Fluoxetine

Mechanism of Action

• Blocking the serotonin transporter (SERT) on the presynaptic neuron, inhibiting reuptake of serotonin (5-HT) from the synaptic cleft. This increases synaptic serotonin availability, which over 2-4 weeks leads to downstream adaptive changes (5-HT receptor desensitization) that underlie its antidepressant/anxiolytic effect - Katzung's Basic and Clinical Pharmacology, p. 843-844
• Fluoxetine has minimal direct effect on norepinephrine or dopamine reuptake, distinguishing it from tricyclics and SNRIs
• It is metabolized in the liver (partly via CYP2D6, which it also potently inhibits) to norfluoxetine, an active metabolite that is itself a potent SSRI
• Unusually long pharmacokinetics: parent drug half-life 1-3 days (acute) to 4-6 days (chronic), and norfluoxetine half-life of 4-16 days. This means steady state takes weeks to reach and washout after stopping takes weeks - clinically relevant when switching to an MAOI or other serotonergic drug - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. Pharmacologic Actions; Stahl's Essential Psychopharmacology

Side Effects

• GI: nausea, diarrhea, dry mouth, decreased appetite
• CNS: insomnia, agitation, anxiety, headache, tremor
• Sexual dysfunction (decreased libido, delayed orgasm/anorgasmia) - can persist after stopping (post-SSRI sexual dysfunction)

• Emotional blunting - apathy, inability to cry, reduced emotional intensity; a frequent cause of discontinuation
• Increased yawning (hypothalamic effect, not fatigue-related)
• Seizures (0.1-0.2%, more common at high doses e.g. ≥100 mg/day) - similar to other antidepressants/placebo
• Extrapyramidal symptoms: akathisia, dystonia, tremor, rigidity (rare); can worsen Parkinson's disease
• Hematologic: impaired platelet aggregation → easy bruising, GI bleeding risk (higher with concurrent NSAIDs/anticoagulants)
• Endocrine: hyperprolactinemia, galactorrhea, gynecomastia
• Hyponatremia/SIADH, especially in elderly or those on diuretics
• Glucose disturbances (acute hypoglycemic tendency; possible long-term hyperglycemia association)
• Rash (~4% of patients; rare severe/systemic allergic reactions)
• Serotonin syndrome - with other serotonergic agents (MAOIs, tryptophan, lithium, tramadol, triptans, other SSRIs)
• Weight/appetite changes, activation/agitation (can unmask mania in bipolar patients)
• Suicidality warning in children/adolescents and young adults (FDA black-box warning), though the TADS trial showed fluoxetine + CBT improved safety/efficacy vs monotherapy - The Maudsley Prescribing Guidelines, 15th ed.
• Discontinuation/withdrawal symptoms occur but are delayed and attenuated due to fluoxetine's long half-life

Contraindications / Cautions

• Concurrent or recent MAOI use - absolute contraindication; risk of serotonin syndrome. Because of fluoxetine's long washout, guidelines require waiting at least 5 weeks after stopping fluoxetine before starting an MAOI (and 2 weeks in the other direction) - Stahl's Essential Psychopharmacology
• Known hypersensitivity to fluoxetine
• Coadministration with pimozide or thioridazine - fluoxetine's CYP2D6 inhibition raises levels of these drugs, increasing QT-prolongation/arrhythmia risk
• Hepatic impairment - reduces clearance significantly (half-life prolonged to ~7.6 days in cirrhosis), requiring dose reduction
• Bleeding disorders / concurrent anticoagulant, antiplatelet, or NSAID use - caution due to platelet effects
• Bipolar disorder without mood stabilizer - risk of triggering mania/mixed states
• History of seizures - caution, dose-related seizure risk
• Pregnancy/breastfeeding - fluoxetine crosses into breast milk; use requires risk-benefit assessment (per Maudsley guidelines, weigh against risks of untreated depression)
• Caution in the elderly and those on diuretics due to hyponatremia risk

Note on recent evidence

• A 2025 systematic review on oral side effects of fluoxetine (dry mouth, taste changes) in depressive disorder patients (PMID: 39954277)
• A 2025 meta-analysis suggesting fluoxetine may modestly affect lipid profiles in overweight/obese individuals (PMID: 39978642)
• A 2024 individual patient data meta-analysis (FOCUS/EFFECTS/AFFINITY pooled) finding fluoxetine does not meaningfully improve functional outcomes after acute stroke and may increase seizure/fracture risk (PMID: 38497332)