Prescribing Antidepressants for Bipolar Depression: What Does the Evidence Say?

Susan L. McElroy, MD

Department of Psychiatry and Neuroscience, University of Cincinnati College of Medicine, and the Lindner Center of HOPE, Mason, Ohio

Although the hallmark feature of bipolar disorder is mania or hypomania, individuals with this disorder spend more time experiencing depressive symptoms.1 When a patient presents with an acute depressive episode, the overall goal for treatment should be to first alleviate the acute mood episode, but, because bipolar disorder is a chronic recurrent illness, clinicians must also establish a foundation for long-term mood stabilization.

AV 1. Types of Drugs Initially Prescribed to Patients With Bipolar Disorder (N = 7,760) (00:37)

Data from Baldessarini et al3

In recent years, antidepressant use in the United States has risen nearly 400%, and antidepressants are currently the most frequently used prescription drug among Americans aged 18 to 44 years.2 No antidepressant is approved as monotherapy for bipolar depression, but antidepressants are commonly prescribed for bipolar disorder. One study3 found that antidepressant monotherapy was the most common initial treatment prescribed to patients with bipolar disorder (AV 1). Antidepressant use for bipolar depression, however, is a controversial practice because of questions regarding efficacy and the risk of inducing a manic switch.

Are Antidepressants Effective for Bipolar Depression?

The use of antidepressants for bipolar depression is questionable because their efficacy has not been established for this condition. The lack of research on bipolar depression treatment is remarkable, particularly when compared with the amount of research on the treatment of major depressive disorder. One large, placebo-controlled trial4 found that paroxetine was no more effective than placebo in the treatment of an acute depressive episode in patients with bipolar I or bipolar II disorder.

Evidence of antidepressants as effective adjunctive treatments with a mood stabilizer is also lacking. Sachs and colleagues5 found no benefit over that of placebo from adding an antidepressant to a mood stabilizer for bipolar depression. However, one notable study6 found that the combination of the atypical antipsychotic olanzapine and the SSRI fluoxetine led to significant improvement in depressive symptoms (P < .001) in patients with bipolar I disorder. The olanzapine-fluoxetine combination subsequently received FDA approval for bipolar depression. The other FDA-approved therapies for bipolar depression are quetiapine and lurasidone, not antidepressants.

Will Antidepressants Induce a Switch to Mania or Hypomania?

AV 2. Response and Manic/Hypomanic Switch Rates for Different Antidepressants (00:40)

Data from Post et al8

Beyond having questionable efficacy for bipolar depression, antidepressants may actually be harmful in some patients. Some evidence suggests that these agents could cause a switch to mania or hypomania when used either as monotherapy7 or in combination with a mood stabilizer.8 Different antidepressants appear to have different propensities for triggering an affective switch, possibly because of their differing mechanisms of action. TCAs and SNRIs, namely venlafaxine, confer the greatest risk, and SSRIs and bupropion confer the least.8 One study8 compared the use of venlafaxine, bupropion, and sertraline as adjuncts to mood stabilizer treatment for bipolar depression. The study found the efficacy of all 3 antidepressants to be comparable, but patients receiving venlafaxine had a significantly higher risk of switching to mania or hypomania (P = .002; AV 2).8 The higher incidence of manic switch with venlafaxine may be because this agent affects reuptake of both serotonin and norepinephrine.

Is Antidepressant Treatment Ever Appropriate in Bipolar Depression?

Although most of the available evidence suggests that antidepressant use should typically be avoided in bipolar disorder, a subset of patients may benefit from antidepressant treatment. A study9 of patients who achieved remission from an episode of bipolar depression with an antidepressant found that those patients who discontinued antidepressant treatment within 6 months of remission had a significantly higher rate of relapse compared with those who continued antidepressant treatment (P = .004). Another notable finding of this study was that antidepressant discontinuation was also associated with a significant increase in the risk of developing mania (P = .003). Thus, patients who respond well to acute antidepressant treatment will likely benefit from ongoing antidepressant treatment to reduce the likelihood of relapse to either a depressive or manic mood.


Current Guidelines for Antidepressant Treatment of Bipolar Depression

According to APA guidelines,10,11 antidepressant monotherapy should be avoided in patients with bipolar depression. The guideline does suggest an antidepressant be added to mood stabilizer treatment for patients who do not respond to first-line treatment with a mood stabilizer alone or for patients who are more severely ill. The APA practice guideline for bipolar disorder was published in 2002,10 with an update in 2005,11 and thus might be superseded by newer evidence.

AV 3. Evaluating Treatment for a Patient With Bipolar Depression (03:09)

The ISBD recently convened a task force to review the use of antidepressants in bipolar disorder. The task force, which consisted of 65 experts from around the world, reviewed 173 studies and concluded that antidepressants have a questionable risk/benefit ratio in bipolar disorder.12 Consensus recommendations were presented at the 2013 ISBD conference (AV 3). According to these guidelines, antidepressant use is only appropriate for bipolar depression when a patient is taking a mood stabilizer and has had a good response to antidepressants in the past. Antidepressants should not be used as monotherapy, and they should be avoided when bipolar depression is associated with psychomotor agitation, mixed features (defined as ≥ 2 manic symptoms), or rapid cycling (defined as having ≥ 4 episodes of depression, mania, or hypomania per year).


Antidepressants are some of the most commonly used prescription agents in the United States, and although their efficacy is well established for unipolar depression, their benefit in treating bipolar depression is questionable. Compelling evidence indicating that these agents are effective treatments for bipolar depression is lacking, but evidence does indicate that these agents may lead to a manic or hypomanic switch in a minority of patients. Clinicians, therefore, should adhere to current guidelines and consensus recommendations by avoiding antidepressant monotherapy and using antidepressants as adjunctive treatments with caution.

Clinical Points

  • Do not prescribe antidepressant monotherapy for patients with bipolar depression
  • Consider prescribing adjunctive antidepressants for patients with bipolar depression who have not responded to a mood stabilizer alone or who have a more severe course of illness
  • Consider adjunctive antidepressant treatment only for patients who have benefited from antidepressant treatment in the past
  • Avoid adjunctive antidepressant treatment in patients experiencing mixed features or rapid cycling

Drug Names

bupropion (Wellbutrin, Aplenzin, and others), fluoxetine (Prozac and others), lurasidone (Latuda), olanzapine (Zyprexa), olanzapine/fluoxetine combination (Symbyax), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel and others), sertraline (Zoloft and others), venlafaxine (Effexor and others)


APA = American Psychiatric Association; FDA = US Food and Drug Administration; ISBD = International Society for Bipolar Disorders; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant


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