What are the indications, off-label uses, receptor binding profile, pharmacokinetics, and pharmacodynamics of fluoxetine (selective serotonin reuptake inhibitor, SSRI)?

Fluoxetine: Comprehensive Clinical Profile

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) with FDA approval for major depressive disorder, obsessive-compulsive disorder (OCD), bulimia nervosa, premenstrual dysphoric disorder, panic disorder, and bipolar disorder (in combination with olanzapine), and is the only antidepressant FDA approved for depression in children/adolescents aged 8 years or older. 1

Indications

FDA-Approved Uses

• Major depressive disorder (adults and children ≥8 years)
• Obsessive-compulsive disorder
• Bulimia nervosa
• Premenstrual dysphoric disorder
• Panic disorder
• Bipolar disorder (in combination with olanzapine) 1

Off-Label Uses

• Anxiety disorders (social anxiety, generalized anxiety, separation anxiety) 1
• Chronic pain syndromes 1
• Post-traumatic stress disorder 1
• Treatment-resistant OCD (at higher doses of 60-80 mg) 1
• Trichotillomania 2
• Pathological jealousy 2
• Social phobia 2

Pharmacodynamics

Mechanism of Action

• Selectively inhibits presynaptic serotonin reuptake in the brain, increasing serotonin availability at the synaptic cleft 1, 3
• This blockade leads to downregulation of inhibitory serotonin autoreceptors over time, heightening serotonergic neuronal firing and increasing serotonin release 1
• Minimal effects on norepinephrine reuptake 4, 5
• Negligible binding to neurotransmitter receptors (muscarinic, histaminergic, and α1-adrenergic) 3, 4
• Both enantiomers (R-fluoxetine and S-fluoxetine) are potent serotonin uptake inhibitors with equivalent pharmacologic activity 3

Therapeutic Effects

• Antidepressant effects typically require 2-6 weeks for clinically significant improvement 1
• In OCD treatment, early reduction (by 4 weeks) of symptom severity is the best predictor of treatment response at 12 weeks 1
• For anxiety disorders, statistically significant improvement may begin within 2 weeks, with clinically significant improvement by week 6 and maximal improvement by week 12 1

Pharmacokinetics

Absorption

• Well absorbed after oral administration 3, 5
• Peak plasma concentrations (15-55 ng/mL after 40 mg dose) occur 6-8 hours after administration 3
• Food may delay absorption by 1-2 hours but does not affect bioavailability 3
• Prozac Weekly (delayed-release formulation) contains enteric-coated pellets that dissolve at pH >5.5, delaying absorption by 1-2 hours 3

Distribution

• Approximately 94.5% protein-bound (albumin and α1-glycoprotein) 3
• Extensive tissue distribution

Metabolism

• Extensively metabolized in the liver primarily through CYP2D6 1, 3
• Converted to active metabolite norfluoxetine via demethylation 3
• S-norfluoxetine is a potent and selective serotonin uptake inhibitor with activity equivalent to parent drug 3
• R-norfluoxetine is significantly less potent 3

Elimination

• Primary route is hepatic metabolism to inactive metabolites excreted by the kidney 3
• Single-dose elimination half-life: 1-3 days 5
• Long-term administration elimination half-life: 4 days (fluoxetine) and 7 days (norfluoxetine) 3, 5
• Nonlinear pharmacokinetics 5
• S-fluoxetine enantiomer is eliminated more slowly and predominates in plasma at steady state 3

Clinical Considerations

Dosing

• Depression and OCD: Typically 20-40 mg once daily 5
• Treatment-resistant OCD may require higher doses (60-80 mg) 1
• Can be administered with or without food 3
• Single daily dosing is possible due to long half-life 1

Special Populations

• CYP2D6 poor metabolizers (approximately 7% of population) may experience higher drug levels and increased side effects 3
• Genetic testing for CYP2D6 and CYP2C19 variants may help guide dosing in some patients, though current guidelines note there is no clear role for routine pharmacogenomic testing 1

Drug Interactions

• Strong inhibitor of CYP2D6, making normal metabolizers resemble poor metabolizers 3
• Caution with drugs metabolized by CYP2D6 (TCAs, phenothiazines, most atypical antipsychotics, propafenone, flecainide) 3
• Contraindicated with thioridazine due to risk of ventricular arrhythmias (minimum 5-week washout period required) 3
• Minimal clinically significant inhibition of CYP3A4 3
• Risk of serotonin syndrome with MAOIs, triptans, linezolid, lithium, tramadol, St. John's Wort 3
• Can increase levels of phenytoin, carbamazepine, haloperidol, clozapine 3
• May prolong half-life of diazepam and increase alprazolam levels 3
• Can increase TCA levels 2-10 fold; effects may persist 3+ weeks after fluoxetine discontinuation 3

Side Effects

• Generally well-tolerated compared to TCAs 6, 7
• Common: nausea, anxiety, insomnia, anorexia, diarrhea, nervousness, headache 5
• May also cause: dry mouth, heartburn, somnolence, dizziness, vivid dreams, changes in appetite, weight changes, fatigue, tremor, bruxism, diaphoresis 1
• Sexual dysfunction can occur 1
• Black box warning for increased suicidality risk in children, adolescents, and young adults 1

Treatment Duration

• OCD treatment guidelines recommend 8-12 weeks to determine efficacy 1
• Maintenance pharmacotherapy for OCD: minimum 12-24 months after achieving remission 1
• Longer treatment may be necessary due to risk of relapse after discontinuation 1
• Abrupt discontinuation rarely causes withdrawal symptoms due to long half-life 6

Monitoring and Safety

• Monitor for suicidal ideation, particularly in first months of treatment and following dose adjustments 1
• Watch for signs of serotonin syndrome, behavioral activation/agitation, hypomania, mania 1
• Greater margin of safety in overdose compared to TCAs, though deaths have been reported with very large ingestions 1

Treatment Resistance

• For OCD patients with inadequate response, options include:
  1. Switching to a different SSRI
  2. Using higher doses of fluoxetine (60-80 mg)
  3. Augmentation with CBT (preferred over medication augmentation)
  4. Augmentation with clomipramine, antipsychotics, or glutamatergic agents 1

Fluoxetine's long half-life provides an advantage in preventing withdrawal symptoms upon discontinuation or missed doses, enhancing treatment adherence and potentially reducing relapse rates 6.