Research report
Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: Post hoc analyses of 47-week data

https://doi.org/10.1016/j.jad.2005.07.011Get rights and content

Abstract

Background

Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania.

Methods

A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5–20 mg/day) to divalproex sodium (500–2500 mg/day) for bipolar manic or mixed episodes (N = 251). Young Mania Rating Scale (YMRS) scores ≥ 20 were required for inclusion. Patients were classified at study entry as “rapid cyclers” if they experienced ≥ 4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline.

Results

A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p = 0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p < 0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific.

Limitations

Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account.

Conclusions

Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment.

Introduction

The treatment of patients with bipolar disorder is rapidly changing and medication options are increasing. To provide timely recommendation by experts, the development of treatment guidelines and algorithms has increased including the recent revised American Psychiatric Association guidelines (Hirschfeld et al., 2002), the Veterans Administration guidelines (Bauer et al., 1999), and Texas Medication Algorithms (Suppes et al., 2005, Rush et al., 2003). There is a need for controlled studies to provide more detail and more refined and specified guidelines (Montgomery et al., 2001).

Rapid cycling, defined as four or more episodes in the previous 12 months (DSM-IV-TR), occurs in about 20% of patients with bipolar disorder at any given time (Calabrese et al., 2000). Few studies using placebo-controlled methodology have exclusively enrolled patients with rapid cycling bipolar disorder (Calabrese et al., 2000, Calabrese et al., 2005). It is recognized that certain specifiers and symptom features of rapid cycling, psychotic symptoms, and mixed states all predict lowered rate of response and often a less-persistent stabilized state or a shorter period of remission and faster recurrence.

Studies that have enrolled substantial numbers of rapid and non-rapid cycling patients provide an opportunity to assess if and to what degree treatment response is affected by recent course of illness. A recent 47-week, double-blind trial compared olanzapine versus divalproex for treatment efficacy (Tohen et al., 2003). The primary analyses found that over the course of the trial, olanzapine-treated patients experienced significantly greater mean YMRS improvement compared to divalproex-treated patients. Median time to symptomatic mania remission was significantly shorter for olanzapine-treated patients. Neither symptomatic mania remission rates over the 47-week trial nor rates of subsequent relapse into mania or depression differed between groups.

This study is the largest to date evaluating the use of an atypical antipsychotic in rapid cycling patients. An unusually high number of patients in each treatment group met DSM-IV criteria for rapid cycling (> 50%), allowing us to test the hypothesis that rapid cycling patients would not respond as well over long-term treatment. The report assesses if rapid cycling status predicts an increased or decreased likelihood of response to either olanzapine or divalproex in this population of bipolar disorder patients, acutely manic or mixed, followed over 47 weeks. Because substantial numbers of patients in each group also met criteria for psychotic symptoms (> 40%), and mixed states (> 40%), we also examined whether these features interacted with cycling status.

Section snippets

Study design

Methods are described in detail in Tohen et al. (2003). Briefly, patients (N = 251), aged 18–75 years, were required to meet DSM-IV diagnostic criteria for a manic or mixed episode, as measured by the Structured Clinical Interview for the DSM-IV, Patient Version (SCID-P; First et al., 1997). A baseline Young Mania Rating Scale (YMRS; Young et al., 1978) total score of at least 20 was required for study entry. Patients were defined as “rapid cyclers” at study entry if they experienced 4 or more

Baseline and illness characteristics

Baseline patient and illness characteristics by rapid/non-rapid cycling and treatment group are summarized in Table 1. Of the 251 randomized patients, 144 were classified as rapid cycling patients, 106 non-rapid cycling and 1 patient's status was unknown. Rapid cycling patients were more likely to have entered the study in a mixed episode (p = 0.053) but less likely to have psychotic features (p = 0.002). Similar baseline means for YMRS, HAMD and CGI scores were recorded for both rapid cycling and

Discussion

The present study was comprised of an acute mania, 3-week, clinical trial (Tohen et al., 2002) with a double-blind extension, allowing cumulative treatment of up to 47 weeks (Tohen et al., 2003). Overall, non-rapid cycling patients showed greater improvement than rapid cycling patients during the extended observation period regardless of treatment. Of note, rapid cycling patients receiving divalproex appeared to be at some advantage over non-rapid cycling patients receiving divalproex; however,

Acknowledgements

This work was sponsored by Eli Lilly and Company. The authors wish to thank Jan Short for editorial assistance with the manuscript.

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  • Cited by (0)

    This work was sponsored by Eli Lilly and Company.

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