Fluoxetine vs Citalopram

## Overview

Fluoxetine and citalopram are both widely used SSRIs. Citalopram is considered the most selective SSRI with minimal off-target activity, while fluoxetine has a more complex pharmacology including potent CYP2D6 inhibition.

## Mechanism of Action

Both inhibit SERT. Citalopram contains a racemic mixture of R- and S-enantiomers; only the S-enantiomer (escitalopram) contributes to SERT inhibition. The R-enantiomer actually slightly impedes S-enantiomer binding, making citalopram slightly less potent than escitalopram at equivalent doses.

## Pharmacokinetics

Citalopram: bioavailability ~80%, half-life 35 hours, minimal CYP inhibition (CYP2D6 very weakly). Fluoxetine: bioavailability ~72%, half-life 1–4 days (norfluoxetine 4–16 days), potent CYP2D6 inhibitor. Citalopram is metabolized by CYP2C19, 3A4, and 2D6, but does not meaningfully inhibit these enzymes.

## QTc Considerations

Citalopram (and escitalopram) prolong the QTc interval in a dose-dependent manner. The FDA issued a safety communication in 2011 limiting citalopram to 40 mg/day (20 mg in elderly, hepatic impairment, CYP2C19 poor metabolizers, or when combined with CYP2C19 inhibitors such as omeprazole). This QTc liability is the most important safety differentiator. Fluoxetine has minimal QTc effects.

## Clinical Efficacy

Both are effective antidepressants with equivalent efficacy in meta-analyses. Citalopram's clean pharmacology and minimal drug interactions make it widely used in primary care and in patients with cardiovascular disease (though QTc monitoring required at higher doses).

## Key Takeaways

- Citalopram: high selectivity for SERT, minimal drug interactions, but QTc risk limits dose
- Fluoxetine: longer half-life, potent CYP2D6 inhibitor, no QTc concern
- Neither preferred in pregnancy over sertraline