Antidepressant Use Okay in Rapid-Cycling Bipolar Disorder?

Deborah Brauser

April 03, 2013

Contrary to current practice guidelines, it may not be necessary to avoid antidepressant monotherapy in patients with rapid-cycling bipolar II disorder, a condition characterized by 4 or more episodes of depression and hypomania in a year.

A randomized, controlled trial of adults with bipolar II disorder showed that after initial stabilization on the selective serotonin reuptake inhibitor fluoxetine, there were no significant differences in depressive relapse or treatment-emergent mood conversion rates between those who received long-term monotherapy maintenance with fluoxetine or those who received the mood stabilizer lithium.

In addition, there were no between-group differences for those who were diagnosed with rapid- or non-rapid-cycling. Currently, clinical guidelines suggest that this patient population should not receive antidepressants without concurrent use of a mood stabilizer.

However, neither treatment was superior to placebo.

"Few double-blind, placebo-controlled trials have examined efficacy and safety of antidepressant v. mood stabiliser monotherapy in bipolar disorder," write Jay D. Amsterdam, MD, from the Depression Research Institute in the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues.

"The failure to identify significant differences in efficacy and safety in the current analysis does not mean that differences do not exist," the investigators add, noting that several caveats should be considered when interpreting the findings.

First, the limited number of patients in the rapid- vs non-rapid-cycling subgroups within each treatment condition meant the study was not powered to detect significant between-group differences in efficacy or mania ratings.

In addition, because all patients were first stabilized with fluoxetine, those who went on to receive fluoxetine maintenance monotherapy "were more likely to stay well and less likely to experience mood conversion episodes."

Still, the results "call into question practice guideline recommendations to avoid maintenance antidepressants" in this patient population, write the researchers.

The study is published in the April issue of the British Journal of Psychiatry.

Potential Limitation?

In the original study, 167 outpatients older than 18 years who had been clinically diagnosed with bipolar II were enrolled. Of these, 148 were initially treated with up to 80 mg/day of fluoxetine monotherapy for 12 weeks. Only those who were found to be stably remitted, as defined by a score of 8 or less on the 17-item Hamilton Rating Scale for Depression (HRSD), entered the maintenance treatment phase.

A total of 81 patients were randomly assigned to receive for 50 weeks of maintenance monotherapy either 10 to 40 mg/day of fluoxetine (n = 28), 300 to 1200 mg/day of lithium (n = 26), or placebo (n = 27).

Of the 81 total patients who underwent randomization, 25 had rapid-cycling bipolar II disorder (64% men; mean age, 35.3 years), and 56 had non-rapid-cycling (41.1% men; mean age, 38.8 years).

Of the 28 patients who received maintenance fluoxetine, 8 had rapid- and 20 had non-rapid-cycling. Of those who received lithium, 9 had rapid- and 17 had non-rapid-cycling. And of those receiving placebo, 8 had rapid- and 19 had non-rapid-cycling.

The HRSD, Young Mania Rating Scale (YMRS), and mood conversion measures were administered to all participants at baseline and at the end of treatment. Number of previous depressive and hypomanic episodes were recorded, along with treatment-emergent depression or hypomania.

Study findings showed that 9 of the patients in the full rapid-cycling subgroup had depressive relapse (36%) vs 29 of the patients in the non-rapid-cycling subgroup (51.8%), a difference that was not statistically significant.

Although the investigators hypothesized that lithium monotherapy would provide greater relapse prevention and fewer treatment-emergent mood episodes, results did not back that up.

Depressive relapse rates among those in the rapid-cycling group were similar for treatment with fluoxetine (28.6%), lithium (34.6%), and placebo (29.6%). No significant between-group differences were found for the rapid- vs non-rapid-cycling groups in odds of relapse (odds ratio, 0.6) or hazard of relapse (hazard ratio, 0.87).

There were also no significant differences in the rates of treatment-emergent syndromal or subsyndromal hypomanic or major or minor depressive episodes, or in the duration of episodes.

Changes in mania scores, as shown on the YMRS, were also not significantly different between any of the groups or subgroups.

Study limitations cited include the fact that "rapid cycling" was defined as a patient having an average of 4 or more affective episodes per year during their entire course of illness. This is in contrast with the criteria used in the Diagnostic and Statistical Manual of Disorders, Fourth Edition (DSM-IV), which specifies that a patient must have experienced 4 or more distinct episodes during the past year.

Current Dogma Challenged

In an accompanying editorial, Michael E. Thase, MD, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and from that school's Mood and Anxiety Disorders Treatment and Research Program, writes that there are few absolutes when it comes to psychiatric therapeutics.

"Nevertheless, one of the most widely endorsed recommendations in practice guidelines is that patients with a rapid-cycling course of bipolar affective disorder should not receive antidepressants, particularly as a monotherapy, that is, without concomitant therapy with a mood stabiliser," notes Dr. Thase.

"The findings of Amsterdam and colleagues...are thus of great interest because they appear to challenge the current dogma," he adds.

However, Dr. Thase, who was not involved with this research, writes that the way that the investigators defined "rapid cycling" and their use of acute-phase fluoxetine monotherapy before the randomization phase may shed some light on the results.

"The longer-term study examined a patient group that was 'enriched' not only for response to fluoxetine, but also for the absence of treatment-emergent affective shifts during fluoxetine monotherapy."

Still, he writes that results do show that there is a subset of patients with bipolar II depression who can remit on fluoxetine monotherapy, can safely continue receiving this treatment for up to 1 year, and "can do well" whether they do or do not have a history of depressive or hypomanic episodes.

"These results do not inform treatment decision for patients who have experienced 4 or more episodes during the year before their decision to seek treatment," Dr. Thase points out.

"Nevertheless, [the study] does suggest that there is little reason to systematically avoid the use of antidepressants for patients with bipolar II depression who have no prior history of antidepressant treatment or who have been treated successfully with antidepressants in the past."

Dr. Thase concludes by noting that clinicians should consider each patient's past response to different treatments.

"It may be that [the investigators'] findings are neither discrepant nor paradigm shifting, but rather reflect important differences in definitions and the vulnerability of their patient population."

The study was supported by a grant from the National Institute of Mental Health and by the Jack Warsaw Fund for Research in Biological Psychiatry. Dr. Amsterdam and 1 of the other 2 coauthors have reported receiving grant or research support from the National Institutes of Health.

Br J Psychiatry. 2013;202:251-252,301-306. Abstract, Editorial


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