Role of Antidepressants in Bipolar Depression

Eduard Vieta, MD, PhD

Department of Psychiatry and the Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain

Bipolar depression is part of a spectrum of mood states that characterize bipolar disorder (AV 1AV 1).1 Clinicians must consider any history of mania or hypomania in addition to depressive symptoms when choosing among treatments. Bipolar disorder is frequently misdiagnosed as depression or unipolar depression, often because patients underreport manic symptoms; for an example of this type of patient, see AV 2AV 2.

Practice guidelines2
do not recommend antidepressant monotherapy in bipolar disorder, but approximately 50% of patients are initially treated with an antidepressant, twice as many than are given anticonvulsants.3 Practice guidelines2 also advise clinicians to discontinue antidepressant therapy during manic episodes. Medications other than antidepressants have evidence for better efficacy in patients with bipolar depression.

Antidepressant Use During Mania

In spite of what is advised in practically all treatment guidelines,2 more than 15% of patients remain on antidepressant treatment during manic episodes.4 To identify factors that influence the prescribing of antidepressants to these patients, my colleagues and I4 analyzed more than 3,500 participants with bipolar disorder. We found that the existence of certain factors at baseline (ie, a mixed episode, rapid cycling, > 1 depressive episode in the last 12 months, and a HAM-D total score of ≥ 5) increased the likelihood of being given an antidepressant. These data suggest that clinicians are trying to treat and prevent depression, even during manic episodes.

Possibility of Switching and Rapid Cycling With Antidepressants in Bipolar Depression

The possibility of antidepressants causing a mood switch from depression to mania is a common concern2; view AV 3AV 3 for an example of an antidepressant-induced manic switch. However, the majority of studies5 do not suggest an increased risk of switch with antidepressants (3.8% vs 4.7% for placebo), although the switch rate with TCAs appears to be higher than with SSRIs or MAOIs. Venlafaxine may also carry a higher rate of switch to mania or hypomania than other antidepressants such as SSRIs and bupropion.6,7 Another serious concern is that antidepressants may shorten the duration of the bipolar cycle and induce rapid cycling. As with research on mood switches, the evidence base concerning rapid cycling is small. Shortening of the cycle length has been observed with TCAs8 but not with SSRIs.9

Efficacy of Antidepressants in Bipolar Depression

Acute efficacy. Few studies have evaluated the efficacy of antidepressant treatment in patients with bipolar depression. Although a systematic review5 determined that antidepressants are effective in the short-term treatment of depressive episodes, this conclusion was largely based on the weight of data from 1 trial10 in which the olanzapine-fluoxetine combination was more efficacious than olanzapine alone and placebo; the effect of fluoxetine monotherapy was not assessed.


Available evidence does not appear to support the use of antidepressants in bipolar depression. In a double-blind, controlled study,11 adjunctive antidepressant therapy was not superior to placebo in achieving durable recovery (8 weeks of euthymia) in patients taking mood stabilizers. Further, Young et al12 found quetiapine, but not paroxetine, to be significantly more effective than placebo in patients with bipolar depression (AV 4AV 4).

Long-term efficacy. Little evidence supports the long-term use of antidepressants for the prevention of further depressive episodes. A double-blind, long-term follow-up study13 found no benefit for combination therapy with lithium and imipramine versus lithium alone. Both the combination treatment and lithium alone were superior to imipramine alone in the prevention of mania, and all 3 treatments were comparable in preventing depressive recurrence. Another study14 observed significantly more manic relapses during imipramine monotherapy than with lithium monotherapy (P < .05).

Modern antidepressants may be more effective in preventing relapse than older ones such as imipramine. A 1-year study15 followed patients with bipolar disorder who were treated to remission from acute depression with a mood stabilizer plus an antidepressant. Antidepressants largely included SSRIs, bupropion, and venlafaxine, with few TCAs and MAOIs. Patients who discontinued the antidepressant within 6 months of achieving remission had a significantly shorter time to depressive relapse than those who continued taking the medication (AV 5AV 5). Manic relapse was not associated with continuation of antidepressants. However, this study15 did not have a randomized design, which is a major limitation. Therefore, long-term adjunctive antidepressant therapy may be appropriate for a subgroup of patients with bipolar disorder, but additional research is needed to make a definite conclusion.

For Clinical Use

A gap exists between the evidence base and the prescription practices for bipolar depression; antidepressants are frequently prescribed, but little evidence supports their use in these patients, especially as monotherapy. The efficacy of adjunctive antidepressant treatment requires further examination. To improve patient outcomes, clinicians should do the following:

  • Inquire about the patient’s mood history, eg, past mania or hypomania, and keep this in mind when choosing among treatments
  • Do not prescribe antidepressant monotherapy for bipolar depressive episodes
  • Discontinue adjunctive antidepressant medications during manic episodes
  • Consider alternative therapies to antidepressants, eg, quetiapine, the olanzapine-fluoxetine combination, lamotrigine, ECT, and psychotherapy

Drug Names

bupropion (Aplenzin, Wellbutrin, and others), fluoxetine (Prozac and others), imipramine (Tofranil and others), lamotrigine (Lamictal and others), lithium (Lithobid, Eskalith, and others), olanzapine (Zyprexa), olanzapine-fluoxetine (Symbyax), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel), venlafaxine (Effexor and others)


CGI-BP=Clinical Global Impression Scale for Bipolar Disorder, ECT=electroconvulsive therapy, HAM-D=Hamilton Rating Scale for Depression, MADRS=Montgomery-Asberg Depression Rating Scale, MAOI=monamine oxidase inhibitor, SSRI=selective serotonin reuptake inhibitor, TCA=tricyclic antidepressant

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