Nefazodone
Atypical antidepressants
Atypical antidepressants
A 5-HT2 antagonist antidepressant related to trazodone. A strong CYP3A4 inhibitor with a boxed warning for life-threatening liver failure.
Quick facts
- Group
- Atypical antidepressants
- Target
- Serotonin 5-HT2A receptor (antagonist); weak serotonin and noradrenaline reuptake inhibition
- Used for
- Major depressive disorder
- Key effects
- Drowsiness and difficulty concentrating · Dry mouth
- Monitor
- Liver tests · Mood and suicidal thoughts
- ATC
- N06AX06
No doses: the clinician sets them by the current guideline.
Mechanism of action
Nefazodone is a phenylpiperazine that blocks central 5-HT2 receptors and inhibits the reuptake of serotonin and noradrenaline. It also blocks alpha-1 adrenergic receptors, which explains postural hypotension. It strongly inhibits CYP3A4, so it raises the levels of many drugs, and it can cause rare but fatal liver failure.
- Nefazodone blocks 5-HT2 receptors
- Weakly blocks serotonin and noradrenaline reuptake
- Alpha-1 block: dizziness on standing
- Strong CYP3A4 inhibition and rare liver failure
Indications
- Major depressive disorder Major depressive disorder →
Adverse effects
Common
- Drowsiness and difficulty concentrating
- Dry mouth, nausea, constipation
- Dizziness and light-headedness
- Weakness
Contraindications
- Use with pimozide, carbamazepine, cisapride, terfenadine or astemizole
- Patients previously withdrawn from nefazodone because of liver injury
- Hypersensitivity to nefazodone or other phenylpiperazine antidepressants
- MAO inhibitors within the previous 14 days
Key interactions
- Triazolam
- Much higher triazolam levels and sedation (CYP3A4 inhibition); the combination is avoided
- Pimozide and cisapride
- Higher levels, QT prolongation and torsades de pointes: contraindicated
- MAO inhibitors
- Serious, sometimes fatal reactions; 14 days are left after an MAOI and at least 7 days after nefazodone before an MAOI
What is monitored
- Liver tests (AST, ALT) and signs of liver injury
- Mood and suicidal thoughts
- Blood pressure on standing
Administration and safety
- Not started in active liver disease or with raised transaminases
- Stopped if signs of liver injury appear, and never restarted after liver injury
Pregnancy and breastfeeding
Human data are limited; use weighs benefit and risk.
Nursing care
- Teaches the patient to report yellow skin or eyes, dark urine, loss of appetite, nausea or malaise at once
- Reviews every other medicine for CYP3A4 interactions, especially benzodiazepines
- Watches for drowsiness and dizziness on standing
- Asks about mood and suicidal thoughts
Pharmacokinetics
- Absorption
- By mouth, with low and variable bioavailability (about 20%)
- Metabolism
- Extensive liver metabolism, with active metabolites
- Half-life
- Short: 2 to 4 hours for the parent drug
Test yourself
Think of the answer, then tap the question to see it.
What is the boxed warning unique to nefazodone among antidepressants?
Life-threatening hepatic failure.
Why is nefazodone contraindicated with pimozide?
It strongly inhibits CYP3A4, raising pimozide levels and the risk of QT prolongation and torsades.
Which receptor block explains postural hypotension with nefazodone?
Alpha-1 adrenergic blockade.
Connections
← Back to the class: Atypical antidepressants
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - NEFAZODONE HYDROCHLORIDE tablet (DailyMed (U.S. National Library of Medicine), 2026); Nefazodone: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).
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Representative model, for educational purposes only.