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Sunday, July 27, 2025

Fluoxetine (Prozac)


Fluoxetine, commonly known by its brand name Prozac, is a selective serotonin reuptake inhibitor (SSRI) that is widely prescribed for various psychiatric and neurological conditions. It was the first SSRI to receive FDA approval in 1987 and remains one of the most commonly used antidepressants worldwide. Fluoxetine is primarily indicated for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder (PMDD). It may also be used off-label for several other mental health conditions.

Pharmacological Classification

  • Therapeutic class: Antidepressant

  • Pharmacologic class: Selective serotonin reuptake inhibitor (SSRI)

  • ATC code: N06AB03

Brand Names

  • Prozac (original brand)

  • Other brands: Fluctin, Sarafem (PMDD-specific), Rapiflux, Olena, Prodep

  • Available as: capsules, tablets, oral solution, and delayed-release formulations

Mechanism of Action

Fluoxetine works by selectively inhibiting the reuptake of serotonin (5-HT) in the presynaptic neurons in the central nervous system. This results in increased extracellular levels of serotonin, enhancing neurotransmission in the serotonergic synapses. The therapeutic effects may be attributed to:

  • Desensitization of serotonin receptors (e.g., 5-HT1A, 5-HT2C)

  • Modulation of prefrontal cortex activity, limbic system stabilization

  • Delayed antidepressant effects typically appear after 2–4 weeks due to neuronal adaptation, despite rapid increases in serotonin levels

It has minimal affinity for adrenergic, cholinergic, histaminergic, or dopaminergic receptors, which contributes to its favorable side effect profile compared to older antidepressants.

Therapeutic Indications

Approved Uses

  • Major Depressive Disorder (MDD) – adults and children aged ≥8

  • Obsessive-Compulsive Disorder (OCD) – adults and children aged ≥7

  • Panic Disorder, with or without agoraphobia

  • Bulimia Nervosa

  • Premenstrual Dysphoric Disorder (PMDD) – marketed under Sarafem

  • Combined with olanzapine for treatment-resistant depression or bipolar depression (fluoxetine/olanzapine combination)

Off-Label Uses

  • Post-traumatic stress disorder (PTSD)

  • Social anxiety disorder

  • Generalized anxiety disorder (GAD)

  • Borderline personality disorder (BPD)

  • Autism-related irritability

  • Premature ejaculation

  • Cataplexy in narcolepsy

  • Fibromyalgia and chronic fatigue syndrome

Dosage and Administration

Adults

  • Depression: Starting dose 20 mg/day in the morning; may increase to 60 mg/day. Usual maintenance: 20–40 mg/day.

  • OCD: Start 20 mg/day; titrate up to 60–80 mg/day as needed.

  • Bulimia: 60 mg/day

  • Panic disorder: Start at 10 mg/day, increase to 20–60 mg/day

  • PMDD: 20 mg/day continuously or intermittently (e.g., during luteal phase)

Children and Adolescents

  • Depression: 10 mg/day starting dose (can increase to 20 mg/day)

  • OCD: Start at 10 mg/day, titrate cautiously; max dose 60 mg/day

Geriatric

  • Use lowest effective dose; start with 10 mg/day if needed

Hepatic impairment

  • Lower starting dose (e.g., 10 mg every other day or daily)

Administration notes

  • Take with or without food

  • Best taken in the morning to reduce risk of insomnia

  • Oral liquid available (20 mg/5 mL) for dose flexibility

  • Fluoxetine has a long half-life (4–6 days), and its active metabolite norfluoxetine persists even longer (7–15 days), allowing once-daily dosing and easier discontinuation

Pharmacokinetics

  • Bioavailability: ~72%

  • Protein binding: ~94.5%

  • Metabolism: Hepatic (CYP2D6, CYP2C9, CYP3A4)

  • Half-life: Fluoxetine ~4–6 days; norfluoxetine ~7–15 days

  • Elimination: Primarily renal (after hepatic metabolism)

