Introduction
The olanzapine fluoxetine combination was FDA approved in 2003 for the treatment of depressive episodes in bipolar I disorder. In 2009 it was granted approval for treatment resistant depression.
This medication consists of the atypical dopamine blocking medication olanzapine and the SSRI fluoxetine. Many people consider olanzapine to be the best antipsychotic not named clozapine (see my video on the best antipsychotic in the world). This comes from the CATIE study where olanzapine proved to be superior to other medications. It has good efficacy, once daily dosing at night, and low risk for cardiac conduction abnormalities (QTc prolongation). However, the side effects including risk for weight gain and metabolic complications have made it a second line option.
My residents often jump to this medication on the inpatient unit, but I usually tell them to use caution because of the side effects and should it not be effective, it leaves you with clozapine as the next option in terms of effectiveness.
Fluoxetine is an antidepressant that has been around a long time with a broad spectrum of indications. It’s long track record and safety profile makes it a go to antidepressant in both the adult and child adolescent populations. Its main disadvantage is drug interactions.
Dosing
People often think you can make this medication by simply combining olanzapine and fluoxetine and do not believe you need to use the brand name combination pills. I would use some caution with that approach.
When we look at the doses in the combination pill, they are ones that are difficult to make with the current available dosages. For example, olanzapine comes in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and finally 20 mg doses.
The fixed-combination capsule (olanzapine/fluoxetine) comes in 3/25 mg, 6/25 mg, 12/25 mg, 6/50 mg, 12/50 mg. The studies leading to approval of this medication were conducted using these doses in a fixed combination. It’s not clear that dosing each individually is effective.
How to Start the Medication
For bipolar depression the olanzapine fluoxetine combination should be started at 6/25 mg dosed at bedtime. With a target dose of 6-12/25-50 mg depending on clinical response.
Labs prior to starting the medication:
You should have a baseline weight, waist circumference, blood pressure, fasting glucose and lipid profile prior to starting the medication
Cost
The combination pill is more expensive than either medication alone. According to Good Rx The 6/25 mg capsule is $140-$150 per month. This is compared to olanzapine 5 mg which costs $9.00 and fluoxetine 20 mg which costs $4.00
Side Effects
Olanzapine: Most common is somnolence (dose related), dry mouth (dose related), constipation (anticholinergic), weight gain (up to 40% incidence and 10-30 lbs. of weight gain is common), increased appetite, EPS (dose related).
Fluoxetine: Nausea, diarrhea, nervousness, abnormal dreams, weight loss, sweating, tremor, sexual side effects, rash, and headaches. Rare increased risk for bleeding when combined with NSAIDs and hyponatremia in the elderly due to SIADH.
Mechanism of action
Olanzapine: Dopamine D-2 and 5-HT2A antagonist that is metabolized by CYP1A2 and CYP2D6
Fluoxetine: serotonin reuptake inhibitor that is metabolized by CYP2D6 and is an inhibitor of CYP 2C9/2C19 and 2D6 with a half-life of 4-6 days and 9 days for the metabolite norfluoxetine
The half-life is important here because what happens when someone stops taking the medication? The olanzapine has a much shorter half-life and will be cleared from the body more rapidly leaving the person exposed to fluoxetine without a mood stabilizing element possibly inducing mania or worsening mood symptoms. This is something to be mindful of when using this combination.
Studies Showing Efficacy
The studies that resulted in FDA approval for bipolar depression in 2003 were short, 8 weeks in duration. A total of 833 patients with bipolar I depression received either olanzapine alone, olanzapine fluoxetine combination (OFC), or placebo. Patients on OFC and olanzapine alone showed a significant reduction in depressive symptoms compared to placebo as early as the end of week 1 of treatment. By the end of 4 weeks the OFC participants saw significantly more improvement than placebo or olanzapine alone. The superiority continued over the final 4 weeks of the study. By the end 24.5% of patients on placebo met remission criteria, 32.8% of the olanzapine only group achieved remission, and 48.8% of the OFC group achieved remission.
For the 2009 approval of OFC in treatment resistant depression, it was based off two eight-week double blind placebo-controlled studies using doses of 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine. 40% of patients receiving the OFC responded to therapy Vs 30% and 26% receiving fluoxetine or olanzapine monotherapy. The starting dose was 6/25 mg and could be titrated to 18/75 mg as tolerated.