Paroxetine vs Escitalopram

## Overview

Paroxetine and escitalopram sit at opposite ends of the SSRI tolerability spectrum. Escitalopram is ranked among the best-tolerated antidepressants; paroxetine carries the most complex side-effect profile in the SSRI class.

## Mechanism of Action

Escitalopram selectively inhibits SERT via primary and allosteric binding sites. Paroxetine inhibits SERT but also has significant muscarinic antagonism, NET inhibition, and potent CYP2D6 inhibition.

## Pharmacokinetics

Escitalopram: half-life 27–32 h, CYP2C19 primary metabolism, minimal CYP inhibition, linear PK, dose-cap 20 mg. Paroxetine: half-life ~21 h, CYP2D6 metabolism with auto-inhibition, nonlinear PK.

## Efficacy and Tolerability

Both are effective antidepressants. Escitalopram is ranked #1 in the Cipriani 2018 meta-analysis combining efficacy and acceptability. Paroxetine is associated with the highest rates of dropout due to adverse effects among SSRIs, particularly sexual dysfunction, weight gain, and discontinuation syndrome on cessation.

## Clinical Considerations

Escitalopram is the preferred choice in elderly patients (no anticholinergic burden), patients with cardiovascular disease (careful with QTc at 20 mg), and patients with multiple medications (no CYP2D6 interaction). Paroxetine should be avoided in pregnancy and generally in elderly patients.

## Key Takeaways

- Escitalopram: best-tolerated, highest-ranked in meta-analysis, minimal interactions
- Paroxetine: anticholinergic side effects, severe discontinuation syndrome, teratogenic
- Neither is preferred in pregnancy; if needed, sertraline is safest overall