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A systematic review of the evidence for the treatment of acute
depression in bipolar I disorder
Michael A. Cerullo and Stephen M. Strakowski
CNS Spectrums / Volume 18 / Issue 04 / August 2013, pp 199 - 208
DOI: 10.1017/S1092852913000102, Published online: 18 March 2013
Link to this article: http://journals.cambridge.org/abstract_S1092852913000102
How to cite this article:
Michael A. Cerullo and Stephen M. Strakowski (2013). A systematic review of the evidence for the treatment of acute
depression in bipolar I disorder. CNS Spectrums, 18, pp 199-208 doi:10.1017/S1092852913000102
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CNS Spectrums (2013), 18, 199–208.
A systematic review of the evidence for the
treatment of acute depression in bipolar I disorder
& Cambridge University Press 2013
Michael A. Cerullo,* and Stephen M. Strakowski
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA
In this article, we examined evidence for the acute treatment of depression in bipolar I disorder, focusing on double-blind,
placebo-controlled studies with a definite primary outcome measure and published in peer review journals. Quetiapine
and olanzapine/fluoxetine are currently approved by the FDA for the treatment of bipolar depression, and a number of
additional agents (including other atypical antipsychotics, mood stabilizers, antidepressants, and novel compounds)
have been studied with varying degrees of efficacy. The medication with the most evidence for efficacy in bipolar
depression is quetiapine, with five studies showing positive efficacy compared to placebo. In contrast, five studies of
lamotrigine were negative, although meta-analyses of the pooled have found some treatment effects. Two studies of
olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating
bipolar depression. Two studies of aripiprazole found no differences compared to placebo. Early research on lithium in
bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria.
To better understand the role of antidepressants, we also examined studies of antidepressants as adjunctive treatment of
bipolar depression in participants taking mood stabilizers or atypical antipsychotics. These studies reported mixed
results for a variety of antidepressants, but the majority found no differences compared to placebo. Other studies of
adjunctive treatment were also discussed. There has been one positive adjunctive study each of lamotrigine, omega-3
fatty acids, modafinil, and armodafinil, while there was one negative trial each of omega-3 fatty acids, ziprasidone,
Received 15 November 2012; Accepted 24 January 2013; First published online 18 March 2013
Keywords: Bipolar disorder, fMRI, Bipolar depression, treatment.
Bipolar disorder is a serious psychiatric illness resulting
in depression and mania that affects approximately 1.5%
of the population and represents a significant source of
individual morbidity and societal cost.1Patients with
bipolar disorder spend considerably more time in
depressive rather than manic episodes, and suffer more
morbidity during depression.2
most treatment studies of bipolar disorder focused on
the treatment of mania or less often on maintenance
treatment.3–5Yet the treatment of bipolar depression
is one of the most difficult psychopharmacological
challenges psychiatrists face. Fortunately, over the last
decade and a half, there has been renewed interest in the
treatment of the depressive phase of bipolar disorder,
and a number of well designed randomized, double-
blind, placebo-controlled trials in several different classes
of medications have been published.4,6Additionally, in
the last few years the number of studies has increased
Until quite recently
enough to allow the first round of meta-analyses.4,6–10
Nevertheless, the total number of well controlled studies
of bipolar depression is relatively small, especially in
comparison to the severity of the problem.4,6Only two
medications are FDA approved for the treatment of
bipolar depression: olanzapine/fluoxetine combination
The focus of this review article is the acute treatment
of depressive episodes in bipolar I disorder. The
literature on the treatment of bipolar type II is very
sparse and will not be discussed in this article.12
Studies were included in this review if they were
the primary treatment for bipolar depression, were
randomized and double-blind, had a placebo arm,
included a clearly defined outcome measure, and were
published in a peer-reviewed journal. The literature
search for appropriate studies used the search engines
PubMed and Scopus. Searches were performed using
the keywords ‘‘bipolar,’’ ‘‘depression,’’ ‘‘treatment,’’
and ‘‘double-blind.’’ Additional manual searches were
made using references of the studies identified as well
as reviewing previous meta-analyses and review
articles. Another initial criterion was that the study
included only participants with bipolar type I disorder.
However, many studies included a mix of bipolar
type I and type II participants, and nearly one-third of
*Address for correspondence: Michael Cerullo, Department of
Psychiatry and Behavioral Neuroscience, University of Cincinnati
COM, 260 Stetson Street, Suite 3200, Cincinnati, OH 45219-0516, USA.
This study was supported by NIMH grants K23MH081214
(Cerullo) and P50MH077138 and R01MH071931 (Strakowski).
39. 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(6): 906–912.
Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness
of adjunctive antidepressant treatment for bipolar
depression. N Engl J Med. 2007; 356(17): 1711–1722.
Calabrese JR, Ketter TA, Youakim JM, et al. Adjunctive
armodafinil for major depressive episodes associated
with bipolar I disorder: a randomized, multicenter,
double-blind, placebo-controlled, proof-of-concept
study. J Clin Psychiatry. 2010; 71(10): 1363–1370.
Saricicek A, Maloney K, Muralidharan A, et al.
Levetiracetam in the management of bipolar depression:
a randomized, double-blind, placebo-controlled trial.
J Clin Psychiatry. 2011; 72(6): 744–750.
Ghaemi SN, Goodwin FK. Antidepressants for bipolar
depression. Am J Psychiatry. 2005; 162(8): 1545–1546.
Goldberg JF, Truman CJ. Antidepressant-induced
mania: an overview of current controversies. Bipolar
Disord. 2003; 5: 407–420.
Tondo L, Vazquez G, Baldessarini RJ. Mania associated
with antidepressant treatment: comprehensive meta-
analytic review. Acta Psychiatr Scand. 2010; 121: 404–414.
Licht RW, Gijsman H, Nolen WA, Angst J. Are
antidepressants safe in the treatment of bipolar
depression? A critical evaluation of their potential
risk to induce switch into mania or cycle acceleration.
Acta Psychiatr Scand. 2008; 118: 337–346.
Frye MA, Grunze H, Suppes T, et al. A placebo-
controlled evaluation of adjunctive modafinil in the
treatment of bipolar depression. Am J Psychiatry.
2007; 164: 1242–1249.
Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty
acids in bipolar disorder. Arch Gen Psychiatry. 1999; 56:
Keck PE, Mintz J, McElroy SL, et al. Double-blind,
randomized, placebo-controlled trials of ethyl-
eicosapentanoate in the treatment of bipolar depression
and rapid cycling bipolar disorder. Biol Psychiatry.
2006; 60: 1020–1022.
Altshuler LL, Post RM, Hellemann G, et al. Impact of
antidepressant continuation after acute positive or
partial treatment response for bipolar depression:
a blinded randomized study. J Clin Psychiatry. 2009;
Ghaemi SN, Ostacher MM, El-Mallakh RS, et al.
Antidepressant discontinuation in bipolar depression:
a systematic treatment enhancement program for
bipolar disorder (STEP-BP) randomized clinical trial
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2010; 71(4): 372–380.
208 M. A. Cerullo and S. M. Strakowski