Nefazodone

Indications

• FDA-approved for the treatment of major depressive disorder in adults, with efficacy demonstrated in short-term controlled trials.
• Chiefly used now when sexual dysfunction or insomnia from serotonergic antidepressants has made other agents unacceptable.
• Off-label for posttraumatic stress disorder, where open trials showed benefit for both hyperarousal and sleep disturbance.
• Off-label for chronic insomnia in depressed patients, since it increases slow-wave sleep rather than suppressing it.
• Rarely first line because of hepatotoxicity risk and the requirement for twice-daily dosing and liver monitoring.
• Safety and effectiveness in pediatric patients have not been established and use under 18 years is not recommended.

Mechanism of action

• Potent postsynaptic 5-HT2A receptor antagonism is the defining action, redirecting serotonergic transmission toward 5-HT1A receptors.
• Blocking 5-HT2A avoids the insomnia, agitation, and sexual dysfunction that arise from unopposed 5-HT2A stimulation by SSRIs.
• Weak inhibition of serotonin and norepinephrine reuptake adds modest monoaminergic enhancement at therapeutic doses.
• Alpha-1 adrenergic blockade produces orthostatic hypotension and contributes to the rare reports of priapism with this drug.
• The metabolite meta-chlorophenylpiperazine is a serotonin agonist that can cause anxiety, especially if CYP2D6 activity is low.

Pharmacokinetics

• Rapidly absorbed with peak concentrations at about 1 hour; bioavailability is low and variable because of extensive first-pass metabolism.
• Parent half-life is only 2 to 4 hours, which is why the drug must be given twice daily despite its long-acting metabolites.
• Metabolized principally by CYP3A4 to hydroxynefazodone, triazoledione, and meta-chlorophenylpiperazine, all pharmacologically active.
• It is itself a potent CYP3A4 inhibitor, which drives the majority of its clinically dangerous drug interactions.
• Nonlinear kinetics mean that dose increases produce disproportionate rises in plasma concentration, so titrate in measured steps.

Dosing

• Start 100 mg PO twice daily in adults, or 50 mg twice daily in older or debilitated patients, to limit sedation and orthostasis.
• Increase by 100-200 mg/day at intervals of no less than 1 week, based on tolerability and clinical response.
• The usual effective range is 300-600 mg/day given in two divided doses; 600 mg/day is the maximum studied dose.
• Supplied as 50, 100, 150, 200, and 250 mg tablets; both doses should be taken at consistent times to smooth concentrations.
• Do not start in patients with active liver disease or baseline transaminase elevations, and never restart after drug-induced liver injury.
• Taper gradually when discontinuing, and allow a 14-day washout before starting a monoamine oxidase inhibitor.

Adverse effects

• Somnolence and dry mouth each affect roughly 25 percent of patients, and nausea about 22 percent, in controlled trials.
• Dizziness affects about 17 percent, and orthostatic hypotension with lightheadedness limits titration in older patients.
• Visual disturbances including blurred vision, scotomata, and visual trails are distinctive and reported by a minority of patients.
• Sexual dysfunction is markedly less frequent than with SSRIs, which is the principal reason clinicians still choose this drug.
• Hepatotoxicity ranges from asymptomatic transaminase rise to fulminant failure requiring transplantation or resulting in death.
• Priapism has been reported rarely and, like the related agent trazodone, constitutes a urologic emergency requiring immediate care.

Monitoring

• Obtain baseline AST and ALT before the first dose and do not start if either is elevated or active liver disease is present.
• Recheck liver enzymes periodically during treatment and promptly for jaundice, anorexia, dark urine, malaise, or right upper quadrant pain.
• Discontinue permanently if AST or ALT rises to 3 times the upper limit of normal or above, and never rechallenge.
• Check orthostatic blood pressure during titration, particularly in older adults and in patients on antihypertensive drugs.
• Monitor for emergent suicidality, agitation, and manic switch in the first weeks and after every dose increase.

Interactions

• Contraindicated with pimozide, cisapride, terfenadine, and astemizole because CYP3A4 inhibition causes fatal QT prolongation.
• Contraindicated with carbamazepine, which both lowers nefazodone levels sharply and accumulates because of CYP3A4 inhibition.
• Contraindicated with monoamine oxidase inhibitors and within 14 days of stopping one because of serotonin syndrome risk.
• Reduce triazolam by 75 percent and alprazolam by 50 percent when coadministered, and avoid simvastatin and lovastatin entirely.
• Raises levels of cyclosporine, tacrolimus, and many other CYP3A4 substrates, requiring dose reduction and concentration monitoring.

Special populations

• Human pregnancy data are limited and no clear teratogenic pattern has emerged, but alternatives with better data are preferred.
• Lactation data are sparse; a case report describes drowsiness and poor feeding in a preterm infant exposed through breast milk.
• Not approved under 18 years, and pediatric use is discouraged given the hepatotoxicity signal and absent efficacy data.
• Start at 50 mg twice daily in adults 65 and older, since plasma concentrations are higher and orthostasis is more likely.
• Contraindicated in active liver disease; no formal renal adjustment is required in mild to moderate kidney impairment.

Clinical pearls

• Check AST and ALT before the first dose; never start with an elevated transaminase.
• Stop permanently at 3 times the upper limit of normal and do not rechallenge.
• The 5-HT2A block is why sexual dysfunction is rare and sleep architecture improves.