Bipolar moving target: Draw a bead on rapid cycling with type-specific therapies
Because no single agent provides ideal bimodal treatment, patients often need more than one medication.
Rapid-cycling bipolar disorder is a moving target, with treatment-resistant depression recurring frequently and alternating with hypomanic/manic episodes (Box). 1,2 Can one medication adequately treat these complicated patients, or is combination therapy necessary? If more than one medication is needed, are some combinations more effective than others?
This article attempts to answer these questions by:
- discussing recent treatment trial results
- suggesting an algorithm for managing hypomanic/manic and depressive episodes in rapid-cycling patients with bipolar disorder types I or II.
Rapid cycling is associated most consistently with female gender and bipolar II disorder 2 (Table); why these two groups are primarily affected is unknown. Results of studies linking rapid cycling with hypothyroidism, gonadal steroid effects, family history, and substance use have been inconsistent and contradictory. 2
Age of onset. Recent studies examining bipolar disorder’s age of onset have contradicted earlier rapid-cycling literature. In two large studies, Schneck et al 3 and Coryell et al 4 found rapid cycling associated with early onset of bipolar illness. The authors note that high rates of rapid cycling in children and adolescents resemble adult rapid cycling and speculate that early-onset bipolar illness might lead to rapid cycling vulnerability. 5
Rapid cycling: Fast and faster
Rapid cycling—defined in DSM-IV-TR as four or more depressive, manic, hypomanic, or mixed episodes in the previous 12 months—is considered a longitudinal course specifier for bipolar I or II disorder.1 Episodes must be demarcated by:
- full or partial remission lasting at least 2 months
- or a switch to a mood state of opposite polarity.
Cycling variations include ultra-rapid (1 day to 1 week), ultra-ultra rapid or ultradian (<24 hours), and continuous (no euthymic periods between mood episodes). Rapid cycling occurs in an estimated 15% to 25% of patients with bipolar disorder, 2 though psychiatrists in specialty and tertiary referral centers see higher percentages because of the illness’ refractory nature.
Transient vs persistent state. Rapid cycling is thought to be either a transient state in long-term bipolar illness or a more chronic expression of the illness. Several studies 6,7 have described rapid cycling as a transient phenomenon, whereas others 8-11 have found a more persistent rapid cycling course during follow-up. Interestingly, a recent study 11 suggested the mood-cycle pattern may be the most important predictor of rapid cycling. Patients with a depression–hypomania/mania-euthymia course demonstrated more-persistent rapid cycling than did those with a hypomania/mania-depression-euthymia course.
Antidepressants. Antidepressants’ role in initiating or exacerbating rapid cycling also remains unclear. Wehr et al 8 found that discontinuing antidepressants contributed to cycling cessation or slowing. However, two prospective studies by Coryell et al 4 that controlled for major depression found no association between antidepressant use and rapid cycling.
More recently, Yildiz and Sachs 12 found a possible gender-specific relationship between antidepressants and rapid cycling. Women exposed to antidepressants before their first hypomanic/manic episode were more likely to develop rapid cycling than women who were not so exposed. This association was not evident in men.
NO DEFINITIVE CHOICES
Any discussion of treating rapid-cycling bipolar disorder is based on limited data, as few prospective studies of this exclusive cohort exist. Many studies report on mixed cohorts of refractory bipolar patients that include rapid cyclers, but separate analyses of rapid-cycling subgroups are not usually reported. Notable exceptions are recent studies by Calabrese et al, which are discussed below.
Lithium. Dunner and Fieve 13 were the first to suggest that rapid-cycling bipolar patients respond poorly to lithium maintenance monotherapy. Later studies, however, suggested that lithium could benefit rapid cyclers, primarily in reducing hypomanic or manic episodes.
Baldessarini et al 10 found that lithium was less effective for rapid than nonrapid cyclers only in reducing recurrence of depressive episodes. Kukopulos et al 14 reported that lithium response in rapid cyclers increased from 16% to 78% after antidepressants were stopped, suggesting that a positive response to lithium may require more limited antidepressant use (or patients not having been exposed to antidepressants at all).
