Fluoxetine (Prozac)

Fluoxetine — Prozac — was the first SSRI, and most of what was learned about the class was learned from it. It came to market in 1988, and it remains, more than three decades later, one of the most prescribed antidepressants in the world. The reason isn't only history. Fluoxetine has a property no other SSRI has, and that property is its half-life.

The parent drug has a half-life of about four to six days. Its active metabolite — norfluoxetine — has a half-life of seven to fifteen days. That means once a patient is at steady state, missing a dose, missing two doses, sometimes missing a week, produces almost no measurable change in plasma level. The drug forgives non-adherence in a way no other SSRI can.

For a patient with depression, that property cuts both ways. The patient who is inconsistent — busy life, ambivalent about medication, occasionally forgetful — benefits from a drug that keeps working when they don't quite take it every day. The patient who needs to change to a different antidepressant pays a cost: fluoxetine takes weeks to wash out. The patient who is going to start an MAOI needs a five-week washout. The patient who is starting a 2D6-metabolized drug needs to know that fluoxetine's potent 2D6 inhibition will linger for weeks after the last pill.

Fluoxetine's clinical character is the long tail. Slower on, slower off, less rebound.

The indications are broad — broader than most SSRIs because fluoxetine has had decades of post-approval research. It is approved for major depression in adults and children down to age eight. It is approved for OCD in children down to age seven, for bulimia, for panic disorder, and for PMDD under the brand name Sarafem. The breadth reflects the class effect — most SSRIs would work for most of these conditions — but fluoxetine is the one that has the studies and the labels.

Side effects are SSRI-typical. GI in the first weeks, often improving by week three. Sexual dysfunction at the full therapeutic dose. Insomnia or activation for some patients — fluoxetine is among the more activating SSRIs, and dosing in the morning often prevents the sleep problem. Decreased appetite is more common than weight gain with this agent, particularly early.

One distinctive property worth knowing: fluoxetine is a potent inhibitor of CYP2D6. That matters when you're combining it with anything else 2D6-metabolized — many psychotropics, tamoxifen (where 2D6 inhibition reduces efficacy), some opioids. Review the medication list at every visit. The interactions persist for weeks after fluoxetine is stopped.

A weekly dosing formulation exists — Prozac Weekly. For the right patient, it removes the daily decision entirely. For most patients, daily dosing is fine, and the long half-life does its quiet work in the background.