nefazodone

General Information

Nefazodone (brand Serzone; generics) is an antidepressant indicated for depression (label).

Its mechanism includes serotonin uptake inhibition with 5-HT2 antagonism and α1 antagonism, contributing to sedation and orthostatic effects in some patients (mechanism/clinical).

The defining safety issue is rare but potentially life-threatening hepatic failure. Labeling highlights a reported U.S. rate of about one case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years and advises weighing this risk when selecting among alternatives (label).

Nefazodone is a strong CYP3A4 inhibitor and has a high interaction burden. Contraindications and major interactions can be clinically limiting in polypharmacy, particularly with sedative-hypnotics and other CYP3A4 substrates (label/clinical).

The compare view, nefazodone evidence feed, and print page support reviewing hepatic risk and interaction constraints alongside alternatives.

Because of hepatic failure risk and major drug–drug interactions, nefazodone is typically reserved for select cases where alternatives have failed or were poorly tolerated. When it is used, follow-up focuses on hepatic symptoms, medication reconciliation, and functional safety in sedation.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Inhibits neuronal uptake of serotonin and norepinephrine and antagonizes 5-HT2 receptors; α1 antagonism contributes to sedation and Orthostatic hypotension (label/mechanism).

Compared with SSRIs, the 5-HT2 antagonism can reduce certain serotonergic side effects, but the interaction burden often dominates clinical decision-making (clinical).

• SERT/NET inhibition with 5-HT2 and α1 antagonism (interaction-limited antidepressant).

Metabolism and Pharmacokinetics

• Rapidly absorbed but undergoes extensive metabolism; absolute bioavailability is low (~20%) and variable (label).
• Parent half-life is 2–4 hours. Radiolabeled “total label” half-life is longer (mean 11–24 hours), reflecting metabolites and distribution (label).
• After oral radiolabeled administration, ~55% of radioactivity is detected in urine and ~20–30% in feces; <1% is excreted unchanged in urine (label).
• Nefazodone is a strong CYP3A4 inhibitor; interactions can markedly increase exposure to co-prescribed CYP3A4 substrates (label).

Dosing and Administration

• Label initiation is typically 200 mg/day divided BID, with titration toward 300–600 mg/day as tolerated; dose increases are commonly spaced at one-week intervals in labeling (label).
• Older adults and medically frail patients are commonly started at lower doses because of sedation and orthostasis risk (label/clinical).
• Because discontinuation symptoms can occur, tapering is commonly used when stopping after longer courses (label/clinical).

Monitoring & Labs

• Baseline assessment for liver disease and review of hepatic warning signs/symptoms at follow-up (label/clinical).
• Medication reconciliation focused on CYP3A4 interactions, including sedative-hypnotics and common non-psychiatric drugs (label/clinical).
• Orthostatic vitals and functional safety (falls risk), especially in older adults and polypharmacy (clinical).
• Suicidality and mood switching surveillance early in treatment and after dose changes (label/clinical).

Nefazodone monitoring is dominated by hepatic safety and interaction management; these risks frequently outweigh potential benefits in polypharmacy.

Adverse Effects

Interactions

• Strong CYP3A4 inhibition drives many interactions; co-prescribed CYP3A4 substrates can have markedly increased exposure (label).
• Labeling lists contraindications with certain CYP3A4 substrates (e.g., triazolam) because of excessive sedation/respiratory depression risk and other serious outcomes (label).
• Many benzodiazepines and sedative-hypnotics require dose reduction or avoidance when combined; polypharmacy review is a common reason nefazodone is not selected (label/clinical).
• MAOIs are contraindicated; washout periods are used to reduce risk of serotonin syndrome and severe reactions (label).
• Additive CNS depression can occur with alcohol, opioids, and sedating antipsychotics; functional safety planning is commonly emphasized (clinical).

Other Useful Information

• If liver injury symptoms emerge (fatigue, anorexia, dark urine, jaundice), clinicians typically stop the medication promptly and evaluate liver tests (label/clinical).
• Because interaction risk is central, medication reconciliation typically includes non-psychiatric drugs (antifungals, macrolides, calcium-channel blockers, statins) in addition to psychotropics (label/clinical).
• When depressive symptoms occur in bipolar disorder, antidepressants are commonly paired with a mood stabilizer and monitored for mood switching; see the bipolar disorder hub for longitudinal care pathways.

References

1. Nefazodone hydrochloride tablets prescribing information — DailyMed (2025)
2. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
3. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)
4. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018)