Alternatives to Antidepressants in Treating Acute Bipolar Depression

Andrew A. Nierenberg, MD

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston

Although bipolar disorder is defined by the presence of mania or hypomania, depressive symptoms constitute the major burden of the illness. Patients with bipolar I disorder are euthymic about half of the time but have depressive symptoms about a third of the time.1 Even more striking, patients with bipolar II disorder experience depressive symptoms about half of the time and spend less than 4% of the time with either hypomania or mixed symptoms.2 Major depressive episodes and subsyndromal depressive symptoms are associated with significant psychosocial impairment for these patients, equal to or worse than that of manic or hypomanic symptoms, while subsyndromal hypomanic symptoms may actually enhance functioning in patients with bipolar II disorder.3

Antidepressant Treatment in Bipolar Depression

A fundamental question in the treatment of bipolar disorder is whether or not antidepressants are effective and safe for use in bipolar depressive episodes. Antidepressant monotherapy without a concurrent mood stabilizer is not recommended due to concern about antidepressant-induced mood-switching, but more research is needed (AV 1AV 1). A meta-analysis4 of 5 placebo-controlled trials, in which three-fourths of the subjects were taking an antidepressant with a concurrent atypical antipsychotic or mood stabilizer, concluded that antidepressants were superior to placebo for the treatment of bipolar depression and did not induce mania more often than placebo. However, sufficient evidence to support the use of antidepressants for bipolar depression was not presented, as the largest trial in the meta-analysis combined the antidepressant with an antipsychotic and the other trials had small sample sizes and methodological problems.

STEP-BD5 was a large, seminaturalistic, and reasonably powered set of studies that contained an embedded randomized trial6 in which an antidepressant (bupropion or paroxetine) or placebo was added to ongoing treatment with a mood stabilizer for bipolar patients with a major depressive episode. At least 8 consecutive weeks of euthymia, called durable recovery, was the primary outcome. No statistically significant difference in durable recovery was found between the antidepressant and placebo groups; in fact, the group that received the placebo had slightly more numerical improvement.6 No difference was found in manic switch rates. Additionally, 70 patients in the STEP-BD study who had achieved durable recovery with antidepressants plus mood stabilizers were then randomly assigned to antidepressant continuation versus discontinuation and followed for 1 to 3 years.7 The study found no significant symptomatic benefit for long-term antidepressant treatment of bipolar depression.

Goldberg et al8 analyzed STEP-BD data to determine if patients in the study who were depressed but had some manic symptoms (ie, mixed state) had better or worse outcomes when they received either an adjunctive antidepressant or placebo. The results showed that adjunctive antidepressant use had no effect on time to recovery and was associated with worse severity of mania at follow-up.

Alternatives to Antidepressant Pharmacotherapy

Lamotrigine. One early study9 of lamotrigine as monotherapy for the acute treatment of bipolar I depression found lamotrigine to be more effective than placebo, but this result was not replicated in 5 subsequent studies.10 However, lamotrigine may be useful for episodes of bipolar depression when used as augmentation. Van der Loos and colleagues11 examined the efficacy of lamotrigine as an add-on to ongoing lithium treatment compared with lithium plus placebo in the acute treatment of patients with bipolar depression. The combination was well tolerated, and significantly (P = .03) more patients responded to the lamotrigine-lithium combination (about 52%) than to lithium plus placebo (about 32%) according to reduction in MADRS scores (AV 2AV 2). Although lamotrigine is not approved for the treatment of acute bipolar depression, it is approved for the prevention of mood episodes during maintenance treatment.

A trial12 conducted in STEP-BD compared outcomes for patients with treatment-resistant depression currently receiving a mood stabilizer plus an antidepressant who were randomly assigned to receive lamotrigine, inositol, or risperidone augmentation. No statically significant differences were found in treatment outcomes, although post hoc analysis suggested that lamotrigine might be superior to inositol and risperidone. Rates of recovery were about 24% with lamotrigine, 17% with inositol, and 5% with risperidone.