Thus, lithium prophylaxis has at least partial efficacy in many rapid cyclers, especially when antidepressants are avoided.
Divalproex. As with lithium, divalproex sodium appears more effective in treating and preventing hypomanic/manic episodes than depressive episodes in bipolar patients with rapid-cycling illness. Six open studies showed that patients who had not responded to lithium tended to do better with divalproex. 15
Calabrese et al then tested the hypothesis that rapid cycling predicts nonresponse to lithium and positive response to divalproex. 16 In a randomized controlled trial, they enrolled 254 recently hypomanic/manic rapid-cycling outpatients in an open-label stabilization phase involving combination lithium and divalproex therapy. Stabilized patients were then randomized to monotherapy with lithium, serum level ≥ 0.8 mEq/L, or divalproex, serum level ≥ 50 mcg/mL. Only 60 patients (24%) met stability criteria for randomization, achieving a persistent bimodal response as measured by continuous weeks of:
- Hamilton depression scale (24-item) score ≤ 20
- Young Mania Rating Scale score ≤ 12.5
- Global Assessment Scale score ≥ 51.
Most nonresponse was attributed to refractory depression.
After 20 months of maintenance therapy, about one-half of patients relapsed on either monotherapy. In the survival analysis, the median time to any mood episode was 45 weeks with divalproex monotherapy and 18 weeks with lithium monotherapy, although this difference was not statistically significant. The small sample size and high dropout rate may have created a false-negative error in this study.
Thus, these data did not show divalproex monotherapy to be more effective than lithium monotherapy in managing rapid-cycling bipolar disorder. The combination proved more effective in treating mania than depression and superior to monotherapy. This finding underscores combination therapy’s importance and the need to use mood stabilizers that also treat the depressed phase of bipolar disorder in rapid cyclers.
Clinical characteristics of rapid cycling
Prevalence approximately 15% to 25% in patients with bipolar disorder
More common in women than men
More common with type II than type I bipolar disorder
Primarily a depressive disease
Low treatment response rates and high recurrence risk
Associated with antidepressant use in some cases
Carbamazepine. Recent data refute earlier reports suggesting that rapid cycling predicted positive response to carbamazepine. Multiple open studies and four controlled studies suggest that carbamazepine—like lithium and divalproex—possesses moderate to marked efficacy in the hypomanic/manic phase but poor to moderate efficacy in the depressed phase of rapid-cycling bipolar disorder. 17
Lamotrigine. Lamotrigine is the first mood-stabilizing agent that has shown efficacy in maintenance treatment of bipolar depression and rapid cycling. In a double-blind, prospective, placebo-controlled trial, Calabrese et al 18 enrolled 324 rapid-cycling patients with bipolar disorder type I or II in an open-label stabilization phase with lamotrigine. The 182 stabilized patients were then randomly assigned to receive either lamotrigine (mean 288 +/- 94 mg/d) or placebo.
For 6 months, 41% of patients receiving lamotrigine and 26% of those receiving placebo remained stable without relapse (P = 0.03), although the difference was statistically significant only for the bipolar II subtype. Lamotrigine appeared most effective in patients with the biphasic pattern of depression-hypomania/mania-euthymia.
Topiramate. Most studies of topiramate in rapid cycling have been retrospective and/or small add-on studies to existing mood stabilizers, with topiramate use associated with moderately or markedly improved manic symptoms. 19 Evidence supports further controlled investigations, particularly because topiramate’s weight-loss effects may help overweight or obese patients.
