There is considerable controversy over the use of antidepressant monotherapy in patients with bipolar II disorder because of concerns over antidepressant-induced mood conversion episodes.10,14,20,22,24,33
In contrast to the current observations of a relatively low mood conversion rate during short-term fluoxetine monotherapy of bipolar II depression, other investigators have reported higher mood conversion rates during antidepressant therapy.19–23,33
Most evidence for an increased risk of mood conversion episodes during anti-depressant therapy derives from retrospective analyses and prospective studies containing mixed populations of bipolar types I and II patients often taking a variety of antidepressant (including tricyclic antidepressants) and mood stabilizer medications.1,10,19–23,33
In general, studies of antidepressant use in bipolar depression have shown good therapeutic efficacy,11–18,33
although this has not been a universal observation.10,19–23
For example, a retrospective study11
observed good antidepressant response with no manic switch episodes in 30 bipolar I and II depressed patients treated with fluoxetine monotherapy or fluoxetine plus lithium therapy. In a prospective study of adjunctive citalopram therapy in bipolar I and II depressed inpatients unresponsive to initial mood stabilizer monotherapy, Kupfer et al18
found a 64% response rate with only a 6.7% mood conversion rate. A more recent randomized trial compared the efficacy and mood conversion rate of adjunctive venlafaxine, sertraline, or bupropion therapy in a mixed population of 228 bipolar I and II depressed patients taking various mood stabilizers and anti-psychotic drugs.10
Overall, 48.7% of the antidepressant trials were rated as “muc h improved” or “very much improved.” However, 19.3% of the antidepressant trials also resulted in a syndromal or subsyndromal mood conversion: 7.9% mania, 11.4% hypomania, and 11.8% subsyndromal hypomania. The risks of mood conversion were 30.8% in bipolar I patients and 18.6% in bipolar II patients, with the ratio of syndromal to subsyndromal conversions being greatest with venlafaxine.
Other studies have not found antidepressant therapy to be of benefit in bipolar depression.10,19–23
One prospective study compared the efficacy and safety of adjunctive bupropion versus desipramine therapy in 19 bipolar I depressed patients taking established lithium therapy34
and found no difference in anti-depressant efficacy between treatments. However, a higher mood conversion rate was seen during desipramine (55%) versus bupropion (11%) therapy (P
< 0.012). A subsequent, double-blind study examined the efficacy and mood conversion rate of bupropion or paroxetine therapy (n = 179) versus placebo (n = 187) in a mixed population of bipolar I and II depressed patients on established mood stabilizer therapy.22
Recovery rates were low during both antidepressant (23.5%) and placebo (27.3%) therapy. Interestingly, the rate of mood conversion episodes was also similar for the antidepressant (10.1%) and placebo (10.7%) groups. There were also no differences in recovery rates between bipolar I and bipolar II patients.
In contrast, studies of homogeneous bipolar II patient populations have found low antidepressant-induced mood conversion rates.13–16,28
For example, we observed a 3.8% mood conversion rate in 89 bipolar II (vs 0% in 89 unipolar) depressed patients receiving fluoxetine monotherapy 20 mg daily for up to 12 weeks.13
Fluoxetine also produced a similar response rate in bipolar II (61%) versus unipolar (51%) depressed patients (χ2
= 1.41, not statistically significant). Fewer bipolar II (24.3%) versus unipolar (39.7%) patients discontinued fluoxetine for lack of efficacy (χ2
= 3.56, P
In a prior 2-phase, double-blind, placebo-substitution trial, we examined the efficacy and mood conversion rate of fluoxetine monotherapy in 37 bipolar II depressed patients.14,15
We observed no change over time in mean YMRS scores at any study visit versus baseline (P
= 0.93), and only 3 patients met DSM-IV
criteria for hypomania, none of which resulted in treatment discontinuation.
More recently, we compared the efficacy and safety of short-term venlafaxine (n = 43) versus lithium (n = 40) monotherapy in bipolar II depression.16
Venlafaxine produced a significantly greater reduction over time in HAM-D scores (P
= 0.017), with no significant increase in mean YMRS score over time in the venlafaxine versus lithium group. Similar findings were observed in rapid versus nonrapid cycling bipolar II depressed patients treated with venlafaxine versus lithium.28
It is noteworthy that the rates of antidepressant-induced mood conversion episodes observed in these studies are less than the 8.6% natural mood conversion rate in unipolar and bipolar II disorders.35
Several caveats should be considered in the interpretation of the current findings. The lack of a mood stabilizer condition constrained our ability to determine the true efficacy and mood conversion rate of fluoxetine monotherapy. It is possible that mood stabilizer monotherapy may have provided similar efficacy with a lower mood conversion rate. The lack of a placebo condition constrained our ability to determine if the observed mood conversion rate during fluoxetine may have represented the background frequency of mood conversion episodes in patients with bipolar II depression.
We did not use a patient-rated daily chrono-log for identifying ultra-short mood conversion episodes.22
Thus, it is possible that we missed the presence of some subsyndromal mood conversion episodes. Although the estimated difference in change in YMRS scores between baseline and week 12 was only 0.3 (95% CI, −0.03 to 0.6) (P
= 0.10), a clinically insignificant change, we note the failure to find a difference over time is not proof that mood conversion episodes did not occur. In addition, we note that this study was not specifically powered to detect the true occurrence rate of mood conversion episodes during fluoxetine monotherapy. Moreover, low mean change in YMRS scores should be interpreted with caution, as this change is based on all patients, the majority of whom did not have hypomanic symptoms. Assessment of change in YMRS should not be based solely on average change per patient, but also on the proportion of patients with elevated YMRS scores. Furthermore, if we combine all 36 patients with any degree of mood conversion, the estimated frequency is 36 ÷ 148 = 24.3% (95% CI, 17.7%–32.1%) (P
< 0.0001). This suggests that the risk of having some degree of mood conversion symptoms is statistically significant.
It is possible that the frequency and severity of mood conversion episodes may have been greater had a longer treatment duration been used. Observations from prior studies of bipolar II depressed patients treated with SRI monotherapy indicate that most mood conversion episodes occur early in treatment and do not result in cycle acceleration or treatment discontinuation.13–16
It is possible that the low syndromal mood conversion rate resulted from a patient sample with more mild bipolar II disorder with a low propensity for developing fluoxetine-induced hypomania. It is also possible that the frequency of mood conversion symptoms may have been higher had affective symptoms not been rated with attribution as to cause. However, rating symptoms (ie, insomnia) without attribution on both YMRS and HAM-D scale would have falsely inflated YMRS scores.
It is possible that some of the patients who were lost to follow-up experienced mood conversion episodes that were not recorded, resulting in a higher mood conversion rate than that reported. Finally, we acknowledge that the open-label study design may have introduced rater bias. Despite this limitation, our observation of a low syndromal hypomania conversion rate during short-term fluoxetine monotherapy supports similar observations from prior studies in bipolar II patients.11–16,18,35