Fluoxetine vs Escitalopram

## Overview

Escitalopram is the S-enantiomer of citalopram and represents one of the most selective SERT inhibitors available. It is generally considered to have a superior efficacy-tolerability balance among SSRIs, as established by the Cipriani 2018 network meta-analysis.

## Mechanism of Action

Both block SERT. Escitalopram's SERT affinity is approximately twice that of racemic citalopram per unit dose because the inactive R-enantiomer of citalopram is absent. Escitalopram also allosterically modulates SERT via a secondary binding site, potentially enhancing its antidepressant effect.

## Pharmacokinetics

Escitalopram: bioavailability ~80%, half-life 27–32 h, primarily metabolized by CYP2C19 (and partially CYP2D6, 3A4). Minimal CYP inhibition. Fluoxetine: bioavailability ~72%, half-life 1–4 days (norfluoxetine 4–16 days), potent CYP2D6 inhibitor. Escitalopram is subject to the same 20 mg/day dose limitation and QTc monitoring requirement as citalopram (from same R-enantiomer reasoning is not applicable here, but the class effect is considered relevant).

## Clinical Evidence

Cipriani et al. 2018 (Lancet) ranked escitalopram highest for combined efficacy and acceptability among 21 antidepressants. Multiple head-to-head trials have shown escitalopram non-inferior or superior to other SSRIs with fewer side effects. Fluoxetine shows equivalent efficacy.

## Key Takeaways

- Escitalopram ranked best for efficacy + acceptability in major network meta-analysis
- Both have minimal non-SERT activity (escitalopram more selective)
- Fluoxetine's ultra-long half-life protects against missed doses; escitalopram has mild discontinuation syndrome
- Escitalopram mild QTc risk; fluoxetine none