Fluoxetine

Indications

• FDA-approved for major depressive disorder in adults and in children and adolescents aged 8 years and older, usually at 20-60 mg/day.
• FDA-approved for obsessive-compulsive disorder from age 7, for bulimia nervosa in adults at 60 mg/day, and for panic disorder.
• FDA-approved in combination with olanzapine for acute bipolar I depression and for treatment-resistant unipolar depression in adults.
• FDA-approved as Sarafem for premenstrual dysphoric disorder, given continuously or only during the luteal phase at 20 mg/day.
• Off-label for social anxiety disorder, generalized anxiety disorder, PTSD, binge-eating disorder, and selective mutism in children.
• Off-label for body dysmorphic disorder and trichotillomania, both of which usually require doses in the higher OCD range.

Mechanism of action

• Potently and selectively blocks the presynaptic serotonin transporter, raising synaptic 5-HT and progressively desensitizing 5-HT1A autoreceptors.
• That slow autoreceptor desensitization is why mood response lags two to six weeks behind the immediate transporter blockade seen on day one.
• Weak 5-HT2C antagonism disinhibits frontal norepinephrine and dopamine release, giving fluoxetine its activating and sometimes anxiogenic early profile.
• Negligible muscarinic, histaminic, and alpha-1 affinity, so it avoids the anticholinergic, sedating, and hypotensive burden of tricyclic antidepressants.
• Potent CYP2D6 inhibition is a property of this molecule rather than a class effect and drives most of its clinically important drug interactions.

Pharmacokinetics

• Well absorbed orally with bioavailability above 60 percent; food delays but does not reduce absorption, so it may be taken with or without meals.
• Half-life is 1 to 4 days for the parent drug and 4 to 16 days for the equipotent active metabolite norfluoxetine, the longest of any SSRI.
• Steady state requires four to five weeks and complete washout takes five to six weeks, which is what governs MAOI switching intervals.
• Metabolized by CYP2D6 and CYP2C9; kinetics are nonlinear above 20 mg/day because the drug inhibits its own clearance as concentrations rise.
• About 94 percent protein bound, extensively distributed to tissue, and eliminated renally as inactive conjugates after hepatic demethylation.

Dosing

• Start 20 mg PO each morning for depression, OCD, or PMDD; in panic disorder begin at 10 mg/day for one week to limit early jitteriness.
• Titrate by 10 to 20 mg increments no more often than every one to two weeks; usual target is 20-60 mg/day and the label maximum is 80 mg/day.
• Bulimia nervosa is dosed directly at 60 mg/day, and OCD commonly needs 40 to 80 mg/day before response is judged inadequate.
• Formulations include 10, 20, and 40 mg capsules, 10 and 20 mg tablets, 20 mg per 5 mL solution, and a 90 mg delayed-release weekly capsule.
• Pediatric dosing starts at 10 mg/day with a target near 20 mg/day; lower-weight children are often maintained at 10 mg/day long term.
• No taper is needed at discontinuation given the long half-life, but reduce dose or use alternate-day dosing in cirrhosis.

Adverse effects

• Nausea in roughly 20 percent, headache, insomnia in 10 to 20 percent, nervousness, tremor, and anorexia are the usual early complaints.
• Sexual dysfunction affects 30-70 percent of treated patients, is the leading cause of nonadherence, and seldom remits with continued exposure.
• More activating than other SSRIs, with early appetite suppression and modest weight loss; long-term weight change is close to neutral.
• Hyponatremia from SIADH occurs mainly in older adults on diuretics and may present as confusion, falls, or seizure within weeks of starting.
• Serotonin syndrome, increased bleeding with NSAIDs or antiplatelets, bruxism, and treatment-emergent mania are the events that change prescribing.
• Rash or urticaria occurs in about 7 percent; the label directs discontinuation if rash is accompanied by systemic features.

Monitoring

• Assess suicidality, activation, and mood switch weekly for the first four weeks and after every dose change, especially in patients under 25.
• Check serum sodium at baseline and again within two to four weeks in older adults, diuretic users, or anyone with new confusion or lethargy.
• Track response with PHQ-9, GAD-7, or Y-BOCS at baseline and every two to four weeks rather than relying on global clinical impression.
• Routine ECG and plasma levels are not required; obtain an ECG only with known long QT or concurrent QT-prolonging medication.
• Screen for bipolar disorder before starting and reassess if sleep need, energy, or goal-directed activity change abruptly during treatment.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one; after stopping fluoxetine wait 5 weeks before any MAOI or linezolid course.
• Contraindicated with pimozide and thioridazine, since CYP2D6 inhibition raises their concentrations and causes dangerous QT prolongation.
• Strong CYP2D6 inhibition roughly doubles aripiprazole, risperidone, atomoxetine, metoprolol, and tricyclic levels and blocks tamoxifen activation.
• Additive serotonergic risk with triptans, tramadol, linezolid, methylene blue, and St. John's wort; watch for clonus, rigidity, and hyperthermia.
• Raises bleeding risk with NSAIDs, aspirin, and anticoagulants, and increases phenytoin and carbamazepine levels through CYP2C9 inhibition.

Special populations

• Human data show no clear teratogenic signal; third-trimester exposure carries small risks of neonatal adaptation syndrome and persistent pulmonary hypertension.
• Relative infant dose in breast milk is higher than for sertraline, so sertraline is generally preferred when starting an SSRI de novo while nursing.
• Approved from age 8 for depression and age 7 for OCD, and it has the strongest pediatric efficacy evidence of any antidepressant.
• In older adults start at 10 mg/day because of hyponatremia, falls, and bleeding risk, and account for the long half-life before adding interacting drugs.
• No adjustment is needed in renal impairment; in hepatic impairment lower the dose or extend the dosing interval to every other day.

Clinical pearls

• Longest half-life of any SSRI: little discontinuation syndrome, but a 5-week washout before any MAOI.
• Most activating SSRI. Dose in the morning and start at 10 mg in panic disorder.
• Strong 2D6 inhibitor: recheck aripiprazole, atomoxetine, metoprolol, tamoxifen, and codeine.