Trimipramine

Trimipramine is strongly sedating, similar to doxepin. While this can help with sleep problems, it also increases risks of falls, daytime drowsiness, and confusion, especially in older adults (34).

Pharmacology

• Less potent at blocking serotonin reuptake than other TCAs.

• Acts mainly through receptor blockade, earning it the label “atypical antidepressant” (32, 33).

• Like other TCAs, it has emerging anti-inflammatory properties, under study for pain and other conditions (16, 1).

Anticholinergic Burden

Trimipramine contributes mild anticholinergic effects compared to drugs like amitriptyline. These can still affect brain function, leading to memory loss, confusion, or delirium, especially in older patients. Over time, this contributes to the anticholinergic burden—the combined load of medicines that interfere with acetylcholine, a key neurotransmitter for memory and attention (11, 12, 13).

Serotonin Syndrome

Although less potent as a serotonin reuptake inhibitor, trimipramine still raises serotonin levels. When combined with other serotonin-boosting medicines (SSRIs, MAO inhibitors, tramadol, opioids) or supplements (tryptophan, St John’s Wort), it can cause serotonin syndrome—a rapid, potentially life-threatening condition (17).

Prolonged QT Interval

Like other TCAs, trimipramine can prolong the QT interval (7). This is a change in the heart’s rhythm that can lead to arrhythmias. Risk is higher in older adults, women, and those with heart disease or electrolyte imbalances (15).

Overdose and Toxicity

Overdose is a recognised risk. Toxicity can appear even at the higher end of the normal therapeutic range. Symptoms are similar to other TCAs and may include convulsions, heart arrhythmias, coma, and low blood pressure (35).

Trimipramine vs Other TCAs

• Sedation: Very strong, similar to doxepin.

• Anticholinergic burden: Milder than amitriptyline, but not negligible.

• Unique profile: “Outsider” in the TCA family due to antipsychotic-like receptor activity (32, 33, 34).

Trimipramine Side Effects

Like other TCAs, trimipramine can cause side effects, though their intensity varies. Compared with amitriptyline, it usually has a lower anticholinergic burden, but it is still very sedating, which increases risks for older adults.

Most Common Side Effects

• Weight gain

• Constipation

• Dry mouth

• Dizziness

• Headache

• Drowsiness (somnolence)

Alpha-Adrenergic Blockade (less pronounced than other TCAs)

• Low blood pressure when standing (orthostatic hypotension)

• Dizziness

• Sedation

Anticholinergic Effects (milder than other TCAs)

• Blurred vision

• Dry mouth

• Difficulty passing urine (urinary retention)

• Fast heart rate (tachycardia)

• Confusion or delirium

Histamine Blockade (very strong)

• Marked sedation

• Increased appetite

• Weight gain

• Confusion or delirium

Other Reported Effects

• Suicidal thoughts or ideation

• Increased risk of seizures

• Abnormal liver function

Genetic differences in CYP2C19 and CYP2D6 can affect treatment:

• Poor metabolisers: Higher drug levels → more side effects (e.g., dizziness, drowsiness, heart rhythm changes). Start at 50% of the usual dose with close monitoring.

• Ultrarapid metabolisers: Break the drug down too quickly → reduced benefit. A different antidepressant may be needed.

• Normal metabolisers: Standard dosing applies, adjusted to individual response.

While pharmacogenomic testing for trimipramine is not yet routine, it may help identify patients at risk of poor tolerance or lack of response.

Related Medications:

Other TCAs with similar pharmacogenetic considerations:

• Imipramine

• Amitriptyline

• Nortriptyline

• Clomipramine

• Doxepin