TRIMIPRAMINE MALEATE

Clinical safety rating: caution

Animal studies have proved adverse effects but may be safe for humans

How it works

Inhibits reuptake of norepinephrine and serotonin, with moderate anticholinergic, sedative, and antihistaminergic effects.

What the body does with it

Metabolism	Hepatic via CYP450 (CYP2D6, CYP2C19, CYP3A4) to active metabolite desmethyltrimipramine; also glucuronidation.
Excretion	Renal: ~70% as metabolites (unchanged <5%); fecal: ~30% via biliary excretion.
Half-life	Terminal elimination half-life: 22–32 hours (mean 24 hours); in elderly or hepatic impairment, may extend to 40–50 hours requiring dose adjustment.
Protein binding	94–96% bound primarily to alpha-1-acid glycoprotein (AAG) and albumin.
Volume of Distribution	17–30 L/kg (mean 25 L/kg), indicating extensive tissue binding and distribution beyond plasma volume.
Bioavailability	Oral: 35–60% due to first-pass metabolism; intramuscular: 70–90% (not commercially available in all regions).
Onset of Action	Oral: Antidepressant effect 2–3 weeks; sedative effect within 1–2 hours. IV (not typical for depression): within 30 minutes for sedative effect.
Duration of Action	Oral: Antidepressant effect sustained for 24 hours with once-daily dosing; sedative effect persists 6–8 hours after a single dose. Steady-state achieved in 5–10 days.

Classification & Brands

Dosing & administration

25-150 mg orally once daily at bedtime, starting at 25 mg and titrating up by 25 mg every 3-4 days.

Dosage form	CAPSULE
Renal impairment	No dosage adjustment required for mild to moderate renal impairment. For severe renal impairment (eGFR <30 mL/min), use with caution; consider reducing dose by 50% or increasing dosing interval.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Start at 50% of normal dose and titrate slowly. Child-Pugh Class C: Contraindicated.
Pediatric use	For adolescents (12-18 years) with depression: 25-50 mg orally once daily at bedtime, starting at 25 mg and titrating up by 25 mg every 5-7 days. Not recommended in children under 12.
Geriatric use	Start at 10-25 mg orally once daily at bedtime, increase by 10 mg every 5-7 days to a maximum of 100 mg/day. Caution with concurrent medications due to anticholinergic effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

MAOIs can cause serotonin syndrome and hyperpyrexia Strong anticholinergic effects may occur with other drugs Increased risk of suicide in children and young adults.

Breastfeeding

Trimipramine is excreted into breast milk in low amounts; relative infant dose estimated at 1-3% of maternal weight-adjusted dose. M/P ratio not established. Limited case reports: adverse effects rare (hypotonia, drowsiness). Caution advised, especially in preterm infants. Monitoring for sedation and poor feeding recommended.

Teratogenic Risk

Trimipramine is a tricyclic antidepressant (TCA) with limited human data. First trimester: observational studies suggest a small increased risk of congenital malformations, particularly cardiovascular defects (RR ~1.2-1.5). Second/third trimester: risk of neonatal withdrawal syndrome (irritability, tachycardia, respiratory distress) and anticholinergic effects (constipation, urinary retention). No specific syndrome reported.

Warnings & precautions

■ FDA Black Box Warning

Suicidal thoughts and behaviors in children, adolescents, and young adults; not approved for pediatric use except for nocturnal enuresis.

Side Effect Profile

Common Effects	Dry mouth
Serious Effects

Absolute Contraindications

Hypersensitivity, concomitant MAOIs or within 14 days, recent myocardial infarction, narrow-angle glaucoma, concurrent use of cisapride or other QT-prolonging drugs, mania, severe hepatic impairment.

Clinical Precautions

Precautions

Serotonin syndrome, anticholinergic effects (e.g., urinary retention, constipation, blurred vision), cardiovascular effects (QT prolongation, orthostatic hypotension), seizures, mania/hypomania, angle-closure glaucoma, bone marrow suppression, hepatic impairment, withdrawal syndrome.

Clinical Tips & Counseling

Drug interactions

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