Olanzapine/Fluoxetine Combination: Indication and Dosing
The olanzapine/fluoxetine combination is FDA-approved for two specific indications in adults: acute treatment of bipolar I depression and treatment-resistant major depressive disorder (defined as failure of two adequate antidepressant trials in the current episode). 1
FDA-Approved Indications
Bipolar I Depression (Adults)
- Start with olanzapine 5 mg + fluoxetine 20 mg once daily in the evening, without regard to meals 1
- Adjust dosing based on efficacy and tolerability within the range of olanzapine 6-12 mg + fluoxetine 25-50 mg 1
- Maximum studied dose: olanzapine 18 mg + fluoxetine 75 mg (safety above this not established) 1
- This is the only FDA-approved combination specifically for bipolar depression in adults 2
Bipolar I Depression (Adolescents 10-17 years)
- Start with olanzapine 2.5 mg + fluoxetine 20 mg once daily in the evening 1
- Maximum studied dose in pediatrics: olanzapine 12 mg + fluoxetine 50 mg 1
- Fluoxetine is the only antidepressant FDA-approved for depression in children/adolescents aged 8+ years, though only in combination with olanzapine for bipolar disorder 2
Treatment-Resistant Depression (Adults Only)
- Start with olanzapine 5 mg + fluoxetine 20 mg once daily in the evening 1
- Effective dose range: olanzapine 6-18 mg + fluoxetine 25-50 mg 1
- Treatment-resistant depression is defined as failure to respond to two separate adequate antidepressant trials (adequate dose and duration) in the current episode 1, 3
- Olanzapine monotherapy is NOT indicated for treatment-resistant depression 1
Special Population Dosing
For patients with hepatic impairment, hypotensive predisposition, slow metabolizers (female, elderly, nonsmokers), or pharmacodynamic sensitivity to olanzapine: start with olanzapine 2.5-5 mg + fluoxetine 20 mg 1
- Dose escalation should be performed with caution in these populations 1
- Both fluoxetine and olanzapine are metabolized through CYP2D6, which exhibits genetic variation 2
- CYP2D6 poor metabolizers have 3.9-fold higher fluoxetine AUC after single doses and are at higher risk for toxicity 2
Duration of Treatment
While optimal treatment duration is not definitively established, both bipolar I disorder and treatment-resistant depression are chronic conditions requiring chronic treatment 1
- Long-term data (76 weeks) support continued efficacy of the combination in treatment-resistant depression 3
- A 24-week open-label study showed sustained benefit in bipolar depression with low mania emergence rate (5.9%) 4
- Healthcare providers should periodically reassess the need for continued pharmacotherapy 1
Efficacy Evidence
The combination demonstrates superior efficacy compared to monotherapy with either agent alone 3, 5, 6
- Number needed to treat (NNT) for antidepressant response vs placebo: 4 (95% CI 3-8) 6
- NNT for remission vs placebo: 5 (95% CI 3-8) 6
- Greater efficacy than lamotrigine in head-to-head comparison for bipolar depression 5, 6, 7
- Among patients starting in non-remission during long-term treatment, 62.5-66.7% achieved remission 4
Safety Considerations
The combination carries a black box warning for treatment-emergent suicidality, particularly in adolescents and young adults 2
- Number needed to harm (NNH) for weight gain ≥7%: 6 (95% CI 4-10) 6
- Associated with weight gain and potential elevations in glucose, lipid, and prolactin levels 5, 7
- Does not increase risk of treatment-emergent mania compared to other treatments 5, 7
- Overall depressive relapse rate in long-term treatment: 27.4% 4
- Risk of serotonin syndrome when combining serotonergic agents; avoid MAOIs entirely 2
Common Pitfalls
- Do not use olanzapine monotherapy for treatment-resistant depression or as monotherapy for bipolar depression 1
- The combination has not been systematically studied in patients over 65 years or under 10 years of age 1
- Safety above olanzapine 18 mg + fluoxetine 75 mg has not been evaluated 1
- Higher SSRI dosing (including fluoxetine) is associated with higher dropout rates due to adverse effects 2