Adult: Initially, 50-75 mg daily in 2-3 divided doses or as a single dose at bedtime; may gradually increase to 150-300 mg daily as necessary. Maintenance dose: Use the lowest effective dose that will maintain remission. Dose must be individualised according to the patient's response and tolerability. Dosage recommendations may vary among individual products and between countries (refer to specific product guidelines). Elderly: Initially, 10-25 mg tid; may gradually increase as necessary. Maintenance dose: Use the lowest effective dose that will maintain remission. Alternative dosage recommendation: Initially, 50 mg daily; may gradually increase up to a Max of 100 mg daily. Dose must be individualised according to the patient's response and tolerability. Dosage recommendations may vary among individual products and between countries (refer to specific product guidelines).
Special Patient Group
Pharmacogenomics:
TCAs are classified as tertiary or secondary amines based on their similar yet distinct chemical structures. Tertiary amines, including trimipramine, are mainly metabolised by CYP2C19, while CYP2D6 metabolises both tertiary and secondary amines into less active forms. Trimipramine is metabolised in the liver to form its major active metabolite, desmethylimipramine.
CYP2C19 and CYP2D6 genes are highly polymorphic. Genetic variation in CYP2C19, affecting the parent drug-to-metabolite ratio, or in CYP2D6, affecting drug clearance, may increase the risk of treatment failure or adverse effects. Genetic testing for CYP2C19 and CYP2D6 may be considered before treatment initiation to help guide dosage adjustments and prevent potential adverse effects.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2016:
CYP2D6
Phenotype and Genotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser (activity score of >2)
Patients carrying duplications of functional alleles e.g. (*1/*1)xN, (*1/*2)xN, (*2/*2)xN
Increased TCA metabolism to less active metabolites as compared to normal metabolisers. Lower plasma levels of the active metabolite may increase the possibility of treatment failure.
Avoid the use of TCA and consider an alternative drug not metabolised by CYP2D6. If TCA use is necessary, consider adjusting to a higher target dose compared to normal metabolisers. Use therapeutic drug monitoring to guide dose adjustments.
CYP2D6 intermediate metaboliser (activity score of 0.5)
Patients carrying 1 decreased function and 1 non-functional allele e.g. *4/*41, *5/*9, *4/*10
Decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma levels of the active metabolite may increase the risk of adverse effects.
Consider a 25% reduction of the recommended initial dose with therapeutic drug monitoring to guide dose adjustments.
CCYP2D6 poor metaboliser (activity score of 0)
Patients carrying only non-functional alleles e.g. *4/*4, (*4/*4)xN, *3/*4, *5/*5, *5/*6
Greatly decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma levels of the active metabolite may increase the risk of adverse effects.
Avoid the use of TCA and consider an alternative drug not metabolised by CYP2D6. If TCA use is necessary, consider a 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.
CYP2C19
Phenotype and Genotype
Implications
Recommendations
CYP2C19 ultrarapid metaboliser
Patients carrying 2 increased function alleles e.g. *17/*17
Increased tertiary amine metabolism as compared to normal metabolisers. Increased conversion of tertiary amines to secondary amines may affect treatment response or adverse effects.
Avoid using trimipramine and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If trimipramine use is necessary, utilise therapeutic drug monitoring to guide dose adjustments.
CYP2C19 rapid metaboliser
Patients carrying 1 normal function allele and 1 increased function allele e.g. *1/*17
Increased tertiary amine metabolism as compared to normal metabolisers. Increased conversion of imipramine to desipramine may affect treatment response or adverse effects.
Avoid using trimipramine and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If trimipramine use is necessary, utilise therapeutic drug monitoring to guide dose adjustments.
CYP2C19 intermediate metaboliser
Patients carrying 1 normal function allele and 1 non-functional allele or 1 non-functional allele and 1 increased function allele e.g. *1/*2, *1/*3, *2/*17
Decreased trimipramine metabolism as compared to normal metabolisers..
Initiate treatment with the recommended dose.
CYP2C19 poor metaboliser
Patients carrying 2 non-functional alleles e.g. *2/*2, *2/*3, *3/*3
Greatly decreased trimipramine metabolism as compared to normal metabolisers. Decreased conversion of tertiary amines to secondary amines may affect treatment response or adverse effects.
Avoid using trimipramine and consider an alternative drug not mainly metabolised by CYP2C19 (e.g. desipramine, nortriptyline). If trimipramine use is necessary, consider a 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.
Administration
Trimipramine May be taken with or without food.
Contraindications
Acute recovery period following MI, any degree of heart block or other cardiac arrhythmias. Concomitant use or within 14 days of discontinuing MAOIs (e.g. linezolid or IV methylene blue).