Gabapentin. Gabapentin’s efficacy in rapid cycling has not been established. Although open-label studies showed a 67% response rate when gabapentin was used as adjunctive therapy, two double-blind, placebocontrolled studies of bipolar patients failed to show efficacy. 20,21
Atypical antipsychotics. Five atypical antipsychotics—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for treating acute mania. Olanzapine is also indicated for bipolar maintenance treatment and has the most data showing efficacy in rapid cycling:
- In a 3-week, placebo-controlled study of 139 patients with bipolar I acute mania, olanzapine (median modal 15 mg/d) reduced manic symptoms to a statistically significantly extent in the 45 rapid cyclers. 22
- A long-term prospective study followed 23 patients—30% of whom were rapid cyclers—who used olanzapine (mean 8.2 mg/d) as an adjunct to mood stabilizers. Manic and depressive symptoms were reduced significantly in the cohort, which was followed for a mean of 303 days. 23
- An 8-week, double-blind, placebo-controlled study 24 compared olanzapine monotherapy with the olanzapine/fluoxetine combination (OFC) in 833 depressed bipolar I patients, of whom 315 (37%) had rapid cycling. Mean olanzapine dosage was 9.7 mg in monotherapy and 7.4 mg in combination therapy; mean fluoxetine dosage was 39.3 mg.
A follow-up analysis 25 showed that rapid cyclers’ depressive symptoms improved rapidly, and this improvement was sustained with OFC but not olanzapine monotherapy. Nonrapid-cycling patients responded to both treatments.
Other atypicals have shown partial efficacy in rapid-cycling bipolar disorder, although the studies have had methodologic limitations. Suppes et al 26 conducted the first controlled trial using clozapine as add-on therapy in a 1-year, randomized evaluation of 38 patients with treatment-refractory bipolar disorder. The 21 rapid cyclers received a mean peak of 234 mg/d. Brief Psychiatric Rating Scale and Clinical Global Improvement scores improved significantly overall, but data specific to the rapid-cycling patients were not reported.
Small, open-label studies using risperidone and quetiapine as adjuncts to mood stabilizers have shown modest efficacy in rapid cycling, usually in treating manic symptoms. A recent 8-week, double-blind, placebo-controlled trial of quetiapine in bipolar depression showed promising results, though its efficacy in rapid cycling was not reported. 27
Because coincidental cycling may give the false appearance of efficacy in the short term, we recommend that you treat rapid cyclers methodically and judge outcomes over several months or cycle-lengths. A general approach includes:
- identify and treat underlying medical illnesses, such as hypothyroidism
- identify and treat comorbid alcohol/drug abuse
- taper or discontinue cycle-inducing agents such as antidepressants or sympathomimetics
- use standard mood stabilizers and/or atypical antipsychotics alone or in combination (Algorithm).
Algorithm Managing manic and depressive phases of rapid-cycling bipolar disorder
Treating acute mania in rapid-cycling patients is similar to managing this phase in nonrapid cyclers. First-tier therapy includes established mood stabilizers such as lithium, divalproex, or atypical antipsychotics. Carbamazepine is usually considered second-tier because of its effects on other medications via cytochrome P-450 system induction, and limited data exist on oxcarbazepine’s efficacy. Lamotrigine has not been proven effective in acute mania. If monotherapy is ineffective, try combinations of mood stabilizers and/or atypical antipsychotics.
Treating the depressed phase in rapid cyclers is far more difficult than treating acute mania and may depend on bipolar subtype:
- Bipolar I patients likely will require one or more mood stabilizers (such as lithium, divalproex, olanzapine) plus add-on lamotrigine.
- Bipolar II patients may benefit from lamotrigine alone.
- Atypical antipsychotics that have putative antidepressant effects without apparent cycle-accelerating effects may also be considered. At this time, olanzapine has the most data.
Given depression’s refractory nature in rapid-cycling bipolar illness, you may need to combine any of the above medications, try electroconvulsive therapy, or use more-experimental strategies such as:
- omega-3 fatty acids
- high-dose levothyroxine/T4.
Antidepressants. Before using antidepressants to treat bipolar depression, consider carefully the risk of initiating or exacerbating rapid cycling. No definitive evidence is available to guide your decision.
Likewise, the optimal duration of antidepressant treatment is unclear, although tapering the antidepressant as tolerated may be prudent after depressive symptoms are in remission.
Psychosocial interventions. Finally, don’t overlook psychosocial interventions. Bipolar-specific psychotherapies can enhance compliance, lessen depression, and improve treatment response. 28