by Sriram Ramaswamy, MD; David Driscoll, PhD; and Lynette M. Smith, PhD

Dr. Ramaswamy is with the Department of Psychiatry, Creighton University School of Medicine, Omaha, Nebraska, and the VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska. Dr. Driscoll is with the VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska. Dr. Smith is with the College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska.

Funding/financial disclosures: This work was supported by an investigator-initiated grant from Shire Pharmaceuticals.

Keywords: carbamazepine, lithium, rapid cycling, bipolar disorder

Innov Clin Neurosci. 2017;14(9–10):3.

Dear Editor:

Rapid cycling bipolar disorder involves the occurrence of four or more episodes of mania and/or major depression within a year and is characterized by a treatment-refractory course with high morbidity. As rapid cycling patients often do not respond well to lithium monotherapy, mood stabilizer combinations have been recommended for long-term treatment.1 Positive findings have been reported in rapid cycling patients treated with lithium combined with mood stabilizers such as carbamazepine as compared to monotherapy.2,3 Extended-release carbamazepine (ERC-CBZ) has important advantages over immediate-release carbamazepine, including reduced fluctuations in serum carbamazepine levels and a decrease in CNS side effects.4 Our objective was to evaluate the safety and efficacy of lithium plus ERC-CBZ for prophylaxis in patients with rapid cycling bipolar disorder.

We recruited 16 patients with DSM-IV defined bipolar disorder with a history of rapid cycling in the past 12 months and on stable lithium therapy for six months or longer. In the preliminary study phase, patients received ERC-CBZ at starting doses ranging from 100mg to 200mg twice daily depending on clinical presentation and titrated up to a maximum dose of 1,600mg/day over a two-week period. All psychotropics other than lithium, ERC-CBZ, and benzodiazepines were then tapered over a two-week period. Patients stabilized on lithium and ERC-CBZ then entered a six-month open-label phase and completed biweekly visits. The primary efficacy measure was time to relapse as estimated using the Kaplan-Meier method. Relapse was defined by (a) a need for additional pharmacotherapy for affective symptoms; (b) hospitalization for an affective episode; and (c) increase of more than 50 percent in Hamilton Depression Rating Scale (HAM-D) and Young Mania Rating Scale (YMRS) scores from baseline. Secondary efficacy measures included changes in symptom severity on the HAM-D, YMRS, and Clinical Global Impression (CGI) scales.

Of the 16 patients who enrolled in the study, 56 percent were men ranging in age from 28 to 59 years (M=39.4). At baseline, the mean HAM-D score was 10.6 (SE=1.7), and the mean YMRS score was 9.6 (SE=2.4). Twelve patients entered the open-label phase. Six patients experienced a relapse with the median time to relapse estimated as 144 days. One patient was lost to follow-up at 14 days, one patient dropped out of the study for SAE at 61 days, and four patients completed the study. The 100-day relapse rate was 27 percent (95% CI: 10–63%). Using repeated measures and a mixed-effects model, HAM-D total score, YMRS total score, and CGI severity and improvement scores did not change significantly between visits 6 and 18 (p>0.1).

Rapid cycling bipolar disorder is highly resistant to treatment, although research evidence regarding optimal treatment for rapid cycling patients has been limited.5 The findings from this study suggest that lithium combined with ERC-CBZ might be safe and effective for prophylaxis in patients with rapid cycling bipolar disorder, although the small sample size and high lost-to-follow-up rate are clear limitations. Randomized controlled trials are needed to validate these preliminary findings.


With regard,

Sriram Ramaswamy, MD, David Driscoll, PhD, and Lynette M. Smith, PhD



  1. Calabrese JR, Shelton MD, Rapport DJ, et al. Current research on rapid cycling bipolar disorder and its treatment. J Affect Disord. 2001;67(1-3):241–255.
  2. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry. 1997;58(11):470–478.
  3. Di Costanzo E, Schifano F. Lithium alone or in combination with carbamazepine for the treatment of rapid-cycling bipolar affective disorder. Acta Psychiatr Scand. 1991;83(6):456–459.
  4. Miller AD, Krauss GL, Hamzeh FM. Improved CNS tolerability following conversion from immediate- to extended-release carbamazepine. Acta Neurol Scand. 2004;109(6):374–377.
  5. Fountoulakis KN, Kontis D, Gonda X, Yatham LN. A systematic review of the evidence on the treatment of rapid cycling bipolar disorder. Bipolar Disord. 2013;15(2):115–137.