Does Olanzapine treat Major Depressive Disorder (MDD)?

Olanzapine Monotherapy Does NOT Treat MDD

Olanzapine as monotherapy is not indicated for major depressive disorder—it is only FDA-approved for MDD when used in combination with fluoxetine for treatment-resistant depression. 1

FDA-Approved Indication

• Olanzapine monotherapy has no FDA approval for treating MDD 1
• The only approved use of olanzapine in MDD is in combination with fluoxetine (20-50 mg) at doses of 5-20 mg olanzapine for treatment-resistant depression, defined as failure to respond to 2 separate antidepressant trials of adequate dose and duration 1
• The FDA label explicitly states: "ZYPREXA monotherapy is not indicated for treatment of treatment resistant depression" 1

When Olanzapine IS Appropriate for Depression

Olanzapine plus fluoxetine combination should be considered specifically for treatment-resistant MDD after documented failure of two adequate antidepressant trials. 1

Treatment-Resistant Depression Protocol

• Start with olanzapine 5 mg plus fluoxetine 20 mg once daily in the evening 1
• Dose range: olanzapine 5-20 mg with fluoxetine 20-50 mg, with demonstrated efficacy at olanzapine 6-18 mg and fluoxetine 25-50 mg 1
• For patients with hepatic impairment, elderly patients, or those with predisposition to hypotension, start with olanzapine 2.5-5 mg plus fluoxetine 20 mg 1

Evidence for Combination Therapy

• The olanzapine/fluoxetine combination demonstrates rapid onset with MADRS scores decreasing 7 points at 0.5 weeks, 11 points at 1 week, and 18 points at 8 weeks, maintained through 76 weeks 2
• Response and remission rates in treatment-resistant depression are 53% and 44% respectively, with a 25% relapse rate 2
• Time-to-relapse is significantly longer with continued olanzapine/fluoxetine combination compared to switching to fluoxetine monotherapy after stabilization 3

Critical Safety Considerations

Weight Gain Risk

• 56% of patients develop clinically significant weight gain (≥7% increase) by 76 weeks of treatment 4
• Mean weight gain is 5.6 kg (12.3 lb) at endpoint, plateauing by 52 weeks 4
• Median time to clinically significant weight gain is 16 weeks 4
• Patients with early rapid weight gain (≤6 weeks) are 4.6 times more likely to gain substantial weight (≥15%) long-term 4

High-Risk Populations for Weight Gain

• Low baseline BMI 4
• Female gender 4
• Younger age 4
• Higher fluoxetine doses 4

Metabolic Monitoring Required

• Monitor for treatment-emergent weight gain and fasting metabolic changes, which are significantly greater with olanzapine/fluoxetine combination than fluoxetine alone 3
• Total cholesterol and systolic blood pressure changes correlate positively with weight change 4

First-Line Alternatives for MDD

Before considering olanzapine/fluoxetine, standard second-generation antidepressants should be tried first, as they have equivalent efficacy with better tolerability profiles. 5, 6

• Sertraline, fluoxetine, or citalopram are appropriate first-line options with no significant differences in general efficacy for MDD 6, 7
• If first-line therapy fails after 6-8 weeks, modify treatment by switching to another SSRI or SNRI before considering augmentation strategies 5
• Approximately 25% of patients achieve remission after switching to another SSRI or venlafaxine 6

Duration of Treatment

• Continue olanzapine/fluoxetine combination chronically in treatment-resistant depression, as this is considered a chronic illness requiring chronic treatment 1
• Periodically reexamine the need for continued pharmacotherapy 1
• Balance the metabolic risks against treatment benefits on an ongoing basis 3