Gepirone

Aka: Gepirone, Exxua

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II. Indications

  1. Major Depression
    1. Limited use due to lower efficacy, adverse effects, Drug Interactions and price in 2025 ($700 per month)

III. Contraindications

  1. QTc Prolongation (>450 msec)
  2. Severe hepatic Impairment (Child Pugh C)

IV. Mechanism

  1. Selective Serotonin 1A Receptor Agonist (5-HT1A Agonist)
    1. Similar to Buspirone

V. Medications

  1. Gepirone ER (Exxua)
    1. Extended-release tablets: 18.2 mg, 36.3 mg, 54.5 mg and 72.6 mg

VI. Dosing: Adults

  1. Standard Adult Protocol
    1. Start Gepirone ER 18.2 mg orally daily with food
    2. Titration schedule as needed
      1. Day 4: May increase to 36.3 mg
      2. Day 7: May increase to 54.5 mg
      3. Day 14: May increase to 72.6 mg
  2. Lower Dose Adult Protocol
    1. Indications
      1. Elderly
      2. Renal Impairment (eGFR <50 ml/min)
      3. Moderate hepatic Impairment (Child Pugh B)
    2. Protocol
      1. Start Gepirone ER 18.2 mg orally daily
      2. May increase up to 36.3 mg orally daily after 7 days

VII. Adverse Effects

  1. Suicidality in pediatric patients (FDA black box warning)
  2. QTc Prolongation
    1. More than other Antidepressants
    2. Obtain Electrocardiogram (EKG) before use
  3. Serotonin Syndrome
    1. Avoid in combination with other serotinergic medications
  4. Other reported adverse effects
    1. Dizziness
    2. Nausea
    3. Insomnia
    4. Abdominal Pain
    5. Dyspepsia

VIII. Safety

  1. Unknown safety in Lactation
  2. Avoid in pregnancy
    1. Third trimester
      1. Associated with persistent Pulmonary Hypertension
    2. Neonatal
      1. Poor adaptation (respiratory distress, Temperature instability, feeding difficulty, hypotonia, irritability)

IX. Drug Interactions

  1. MAO Inhibitors
    1. Avoid within 14 days of Gepirone
  2. Drugs That Prolong the QTc Interval
    1. Avoid in combination with Gepirone
  3. Strong CYP3A4 inhibitors and inducers
    1. Avoid in combination with Gepirone

X. Efficacy

  1. Developed 1986 and rejected by the FDA 3 times in 20 years (2002, 2004, 2007) up to its approval in 2023
    1. Studies showed low efficacy compared to Placebo
    2. Approved based on short-term studies (8 weeks)
    3. No proven efficacy in children (and carries the same Suicidality black box warning as other Antidepressants)

XI. Resources

  1. Gepirone ER (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=28b360dc-6337-4cae-a5bb-79f974b5a3b2

XII. References

  1. (2024) Presc Lett 31(5): 25
  2. Foster (2025) Am Fam Physician 111(1):87-8 [PubMed]

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