Are Zoloft (sertraline) and Prozac (fluoxetine) metabolized the same way?

Are Zoloft and Prozac Metabolized the Same Way?

No, Zoloft (sertraline) and Prozac (fluoxetine) are metabolized through different pathways and have substantially different metabolic profiles, with fluoxetine being primarily metabolized by CYP2D6 to form an active metabolite (norfluoxetine), while sertraline has less reliance on CYP450 enzymes and lower potential for clinically significant drug interactions. 1, 2

Primary Metabolic Differences

Fluoxetine (Prozac) Metabolism

• Fluoxetine is extensively metabolized in the liver primarily through CYP2D6 to form its active metabolite norfluoxetine, which is also a potent serotonin reuptake inhibitor 2, 3
• The elimination half-life of fluoxetine is 1-3 days after acute administration and 4-6 days after chronic administration, while norfluoxetine has an even longer half-life of 4-16 days 3
• Approximately 7% of the population are CYP2D6 poor metabolizers who achieve 3.9-fold higher drug levels at 20 mg doses, and up to 11.5-fold higher levels at 60 mg doses 2
• Fluoxetine itself is a potent inhibitor of CYP2D6, converting approximately 43% of extensive metabolizers to poor metabolizers at 20 mg/day 1, 2

Sertraline (Zoloft) Metabolism

• Sertraline has minimal effects on CYP450 isoenzymes compared to other SSRIs, resulting in a lower propensity for drug interactions 1
• Sertraline does not produce clinically important inhibition of CYP2D6 at lower doses, though it has the potential for some 2D6 inhibition at higher doses 4
• The pharmacokinetics of sertraline are not significantly affected by age or renal impairment 5

Clinical Implications of These Metabolic Differences

Drug Interaction Risk

• For patients taking multiple medications, sertraline is preferred over fluoxetine due to its lower potential for clinically significant drug interactions 1
• Fluoxetine's potent CYP2D6 inhibition can increase plasma concentrations of co-administered drugs metabolized by this enzyme, particularly those with narrow therapeutic indices like tricyclic antidepressants and Type 1C antiarrhythmics 4, 3
• The FDA has issued safety labeling changes for fluoxetine regarding increased risk in CYP2D6 poor metabolizers, particularly related to QT prolongation 2

Duration of Effect After Discontinuation

• A critical pitfall with fluoxetine is that active drug persists in the body for weeks after discontinuation due to the long half-lives of both fluoxetine and norfluoxetine 3
• This requires a 5-week washout period before introducing MAOIs or other serotonergic drugs to avoid serotonin syndrome 5
• Sertraline, with its shorter half-life (approximately 1 day), clears much more rapidly 5

Genetic Considerations

• In patients who are known CYP2D6 poor metabolizers, sertraline is recommended over fluoxetine to minimize the risk of adverse effects 1
• Poor metabolizers on fluoxetine are at higher risk of toxicity due to elevated blood levels, particularly at higher doses used for conditions like OCD 2

Monitoring Considerations

• Therapeutic drug monitoring may be particularly valuable with fluoxetine in patients with suspected altered metabolism or when drug interactions are a concern 2
• Plasma concentrations may not necessarily be predictive of clinical response, but monitoring can help avoid toxicity 3

Common Pitfalls to Avoid

• Do not assume equivalent drug interaction profiles between these medications when prescribing concomitant medications metabolized by CYP2D6 1, 6
• Do not use standard washout periods when switching from fluoxetine to other antidepressants or MAOIs; fluoxetine requires 5 weeks versus the typical 1-2 weeks for sertraline 5
• Do not overlook genetic testing for CYP2D6 status when considering fluoxetine, especially at higher doses or in patients with multiple medications 2
• Despite metabolic differences, both medications can still contribute to serotonin syndrome when combined with other serotonergic drugs 1