fluoxetine

**Mechanism:** Selectively blocks the presynaptic serotonin transporter (SERT), which increases synaptic 5-HT. Therapeutic effect takes about 4-6 weeks, probably because of downstream adaptations such as 5-HT1A autoreceptor desensitization and increased BDNF/neuroplasticity.

**Pharmacokinetics:** - Metabolized by CYP2D6 to norfluoxetine (active). Half-life is ~1-3 days for fluoxetine and ~7-15 days for norfluoxetine. - Fluoxetine is a strong CYP2D6 inhibitor (and a mild-moderate CYP2C19 inhibitor). It raises levels of TCAs, antipsychotics, beta-blockers (metoprolol), and codeine/tramadol. Codeine and tramadol are prodrugs activated by CYP2D6, so their analgesia is reduced. - Tamoxifen is also activated by CYP2D6. Avoid combining it with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. - The long half-life means a 5-week washout is needed before starting an MAOI (2 weeks for most other SSRIs).

**Indications:** - Major depressive disorder (including adolescents, ≥8 years old; it is the SSRI with the strongest pediatric evidence) - OCD - Bulimia nervosa (the only FDA-approved drug for it) - Panic disorder - PMDD - Also used for PTSD, social anxiety disorder, and binge-eating disorder - Combined with olanzapine (Symbyax) for treatment-resistant depression and bipolar depression

**Adverse effects:** - GI upset, headache, insomnia or activation, anxiety early in treatment - Sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation), a common reason for nonadherence - Hyponatremia from SIADH, especially in older adults - Increased bleeding risk (platelet serotonin depletion), especially with NSAIDs or anticoagulants - Serotonin syndrome, especially with MAOIs, meperidine, tramadol, linezolid, triptans, St. John's wort, MDMA, or dextromethorphan. It presents with hyperthermia, clonus, hyperreflexia, agitation, diaphoresis, diarrhea, and autonomic instability. Treat with discontinuation, benzodiazepines, and cyproheptadine (a 5-HT2A antagonist). - Boxed warning for increased suicidal ideation in children, adolescents, and young adults (<25 years) early in treatment - QT prolongation (less than citalopram) - Can precipitate mania or hypomania in undiagnosed bipolar disorder - Neonatal risks: first-trimester exposure is associated with a small increased risk of cardiac malformations (paroxetine is the best known), and third-trimester exposure with persistent pulmonary hypertension of the newborn and neonatal adaptation syndrome

**Discontinuation syndrome:** Fluoxetine has the lowest risk because it self-tapers. Paroxetine has the highest risk (short half-life plus anticholinergic effects). Symptoms are flu-like illness, dizziness, "brain zaps," irritability, and insomnia.

**High-yield comparisons:** - Paroxetine: most anticholinergic, most weight gain, worst discontinuation syndrome, and avoided in pregnancy. - Sertraline: preferred in cardiac disease (e.g., post-MI) and has less drug interaction risk. - Citalopram/escitalopram: dose-dependent QT prolongation. - Fluoxetine: longest half-life, most activating (less sedating), and the only SSRI approved for bulimia.

**Management pearls:** Taking it in the morning limits insomnia. Check sodium in older adults. If a patient is switching from fluoxetine to an MAOI, wait ≥5 weeks. If a patient has an inadequate response, increase the dose, switch agents, or augment.