Fluoxetine vs Sertraline
## Overview
Fluoxetine and sertraline are among the most prescribed SSRIs globally. Both inhibit the serotonin reuptake transporter (SERT) to increase synaptic serotonin, but they differ importantly in half-life, drug interaction profile, and approved indications.
## Mechanism of Action
Both selectively block SERT, preventing reuptake of 5-HT from the synaptic cleft. This leads to enhanced serotonergic neurotransmission over weeks, correlating with clinical antidepressant and anxiolytic effects. Neither has significant affinity for adrenergic, histaminergic, or muscarinic receptors at therapeutic doses.
## Pharmacokinetics
Fluoxetine is unique among SSRIs for its extraordinarily long half-life: the parent compound has a half-life of 1–4 days, and its active metabolite norfluoxetine has a half-life of 4–16 days, resulting in effective elimination taking 5–6 weeks. This makes fluoxetine the only SSRI where discontinuation syndrome is clinically rare. Sertraline has a half-life of 26 hours (active metabolite desmethylsertraline: ~66 h), with full washout in 1–2 weeks.
## Drug Interactions
Fluoxetine is a potent inhibitor of CYP2D6 and a moderate inhibitor of CYP2C9/2C19. This creates significant interactions with antidepressants (TCAs, MAOIs), antipsychotics (haloperidol), and antiarrhythmics metabolized by CYP2D6. Sertraline inhibits CYP2D6 weakly at therapeutic doses, making it the preferred SSRI in patients on multiple medications.
## Pharmacodynamics
Both produce equivalent antidepressant efficacy in meta-analyses of head-to-head trials. Sertraline has FDA indications for MDD, OCD, panic disorder, PTSD, PMDD, and social anxiety disorder — arguably the broadest SSRI indication profile. Fluoxetine also has FDA approval for bulimia nervosa and bipolar depression (with olanzapine).
## Clinical Evidence
The STAR*D trial (largest real-world antidepressant study) treated patients with citalopram first-line; sertraline and other SSRIs as second-line alternatives. Cipriani et al. 2018 network meta-analysis found sertraline had the best balance of efficacy and acceptability among antidepressants.
## Key Takeaways
- Fluoxetine: longest half-life (norfluoxetine ~14 days), safest if doses missed, least discontinuation syndrome
- Sertraline: broad indications, fewest drug interactions among SSRIs, preferred for polypharmacy
- Both equivalent in antidepressant efficacy; sertraline often first-line per guidelines
निष्कर्ष
Sertraline is generally preferred as first-line for MDD and most anxiety disorders due to its broad indications and minimal drug interaction profile. Fluoxetine is preferred when patient adherence is a concern (long half-life prevents missed-dose effects) or for bulimia nervosa.