When should Prozac (fluoxetine) be started versus Zoloft (sertraline) for major depressive disorder?

When to Start Prozac vs Zoloft for Major Depressive Disorder

For treatment-naïve patients with major depressive disorder, choose between Prozac (fluoxetine) and Zoloft (sertraline) based on adverse effect profiles, cost, and patient-specific factors rather than efficacy, as both medications are equally effective. 1

Efficacy: No Meaningful Difference

Both fluoxetine and sertraline demonstrate equivalent antidepressant efficacy for major depressive disorder. 1

• Multiple guidelines from the American College of Physicians confirm that existing evidence does not justify choosing any second-generation antidepressant over another based on greater efficacy. 1
• Head-to-head trials show similar response and remission rates between sertraline and fluoxetine. 2, 3
• Both medications are FDA-approved for major depressive disorder in adults and pediatric populations. 4

Decision Algorithm: Choose Based on These Factors

1. Patient Age

For older adults (>60 years), prefer sertraline over fluoxetine. 1

• Sertraline is specifically recommended for older patients with depression. 1
• Fluoxetine should generally be avoided in older adults due to higher rates of adverse effects. 1
• The American Family Physician guideline explicitly lists sertraline as preferred and fluoxetine as generally avoided in this population. 1

2. Specific Symptom Profiles

For depression with psychomotor agitation, prefer sertraline. 1

• Sertraline demonstrates better efficacy for managing psychomotor agitation compared to fluoxetine. 1
• Sertraline shows superior performance on agitation-related items in head-to-head trials. 2, 5

For depression with melancholia, prefer sertraline. 1

• Limited evidence suggests sertraline has greater response rates than fluoxetine for melancholic features. 1

For depression with insomnia, prefer sertraline. 2

• Sertraline shows significantly superior performance on sleep-related measures, including insomnia onset. 2

For depression with prominent anxiety, consider either medication equally. 1

• Both medications show similar efficacy for treating accompanying anxiety symptoms. 1

3. Adverse Effect Considerations

Sexual dysfunction: Both medications carry similar risk. 1

• Paroxetine has higher rates of sexual dysfunction than both fluoxetine and sertraline, but fluoxetine and sertraline are comparable. 1

Discontinuation syndrome: Prefer fluoxetine if adherence is uncertain. 1

• Sertraline is associated with discontinuation syndrome (along with paroxetine and fluvoxamine). 1
• Fluoxetine's longer half-life (2-7 days for fluoxetine, 4-15 days for norfluoxetine) provides protection against withdrawal symptoms from missed doses. 6

Drug interactions: Prefer sertraline for fewer interactions. 1

• Fluoxetine and sertraline both interact with drugs metabolized by CYP2D6. 1
• However, fluoxetine's long half-life requires extended washout periods (up to 5 weeks) before switching to TCAs or MAOIs. 6

4. Breastfeeding Mothers

For breastfeeding mothers, prefer sertraline over fluoxetine. 1

• Sertraline transfers in lower concentrations and produces undetectable infant plasma levels. 1
• Fluoxetine produces the highest infant plasma concentrations among SSRIs. 1
• Adverse effects in infants are documented more often with fluoxetine exposure than other SSRIs. 1

5. Dosing Considerations

Sertraline may provide faster response at adequate doses. 3

• Sertraline 100 mg/day shows earlier treatment response (by week 4) compared to sertraline 50 mg/day. 3
• Starting sertraline at 50 mg with rapid titration to 100 mg may optimize early response. 3
• Fluoxetine 20 mg/day shows intermediate response timing. 3

Implementation Strategy

Start with sertraline 50 mg daily, increase to 100 mg within 1-2 weeks if tolerated. 3

• For fluoxetine, start 20 mg daily; increase intervals can be 3-4 weeks due to longer half-life. 1
• Assess response at 6-8 weeks; modify treatment if inadequate response. 1
• Monitor closely within 1-2 weeks of initiation for suicidality, agitation, and adverse effects. 1

Continue treatment for 4-9 months after satisfactory response for first episode. 1

• For patients with ≥2 prior episodes, consider longer duration (years to lifelong). 1

Common Pitfalls to Avoid

• Do not assume one SSRI is more effective than another—efficacy differences are not clinically meaningful. 1
• Do not use inadequate doses—sertraline 50 mg may be subtherapeutic; titrate to 100 mg or higher. 3
• Do not forget to monitor early—suicidality risk is highest in first 1-2 months. 1
• Do not switch immediately from fluoxetine to MAOIs or TCAs—requires 5-week washout period. 6