Correspondence

Adjunctive Antidepressant Treatment for Bipolar Depression

N Engl J Med 2007; 357:614-616August 9, 2007

Article

To the Editor:

Sachs et al. (April 26 issue)1 report that adding an adjunctive antidepressant drug offers no benefit over continued mood-stabilizer monotherapy in the treatment of bipolar depression. This finding contradicts some previous studies and the experience of many clinicians. In his thoughtful accompanying editorial, Belmaker2 identifies possible reasons for this discrepancy, including diagnostic heterogeneity and changes in the manifestation of bipolar disorder during the past 20 years. These observations are perhaps too circumspect.

The past two decades have seen a marked increase in the diagnosis of bipolar disorder by North American psychiatrists.3 This trend has many origins: a reaction to past underdiagnosis, a belief that this disorder is more treatable and less stigmatizing than some alternative diagnoses, and an insufficiently critical application of the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), as well as a genuine conviction on the part of some authorities that this is indeed a widely prevalent condition.4 More recently, direct-to-consumer advertising by pharmaceutical companies has exacerbated the trend. To the extent that the diagnostic boundaries of bipolar disorder are allowed to expand, the benefits of specific pharmacologic treatments are likely to decline.

Lawrence H. Price, M.D.
Audrey R. Tyrka, M.D., Ph.D.
Butler Hospital, Providence, RI 02906
lawrence_price_md@brown.edu

Dr. Price reports receiving lecture fees from AstraZeneca. No other potential conflict of interest relevant to this letter was reported.

4 References

1
Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007;356:1711-1722
Full Text | Web of Science | Medline

2
Belmaker RH. Treatment of bipolar depression. N Engl J Med 2007;356:1771-1773
Full Text | Web of Science | Medline

3
Patten SB. Does almost everybody suffer from a bipolar disorder? Can J Psychiatry 2006;51:6-8
Web of Science | Medline

4
Akiskal HS. Validating `hard' and `soft' phenotypes within the bipolar spectrum: continuity or discontinuity? J Affect Disord 2003;73:1-5
CrossRef | Web of Science | Medline

To the Editor:

Sachs et al. do not consider the heterogeneity of bipolar depression, concluding that adding antidepressants to mood stabilizers for patients with this condition is not effective. This finding, which contradicts the results of previous studies,1 could lead to possible deleterious consequences for patients. As suggested in the editorial by Belmaker, the low recruitment rate (366 of 2689 patients with at least one major depressive episode) may reflect a selection bias.

There is considerable clinical heterogeneity in bipolar depression.2 It is possible to distinguish two types of bipolar depression, one characterized by a global inhibition and the other by activation features.3 Inhibited depressions appear to share common mechanisms with unipolar depression,4 and failing to treat such conditions with antidepressant drugs may increase the risk of suicide. Activated depressions are closer to mixed states and may be worsened by antidepressants. This differential response to treatment may account for the lack of efficacy of antidepressants reported in the study by Sachs et al., which did not assess heterogeneity.

Chantal Henry, M.D., Ph.D.
University Bordeaux 2, 33076 Bordeaux, France
chenry@ch-perrens.fr

Jacques Demotes-Mainard, M.D., Ph.D.
INSERM-ECRIN, 75013 Paris, France

Marion Leboyer, M.D., Ph.D.
INSERM Unité 841, 94000 Créteil, France

4 References

1
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry 2004;161:1537-1547
CrossRef | Web of Science | Medline

2
Benazzi F. Bipolar disorder -- focus on bipolar II disorder and mixed depression. Lancet 2007;369:935-945
CrossRef | Web of Science | Medline

3
Henry C, M'Baïlara K, Poinsot R, et al. Evidence for two types of bipolar depression using a dimensional approach. Psychother Psychosom (in press).

4
Oquendo MA, Hastings RS, Huang Y-Y, et al. Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography. Arch Gen Psychiatry 2007;64:201-208
CrossRef | Web of Science | Medline

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 drug5 — 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, Louisville, KY 40202
rselma01@louisville.edu

5 References

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
Web of Science | Medline

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 | Web of Science | 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 | Web of Science | Medline

4
Amsterdam JD, Garcia-Espana 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 | Web of Science | 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[Erratum, Arch Gen Psychiatry 2004;61:176.]
CrossRef | Web of Science | Medline

Author/Editor Response

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 study1 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.

Gary S. Sachs, M.D.
Harvard Medical School, Boston, MA 02115

Charles Bowden, M.D.
University of Texas Health Science Center, San Antonio, TX 78229-3900

Michael E. Thase, M.D.
University of Pennsylvania, Philadelphia, PA 19104

1 References

1
Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology 2003;28:1374-1382
CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1
Emanuel Severus, Nadine Schaaff, Hans-Jürgen Möller. (2011) State of the Art: Treatment of Bipolar Disorders. CNS Neuroscience & Therapeuticsno-no
CrossRef