What is the efficacy and safety of using olanzapine (atypical antipsychotic) and fluoxetine (selective serotonin reuptake inhibitor, SSRI) in combination?

From the Guidelines

The combination of olanzapine and fluoxetine is a viable treatment option for bipolar depression and treatment-resistant depression, with a synergistic antidepressant effect that can be more effective than either medication alone, as supported by the FDA approval for bipolar depression in adults 1. When using this combination, it is essential to consider the potential side effects, including weight gain, increased appetite, drowsiness, dry mouth, and metabolic changes, and to monitor patients regularly for these effects 1.

• Typical dosing for bipolar depression starts at 6 mg olanzapine/25 mg fluoxetine once daily, with adjustments based on response and tolerability.
• The combination works by combining olanzapine's effects on dopamine and serotonin receptors with fluoxetine's selective serotonin reuptake inhibition.
• Regular monitoring of weight, blood glucose, lipids, and mental status is necessary to minimize the risk of adverse effects.
• Caution should be exercised when using this combination in elderly patients and those with cardiovascular disease, diabetes, or liver problems, as they may be more susceptible to adverse effects 1.
• Abrupt discontinuation of the combination should be avoided to prevent withdrawal symptoms, and patients should be gradually tapered off the medication if discontinuation is necessary. The most recent and highest quality study on this topic is from 2016, which discusses the pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants, including the combination of olanzapine and fluoxetine 1.
• This study highlights the importance of individualizing treatment selection for patients with major depressive disorder, taking into account genetic variation and other factors that may affect treatment response and adverse effects.
• The study also notes that fluoxetine is FDA approved for major depressive disorder, OCD, bulimia nervosa, premenstrual dysphoric disorder, panic disorder, and bipolar disorder (in combination with olanzapine), and is the only drug FDA approved for major depression in children/adolescents aged 8 years or older 1.

From the FDA Drug Label

Children and Adolescents (10-17 years of age) Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2. 5 mg of oral olanzapine and 20 mg of fluoxetine. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies Safety and efficacy of ZYPREXA and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of ZYPREXA and fluoxetine). Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies

The efficacy and safety of using olanzapine and fluoxetine in combination has been established in clinical trials, with antidepressant efficacy demonstrated in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg 2. The combination is indicated for:

• Bipolar I disorder: including depressive episodes associated with bipolar I disorder
• Treatment resistant depression: major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode Key considerations:
• Dosing: oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals
• Dose adjustments: if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg
• Special populations: dose modification may be necessary in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination 2

From the Research

Efficacy of Olanzapine and Fluoxetine Combination

• The combination of olanzapine and fluoxetine is effective in the treatment of patients with acute bipolar depression, with an efficacy greater than that of olanzapine alone or lamotrigine 3, 4.
• The number needed to treat for antidepressant response for olanzapine-fluoxetine combination versus placebo in the 8-week trials was 4 (95% CI 3 - 8), and that for remission was 5 (95% CI 3 - 8) 5.
• The combination improves depressive symptoms and symptom severity in patients with acute bipolar depression, with a robust clinical effect acutely and a low rate of induction of mania or mixed states 6.

Safety of Olanzapine and Fluoxetine Combination

• The combination of olanzapine and fluoxetine is generally well tolerated, although it is associated with weight gain and potential elevations in glucose, lipid, and prolactin levels 3, 4.
• Single-digit numbers needed to harm (NNH) values were observed for the treatment-emergent adverse events of weight gain (NNH 7,95% CI 5 - 16) and diarrhea (NNH 9,95% CI 5 - 30) 5.
• The combination does not increase the risk of treatment-emergent mania, but it is associated with a higher incidence of treatment-emergent adverse events, weight gain, and elevation in metabolic factors compared to lamotrigine 5.

Comparison with Other Treatments

• Olanzapine-fluoxetine combination demonstrates statistically significantly greater improvement in depressive and manic symptoms compared to lamotrigine, but it has a higher incidence of treatment-emergent adverse events 5.
• Indirect comparisons suggest similar efficacy outcomes between olanzapine-fluoxetine combination and quetiapine monotherapy, but different tolerability profiles, with quetiapine principally being associated with sedation 5.
• The role of olanzapine-fluoxetine combination in the treatment of bipolar depression remains unclear due to the lack of comparisons to mood stabilizers combined with each other and/or antidepressants 7.