RESEARCH MONOGRAPH · KDC-MN-201
Fluoxetine
Fluoxetine is the original Prozac, the drug that made SSRIs household vocabulary in the 1990s. It works by blocking the pump that pulls serotonin back into the nerve cell that released it, leaving more of the signal sitting in the gap between brain cells. Eli Lilly synthesized it in 1972; the FDA approved it in 1987. It is unusually long-lived in the body (the active leftover sticks around for over a week), which makes it forgiving of missed doses but also slow to clear if a doctor needs to switch medications. It also blocks the liver enzyme CYP2D6, which matters for drug interactions. Decades of trials in depression, OCD, bulimia, and anxiety have made it one of the most studied psychiatric drugs ever. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Selective serotonin reuptake inhibitor
The first widely prescribed SSRI; a long-acting serotonergic antidepressant and a foundational reference compound for serotonin pharmacology.
Abstract
Fluoxetine ((R/S)-N-methyl-3-phenyl-3-[(alpha,alpha,alpha-trifluoro-p-tolyl)oxy]propylamine; CAS 54910-89-3; molecular formula C17H18F3NO; molecular weight 309.33) is a phenoxyphenylpropylamine SSRI synthesized at Eli Lilly in 1972 and approved by the FDA in 1987 as the first commercial SSRI under the trade name Prozac. The compound exhibits high affinity for the serotonin transporter (SERT, Ki approximately 1 nM) with comparatively weak activity at the norepinephrine transporter (Ki approximately 240 nM) and the dopamine transporter. Notable for an extraordinarily long elimination half-life (1 to 3 days for the parent compound, 7 to 15 days for the active norfluoxetine metabolite) which renders steady-state achievement slow but mitigates discontinuation syndrome. Pharmacologically distinguished from later SSRIs by 5-HT2C antagonism that contributes to noradrenergic and dopaminergic disinhibition in the prefrontal cortex, partially explaining the activating subjective profile. Hepatic metabolism is via CYP2D6 (primary) and CYP3A4 (secondary); the compound is itself a potent CYP2D6 inhibitor, producing clinically significant interactions with TCAs, antipsychotics, and beta-blockers. Used widely as a reference SSRI in serotonergic mechanism studies, animal models of depression, and as a positive control in receptor binding and reuptake assays.
Mechanism of action
High-affinity SERT inhibition; secondary 5-HT2C antagonism; weak NRI activity. Active metabolite norfluoxetine drives steady-state effect. Potent CYP2D6 inhibitor.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Wong DT, et al. A selective inhibitor of serotonin uptake: Lilly 110140. Life Sci 1974.
- Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 2000.
- Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. J Affect Disord 1998.
- Wernicke JF. The side effect profile and safety of fluoxetine. J Clin Psychiatry 1985.
Read the full monograph
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The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.