Long-term antidepressant therapy of bipolar disorder has received relatively little attention (30
). Although some practice guidelines have recommended the cautious use of antidepressants in bipolar depression, these guidelines differ widely on the optimum duration of antidepressant therapy (9
). Moreover, most guidelines extrapolate from studies of patients taking tricyclic antidepressants or from studies of mixed bipolar I and II patient populations (10
). While all practice guidelines recommend discontinuing antidepressants after recovery from depression (1
), this approach has not been adequately examined.
Although the benefit of antidepressant therapy in bipolar II disorder is supported by some studies (7
), other studies have not confirmed this benefit or have reported an increase in mood conversions during antidepressant use (10
). A naturalistic study that reviewed outcomes of 54 bipolar patients receiving combined therapy with lithium plus an antidepressant for up to 5 years found that 50% of them remained well for 17.2 months longer than patients receiving lithium monotherapy (32
). Manic conversions occurred in only 14% of patients (primarily taking tricyclic antidepressants). More recently, Kupfer et al. (18
) observed a sustained remission rate of 67% over 24 weeks in 21 bipolar type I and II patients who responded to adjunctive citalopram therapy in combination with lithium therapy.
A nonrandomized case-control study (17
) reported significantly fewer depressive relapses in bipolar patients who continued antidepressants (32%) compared with those who did not (68%). Moreover, antidepressant use was not associated with a greater mood conversion rate. However, this observational study included only 15% of the patients who initiated antidepressant treatment and continued it for 6 months. A subsequent retrospective study (33
) that examined relapse rates in recovered bipolar patients who either continued (N=19) or discontinued (N=25) antidepressant therapy found that after 1 year of treatment, depressive relapse occurred in 68% of those who discontinued therapy and 32% of those who did not. Moreover, patients who continued therapy for at least 6 months were less likely to relapse (33
Finally, we conducted a 26-week randomized double-blind placebo-substitution study of fluoxetine monotherapy in recovered bipolar II patients (19
). In that study, 43% of patients receiving fluoxetine and all of those receiving placebo relapsed during continuation therapy (p=0.08). While the mean increase in YMRS score in that study was slightly higher in the fluoxetine group than in the placebo group (mean=3.0 [SD=1.8] compared with mean=0.2 [SD=0.4], p=0.01), the difference between groups was not clinically meaningful. Moreover, no hypomanic episodes were observed.
Findings from the present study are not definitive. Several limitations and caveats should be considered in their interpretation. For example, although the removal of the combined lithium-plus-fluoxetine condition increased the cohort sizes, the study still had only limited power to detect more than a substantial superiority of fluoxetine monotherapy. Moreover, it is possible that the lithium-plus-fluoxetine condition would have provided even greater efficacy than fluoxetine or lithium monotherapy.
We did not employ a patient-rated chrono-record for identifying ultrashort mood conversion episodes (10
). It is possible that we missed some subsyndromal hypomanic episodes that occurred between study visits. However, the proportion of patients in each group with even modest increases in YMRS score was neither statistically significant nor clinically meaningful.
The frequency and severity of mood conversion symptoms might have been greater if depressive and hypomanic symptoms had been rated without attribution as to cause or if we had used different threshold criteria (10
). Moreover, rating insomnia on both the HAM-D and YMRS could have inflated YMRS scores. While such inflation is possible, a similar effect would be expected for all treatment conditions. We found no significant differences in YMRS scores among groups.
It is possible that the frequency and severity of mood conversion episodes would have been greater if treatment duration had been longer. However, we found no clinically meaningful increase in YMRS scores after day 70. This observation supports earlier studies of antidepressant use in bipolar II patients (7
It is possible that the low mood conversion rate observed in this study resulted from the use of an “enriched” bipolar II population with more mild illness and a lower propensity for fluoxetine-induced mood conversions. However, the illness severity of patients in this study was similar to that of bipolar patients in prior studies that found similar frequencies of mood conversions during antidepressant monotherapy (10
It is possible that we underestimated the frequency of subsyndromal hypomanic episodes by employing the YMRS cut-point values of 8 and 12. Also, this study was not powered to detect a difference in YMRS score between treatment groups (and, as noted earlier, failure to identify significant differences in YMRS scores between groups does not constitute proof that differences do not exist).
Finally, while it is possible that a delayed effect of fluoxetine withdrawal affected relapse rates in the lithium and placebo groups, the rate of relapse during the initial 50 days of double-blind therapy was similar for all treatment groups ().