Fluoxetine

Selective serotonin reuptake inhibitors

ATC code: N06AB03 (Fluoxetine)

Mechanism of action

Selectively blocks serotonin reuptake at the presynaptic membrane. Its distinguishing feature is a long half-life: 1-4 days for fluoxetine itself and 7-15 days for the active metabolite norfluoxetine. A missed dose therefore barely affects plasma levels, and withdrawal syndrome on discontinuation is less common than with other SSRIs.

Indications

Bulimia nervosa

First line

The only SSRI with FDA approval for bulimia nervosa. Recommended dose is 60 mg daily, higher than the standard antidepressant dose. In RCTs, fluoxetine reduced binge-purge episode frequency by 50-67% versus placebo. The effect is independent of comorbid depression.

Major depressive disorder

First line

First-line treatment for major depressive disorder in adults. Efficacy confirmed in numerous RCTs and meta-analyses. Starting dose is 20 mg daily; therapeutic effect develops over 2-4 weeks. The long half-life allows once-daily dosing. Side-effect profile is comparable to sertraline.

Obsessive-compulsive disorder

First line

First-line OCD treatment. Doses above the antidepressant range are usually needed – 40-80 mg daily. Response develops more slowly than in depression: efficacy should be assessed no earlier than 8-12 weeks at an adequate dose.

Practical notes

Timing and administration

Take once daily in the morning, with or without food. Morning dosing is preferred because of the activating effect – evening doses can disturb sleep. For bulimia the dose is 60 mg; for OCD it is titrated to 40-80 mg. If a dose is missed, the long half-life prevents critical concentration drops.

Special situations

The long half-life is a double-edged sword. Advantage: minimal withdrawal syndrome and missed-dose resilience. Disadvantage: drug interactions persist 5-6 weeks after discontinuation. Fluoxetine is a potent CYP2D6 inhibitor. When switching to another antidepressant, a washout period is required. MAOIs must not be combined – a minimum 5-week gap is needed.

Safety

Boxed warning

Antidepressants increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults under 25. Suicidality monitoring is mandatory during the first weeks of treatment and after dose changes.

Contraindications

Concurrent MAOI use or within 14 days of MAOI discontinuation
Concurrent use of thioridazine or pimozide
Hypersensitivity to fluoxetine

Serious adverse effects

Serotonin syndrome (when combined with serotonergic agents)
Suicidal behavior in young adults under 25 (FDA black box)
Hyponatremia (SIADH), particularly in elderly
QT prolongation in overdose

Common adverse effects

Nausea, diarrhea
Headache
Insomnia, anxiety
Sexual dysfunction – decreased libido, anorgasmia
Decreased appetite
Tremor

PregnancyFDA C

FDA category C. Third-trimester use is associated with neonatal adaptation syndrome – respiratory distress, irritability, tremor. The decision to continue during pregnancy balances the risk of untreated maternal depression.

Breastfeeding

Passes into breast milk. Fluoxetine and norfluoxetine are detectable in infant serum. Per LactMed, SSRIs with shorter half-lives (sertraline, paroxetine) are preferred during breastfeeding.