Fluoxetine

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Fluoxetine

Prozac

Fluoxetine, marketed as Prozac, was the first selective serotonin reuptake inhibitor (SSRIs) brought to market and the medicine that opened the SSRI era. It was discovered at Eli Lilly's laboratories in Indianapolis on 24 July 1972 by a team that included the chemists Bryan Molloy and Klaus Schmiegel and the pharmacologist David Wong,^[4] approved by the FDA in December 1987, and launched in the United States as Prozac in January 1988. It is notable for the extremely long half-life of its active metabolite norfluoxetine, which gives the medicine an unusually mild discontinuation profile and makes it useful as a bridge in tapering patients off shorter-acting serotonergic medicines.

History

The compound that became fluoxetine emerged from an Eli Lilly program that began in the late 1960s under Molloy and Schmiegel, who synthesized a series of aryloxyphenylpropylamines starting from the antihistamine diphenhydramine as a structural lead. Wong, who had followed the European literature implicating serotonin in mood regulation, proposed screening the new compounds specifically for serotonin uptake inhibition. On 24 July 1972 the team identified the compound then designated Lilly 110140 as a potent and selective inhibitor of serotonin uptake in rat brain synaptosomes. The finding was published in 1974 as the first description of what is now known as a selective serotonin reuptake inhibitor.^[4]

Lilly renamed the compound fluoxetine in 1975, filed an investigational application with the FDA, and pursued clinical development through the late 1970s and early 1980s. The FDA approved fluoxetine for major depressive disorder in December 1987, and Lilly launched it as Prozac in January 1988. The marketing name itself was a departure: medicines had historically been named to reflect chemical structure, and Prozac was among the first to be commissioned from an outside naming firm. Within five years of launch Prozac was one of the most prescribed medicines in the United States, and Peter Kramer's 1993 book Listening to Prozac made the SSRI era a subject of popular discussion. Lilly's US patent expired in August 2001, after which generic fluoxetine became broadly available.

Fluoxetine is a prescription-only medicine in the United States. It remains on the WHO Model List of Essential Medicines and is one of the most widely prescribed serotonergic medicines worldwide. The serotonergic framing under which the medicine was discovered and marketed has not aged uniformly well; the TrkB/BDNF account of its mechanism, developed primarily in the 2000s, is the principal contemporary alternative and is reflected in the mechanism field above.

Experience

👥 No personal reports yet

⚕ 1 provider report · avg efficacy 40.0/100 · avg side-effect burden 40.0/100 · 150 patients managed total

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Problems

Depressive disorders1.0n=1

Anxiety disorders broadly4.0n=2

Including generalized anxiety, panic, and social anxiety.

Panic disorder1.3n=2

Obsessive-compulsive disorder3.0n=1

PTSD0.1n=1

Potentially.

Premature ejaculation0.1n=2

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Titration strategies

Standard adult or child+1

Start no higher than 10 mg for the first dose. May increase by 10 mg every 2–12 weeks, or remain at 10 mg if the response is adequate, up to a typical starting maximum of 40 mg. Absolute max: 80 mg.

OCD+1

Start at 10 mg daily; increase by 10–20 mg every 2–6 weeks, up to 80 mg. OCD typically requires elevated doses (60–80 mg).

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Effects

Anxiolysis👤 no reports yet⚕️ ~33% +67.0 (n=1)
Classically starting at 3–4 weeks and improving for another 8–12.
Delayed orgasm/ejaculation👤 0% — (n=3)⚕️ ~80% +38.0 (n=1)
Mood enhancement👤 no reports yet⚕️ ~5% +67.0 (n=1)
Nausea👤 no reports yet⚕️ ~5% -33.0 (n=1)
Common, often improves over 1–2 weeks.
Decreased libido👤 no reports yet⚕️ ~33% -100.0 (n=1)
Temporary erectile dysfunction👤 no reports yet⚕️ ~20% -67.0 (n=1)
Persistent Sexual Dysfunction👤 no reports yet⚕️ ~0% -100.0 (n=1)
Historically associated with SSRIs.

Anorgasmia👤 no reports yet⚕️ ~5% -100.0 (n=1)

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Pharmacokinetics

Absorption

70–90%^[5] oral bioavailability.

Distribution

Fluoxetine has plasma protein binding of approximately 94.5%, bound to albumin and alpha-1 glycoprotein. Fluoxetine readily crosses the blood–brain barrier, with a brain-to-plasma ratio of 2.6:1 in humans. The volume of distribution (Vd) of fluoxetine and its metabolite ranges between 20 to 42 L/kg. Some studies report that fluoxetine has the maximum volume of distribution (Vd) of any SSRI (between 14 and 100 L/kg).^[5]

Metabolism

Fluoxetine's active metabolite is norfluoxetine, produced when the cytochrome P450 enzyme (CYP2D6) acts on it. Prescribers must remember that fluoxetine has several med-med interactions due to its metabolism through the CYP2D6 isoenzyme. Additionally, norfluoxetine can have an inhibitory effect on CYP3A4. Fluoxetine has an elimination half-life of 1 to 3 days after a single dose and 4 to 6 days with chronic dosing, and its active metabolite norfluoxetine has a half-life of 4 to 16 days.^[2] Approximately 7% of individuals definitively exhibit poor metabolism of fluoxetine due to reduced activity of CYP2D6.^[5]

Interactions

Pharmacogenomic + mechanism interactions5 edges

Pharmacokinetic mechanismSubstrate / metabolism relationships from primary literature

Enzyme:CYP2D6 inhibitor strong Primary 90 / 100

FDA Drug Interactions Table: strong index inhibitor of CYP2D6.