the Diagnostic and Statistical Manual of the APA (1994).
According to DSM-IV, the course specifier of rapid cycling applies to “at least 4 episodes of a mood disturbance in the previous 12 months that meet criteria for a manic episode, a hypomanic episode, or a major depressive episode.” The episodes must be demarcated by a full or partial remission lasting at least 2 months or by a switch to a mood state of opposite polarity.
Early reports noted that patients suffering from RCBD did not respond adequately when treated with lithium.1 Other observations indicated that divalproex was more effective in this patient population, particularly for the illness’ hypomanic or manic phases.2 We hope that the following evaluation of these and other drug therapies will prove helpful.
Watch out for antidepressants
Most concerning has been the frequency and severity of treatment-refractory depressive phases of RCBD that may be exacerbated by antidepressant use (cycle induction or acceleration). Indeed, the frequent recurrence of refractory depression has been described as the hallmark of this bipolar disorder variant.3
Lithium: the scale weighs against it
Although an excellent mood stabilizer for most patients with bipolar disorder, lithium monotherapy is less than ideal for patients with the rapid-cycling variant, particularly in treatment or prevention of depressive or mixed episodes. The efficacy of lithium is likely decreased by the concurrent administration of antidepressant medication and increased when administered with other mood stabilizers.
The landmark article by Dunner and Fieve,1 which described a placebo-controlled, double-blind maintenance study in a general cohort of 55 patients, tried to clarify factors associated with the failure of lithium prophylaxis in bipolar disorder. Rapid cyclers comprised 20% of the subjects and 80% were nonrapid cyclers. Rapid cyclers were disproportionately represented in the lithium failure group. Lithium failures included 82% (9 of 11) of rapid cyclers compared to 41% (18 of 44) of nonrapid cyclers. Lithium failure was defined as (1) hospitalization for, or (2) treatment of, mania or (3) depression during lithium therapy, or as mood symptoms that, as documented by rating scales, were sufficient to warrant a diagnosis of mild depression, hypomania, or mania persisting for at least 2 weeks.
Kukopulos et al4 replicated the findings of Dunner and Fieve in a study of the longitudinal clinical course of 434 bipolar patients. Of these patients, 50 were rapid cyclers and had received continuous lithium therapy for more than a year, with good to partial prophylaxis in only 28%. Maj and colleagues5 published a 5-year prospective study of lithium therapy in 402 patients with bipolar disorder and noted the absence of rapid cycling in good responders to lithium but an incidence rate of 26% in nonresponders to lithium.
Other investigators have reported better response in RCBD. In a select cohort of lithium-responsive bipolar I and II patients, Tondo et al6 concluded that lithium maintenance yields striking long-term reductions in depressive and manic morbidity, more so in rapid cycling type II patients. This study, however, was in a cohort of lithium responders and excluded patients who had been exposed to antipsychotic or antidepressant medications for more than 3 months, those on chronic anticonvulsant therapy, and those with substance abuse disorders.