SSRI (Selective Serotonin Reuptake Inhibitors): Important Facts to Know

SSRI (Selective Serotonin Reuptake Inhibitors): Important Facts to Know

(1) Do SSRIs have Active Metabolites?

  • Fluoxetine (Norfluoxetine with half life of 7–14 days).

Note: R-norfluoxetine is not active in terms of serotonin inhibition, while S-norfluoxetine is a more potent serotonin reuptake inhibitor than the parent drug. (Source: Neuropharmacology. 1992;31(10):997–1000)

  • Sertraline (N-desmethylsertraline with half life of 2–3 days)

Note: N-desmethylsertraline has limited activity and is less potent than sertraline as a serotonin uptake inhibitor.

  • Escitalopram (S-demethylcitalopram):

Note: this is present at approximately 1/3rd the level of escitalopram. however this metabolite is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram.

  • Citalopram (Demethylcitalopram):

Note: Studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram.

  • Fluvoxamine and Paroxetine: no metabolites.


(1.a) What is the clinical implication of SSRIs with long-acting metabolites?

  • Less problem if patient misses their dose and less risk of discontinuation syndrome.
  • Problematic if toxicity develops or drug-drug interactions develops- symptoms will persist for long duration after drug discontinuation.


Source: D.A. Ciraulo and R.I. Shader (eds.), Pharmacotherapy of Depression

(2) Do SSRIs have Long Acting Formulations?

  • Fluoxetine:
    1. PROZAC Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg of fluoxetine.


  1. Clinical Fact: Separate the first 90 mg weekly dose and the last 20 mg once-daily dose by 1 week.


  • Paroxetine CR:
  1. Dosage: 25 mg to 62.5 mg once a day.
  2. Clinical Fact: Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be swallowed whole. 


  • Fluvoxamine CR:
  1. Recommended starting dose is 100 mg at bedtime, with weekly increases of 50 mg as tolerated to maximum effect, not to exceed 300 mg/day.

(3) Which Cytochrome P450 is inhibited by SSRIs (Important for Drug Interactions)?

  • Fluoxetine: Strong inhibition for 2D6 and Moderate inhibition for 2C19.
  • Sertraline: Moderate inhibition for 2C19.
  • Paroxetine: Strong inhibition for 2D6.
  • Fluvoxamine: Strong inhibition for 2C19 and 1A2.
  • Citalopram: None
  • Escitalopram: None

Please do post your questions or comments below. 

Dr. Harvinder Singh, M.D. (Admin)

Enroll in our online course to have access to all important clinically relevant psychiatry topics in one place.

Related Articles