Special Precautions
Patient with major depressive disorder, history of suicidal-related events or a significant degree of suicidal ideation, bipolar disorder; risk factors for QT interval prolongation (e.g. congenital long QT syndrome, bradycardia, uncorrected electrolyte imbalance), hyperthyroidism, diabetes mellitus, seizure disorder and its risk factors (e.g. history of seizures, head trauma, brain damage, alcoholism); decreased gastrointestinal motility, paralytic ileus, benign prostatic hyperplasia, urinary retention, xerostomia, angle-closure glaucoma, visual problems; risk factors for orthostatic hypotension (e.g. hypovolaemia, cerebrovascular disease). Patients undergoing surgery or electroconvulsive therapy. CYP2C19 ultrarapid, rapid, and poor metabolisers. CYP2D6 ultrarapid, intermediate, and poor metabolisers. Avoid abrupt withdrawal. Renal and hepatic impairment (including patients with hepatic encephalopathy). Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal thinking and behaviour, precipitation of hypomanic or manic episodes, CNS depression, QT interval prolongation (dose-dependent), anticholinergic effects (e.g. blurred vision, constipation, urinary retention, xerostomia), bone fractures, orthostatic hypotension, altered blood glucose regulation, lowers seizure threshold, pupillary dilation which may lead to angle-closure glaucoma, withdrawal symptoms (particularly if abruptly discontinued). Cardiac disorders: Arrhythmias, heart block, palpitation, MI, tachycardia. Eye disorders: Accommodation disturbances. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal cramps. General disorders and administration site conditions: Fatigue. Hepatobiliary disorders: Cholestatic jaundice. Nervous system disorders: Dizziness, headache, drowsiness, paraesthesia, peripheral neuropathy, tremor. Psychiatric disorders: Insomnia, agitation, anxiety, confusion, disorientation, delusion, hallucinations, restlessness. Renal and urinary disorders: Urinary hesitation. Reproductive system and breast disorders: Changes in libido, gynaecomastia, galactorrhoea. Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, diaphoresis, alopecia, skin photosensitivity. Potentially Fatal: Serotonin syndrome.
This drug may cause drowsiness or sedation, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor blood pressure, heart rate (in patients with preexisting cardiac disease or those at increased risk for QT-prolonging effects); LFTs, blood glucose, electrolytes (e.g. potassium, magnesium, sodium) at baseline and as clinically indicated; weight and BMI (at baseline and periodically). Perform ECG, especially in patients with CV disease or those at risk for QT-prolonging effects. Closely monitor for clinical worsening, suicidality, unusual changes in behaviour (particularly at 1-2 months of treatment initiation or during dose adjustments).
Overdosage
Symptoms: Drowsiness, confusion, agitation, dilated pupils, urinary retention, hypothermia, severe hypotension, convulsions, QT interval prolongation, torsade de pointes and coma. Management: Symptomatic and supportive treatment. Secure the airway and establish an IV line. Perform gastric lavage followed by activated charcoal if the patient is fully conscious. Administer sodium lactate IV for acidosis and propranolol or IV pyridostigmine bromide for supraventricular tachycardia. Convulsions may be controlled with benzodiazepines (e.g. IV diazepam) or other anticonvulsants (e.g. phenobarbital, phenytoin). Perform ECG and continuously monitor cardiac function.
Drug Interactions
Increased risk of QT interval prolongation with class IA and III antiarrhythmics, macrolide antibiotics, fluoroquinolones, certain antifungals, antipsychotics. May reduce the antihypertensive effects of clonidine, betanidine, debrisoquine, and guanethidine. May increase metabolism rate with barbiturates. Concurrent use of anaesthetics may increase the risk of arrhythmia and hypotension. Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (e.g. IV methylthioninium chloride, linezolid), serotonergic agents (e.g. triptans, TCAs, fentanyl, lithium, tramadol, buspirone, tryptophan), buprenorphine.
Food Interaction
Increased risk of serotonin syndrome with St. John's wort. May enhance the CNS depressant effects of alcohol.
Action
Description: Mechanism of Action: Trimipramine is a dibenzazepine tricyclic antidepressant with antimuscarinic and sedative properties. Its mechanism of action is unknown, but its antidepressant effect is thought to result from postsynaptic sensitisation to serotonin. Onset: Depression: 1-2 weeks (initial effect). Pharmacokinetics: Absorption: Readily absorbed. Bioavailability: 18-63%. Time to peak plasma concentration: 1-6 hours. Distribution: Plasma protein binding: Approx 95%. Volume of distribution: 31 L/kg. Metabolism: Metabolised in the liver to form desmethylimipramine (major active metabolite); undergoes significant first-pass effect. Excretion: Via urine (mainly as metabolites). Elimination half-life: 7-40 hours.
Chemical Structure
Trimipramine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5584, Trimipramine. https://pubchem.ncbi.nlm.nih.gov/compound/Trimipramine. Accessed July 29, 2025.
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