Fluoxetine - Drug Monograph

Introduction

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant that has been widely used in clinical practice since its approval by the FDA in 1987. It is one of the most commonly prescribed antidepressants worldwide and is also approved for multiple psychiatric conditions beyond major depressive disorder.

Mechanism of Action

Fluoxetine exerts its therapeutic effects primarily through potent inhibition of serotonin reuptake at the presynaptic neuronal membrane. It selectively blocks the serotonin transporter (SERT), increasing synaptic concentrations of serotonin in the central nervous system. This enhanced serotonergic activity is believed to mediate its antidepressant and anxiolytic effects. Fluoxetine has minimal affinity for adrenergic, cholinergic, GABA, dopamine, or histaminergic receptors.

Indications

FDA-approved indications:

• Major depressive disorder (MDD)
• Obsessive-compulsive disorder (OCD)
• Panic disorder
• Bulimia nervosa
• Premenstrual dysphoric disorder (PMDD)

Off-label uses:

• Social anxiety disorder
• Post-traumatic stress disorder
• Generalized anxiety disorder
• Vasovagal syncope
• Fibromyalgia

Dosage and Administration

• Depression: Initial dose 20 mg daily, may increase after several weeks
• OCD: 20-80 mg daily
• Panic disorder: 10-60 mg daily
• Bulimia: 60 mg daily
• PMDD: 20 mg daily

Available formulations: tablets (10, 20, 60 mg), capsules (10, 20, 40 mg), liquid solution (20 mg/5 mL)

Pharmacokinetics

Contraindications

• Concomitant use with MAOIs or within 14 days of MAOI use
• Concomitant use with pimozide
• Known hypersensitivity to fluoxetine
• Uncontrolled narrow-angle glaucoma

Warnings and Precautions

• Serotonin syndrome risk
• Activation of mania/hypomania
• Seizure risk (0.2%)
• Abnormal bleeding risk
• Hyponatremia
• QT prolongation
• Discontinuation syndrome
• Pregnancy considerations: Potential neonatal complications

Drug Interactions

• MAOIs: Risk of serotonin syndrome
• Other serotonergic drugs: Increased serotonin syndrome risk
• Drugs that prolong QT interval: Additive effects
• Warfarin: Increased bleeding risk
• CYP2D6 substrates: Reduced metabolism
• Triptans: Increased serotonin syndrome risk
• NSAIDs/aspirin: Increased bleeding risk

Adverse Effects

• Headache
• Nausea
• Insomnia
• Fatigue
• Diarrhea
• Dry mouth
• Nervousness
• Anxiety

• Serotonin syndrome
• Suicidal ideation
• Seizures
• Mania
• Hyponatremia
• Bleeding events
• Allergic reactions
• QT prolongation

Monitoring Parameters

• Mental status and suicidal ideation (especially during initiation)
• Therapeutic response and side effects
• Blood pressure and heart rate
• Electrolytes (particularly sodium)
• Bleeding signs and symptoms
• Weight changes
• Liver function tests (periodically)
• ECG in patients with cardiac risk factors

Patient Education

• Take as prescribed; do not abruptly discontinue
• Therapeutic effects may take 4-6 weeks
• Report worsening depression or suicidal thoughts immediately
• Avoid alcohol consumption
• Use caution when driving or operating machinery
• Report unusual bleeding or bruising
• Inform all healthcare providers about fluoxetine use
• Use reliable contraception
• Report symptoms of serotonin syndrome (agitation, hallucinations, fever)

References

1. FDA Prescribing Information: Prozac (fluoxetine) 2. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013. 3. Hirsch M, Birnbaum RJ. Fluoxetine: drug information. UpToDate; 2023. 4. Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366. 5. Hiemke C, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62. 6. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010.