Atypical antipsychotics. Although the addition of antidepressants to mood stabilizers appears to be ineffective, the combination of the antidepressant fluoxetine and the atypical antipsychotic olanzapine has shown efficacy for bipolar depression. Tohen and colleagues13 compared the efficacy of the olanzapine-fluoxetine combination with olanzapine monotherapy or placebo for the acute treatment of bipolar I depression. Olanzapine monotherapy was more effective than placebo (P < .001), but the olanzapine-fluoxetine combination was significantly more effective than olanzapine monotherapy (P < .02). Remission rates were approximately 49% for olanzapine-fluoxetine, 33% for olanzapine monotherapy, and 25% for placebo.


In a head-to-head study by Brown and colleagues,14 patients being treated for acute bipolar I depression with the olanzapine-fluoxetine combination experienced significantly greater change from baseline on CGI-S and MADRS scores than patients treated with lamotrigine monotherapy (P = .002). Although response rates did not significantly differ between the combination and lamotrigine groups (68.8% vs 59.7%, respectively), time to response was shorter for the olanzapine-fluoxetine group. The olanzapine-fluoxetine group had more treatment-emergent adverse events, while the lamotrigine group had a higher incidence of suicidal and self-injurious behavior. The olanzapine-fluoxetine combination is approved by the FDA for the treatment of acute bipolar depression, but clinicians should monitor for side effects associated with olanzapine, such as sedation and metabolic syndrome.

Other atypical antipsychotic agents may be useful for treating acute bipolar depression. In 2 studies15,16 of quetiapine monotherapy in patients with bipolar I or II depression, significant improvement was found on MADRS scores with quetiapine at a dose of either 600 mg/d or 300 mg/d compared with placebo (P ≤ .001), although the higher dose was associated with more treatment discontinuation owing to adverse events than the lower dose. As with olanzapine, patients receiving quetiapine should be monitored for metabolic syndrome. Quetiapine monotherapy is approved by the FDA for the treatment of acute bipolar depression.

However, not all atypical antipsychotics appear to have efficacy in bipolar depression. Patients taking risperidone showed a poor recovery rate in STEP-BD,12 and in 2 studies17 aripiprazole failed to achieve statistical difference in efficacy over placebo for treating acute bipolar I depression.

Modafinil. Modafinil, which has FDA approval for improving wakefulness in patients with various sleep disorders, was examined as an adjunctive treatment for patients with bipolar disorder who had not adequately responded to a mood stabilizer. Both response and remission rates were significantly higher for those receiving modafinil compared with placebo, suggesting a possible role for modafinil in treating bipolar depression (AV 3AV 3).18

Adjunctive Psychosocial Interventions

The effectiveness of intensive psychosocial interventions (ie, cognitive behavioral therapy, family-focused therapy, and interpersonal and social rhythm therapy) was compared with less intensive group psychoeducation for patients in the STEP-BD study.19 Patients receiving an intensive psychosocial intervention in addition to pharmacotherapy over 1 year had better recovery rates and recovered from depression 110 days earlier than those receiving pharmacotherapy and mild psychoeducation. No difference in outcomes among the 3 intensive psychotherapies was found. Although many patients will require polypharmacy for acute and long-term treatment of bipolar disorder, structured psychosocial interventions are a useful component in the management of bipolar depression.

For Clinical Use

  • Insufficient evidence exists to support the efficacy of antidepressants for treating bipolar depression
  • Available evidence supports the olanzapine-fluoxetine combination or quetiapine monotherapy for the treatment of acute bipolar major depressive episodes; some evidence suggests lamotrigine or modafinil augmentation may be helpful, but additional research is needed
  • Structured psychosocial interventions used in conjunction with pharmacotherapy improve recovery rates in bipolar depression


aripiprazole (Abilify), bupropion (Wellbutrin, Aplenzin, and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), modafinil (Provigil), olanzapine (Zyprexa), olanzapine-fluoxetine combination (Symbyax), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel), risperidone (Risperdal and others)


CGI-S = Clinical Global Impressions-Severity of Illness scale
FDA = US Food and Drug Administration
IDS = Inventory of Depressive Symptomatology
MADRS = Montgomery-Åsberg Depression Rating Scale
STEP-BD = Systematic Treatment Enhancement Program for Bipolar Disorder

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