Evidence-Based Reviews

Antidepressants in bipolar disorder: 7 myths and realities

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Dispelling misconceptions leads to rationale-based steps for treating bipolar depression



Few topics are as controversial as the role of antidepressants for patients with bipolar disorder. Although depression usually is the predominant, most enduring mood state in bipolar disorder, clinicians often face uncertainty about using antidepressants because of concerns about safety and efficacy. Whether and when to use antidepressants for bipolar depression hinges on complex parameters that preclude any single, simple rule.

Rather than asking if antidepressants are useful or detrimental for depressed patients with bipolar disorder, a more practical question might be: Under what circumstances are antidepressants likely to be beneficial, deleterious, or ineffective for an individual patient? Because “real world” patients often have idiosyncrasies that defy practice guidelines’ generic treatment recommendations, clinicians who practice in the proverbial trenches need strategies to tailor treatments to each patient that are informed—but not dictated—by evidence-based research.

Early suspicions

Concerns that antidepressants might precipitate mania were first described with tricyclic antidepressant (TCA) use in Europe in the 1960s. After bupropion and selective serotonin reuptake inhibitors (SSRIs) emerged, some clinicians believed they posed a lesser risk for this phenomenon compared with TCAs1,2 or monoamine oxidase inhibitors (MAOIs).3

Antidepressants’ potential to induce short-term mania/hypomania following acute exposure has been weighed against the longer-term risk for worsening illness course by increasing frequency of subsequent episodes (so-called cycle acceleration). In the 1980s, some researchers suggested that rapid cycling might—at least in some instances—represent an iatrogenic phenomenon caused by long-term antidepressant use. These issues remain controversial, but more than 20 years of research suggest that antidepressants induce mania or accelerate cycling in a smaller minority of bipolar disorder patients than was once thought.

Table 1 and Table 2 summarize findings from randomized controlled studies that have examined antidepressants’ efficacy for acute bipolar depression. Except for a study of fluoxetine plus olanzapine,4 no large-scale placebo-controlled trial has demonstrated superior antidepressant response to a mood stabilizer plus antidepressant compared with a mood stabilizer alone.

Table 1

Antidepressants for bipolar depression: SSRIs and SNRIs*

Acute efficacyReported switch risk
Fluoxetine (SSRI)
86% response rate after 3 weeks in 6-week double-blind randomized comparison with imipramine or placeboa0%
38% response rate after 8 weeks of placebo-controlled monotherapy in bipolar II or NOS subjectsb0%
56% response rate over 8 weeks in combination with olanzapine; significantly better than placebo plus olanzapine (30%)c6%
Paroxetine (SSRI)
Same as placebo when added to an antimanic drug (STEP-BD) for up to 26 weeksd10.1% (reported only jointly for paroxetine or bupropion)
36% response rate (no different from placebo) when coadministered with therapeutically dosed lithium over 10 weekse7%
Same as divalproex plus lithium when coadministered with divalproex or lithium over 6 weeks (actual response rates not reported)f0%
43% response (coadministered with lithium, divalproex, or carbamazepine) over 6 weeksg3% (not statistically significantly different from venlafaxine comparison arm)
Sertraline (SSRI)
41% improved (comparable to rates seen with bupropion [33%] or venlafaxine [36%] when coadministered with a mood stabilizer over 10 weeks)h12%
Venlafaxine (SNRI)
36% improved (comparable to rates seen with bupropion [33%] or sertraline [41%]) when coadministered with a mood stabilizer over 10 weeksh6%
48% response (coadministered with lithium, divalproex, or carbamazepine) over 6 weeksg13% (not statistically significantly different from paroxetine comparison arm)
*No data are available for citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, or milnacipran
NOS: not otherwise specified; SNRI: serotonin/norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; STEP-BD: Systematic Treatment Enhancement Program for Bipolar Disorder
a. Cohn JB, Collins G, Ashbrook E, et al. A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmaol. 1989;4:313-322.
b. Amsterdam JD, Shults J. Fluoxetine monotherapy of bipolar type II and bipolar NOS major depression: a double-blind, placebo-substitution, continuation study. Int Clin Psychopharmacol. 2005;20:257-264.
c. 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.
d. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
e. 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.
f. Young LT, Joffe RT, Robb JC, et al. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry. 2000;157:124-126.
g. Vieta E, Martinez-Aran A, Goikolea JM. A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry. 2002;63:508-512.
h. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.


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