Comparison of Rapid-Cycling and Non-Rapid-Cycling Bipolar I Manic Patients During Treatment With Olanzapine: Analysis of Pooled Data

Eduard Vieta, M.D., Ph.D.; Joseph R. Calabrese, M.D.; John Hennen, Ph.D.;Francesc Colom, Ph.D.; Anabel Martínez-Arán, Ph.D.;Jose Sánchez-Moreno, Psy.D.; Lakshmi N. Yatham, M.D.;Mauricio Tohen, M.D., Dr.P.H.; and Ross J. Baldessarini, M.D.

Introduction: Rapid-cycling (RC) bipolar disorder patients experience high levels of morbidity, typically respond unsatisfactorily to available treatments, and, so, require additional studies of novel treatments. We report on the first controlled study comparing acute and continuous clinical outcomes in RC and non-RC manic patients treated with olanzapine.

Method: We analyzed data pooled from 2 placebo-controlled, double-blind, 3- to 4-week trials of olanzapine in mania (N = 254), 1 with an open-label extension up to 1 year (N = 113) and controlled supplementation with lithium or fluoxetine as needed, to compare demographic, clinical, and outcome measures between RC and non-RC subgroups of 254 DSM-IV bipolar I manic subjects.

Results: RC (N = 90, 35%) versus non-RC subjects (N = 164, 65%) were younger at intake (p = .02), less often psychotic (p < .0001), and more likely to have familial bipolar disorder (p < .0001), abused substances (p = .01), more previous hospitalizations (p = .004), and many more illness episodes (p < .001). In initial blinded trial outcomes, relative responses (>= 50% improvement of mania) to olanzapine/placebo were similar in RC and non-RC subjects, though early responses to olanzapine favored RC over non-RC subjects (p = .003), and long-term outcomes favored non-RC subjects (p = .05). Fewer RC subjects achieved strictly defined initial symptomatic remission (p = .014) within a year; RC subjects were more likely to experience recurrences (p = .002), especially of depressive illness (< .001), and had more rehospitalizations (p = .01) and suicide attempts (p = .03).

Conclusions: RC bipolar I patients showed major initial differences and more rapid initial clinical changes, especially toward depression, with less favorable long-term outcomes than non-RC cases during treatment with olanzapine. Inclusion of RC bipolar disorder patients can complicate therapeutic trials, but these patients require further study for differential responsiveness to innovative treatments with methods of assessing clinical response that take their mood instability into account.

(J Clin Psychiatry 2004;65:1420-1428)

Received Feb. 24, 2004; accepted June 7, 2004. From the Bipolar Disorders Program, Department of Psychiatry, Hospital Clinic, University of Barcelona, IDIBAPS (Drs. Vieta and Sánchez-Moreno), and Institut d'Investigacions Biomédiques Agustí Pi Sunyer (Drs. Colom and Martínez-Arán), Barcelona Stanley Foundation Center, Barcelona, Spain; the Mood Disorders Program, Case-Western Reserve University School of Medicine, Cleveland, Ohio (Dr. Calabrese); the Department of Psychiatry and Neuroscience Program, Harvard Medical School, Boston, Mass. (Drs. Hennen, Tohen, and Baldessarini); the Biostatistics Laboratory (Dr. Hennen), Bipolar & Psychotic Disorders Program (Drs. Hennen and Baldessarini), McLean Hospital, Belmont, Mass.; the Department of Psychiatry, College of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr. Yatham); and Lilly Research Laboratories, Indianapolis, Ind. (Dr. Tohen).

Supported, in part, by awards from the Stanley Medical Research Institute, Bethesda, Md., Fundació Roviralta, Barcelona, Spain, the Red CIEN IDIBAPS-ISCIII RTIC C03/06, Barcelona, Spain, and grant TV2510 from the Fundació Marató de TV3, Barcelona, Spain (Dr. Vieta); by grants from Eli Lilly Research Center, Indianapolis, Ind. (Dr. Hennen); and by the Bruce J. Anderson Foundation, New York, N.Y., and the McLean Private Donors Neuropsychopharmacology Research Fund, Boston, Mass. (Dr. Baldessarini). The trials on which this study is based were supported by Eli Lilly and Company, Indianapolis, Ind.

Financial disclosure can be found at the end of this article.

Angela Evans, Ph.D., of Eli Lilly provided valuable logistical support.

Corresponding author and reprints: Eduard Vieta, M.D., Ph.D., Clinical Institute of Psychiatry and Psychology, Hospital Clínic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain (e-mail: evieta@clinic.ub.es).