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Mood Stabilizer Monotherapy versus Adjunctive Antidepressant for Bipolar Depression: The STEP-BD Trial 

Mood Stabilizer Monotherapy versus Adjunctive Antidepressant for Bipolar Depression: The STEP-BD Trial
Mood Stabilizer Monotherapy versus Adjunctive Antidepressant for Bipolar Depression: The STEP-BD Trial

João Paulo De Aquino

, and Robert Beech

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Subscriber: null; date: 23 October 2019

The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch.

The STEP-BD Investigators1

Research Question:

Among patients with bipolar disorder receiving mood-stabilizing agents, does adjunctive antidepressant therapy reduce the symptoms of bipolar depression without increasing mania?


The National Institute of Mental Health; Glaxo Wellcome and SmithKlineBeecham (now GlaxoSmithKline) donated the antidepressant drugs.

Year Study Began:


Year Study Published:


Study Location:

Outpatient clinics affiliated with academic medical centers in the United States. All eight study sites had bipolar specialty programs caring for at least 100 active patients and were deemed to be demographically diverse by the STEP-BD lead investigators.

Who Was Studied:

Patients aged ≥18 years old who met DSM-IV criteria for a major depressive episode (MDE) associated with DSM-IV diagnosis of bipolar I or bipolar II disorder. The majority of individuals in both treatment groups had experienced one or more MDEs prior to study entry.

Who Was Excluded:

Individuals with a history of intolerable side effects or unsatisfactory response to adequate trials of bupropion and paroxetine, substance use disorders requiring current short-term targeted treatment, and prior adjunctive antipsychotic drugs or immediate dose adjustment of a long-term antipsychotic medication.

How Many Participants:


Study Overview:

See Figure 4.1 for a summary of the study design.

Study Intervention:

This study was completed in a double-blind fashion. All patients were started on one of the following mood stabilizing regimens: lithium, valproic acid, lithium plus valproic acid, or carbamazepine. The study was later amended to include any FDA-approved anti-mania treatment. Mood stabilizers were titrated to the recommended therapeutic levels.

Individuals randomized to the mood stabilizer plus antidepressant group received either bupropion or paroxetine in addition to a mood stabilizer. These antidepressants were selected by the STEP-BD team of investigators as they were deemed to have a low rate of affective switch to represent the standard of antidepressants commonly prescribed for bipolar depression at the time of the study and due to the fact they have different mechanisms of action and side-effect profiles. Paroxetine was started at 10 mg daily and titrated up to a maximum of 40 mg daily. Bupropion (sustained-release) was started at 150 mg daily and titrated up to a maximum of 375 mg daily.

Individuals randomized to the mood stabilizer plus placebo group received one of the three previously mentioned mood stabilizers plus placebo.


26 weeks


Primary outcome: Durable recovery, (≥8 consecutive weeks of euthymia, defined as no more than two depressive or two manic symptoms). Secondary outcomes: Treatment remission (1–7 consecutive weeks of euthymia), treatment-effectiveness response (50% improvement from baseline symptom subscale for depression (SUM-D) score, from the mood modules of the Structured Clinical Interview for DSM-VI (SCID), without meeting criteria for hypomania or mania), treatment-emergent affective switch (hypomania/mania or required clinician intervention for mood intervention), and discontinuation of a study medication because of an adverse event.


  • There were no significant differences between the groups in treatment effectiveness; however, there was a nonsignificant trend toward worse outcomes among patients in the mood stabilizer plus antidepressant versus the mood stabilizer plus placebo groups (see Table 4.1).

  • Although not effective, the antidepressants were well tolerated: Treatment-emergent affective switch occurred in 10% of both the antidepressant/mood stabilizer and placebo/mood stabilizer groups.

  • The rates and types of adverse reactions were also similar in the antidepressant and placebo groups (Table 4.1).

Table 4.1 Summary of the Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression Results


Mood stabilizer + Antidepressant (N = 179) (%)

Mood stabilizer + Placebo (N = 187) (%)

P value

Durable recovery (primary outcome)




Transient remission




Treatment-effectiveness response




Treatment-emergent affective switch




Discontinuation of study because of an adverse event




Criticisms and Limitations:

Since the study had strict eligibility requirements, it may have excluded certain groups of patients, such as those with prior treatment of any of the study antidepressants, limiting the generalizability of the findings. Another potential source of bias is that only patients with good insight and motivation to receive treatment could be involved in the study, due to the requirements for informed consent. As a result, results may not generalize to patients with limited insight or other groups unable or unwilling to consent.

The primary outcome of this study was “durable recovery,” defined as 8 consecutive weeks of euthymia; however, longer-term outcomes were not assessed.

Furthermore, some common symptoms of bipolar disorder such as mood instability and impulsivity were not measured.

