Fluoxetine
Fluoxetine
Generic Name
Fluoxetine
Mechanism
- Potent and selective inhibition of the serotonin transporter (SERT) in the presynaptic neuron.
- Prolongs extracellular serotonin concentration, enhancing serotonergic neurotransmission.
- Minimal affinity for norepinephrine, dopamine, histamine, or adrenergic receptors → lower prevalence of anticholinergic or alpha‑blocking side‑effects relative to older tricyclics.
- *Clinical implication*: Rapid onset of pharmacologic action (within 1–2 weeks) but may take 4–6 weeks for full clinical benefit.
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Pharmacokinetics
| Parameter | Key Details |
| Absorption | Oral bioavailability ~ 90 %; peak plasma conc. 1–3 h post‑dose. |
| Metabolism | Hepatic microsomal (CYP2D6, CYP2C9). Active metabolite 4‑hydroxy‑fluoxetine (nor‑fluoxetine) has a long half‑life. |
| Half‑life | 4–6 days for fluoxetine; 5–7 days for nor‑fluoxetine, enabling once‑daily dosing. |
| Elimination | Renal (≈ 60 % unchanged) and hepatic excretion. |
| Drug interactions | Serotonin‑synergistic agents (MAOIs, triptans, linezolid, duloxetine) → serotonin syndrome; CYP2D6 inhibitors (paroxetine, fluvoxamine) ↓ fluoxetine levels minimally. |
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Indications
- Major Depressive Disorder (MDD) – adults & adolescents 12+ years.
- Obsessive‑Compulsive Disorder (OCD) – adults, children ≥10 years.
- Bulimia Nervosa – adults (cred. endorse weight‑dependent dosing).
- Panic Disorder – adults & adolescents ≥12 years.
- Premenstrual Dysphoric Disorder (PMDD) – adults, 1‑dose regimen before menses.
- Post‑traumatic Stress Disorder (PTSD) – off‑label, adjunct in certain patients.
- Anankastic Personality Disorder – off‑label, limited evidence.
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Contraindications
- Absolute contraindication: *Selupren* (MAOIs) within 14 days of fluoxetine; simultaneous use not advised.
- Severe hepatic impairment – reduced metabolism; start lower; monitor.
- Severe renal impairment – accumulation of active metabolite; usually safe but monitor.
- Pregnancy Category B – limited data; use if benefits outweigh risks.
- Breastfeeding – excreted in milk; cautious; minimal data.
Warn
• *Serotonin syndrome:* ↑SNA; severe agitation, hyperthermia, neuromuscular instability.
• *QTc prolongation* at high doses; baseline ECG recommended in high‑risk patients.
• *Suicidal ideation in adolescents* – monitor for mood shifts.
• *Drug interactions* with potent CYP2D6 inhibitors/inducers alter levels.
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Dosing
| Condition | Starting dose | Titration | Max dose | Notes |
| MDD | 20 mg PO once daily | Increase by 20 mg every 4–6 days | 80 mg/day | Aim for 20 mg initial for most adults. |
| OCD | 20 mg PO day 1 | 20–40 mg/day increments | 80 mg/day | 2–4 weeks needed to reach therapeutic level. |
| Bulimia | 20 mg PO day 1 | 20 mg/daily | 40 mg/day | Short‑term course (4–6 weeks). |
| Panic Disorder | 20 mg PO | 20 mg increments | 80 mg/day | Some patients benefit from 10 mg thrice daily. |
| PMDD | 20 mg PO (one dose) | 20 mg/ day outside menses | 15 mg/ day on menses | Alternate with 20 mg/daily regimen if continuing. |
Administration notes
• Take with or without food; food may reduce nausea.
• Taper over 4–6 weeks to avoid discontinuation syndrome (psychomotor agitation, nausea, insomnia).
• Oral suspension available for patients with dysphagia.
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Adverse Effects
Common (≥10 %)
• Nausea, headache, insomnia, dry mouth, constipation, sexual dysfunction (decreased libido, anorgasmia).
• Sweating, tremor, anxiety.
Serious (≤1 %)
• Serotonin syndrome (neuromuscular excitability, hyperthermia).
• Suicidal ideation/behavior (especially in adolescents/young adults).
• Severe allergic/hypersensitivity reaction (urticaria, angioedema).
• Hyponatremia (especially in elderly).
• QTc prolongation (rare).
Stop if: suicidal thoughts, severe dysphoria or hopelessness, uncontrolled hypertension, or new neurological symptoms.
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Monitoring
- Baseline: CBC, liver function tests, electrolytes, ECG if QTc risk, mental status in minors.
- During therapy:
- Weight, mood check‑ins at 2–4 week intervals.
- Serotonin syndrome signs, electrolyte panel quarterly.
- ECG if dose >60 mg or comorbid cardiac disease.
- Discontinuation: gradual taper; watch for withdrawal shivering or flu‑like symptoms.
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Clinical Pearls
- Long half‑life is double‑edged: Good in steady‑state maintenance, but risk of lingering adverse effects after abrupt stop.
- CYP2D6 polymorphism matters: Rapid metabolizers may need higher doses; poor metabolizers may have higher risks of sexual dysfunction and GI upset.
- Fluoxetine + St. John’s Wort → increased serum fluoxetine → elevated serotonin risk.
- Use in adolescence: Start at 20 mg, monitor closely for emergent suicidality; consider adding psychotherapy.
- PMDD dosing nuance: 20 mg daily for 3–5 days postpartum each month is an alternative to a single pre‑menstrual dose; may enhance compliance.
- Drug disposal: Fluoxetine’s long half‑life (~5 days) means residual drug may persist in patient for weeks; careful give‑away of unused meds.
- Taper schedule: 20 mg → 15 mg → 10 mg → 5 mg over 4–6 weeks; skipping steps may precipitate withdrawal.
- Non‑adherence: Because of once‑daily dosing, missed doses are often self‑corrected; self‑reinsertion doesn't cause toxicity because of long half‑life.
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