Brief reportAntidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial
Introduction
Rapid cycling in bipolar disorder (BD) is a descriptor that defines a subset of patients that have a large number of episodes over short periods of time. Specifically, rapid cycling is defined as having 4 or more episodes in a 12 months periods, but many patients may have significantly more episodes. The prevalence of rapid cycling in populations of bipolar patients varies with different studies. In large International multi-site studies (e.g., The Stanley Bipolar Network), or in European countries (the EMBLEM study) the rates are somewhat low at 17.6% and 17.3%, respectively (Kupka et al., 2005, Cruz et al., 2008). However, the rates are higher in the United States, comprising 25.8% of patients in the Collaborative Depression Study (Coryell et al., 2003), and 34.7% of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (Baldassano et al., 2005). In a non-selected American community sample, the prevalence of rapid cycling is approximately 33% of all patients with any BD (Nierenberg et al., 2010). Individuals with rapid cycling generally have a younger age of onset, greater disease burden, and greater exposure to antidepressants (Kilzieh and Akiskalk, 1999, Azorin et al., 2008). Excess representation in women (Baldassano et al., 2005, Nierenberg et al., 2010, Kilzieh and Akiskalk, 1999), and increased suicidal risk are not consistent finding (Nierenberg et al., 2010, Kilzieh and Akiskalk, 1999). Rapid cycling does not appear to be a separate entity, and does not breed true (Kilzieh and Akiskalk, 1999). Rather, it appears to be a state that starts and stops, with an average duration of some two years (Coryell et al., 2003). What causes rapid cycling is of significant importance.
Whether or not antidepressants (AD) cause rapid cycling in bipolar disorder (BD) is a controversial issue, with some studies supporting (Kukopulos et al., 1983, Ghaemi et al., 2004, Schneck et al., 2008), and others opposing (Lewis and Winokur, 1982, Coryell et al., 2003), a causal relationship. Antidepressants are the most commonly prescribed class of medication in BD (Baldessarini et al., 2008). If they cause or worsen rapid-cycling, found in about 25% of patients with BD (Goodwin and Jamison, 2007), this presents a major public health problem. Safely and effectively treating rather than exacerbating mood episodes in the most severely ill among this patient population is a priority.
In the past, there have been no randomized clinical trials (RCT) relevant to this question with new generation antidepressants; all other studies have been naturalistic or observational in nature. We report here an analysis from the first RCT of modern antidepressants that addresses this topic (Ghaemi et al., 2010).
Section snippets
Methods
This report presents an a priori secondary analysis of an open randomized clinical trial within the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study cohort (Ghaemi et al., 2010). Subjects (n=68) were diagnosed with DSM-IV BD types I, II, or NOS and achieved clinical recovery (at least two months of euthymia) from an index episode of acute BD major depression while treated with an AD and a mood-stabilizer. They were then randomized to AD-continuation (n=31) or
Results
The overall sample, 54% of which was female, had a mean age of 43.4±13.1 years, experienced 1.1±1.35 total episodes/year, most of which were depressive (0.8±1.05). Diagnostic subtype was type I bipolar disorder in 69% and type II in 31%. Mean follow-up duration of the sample was 1.66±0.99 years, and subjects spent 72.9%±23.1% of follow-up time well (not meeting DSM-IV syndromal criteria for mood episodes). In the overall sample of 68 patients, 28% were rapid cyclers (n=18).
Between-group
Discussion
In this sample, long-term continuation of antidepressants was associated with more mood episodes in patients with rapid-cycling bipolar disorder, particularly with three-fold increased rate of depressive episodes in the first year of follow-up. These data represent the first randomized data with new generation antidepressants, and they confirm the only other randomized study, conducted with tricyclic antidepressants.
This sample consists of a selected population of patients who had responded to
Conclusion
Even with pre-selection for good antidepressant response and absence of acute mania related to antidepressants, and despite concurrent mood stabilizer treatment, a priori analysis of rapid cycling status predicted more depressive episode criteria in those who continued antidepressant treatment as opposed to discontinued antidepressant treatment. This decreased efficacy of antidepressants supports previous claims of limited clinical utility and lack of safety in long term treatment of BD
Role of funding source
The study was funded by a grant from the NIMH, United States. The NIMH approved the design of the study, but was not involved in the data collection, data analysis, or manuscript preparation for the study.
Conflicts of interest
Dr. El-Mallakh currently has research grant support from Merck and is on the speakers' bureau of AstraZeneca, Otsuka, and Sunovion. Dr. Ghaemi currently has a research grant with Takeda Pharmaceuticals North America, and has provided research consultation in the past year to Sunovion. None of the other authors have any conflicts of interest to report.
Contributors' roles
Rif S. El-Mallakh performed some of data collection and paper writing.
Paul A. Vöhringer performed most of data analysis.
Michael M. Ostacher performed much of data collection and some of the writing.
Claudia F. Baldassano performed some of data collection and some of the writing.
Niki S. Holtzman BA assisted with much of the data analysis.
Elizabeth A. Whitham was study coordinator and data maintenance.
Sairah B. Thommi was study coordinator and data maintenance.
Frederick K. Goodwin supervised study
Acknowledgments
This research was supported by NIH grant MH-64189 to SNG.
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