Evidence-Based Reviews

Bipolar moving target: Draw a bead on rapid cycling with type-specific therapies

Current Psychiatry. 2004 November;3(11):13-22

Because no single agent provides ideal bimodal treatment, patients often need more than one medication.

References

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed, text rev). Washington, DC: American Psychiatric Association, 2000.

2. Kupka RW, Luckenbaugh DA, Post RM, et al. Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies. J Clin Psychiatry 2003;64(12):1483-94.

3. Schneck CD, Miklowitz DJ, Calabrese JR, et al. Phenomenology of rapid cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program. Am J Psychiatry 2004;161(10):1902-8.

4. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry 2003;60(9):914-20.

5. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric comorbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3:202-10.

6. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry 1992;49:126-31.

7. Maj M, Magliano L, Pirozzi R, et al. Validity of rapid cycling as a course specifier for bipolar disorder. Am J Psychiatry 1994;151:1015-19.

8. Wehr TA, Sack DA, Rosenthal NE, Cowdry RW. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry 1988;145:179-84.

9. Bauer MS, Calabrese J, Dunner DL, et al. Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry 1994;151:506-15.

10. Baldessarini RJ, Tondo L, Floris G, Hennen J. Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients. J Affect Disord 2000;61:13-22.

11. Koukopoulos A, Sani G, Koukopoulos AE, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord 2003;73:75-85.

12. Yildiz A, Sachs GS. Do antidepressants induce rapid cycling? A gender-specific association. J Clin Psychiatry 2003;64:814-18.

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15. Calabrese JR, Woyshville MJ, Kimmel SE, Rapport DJ. Predictors of valproate response in bipolar rapid cycling. J Clin Psychopharmacol 1993;13:280-3.

16. Calabrese JR, Shelton M, Rapport DJ, et al. A double-blind 20 month maintenance study of lithium vs. divalproex in rapid-cycling bipolar disorder [presentation]. Pittsburgh, PA: Fifth International Conference on Bipolar Disorder, June 12-14, 2003.

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21. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000;20(6):607-14.

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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.

CLINICAL CHARACTERISTICS

Rapid cycling is associated most consistently with female gender and bipolar II disorder² (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 al³ and Coryell et al⁴ 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

Box

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 study¹¹ 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 al⁸ found that discontinuing antidepressants contributed to cycling cessation or slowing. However, two prospective studies by Coryell et al⁴ that controlled for major depression found no association between antidepressant use and rapid cycling.

More recently, Yildiz and Sachs¹² 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 Fieve¹³ 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 al¹⁰ found that lithium was less effective for rapid than nonrapid cyclers only in reducing recurrence of depressive episodes. Kukopulos et al¹⁴ 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: