Fluoxetine

Like other SSRIs, fluoxetine increases serotonin activity by blocking its reuptake into nerve cells [2]. For depression, adults usually start at 20 mg each morning; the label notes that 20 mg is enough for most people and that the maximum is 80 mg a day [1].

Fluoxetine is a 50/50 mixture of two mirror-image forms, R- and S-fluoxetine, which block serotonin uptake about equally in animal studies. The liver removes a methyl group to make norfluoxetine, its only identified active metabolite. S-norfluoxetine is about as potent as fluoxetine, while R-norfluoxetine is much weaker [1]. CPIC describes CYP2D6 as the enzyme that makes S-norfluoxetine, with CYP2D6 and CYP2C9 both making R-norfluoxetine [2].

What sets fluoxetine apart is how long it lasts. Its half-life is 1 to 3 days after a single dose and 4 to 6 days with regular use, and norfluoxetine's is 4 to 16 days. Levels keep rising for weeks: steady state is reached after about 4 to 5 weeks, and active drug remains in the body for weeks after the last dose. Liver disease lengthens these times further; in people with cirrhosis the half-life of fluoxetine averaged 7.6 days [1].

CYP2D6 genotype does change how fluoxetine is processed, but not in a way that points to a dose. The label describes a study in CYP2D6 poor metabolizers: they cleared S-fluoxetine more slowly and had more of it and less S-norfluoxetine, while R-fluoxetine was handled normally. The combined level of the four active forms was not significantly higher than in normal metabolizers, so the net effect was essentially the same. Other, non-CYP2D6 pathways also clear fluoxetine [1].

CPIC reached the same conclusion in 2023. Ultrarapid and poor metabolizers have clearly different ratios of fluoxetine to norfluoxetine, but the total may not differ much between groups, and there are few data on whether the shift changes outcomes or safety. CPIC therefore gives no genotype-based recommendation and rates the fluoxetine and CYP2D6 pair level C [2]. Level C means there are published studies, some with a mechanistic rationale, but no prescribing action is recommended, for reasons such as genetics making no convincing difference to dosing or the evidence being weak [4].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) makes CYP2D6-based recommendations for paroxetine, fluvoxamine, venlafaxine and vortioxetine, and CYP2C19-based recommendations for citalopram, escitalopram and sertraline, but none for fluoxetine [2].

The FDA label gives no genotype-based dose either. FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling lists CYP2D6 for fluoxetine because the label discusses it in its warnings, drug interactions and pharmacology sections [5], and fluoxetine does not appear in FDA's Table of Pharmacogenetic Associations [6]. The label's CYP2D6 content is about interactions: fluoxetine is primarily metabolized by CYP2D6, so other CYP2D6 inhibitors can raise its levels, and fluoxetine in turn inhibits CYP2D6 [1].

FDA lists fluoxetine as a strong inhibitor of both CYP2D6 and CYP2C19 [3], and CPIC notes that fluoxetine and paroxetine are both potent CYP2D6 inhibitors, through different mechanisms [2]. The label puts the effect plainly: fluoxetine "may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer" [1]. When a drug changes metabolism like this it is called phenoconversion, and it is common: in a study of 900 adults taking venlafaxine for depression, 4% were CYP2D6 poor metabolizers by genotype but 27% had drug-level ratios typical of poor metabolizers [7].

Examples from the labels

The fluoxetine label reports that previously stable levels of imipramine and desipramine rose more than 2- to 10-fold when fluoxetine was added, an effect that can last 3 weeks or more after fluoxetine is stopped. It advises starting narrow-margin CYP2D6 drugs, such as tricyclics, flecainide and propafenone, at the low end of the dose range in anyone taking fluoxetine or who took it in the previous 5 weeks. It contraindicates pimozide and thioridazine, whose levels fluoxetine can raise and which can prolong the QT interval of the heartbeat, and says thioridazine should not be given within 5 weeks of stopping fluoxetine. It also reports higher levels of haloperidol, clozapine, phenytoin and carbamazepine with fluoxetine [1]. The vortioxetine label tells prescribers to halve the vortioxetine dose when a strong CYP2D6 inhibitor such as fluoxetine is added [8].

What this means for your report

The CYP2D6 and CYP2C19 results in a Gene2Rx report describe your genes. While you take fluoxetine, and for weeks after stopping, the advice in the report for CYP2D6 medicines such as amitriptyline or nortriptyline, and for medicines CPIC describes as extensively metabolized by CYP2C19, such as citalopram, escitalopram and sertraline, may not match how your enzymes are working [2]. CPIC notes that there is no agreed method for adjusting a predicted phenotype for an inhibitor [2]. Bring the report and your full medicine list to your prescriber or pharmacist. Do not start, stop or change fluoxetine or any other medicine because of a genetic result without talking to your prescriber.

A genetic test cannot show the effect of fluoxetine on your enzymes; only the medicine list can. Consumer arrays from 23andMe, AncestryDNA and MyHeritage are not clinical-grade tests, and their raw data is labeled as not for medical use; a normal result means none of the assessed variants was found among the positions your data covers.

Why isn't fluoxetine in my report?

Because no guideline gives a genotype-based recommendation for it; see Why there is no genotype-based dose.

How long does fluoxetine keep affecting other medicines after I stop?

Weeks. The label cites 5 weeks for several interactions and reports tricyclic levels staying raised for 3 weeks or more [1].

1. Prozac (fluoxetine) capsules (Dista Products Company): prescribing information. DailyMed, US National Library of Medicine. Indications, dosing, CYP2D6 inhibition, contraindications and pharmacokinetics.
2. Bousman CA et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther (2023). CPIC recommendations and the evidence behind them.
3. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP2C19 inhibitors and inducers.
4. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
5. US Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. Which label sections mention CYP2D6 for fluoxetine.
6. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
7. Preskorn SH et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry (2013). How often measured CYP2D6 activity differs from genotype in practice.
8. Trintellix (vortioxetine) tablets (Takeda): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, the CYP2D6 poor metabolizer maximum dose and interactions.