Serotonin Modulators

Serotonin modulators combine serotonin reuptake inhibition with direct receptor effects. The group includes vortioxetine, vilazodone, trazodone and nefazodone. They are used in depression, with trazodone also widely used at low dose for insomnia.

Mechanism. Vortioxetine inhibits the serotonin transporter, agonises 5-HT1A, partially agonises 5-HT1B and antagonises 5-HT3 and 5-HT7. Vilazodone combines serotonin transporter inhibition with 5-HT1A partial agonism. Trazodone blocks 5-HT2A, alpha-1 and histamine H1 receptors, and weakly the serotonin transporter. Nefazodone blocks 5-HT2A and weakly reuptake.

Pharmacokinetics. Vortioxetine half-life 66 hours, metabolised by CYP2D6. Trazodone half-life 5 to 9 hours, metabolised by CYP3A4 to an active metabolite.

Agent	Dosing
Vortioxetine	10 mg daily (5 mg if poorly tolerated or older adults), up to 20 mg
Vilazodone	10 mg with food, increased to 20 to 40 mg
Trazodone	Depression 150 mg daily in divided doses or at night, rising to 300 mg; insomnia 25 to 100 mg at night
Nefazodone	100 mg twice daily, up to 300 mg twice daily; withdrawn in most markets

Differences. Vortioxetine has less sexual dysfunction and benefit for cognitive symptoms. Trazodone is sedating and carries priapism risk. Nefazodone caused liver failure and is largely unavailable.

Depression with sexual dysfunction on an SSRI: vortioxetine or vilazodone.
Depression with insomnia: trazodone at night, alone or added to an SSRI.
Cognitive symptoms in depression: vortioxetine.
Insomnia in older adults and in dementia agitation: trazodone at low dose (off-label), with attention to falls.
Stopping: taper over 1 to 2 weeks for vortioxetine and trazodone.
Cost: trazodone is inexpensive; vortioxetine and vilazodone are costly.

Special groups. Pregnancy: limited data; trazodone has the most experience. Breastfeeding: avoid vortioxetine and vilazodone; trazodone gives low infant exposure. Children: not used. Older adults: trazodone causes postural hypotension, so start low. Kidney impairment: no adjustment. Liver impairment: avoid nefazodone; reduce trazodone. Regional: trazodone availability varies; ritonavir and ketoconazole raise trazodone levels.

Adverse effects. Nausea (vortioxetine), headache, sedation, dizziness, postural hypotension (trazodone), QT prolongation (trazodone), priapism (trazodone, rare), and serotonin syndrome.

Priapism. An erection lasting over 4 hours is a urological emergency that can cause permanent damage; the drug is stopped and the patient is warned.

Contraindications. Monoamine oxidase inhibitors within 14 days and linezolid.

Interactions. Strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine) require halving the vortioxetine dose. Rifampicin and carbamazepine raise the vortioxetine dose need. CYP3A4 inhibitors raise trazodone levels. Tramadol and triptans add serotonin syndrome risk.

Monitoring. Blood pressure and heart rate, ECG with cardiac disease or QT drugs, and mood and suicidality.

Referral and escalation. Priapism (urgent), serotonin syndrome, or persistent hypotension.

Serotonin Modulators

Class Overview And Mechanism

Members And Differences

Clinical Use And Selection

Class Safety And Monitoring