Volume 357:614-616 August 9, 2007 Number 6
Adjunctive Antidepressant Treatment for Bipolar Depression
To the Editor: The trial by Sachs and colleagues is the latest in a string of studies showing that the addition of antidepressants to mood stabilizers in depressed bipolar patients is of minimal benefit.(1,2) However, antidepressants given in the absence of a mood stabilizer — either alone (in type II illness) (3,4) or added to a second-generation antipsychotic drug (5) — are effective in treating bipolar depression. The major difference in the design of these studies is the absence or presence of mood stabilizers. When mood stabilizers (lithium or valproate, carbamazepine, or lamotrigine) are used, antidepressants are of minimal benefit. This finding has traditionally been interpreted as showing that mood stabilizers have an intrinsic antidepressant effect, which cannot be augmented by the antidepressant agent. An alternative interpretation that would reconcile the discrepant data is that mood stabilizers may actually interfere with or block the effect of antidepressant drugs. This distinction is important, since it would alter the approach to treating depression in patients with bipolar disorder. Studies that specifically examine this question need to be performed.
Rif S. El-Mallakh, M.D.
University of Louisville School of Medicine
1. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001;158:906-912. [Free Full Text]
2. Post RM, Leverich GS, Nolen WA, et al. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord 2003;5:396-406. [CrossRef][ISI][Medline]
3. Amsterdam J. Efficacy and safety of venlafaxine in treatment of bipolar II major depressive episode. J Clin Psychopharmacol 1998;18:414-417. [CrossRef][ISI][Medline]
4. Amsterdam JD, Garcia-España F, Fawcett J, et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol 1998;18:435-440. [CrossRef][ISI][Medline]
5. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079-1088.
The authors reply: Price and Tyrka comment on several trends related to the diagnosis of bipolar disorder, which raise concerns we share. However, as we detailed in our article, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) rigorously applied DSM-IV criteria both in the selection of subjects at initial entry into the program and for inclusion in the randomized study of acute depression. We do not believe our results necessarily contradict those of previous studies. Instead, we suggest that our conclusions differ from those of previous studies largely because in our study, durable recovery was the primary outcome variable. As we stated, the results of our cross-sectional, last-observation-carried-forward analyses, as typically applied in most previous studies of short-term treatment, revealed a proportion of subjects treated with antidepressants who had rates of successful outcome similar to those reported in previous studies. However, mood stabilizers alone provided an equivalent benefit in the depressed subjects with bipolar disorder whom we studied.
Dr. Henry and colleagues raise the issue of heterogeneity and suggest a differential response on the basis of two principal subtypes of depression in bipolar disorder: global inhibition and activation. Although their proposed typology is potentially interesting, the existence of such heterogeneity is unlikely to account for the absence of difference between study groups in our randomized study. Notably, no increase in suicidality was observed in subjects treated without standard antidepressants. STEP-BD does plan to examine symptom profiles obtained at baseline as predictors of treatment outcome.
Dr. El-Mallakh makes a scientific point that cannot be adequately resolved currently. Treating acute bipolar depression for short periods with antidepressants alone could result in higher response rates than the use of antidepressants in combination with mood stabilizers. However, a blinded maintenance study (1) reported lower response rates when patients with bipolar disorder who were receiving placebo under double-blind conditions became depressed and received adjunctive antidepressants, as compared with the response rates observed when the antidepressants were added to mood stabilizers in a blinded fashion. To our knowledge, no published study has had design features that directly address Dr. El-Mallakh's supposition, which requires that patients be randomly assigned to receive antidepressants in combination with a mood stabilizer or as monotherapy. Since evidence-based treatment guidelines consistently recommend the concurrent use of a mood stabilizer, it is likely that ethical concerns, as well as concerns about practical complexities and study costs, account for the lack of such initiatives.
Dr. Belmaker's concern about limited generalizability and low recruitment rates in our study requires some clarification. Unlike most clinical trials, STEP-BD enrolled a large number of patients with bipolar disorder who were seeking treatment. However, the relatively low percentage of depressed patients who underwent randomization reflected the large number of patients who were ineligible owing to previous treatment with both bupropion and paroxetine, an unwillingness to accept treatment with approved mood stabilizers, or an unwillingness to taper the dose of a current antidepressant medication. However, we acknowledge that results from our study may not apply to all antidepressants, since our study examined only bupropion and paroxetine.