Contraindications

  • Known hypersensitivity to fluoxetine or any excipients

  • Concomitant use with MAO inhibitors, linezolid, or IV methylene blue (risk of serotonin syndrome)

  • Use with pimozide or thioridazine (QT prolongation risk)

  • Recent use of disulfiram (in oral solution containing alcohol)

Warnings and Precautions

  • Suicidal ideation: Especially during initiation in children, adolescents, and young adults

  • Serotonin syndrome: Risk when combined with other serotonergic drugs

  • QT prolongation: High doses or co-administration with other QT-prolonging agents

  • Mania/hypomania: May precipitate in bipolar patients

  • Seizure threshold: May be lowered at high doses

  • Weight changes: Typically weight loss in early treatment

  • Bleeding risk: Increased when combined with NSAIDs, antiplatelets, or anticoagulants

  • Hyponatremia/SIADH, especially in elderly

  • Withdrawal symptoms: Rare due to long half-life, but may still occur with abrupt cessation

  • Angle-closure glaucoma: SSRIs may cause pupillary dilation

Adverse Effects

Very Common (≥10%)

  • Insomnia

  • Headache

  • Nausea

  • Diarrhea

  • Fatigue

  • Anxiety

  • Sweating

Common (1–10%)

  • Sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation)

  • Weight loss

  • Tremor

  • Drowsiness

  • Dry mouth

  • Indigestion

  • Rash

  • Visual disturbances

Uncommon to Rare (<1%)

  • Mania

  • Suicidal thoughts

  • Seizures

  • QT prolongation

  • SIADH / hyponatremia

  • Serotonin syndrome

  • Angle-closure glaucoma

  • Allergic reactions, urticaria, anaphylaxis (rare)

Drug Interactions

Contraindicated or Serious

  • MAO inhibitors: Risk of fatal serotonin syndrome – at least 14-day washout required

  • Thioridazine, pimozide: Risk of QT prolongation and Torsades de Pointes

  • Tramadol, fentanyl, MDMA: Enhanced serotonin syndrome risk

  • Linezolid, methylene blue: Risk of serotonin syndrome

  • Warfarin, NSAIDs, aspirin: Increased bleeding risk

  • Tamoxifen: Fluoxetine inhibits CYP2D6, potentially reducing tamoxifen efficacy

Other interactions

  • CYP2D6 substrates: May increase levels of drugs like codeine, metoprolol, TCAs

  • Other antidepressants: Risk of additive CNS effects or serotonin toxicity

  • Alcohol: Not recommended; may potentiate sedation and impair cognition

  • Benzodiazepines: Possible increased sedation

Pregnancy and Lactation

Pregnancy

  • Category C (USA), not teratogenic but may be associated with:

    • Neonatal withdrawal symptoms (e.g., irritability, feeding difficulty)

    • Persistent pulmonary hypertension of the newborn (PPHN)

  • Use only if benefit outweighs risk; avoid use late in third trimester

Breastfeeding

  • Excreted into breast milk in small amounts

  • May cause irritability or poor feeding in infant, but usually considered compatible

Use in Special Populations

  • Elderly: Increased risk of hyponatremia; dose cautiously

  • Hepatic impairment: Use lower starting doses

  • Renal impairment: No dosage adjustment usually required

  • Children and adolescents: Monitor closely for behavioral changes

Clinical Pearls

  • Longest half-life among SSRIs: Reduces need for tapering

  • Low risk of withdrawal symptoms relative to paroxetine or venlafaxine

  • Delayed therapeutic onset: 2–4 weeks for mood, up to 12 weeks for OCD

  • Beneficial in bulimia nervosa: Only antidepressant with FDA approval for this indication

  • Avoid abrupt discontinuation despite long half-life

  • Consider switching to a shorter-acting SSRI before initiating MAOIs




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