Trazodone

Trazodone is a serotonin antagonist and reuptake inhibitor used for major depression, particularly with insomnia or anxiety, and widely used off-label at low doses for insomnia. It is sedating and can cause postural hypotension, rarely priapism, and has less anticholinergic effect than tricyclic antidepressants.

Classification. Triazolopyridine antidepressant, serotonin antagonist and reuptake inhibitor.

Mechanism. Strong antagonism of 5-HT2A, histamine H1 and alpha-1 adrenergic receptors, with weaker serotonin reuptake inhibition at higher doses. At low doses sedation predominates.

Pharmacokinetics. Well absorbed; food delays absorption and lowers peak concentration. Metabolised by CYP3A4 to m-chlorophenylpiperazine (active). Half-life about 5 to 9 hours. Levels rise with strong CYP3A4 inhibitors.

All regimens are oral with no loading dose.

Major depression, adults.

• Start 75 to 100 mg daily in divided doses or as a single bedtime dose.
• Titration: increase by 50 mg every 3 to 7 days.
• Usual 150 to 300 mg daily. Maximum 400 mg daily as an outpatient; up to 600 mg daily in hospital under specialist care.
• Duration: at least 6 months after remission.

Insomnia (off-label). 25 to 100 mg at bedtime; start 25 to 50 mg. Review need at 2 to 4 weeks.

Dose limits. Older adults: start 100 mg daily in divided doses; usual maximum 300 mg daily. Strong CYP3A4 inhibitors (ketoconazole, ritonavir): reduce the dose; strong inducers (carbamazepine, rifampicin) may lower levels.

Contraindications. Recent myocardial infarction, MAOI use now or within 14 days of stopping it, hypersensitivity. Caution in cardiac disease, arrhythmia and QT risk.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Priapism (a urological emergency), postural hypotension and syncope, QT prolongation and arrhythmia, serotonin syndrome, hyponatraemia, mania, seizures (rare), hepatotoxicity (rare).

Common adverse effects. Sedation, dizziness, dry mouth, headache, nausea, blurred vision, constipation, postural hypotension.

Interactions. Strong CYP3A4 inhibitors raise levels. Carbamazepine and rifampicin lower levels. QT-prolonging drugs, antihypertensives, alcohol and sedatives add to effects. Serotonin syndrome risk rises with tramadol, triptans, linezolid and other serotonergic drugs. Warfarin effect may change.

Common prescribing errors. Rapid dose escalation causing hypotension and falls; failing to warn about priapism; prescribing with QT-prolonging drugs without an ECG.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk.
• Breastfeeding: low infant levels; acceptable with infant monitoring for sedation.
• Children: not advised in under 18 years.
• Older adults: start low; falls and hyponatraemia.
• Kidney impairment: no adjustment; start low in severe impairment.
• Liver impairment: reduce the dose and monitor liver tests.

Formulations. Tablets 50 mg, 100 mg and 150 mg; capsules 50 mg and 100 mg; modified-release and liquid forms in some regions. Take after food to reduce dizziness and nausea, with the larger dose at night.

Baseline. Lying and standing blood pressure, mood history including past mania, suicide risk, sodium in older adults, ECG if cardiac disease or QT risk, liver tests if liver disease, medicines list.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality and orthostatic symptoms. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic. Counsel on priapism.

Stopping. Taper over at least 4 weeks for antidepressant doses; low-dose insomnia treatment can usually be stopped without tapering.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania or failure of two adequate courses. An erection lasting over 4 hours needs emergency urology care. Syncope or QT prolongation needs urgent assessment.