Trimipramine is a tricyclic antidepressant (TCA) primarily used to treat depression, anxiety, and insomnia. It works by influencing neurotransmitters in the brain, mainly serotonin and norepinephrine, which play key roles in mood regulation. Unlike most TCAs, trimipramine is considered an atypical agent because it weakly inhibits serotonin and norepinephrine reuptake, with its therapeutic effects largely attributed to its strong antihistaminic, anticholinergic, and antiadrenergic actions. Developed in the late 1950s and introduced in the early 1960s following the discovery of imipramine, trimipramine was designed to enhance sedative properties while maintaining antidepressant efficacy. Over time, it became known for its calming and sleep-promoting effects, making it useful for patients with depression accompanied by anxiety or insomnia. Although newer antidepressants such as SSRIs and SNRIs are now more commonly used, trimipramine remains a valuable option for certain patients who do not respond to other treatments.
BRAND NAMES
Surmontil: The most recognized brand name, which has been marketed in the United States and other countries.
Trimip: An alternative brand name mentioned by RxList.
Tripramine: Another brand name listed in RxList's drug information.
Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine: These brand names have also been marketed for trimipramine in various parts of the world.
MECHANISM OF ACTION
Trimipramine is an atypical tricyclic antidepressant whose mechanism of action differs from that of typical TCAs. It exerts only weak inhibitory effects on the reuptake of serotonin and norepinephrine, suggesting that its antidepressant and anxiolytic actions are mainly due to its influence on various neurotransmitter receptors. Trimipramine has strong antihistaminic, anticholinergic, and antiadrenergic properties, which contribute to its sedative and calming effects. Its potent histamine H₁ receptor blockade produces marked sedation, making it especially useful in patients with depression accompanied by anxiety or insomnia. Overall, trimipramine’s therapeutic effects result from its complex interaction with multiple neurotransmitter systems rather than a single dominant mechanism.
PHARMACOKINETICS
Absorption
Trimipramine is efficiently absorbed after oral administration; however, its absorption shows considerable variability and reduced bioavailability because a significant portion of the drug undergoes first-pass metabolism in the liver.
Distribution
The volume of distribution for trimipramine is about 31 L/kg, indicating extensive distribution into body tissues. A study published in the Journal of Analytical Toxicology in 1983 reported a comparable value of 30.9 ± 3.5 L/kg, supporting its wide tissue penetration.
Metabolism
Trimipramine undergoes hepatic metabolism mainly via the enzyme CYP2C19, which converts it into its active metabolite desmethyltrimipramine. Both trimipramine and desmethyltrimipramine are further metabolized by CYP2D6 through hydroxylation, leading to their inactivation. Genetic variations in these enzymes can influence the rate of metabolism, meaning that some individuals may process the drug more slowly or more rapidly, potentially affecting its therapeutic efficacy and the likelihood of side effects.
Excretion
Trimipramine is extensively metabolized in the liver before being excreted through both the urine and feces. Animal studies have shown that shortly after ingestion, both the parent compound and its monodemethylated metabolite appear in the bloodstream. Within 72 hours, dogs excreted approximately 1.5–8% of the administered dose in urine and 2–25% in feces, while rabbits excreted about 10–20% in urine and less than 2% in feces, indicating species-dependent differences in elimination pathways.
PHARMACODYNAMICS
Trimipramine is a tricyclic antidepressant (TCA) with a distinctive and complex pharmacodynamic profile that sets it apart from other drugs in its class. Unlike most TCAs, it only weakly inhibits the reuptake of monoamines such as serotonin and norepinephrine but acts as a strong antagonist at several neurotransmitter receptors. This receptor-blocking activity contributes to its sedative, anxiolytic, and antidepressant effects, making it particularly useful in treating depression accompanied by anxiety or insomnia.
ADMINISTRATION
Trimipramine is primarily administered orally in the form of tablets or capsules. It is usually taken once daily at bedtime due to its strong sedative effects, which can help with sleep in patients with depression and insomnia. The drug can be taken with or without food, although taking it with meals may help reduce gastrointestinal discomfort. Intravenous administration is not commonly used, as oral dosing is effective and preferred. Dosage should be individualized based on patient response, age, and comorbid conditions, and gradual titration is recommended to minimize side effects.
DOSAGE AND STRENGTH
Trimipramine is available in oral tablet or capsule form.
Adult dosage: The usual starting dose is 75 mg per day, typically administered at bedtime because of its sedative effects. Depending on clinical response and tolerance, the dose can be gradually increased to a typical therapeutic range of 150–200 mg per day, with some patients requiring up to 300 mg per day in divided doses.
Elderly patients: Lower starting doses (e.g., 25–50 mg/day) are recommended, with careful titration due to increased sensitivity and risk of side effects.
Available strengths: Commonly 10 mg, 25 mg, 50 mg, and 75 mg tablets or capsules.
FOOD INTERACTIONS
Trimipramine can be taken with or without food, as food does not significantly affect its absorption. However, taking the medication with meals may help reduce gastrointestinal side effects such as nausea or upset stomach. Patients are generally advised to avoid alcohol while taking trimipramine, as it can increase sedation and enhance the drug’s central nervous system depressant effects. There are no major known interactions with specific foods that reduce the drug’s effectiveness.
DRUG INTERACTIONS
Trimipramine can interact with several drugs, including MAO inhibitors, other CNS depressants, antihypertensives, and serotonergic agents, which may increase sedation, hypotension, or the risk of serotonin syndrome. Additionally, medications metabolized by CYP2D6 or CYP2C19 can alter trimipramine levels, so careful monitoring is recommended when it is combined with other drugs affecting the central nervous system, blood pressure, or liver metabolism.
CONTRAINDICATIONS
Trimipramine is contraindicated in patients with hypersensitivity to tricyclic antidepressants, recent myocardial infarction, narrow-angle glaucoma, severe urinary retention, or severe liver impairment. It should not be used with MAO inhibitors due to the risk of serotonin syndrome or hypertensive crises. Caution is also advised in the elderly and those with seizure disorders, prostate enlargement, or cardiovascular disease.
SIDE EFFECTS
Central nervous system effects.
Anticholinergic effects.
Gastrointestinal issues.
Sexual dysfunction.
Heart problems.
Psychological changes.
Serotonin syndrome.
Neurological issues.
Allergic reaction.
Vision problems.
Liver issues.
OVERDOSE
Anticholinergic effects.
Cardiovascular effects.
Ventricular arrhythmias.
Hypotension.
Conduction delays.
Central nervous system Issues.
Respiratory effects.
Acidosis and electrolyte abnormalities.
TOXICITY
Trimipramine toxicity, typically occurring after an overdose, mainly impacts the central nervous system (CNS) and cardiovascular system. As a tricyclic antidepressant, it can produce severe and potentially life-threatening effects such as seizures, cardiac arrhythmias, and coma. Although trimipramine generally has a more favorable cardiovascular safety profile compared to other TCAs, the risk of serious toxicity rises sharply with higher doses.