Other Relevant Studies and Information:

  • Similar findings were obtained in a meta-analysis published the next year that included data from seven smaller studies.2

  • A one-year follow-up of STEP-BD found similar results in subjects treated openly at the same treatment centers. Antidepressant use was associated with somewhat worse outcomes than management of bipolar depression without any standard antidepressants, especially for patients with rapid-cycling bipolar disorder.3

  • A double-blind controlled trial randomized depressed bipolar patients to quetiapine, paroxetine, or placebo found paroxetine was no better than placebo.4

  • One randomized double-blind study compared antidepressants with respect to their propensity for causing affective switching. This study found higher switch rates of switching with venlafaxine than with bupropion or sertraline.5

  • American Psychiatric American (APA) practice guidelines place mood stabilizers as first-line treatment for bipolar depression before an antidepressant adjunct is considered and recommend maintaining treatment with a mood stabilizer to mitigate the risk of antidepressant-induced mania or increased cycling.6 To date, the only FDA-approved antidepressants for the depressive phase of bipolar disorder are olanzapine-fluoxetine combination, quetiapine, and lurasidone.

Summary and Implications:

In this randomized, multicenter, double-blind, placebo-controlled trial, adding an antidepressant to a mood stabilizer was not effective for treating bipolar depression. Adjunctive antidepressant therapy did not increase affective switching to mania relative to placebo therapy, however. Based on this and other studies, guidelines from the APA recommend mood stabilizers as first-line treatment for bipolar depression and indicate that adjunctive antidepressant therapy should only be considered in refractory cases.

Clinical Case: Mood Stabilizer Monotherapy Versus Adjunctive Antidepressant in Bipolar Depression

Case History

A 33-year-old single woman states she has been intermittently depressed for 15 years. Her current symptoms include hypersomnia, increased appetite, craving carbohydrates/sweets, feeling like she is “nailed to the bed in the mornings,” and crying spells. She sometimes “prays she will not wake up” and is irritable and anxious. No evidence of psychosis or prior suicide attempts. At times, she can feel more self-confident, “project a different self,” and be more impulsive and has decreased need for sleep for approximately 1-week periods. She has a family history of bipolar disorder. She says all antidepressants “work for a while, then stop.” Her only current medication is lithium.

Based on the results of the STEP-BD, how should this patient be treated?

Suggested Answer

STEP-BD found that that monotherapy with a mood stabilizer is as effective as dual therapy with a mood stabilizer plus an antidepressant for individuals with bipolar depression.

The clinical picture as previously presented is typical of a patient in the STEP-BD study. Based on these results, the addition of an antidepressant like bupropion or paroxetine would not provide additional benefit. While clinical history and past response to similar treatments remain important factors in treatment decisions,7 it is important to emphasize there are alternatives to pharmacotherapy, such as psychosocial interventions with reasonable evidence to treat depressive morbidity in bipolar disorder.8


1. Sachs, G. S., Nierenberg, A. A., Calabrese, J. R., Marangell, L. B., Wisniewski, S. R., Gyulai, L., . . . & Ketter, T. A. (2007). Effectiveness of adjunctive antidepressant treatment for bipolar depression. New England Journal of Medicine, 356(17), 1711–1722.Find this resource:

2. Ghaemi, S. N., Wingo, A. P., Filkowski, M. A., & Baldessarini, R. J. (2008). Long‐term antidepressant treatment in bipolar disorder: Meta‐analyses of benefits and risks. Acta Psychiatrica Scandinavica, 118(5), 347–356.Find this resource:

3. Schneck, C. D., Miklowitz, D. J., Miyahara, S., Araga, M., Wisniewski, S., Gyulai, L., . . . Sachs, G. S. (2008). The prospective course of rapid-cycling bipolar disorder: Findings from the STEP-BD. American Journal of Psychiatry, 165(3), 370–377.Find this resource:

4. McElroy, S. L., Weisler, R. H., Chang, W., Olausson, B., Paulsson, B., Brecher, M., . . . Young A. H. (2010). A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). Journal of Clinical Psychiatry, 71(2), 163–174.Find this resource:

5. Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Jr., . . . Post, R. M. (2006). 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. American Journal of Psychiatry, 163(2), 232–239.Find this resource:

6. American Psychiatric Association. (2002). Practice guideline for the treatment of patients with bipolar disorder (revision). Washington, DC: Author.Find this resource:

    7. Belmaker, R. H. (2007). Treatment of bipolar depression. New England Journal of Medicine, 356, 1771–1773.Find this resource:

    8. Miklowitz, D. J., Otto, M. W., Frank, E., Reilly-Harrington, N. A., Wisniewski, S. R., Kogan, J. N., . . . Sachs, G. S. (2007). Psychosocial treatments for bipolar depression: A 1-year randomized trial from the Systematic Treatment Enhancement Program. Archives of General Psychiatry, 64, 419–426.Find this resource: