Rapid Cycling in Bipolar Disorder: Overview and Expert Perspectives

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Rapid cycling appears to be a transitory phenomenon that constitutes a worsening of bipolar disorder.
Rapid cycling appears to be a transitory phenomenon that constitutes a worsening of bipolar disorder.

Although the concept of rapid cycling in bipolar disorder was introduced in the 1970s, and up to one-third of hospitalized patients with bipolar disorder currently receive this diagnosis, there remains a lack of clarity regarding its usefulness as a course specifier and its value in treatment planning and prognosis.1,2 For example, patients with ultrarapid cycling, characterized by cycles occurring over a period of days or weeks, are often classified as having mixed episodes instead of rapid cycling.2

To date, research findings have been insufficient to elucidate the prevalence, course, and clinical correlates of rapid cycling, and it is unclear to what extent “the rapid-cycling phenotype may represent the ultimate expression of a distinct affective instability with unique biological, familial/genetic, and behavioral components,” wrote the authors of research published in 2014 in the Journal of Clinical Psychiatry.2 To clarify these factors, they conducted a systematic review of 119 articles on the topic. Their findings are summarized below.

  • The 12-month and lifetime prevalence of rapid cycling among patients with bipolar disorder ranged between 5.0%-33.3% and 25.8%-43.0%, respectively.
  • It appears that rapid cycling is related to earlier age at onset of bipolar disorder, longer illness course, more substance abuse, and increased suicidality.
  • While the etiology of rapid cycling is unclear, findings suggest triggering or causal roles for hypothyroidism (observed in nearly 50% of patients with rapid cycling)3-6 and antidepressant use, with studies indicating antidepressant-induced rapid cycling in 3% to 50% of patients.7-9 However, experts are not in agreement regarding the potential causative role of these factors.
  • Findings regarding potential genetic links were inconclusive.

Rapid cycling appears to be a “transitory phenomenon rather than a stable pattern that characterizes the individual patient and… constitutes a worsening of the primary disorder,” wrote the authors. “There is no good evidence that rapid cycling represents a discrete subtype. Early recognition of this pattern can lead to better treatment strategy and improvement of the long-term course.”

Psychiatry Advisor checked in with experts to learn more about rapid cycling in bipolar disorder and related treatment implications. Francis M. Mondimore, MD, associate professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, director of the Mood Disorders Clinic at Johns Hopkins Bayview Medical Center, and author of Bipolar Disorder: A Guide for Patients and Families; and Descartes Li, MD, clinical professor of psychiatry at the University of California, San Francisco, and director of the UCSF Bipolar Disorder Program, shared their insights on this challenging condition.

Psychiatry Advisor: Who is at risk for rapid cycling in bipolar disorder?

Dr Mondimore: Rapid cycling was formerly considered a subtype of bipolar disorder, but it is now recognized that many patients will go through periods of rapid cycling during the course of their illness. Patients with bipolar I disorder are at higher risk. Studies have identified hypothyroidism and female gender as other risk factors.2 There is some evidence that antidepressant medications can shift patients with bipolar disorder into periods of rapid cycling.

Dr Li: Individuals with bipolar disorder who take antidepressants appear to be at significantly increased risk.10 Other risk factors include younger age, female gender, substance abuse, childhood physical and/or sexual abuse, and thyroid dysfunction.

Psychiatry Advisor: What are some recommendations for the early recognition of rapid cycling, and when this pattern is recognized in a patient, how can it be managed?

Dr Mondimore: Rapid cycling in bipolar disorder is defined as having 4 or more mood episodes annually. There is little research on the optimal treatment of rapid cycling. Optimizing doses of mood-stabilizing medications such as lithium is important. There is some research support for treatment with thyroid hormones.11 Discontinuing antidepressant medication is another recommendation.

Dr Li: Mood charting can be helpful, but mostly [there will be] a high index of suspicion in both patient and doctor. People often get confused with mood lability and rapid cycling. The primary treatment goal is to stop cycling. If the patient is taking antidepressants, they should be discontinued. The next step is to optimize mood stabilizer treatment – lithium or divalproex. Carbamazepine can be used as an augmenting agent to mood stabilizers. Atypical antipsychotics such as olanzapine or quetiapine can be tried. There is also some evidence for lamotrigine. Electroconvulsive therapy has been tried with some success.

Psychiatry Advisor: What are some of the comorbid conditions that tend to occur with rapid cycling in bipolar disorder?

Dr Mondimore: Patients with rapid cycling are at higher risk for alcoholism and other addictions, and substance abuse treatment is an important adjunct intervention for these patients.

Dr Li: Substance abuse and suicidal behavior are associated with rapid cycling, and these need to be addressed.

Psychiatry Advisor: What is well understood about rapid cycling, and conversely, what do we still need to learn?

Dr Mondimore: The biology of rapid cycling in bipolar disorder remains a mystery. A higher-than-expected proportion of patients with rapid-cycling bipolar disorder have been found to have abnormal levels of thyroid hormones, suggesting a connection to thyroid physiology, but the details and mechanisms of such a connection are unknown. Brain imaging studies are leading to a much better understanding of bipolar disorder and are likely to illuminate this aspect of the illness as well.

Dr Li: We do not know the full implications of rapid cycling; we know it is associated with worse outcomes, but not much else. Rapid cycling is still a difficult-to-treat condition, and our current treatments are only somewhat effective. We have no data about whether oxcarbazepine would work for rapid cycling. There is also a paucity of data on other medications.

References

  1. Dunner DL, Fieve RR. Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry. 1974;30(2):229-233.
  2. Carvalho AF, Dimellis D, Gonda X, Vieta E, Mclntyre RS, Fountoulakis KN. Rapid cycling in bipolar disorder: a systematic review. J Clin Psychiatry. 2014;75(6):e578-586.
  3. Azorin JM, Kaladjian A, Adida M, et al. Factors associated with rapid cycling in bipolar I manic patients: findings from a French national study. CNS Spectr. 2008;13(9):780-787.
  4. Bauer M, Beaulieu S, Dunner DL, Lafer B, Kupka R. Rapid-cycling bipolar disorder: diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162.
  5. Cowdry RW, Wehr TA, Zis AP, Goodwin FK. Thyroid abnormalities associated with rapid-cycling bipolar illness. Arch Gen Psychiatry. 1983;40(4):414-420. 
  6. Kusalic M. Grade II and grade III hypothyroidism in rapid-cycling bipolar patients. Neuropsychobiology. 1992;25(4):177-181. 
  7. 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(2):179-184.
  8. Goodwin F, Jamison K. Manic-Depressive Illness. Second edition. New York, NY: Oxford University Press; 1990.
  9. Yatham LN, Calabrese JR, Kusumakar V. Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options. Bipolar Disord. 2003;5(2):85-97.
  10. Valentí M, Pacchiarotti I, Undurraga J, et al. Risk factors for rapid cycling in bipolar disorder. Bipolar Disord. 2015;17(5):549-559.
  11. Walshaw PD, Gyulai L, Bauer M, et al. Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 ) [published online June 4, 2018]. Bipolar Disord. doi:10.1111/bdi.12657
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