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Authors' reply

Published online by Cambridge University Press:  02 January 2018

Jay D. Amsterdam*
Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, USA. Email:; Lola Luo, Justine Shults, Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, USA
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Copyright © Royal College of Psychiatrists, 2013 

We appreciate Dr Eppel's thoughtful comments. Our study was an exploratory analysis of fluoxetine monotherapy in patients with rapid-cycling bipolar II disorder v. patients with non-rapid-cycling bipolar II disorder. It was a secondary analysis from our National Institute of Mental Health-funded, prospective placebo-controlled study designed to compare the safety and efficacy of long-term fluoxetine v. lithium monotherapy in preventing relapse and recurrence of bipolar II major depressive episode. Reference Amsterdam and Shults1

We respectfully disagree with Dr Eppel's assertion that we drew unfounded conclusions from our results. We acknowledged the limited sample size, the exploratory nature of the analyses, and the fact that our findings are not definitive. We also acknowledged that larger sample sizes would be needed to detect small differences in mood conversion rates between groups.

Dr Eppel described a low completion rate for the study. In this regard, we previously explained to Dr Eppel the design of our peer-reviewed study and the fact that the response rate was based on patients who entered the entire trial. Reference Shults and Amsterdam2 We also explained that (in the primary analysis) if we conservatively assumed that all patients who were ‘lost to follow-up’ had relapsed, then the percentage of patients who remained well would be computed as the percentage of patients who completed the study, or 39.3% (n = 11/28) for fluoxetine, 19.2% (n = 5/26) for lithium, and 25.9% (n = 7/27) for placebo. Reference Shults and Amsterdam2

We also disagree with Dr Eppel's claim that ‘It is not possible to justify the conclusion that antidepressant monotherapy has a place in the treatment of rapid-cycling bipolar disorder based on these small numbers’. We submit that we did not draw this conclusion. Rather, we clearly reported that ‘Although not definitive, these findings suggest that maintenance lithium or fluoxetine monotherapy are similar to placebo in preventing depressive relapse and treatment-emergent conversion episodes during long-term relapse-prevention therapy of rapid- and non-rapid-cycling disorder’.

Dr Eppel cites one review article, based largely on uncontrolled studies in the literature, to support his assertion that there is evidence that antidepressants can lead to an increased risk of morbidity and mortality. In contrast, we presented prospective controlled data showing no significant increase in cycling frequency, mood conversion rates or worse efficacy during antidepressant monotherapy. Nevertheless, we clearly noted the caveat that the current study results are not definitive owing to the small sample size and exploratory nature of the analysis.


1 Amsterdam, JD, Shults, J. Efficacy and safety of long- term fluoxetine versus lithium monotherapy of bipolar type II disorder: randomized, double-blind, placebo-substitution trial. Am J Psychiatry 2010; 167: 792800.CrossRefGoogle Scholar
2 Shults, J, Amsterdam, JD. Response to Eppel Letter. Am J Psychiatry 2010; 167: 1408–9.CrossRefGoogle Scholar
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