Fluoxetine

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used for major depression, obsessive-compulsive disorder, bulimia nervosa and panic disorder. Its main distinguishing features are a very long duration of action through an active metabolite, strong inhibition of CYP2D6, and an activating rather than sedating profile.

Classification. SSRI, phenylpropylamine structure, supplied as a racemic mixture.

Mechanism. Blocks the presynaptic serotonin transporter and raises synaptic serotonin. Antagonism of 5-HT2C receptors by fluoxetine and norfluoxetine may add to the activating effect and to the benefit in bulimia. Clinical response usually builds over 2 to 4 weeks.

Pharmacokinetics. Well absorbed orally and unaffected by food. Metabolised mainly by CYP2D6 to norfluoxetine, which is active. Half-life of fluoxetine is about 1 to 3 days after a single dose and 4 to 6 days with long-term use; norfluoxetine 4 to 16 days. Kinetics are nonlinear because fluoxetine inhibits its own metabolism, and effects persist for about 5 weeks after the last dose.

All regimens are oral, with no loading dose and no intravenous form.

Major depression, adults (first-line).

• Start 20 mg once daily in the morning.
• Titration: if response is inadequate after 3 to 4 weeks, increase in steps of 10 to 20 mg. Because steady state takes weeks, do not adjust more often than every 2 to 4 weeks.
• Maintenance: lowest effective dose, usually 20 mg daily. Maximum 60 mg daily (some regions permit 80 mg).
• Duration: continue at least 6 months after remission; 2 years or more for recurrent illness.

Obsessive-compulsive disorder.

• Start 20 mg daily. Usual range 20 to 60 mg daily; maximum 60 mg daily (80 mg in some regions).
• Higher doses are often needed. Judge response only after 8 to 12 weeks at an adequate dose.

Bulimia nervosa.

• 60 mg daily, reached by starting at 20 mg and increasing over several days. Combine with psychological therapy.

Panic disorder (licensed in some regions).

• 10 mg daily for 1 week, then 20 mg daily. Maximum 60 mg daily.

Children and adolescents aged 8 years and over with moderate to severe depression, after psychological therapy has been tried.

• 10 mg daily for 1 to 2 weeks, then 20 mg daily. Usual maximum 20 mg daily; in lower-weight children the dose may stay at 10 mg.

Premenstrual dysphoric disorder (licensed in some regions). 20 mg daily continuously or in the luteal phase only.

Contraindications. Monoamine oxidase inhibitor use now or within 14 days of stopping it; an MAOI must not be started within 5 weeks of stopping fluoxetine. Pimozide, thioridazine, linezolid and intravenous methylene blue. Hypersensitivity.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in children, adolescents and adults under 25 years. Serotonin syndrome, hyponatraemia (SIADH), gastrointestinal and other bleeding, mania or hypomania, seizures, QT prolongation (uncommon), angle-closure glaucoma.

Common adverse effects. Nausea, headache, insomnia, anxiety, tremor, sweating, reduced appetite, diarrhoea, sexual dysfunction.

Interactions. Strong CYP2D6 inhibition raises tricyclic antidepressants, metoprolol, flecainide, propafenone, atomoxetine, risperidone and haloperidol. It reduces the activation of codeine and tramadol and the formation of endoxifen from tamoxifen, so tamoxifen is avoided. Phenytoin and warfarin levels or effect can rise. Serotonin syndrome risk rises with tramadol, triptans, lithium, linezolid and St John’s wort. Bleeding risk rises with NSAIDs, aspirin and anticoagulants.

Common prescribing errors. Raising the dose too quickly despite the long half-life; starting an MAOI too soon after stopping; missing CYP2D6 interactions; starting in undiagnosed bipolar disorder without a mood stabiliser.

Special groups.

• Pregnancy: use only if benefit outweighs risk. First-trimester exposure carries a small absolute increase in cardiac malformation risk. Late exposure can cause neonatal adaptation symptoms and a small increase in persistent pulmonary hypertension of the newborn.
• Breastfeeding: infant exposure is higher than with sertraline or paroxetine because of the long half-life; it is not the first choice.
• Children: licensed from 8 years for depression; monitor closely for activation and suicidality.
• Older adults: higher risk of hyponatraemia, falls and bleeding; start at 10 mg and check sodium.
• Kidney impairment: no adjustment for mild to moderate; use lower or less frequent dosing in severe impairment.
• Liver impairment: halve the dose or give on alternate days in cirrhosis.

Formulations. Capsules and tablets (10 mg and 20 mg widely; 60 mg tablet in some regions) and oral liquid 20 mg/5 mL. Give in the morning with or without food. No dilution or infusion.

Baseline. Mood history including past mania, suicide risk, medicines list, pregnancy status, sodium in older adults or those on diuretics, bleeding risk.

Monitoring. Review within 1 to 2 weeks of starting and after each dose change for suicidality, agitation and akathisia. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic. If there is no improvement after 4 to 6 weeks at an adequate dose, increase the dose or switch.

Stopping. Taper over at least 4 weeks. The long half-life makes severe discontinuation symptoms uncommon.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania, or failure of two adequate courses. Suspected serotonin syndrome needs emergency care.