Fluoxetine vs Paroxetine
## Overview
Fluoxetine and paroxetine are both potent CYP2D6 inhibitors among the SSRIs, but they differ dramatically in half-life, tolerability profile, and risks in specific populations. Paroxetine is associated with the most pronounced discontinuation syndrome of any SSRI.
## Mechanism of Action
Both block SERT. Paroxetine additionally has meaningful anticholinergic activity (muscarinic receptor antagonism), which distinguishes it from most other SSRIs and contributes to its side effect profile: dry mouth, constipation, urinary retention, and cognitive blunting.
## Pharmacokinetics
Fluoxetine's half-life (parent + norfluoxetine) extends to 4–16 days. Paroxetine's half-life is 21 hours, with no active metabolites. Paroxetine undergoes auto-inhibition of its own CYP2D6 metabolism (saturable pharmacokinetics), meaning small dose increases lead to disproportionately large plasma level increases. Abrupt discontinuation of paroxetine causes severe discontinuation syndrome (FINISH mnemonic: Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal).
## Pharmacodynamics
Both are equipotent antidepressants. Paroxetine has FDA approval for MDD, OCD, panic disorder, social anxiety disorder, GAD, PTSD, and premenstrual dysphoric disorder. Fluoxetine is approved for MDD, OCD, bulimia nervosa, panic disorder, and bipolar depression (with olanzapine).
## Safety: Pregnancy
Paroxetine is the only SSRI classified as Pregnancy Category D (now PLLR-based narrative) due to evidence linking first-trimester exposure to cardiac septal defects (especially ventricular septal defects) and neonatal adaptation syndrome. Fluoxetine is generally preferred over paroxetine in pregnant patients when an SSRI is necessary.
## Key Takeaways
- Both potent CYP2D6 inhibitors; significant drug interactions with TCA, antipsychotics
- Paroxetine: worst discontinuation syndrome, anticholinergic effects, teratogenic risk
- Fluoxetine: long half-life protects against discontinuation syndrome, preferred in pregnancy
บทสรุป
Fluoxetine is preferred over paroxetine in most cases due to paroxetine's teratogenicity, severe discontinuation syndrome, and anticholinergic burden. Paroxetine may be selected for patients with significant anxiety components when other SSRIs have failed, and when pregnancy is not a consideration.