Pharmacology Update

Olanzapine and Fluoxetine Capsules (Symbyax—Lilly)

By William T. Elliott, MD, FACP, and James, Chan PhD, PharmD

The FDA has approved a combination of olanzapine and fluoxetine for the treatment of depressive episodes associated with bipolar disorder. Olanzapine is an atypical antipsychotic and fluoxetine is a selective serotonin reuptake inhibitor. The combination is marketed by Eli Lilly and Company as Symbyax.


Olanzapine/fluoxetine is indicated for the treatment of depressive episodes associated with bipolar disorder.1


The recommended initial dose is olanzapine 6 mg/fluoxetine 25 mg once daily in the evening. The dose may be titrated to 12 mg of olanzapine and 50 mg of fluoxetine based on antidepressive effectiveness and tolerability.1 Symbyax is available as 6 mg/25 mg, 6 mg/50 mg, 12 mg/25 mg, and 12 mg/50 mg.

Potential Advantages

Olanzapine/fluoxetine has been reported to be more effective than olanzapine alone in bipolar depression.2 Olanzapine/fluoxetine may provide an effective and convenient treatment option for some patients with bipolar depression.

Potential Disadvantages

The combination limits flexibility in optimizing drug combination selection and dosing. Most common adverse events are asthenia, somnolence, weight gain, dry mouth, and increased appetite. About 10% (vs 4.6% for placebo) of patients discontinued treatment in placebo-controlled clinical trials due to adverse events.1


Olanzapine/fluoxetine is the first combination product to be approved for bipolar disorder. Its efficacy was supported by 2, 8-week, randomized, double-blind, controlled studies in patients with bipolar I disorder. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). This is a 10-item clinician rated scale ranging from 0 to 60. Secondary endpoints included treatment emergent mania and disease remission. Eligible patients had MADRS score of at least 20 and a history of at least 1 previous manic or mixed episode that required treatment with a mood stabilizer or an antipsychotic agent.1,2 A total of 833 were randomized; 377 to placebo, 370 to olanzapine (5 mg initially and may be titrated to 20 mg/d), and 86 to olanzapine/fluoxetine (6 mg/25/d initially and may be titrated to 12 mg/50 mg).

The percent of responders (> 50% improvement in MADRS) were 56.1% for olanzapine/fluoxetine, 39% for olanzapine, and 30.4% for placebo. Median time to response was 21 days, 55 days, and 59 days for olanzapine/fluoxetine, olanzapine, and placebo respectively.

Remission rates were 48.8%, 32.8%, and 24.5% respectively. Olanzapine/fluoxetine was statistically different than olanzapine and placebo in all the above end points. No significant difference was observed in treatment-emergent mania among the three groups. Most common side effects were somnolence (21%), weight gain (17%), dry mouth (16%), increased appetite (13%), and asthenia (13%).2 No comparisons between olanzapine/fluoxetine and lithium or other drugs or drug combinations have been published. The wholesale cost of olanzapine/flu oxetine is about $6.50 per day for 6 mg of olanzapine and about $10 per day for 12 mg of olanzapine.

Clinical Implications

Bipolar disorders have a lifetime prevalence of 1.6- 1.8%.3 Bipolar I depression is characterized by episodes of mania and depression while bipolar II is characterized by hypomania and depression. Treatment involves managing acute manic and depressive episodes and stabilizing mood fluctuation. This may require various combinations of mood stabilizers and antidepressants.4 For acute depression in bipolar patients not yet in treatment for bipolar disorder, the American Psychiatric Association (APA) recommends initiating with lithium or lamotrigine. An alternative is lithium with an antidepressant. For patients with breakthrough depressive episodes APA recommends adding lamotrigine, bupropion, or paroxetine.5 Other treatments have included anticonvulsants (eg, valproate, carbamazepine) atypical antipsychotics (eg, olanzapine, risperidone).5 Olanzapine is currently FDA approved for acute mixed or manic episodes associated bipolar I disorder and may be appropriate as monotherapy for less ill patients.5 The combination of olanzapine and fluoxetine has been shown to be more effective in bipolar I depression than olanzapine alone. The use of this combination is, however, limited by its lack of flexibility and clinical experience. 

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.


1. Symbyax Product Information. Eli Lilly and Company. December 2003.

2. Tohen M, et al. Arch Gen Psychiatry. 2003;60: 1079-1088.

3. Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19.

4. Malhi GS, et al. CNS Drugs. 2003;17(1):9-25.

5. American Psychiatric Association Guidelines for Treatment of Patients with Bipolar Disorders. 2002.