Trimipramine Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Trimipramine (brand name Surmontil) is a tricyclic antidepressant used to help manage mood disorders. It is one of the older classes of antidepressants and is less commonly prescribed than newer agents but remains an option when first-line treatments are not effective or tolerated.

This medication is primarily used for major depressive disorder and may be used off-label for insomnia in some patients. By blocking the reuptake of neurotransmitters serotonin and norepinephrine in the brain, trimipramine helps restore balance in mood regulation and can improve symptoms of depression and sleep disturbances.

Trimipramine works by inhibiting transport proteins that clear neurotransmitters from the synaptic space, which increases the availability of serotonin and norepinephrine. It also has some antagonism at histamine and muscarinic receptors, which can contribute to sedation and certain side effects.

Relevant Genes and Their Roles

Two liver enzymes, CYP2D6 and CYP2C19, play key roles in how trimipramine is processed in the body. CYP2D6 is responsible for breaking trimipramine into less active metabolites, while CYP2C19 helps convert tertiary amine structures into secondary amines. Variations in these genes can change how quickly or slowly the drug is cleared.

Genetic differences (called polymorphisms) can lead to categories such as poor or ultra-rapid metabolizers. A “poor metabolizer” has less active enzyme and may clear trimipramine slowly, raising drug levels and side effect risk. An “ultra-rapid metabolizer” has highly active enzyme and may clear the drug too quickly, reducing its effectiveness.

Impact of Genetics on Drug Response

Depending on whether someone is an ultra-rapid, rapid, normal, intermediate or poor metabolizer of CYP2D6 or CYP2C19, trimipramine levels can be lower or higher than expected. Rapid metabolizers may have sub-therapeutic concentrations and a higher risk of treatment failure, while poor metabolizers may accumulate the drug and experience more side effects or toxicity.

Expected Clinical Effects of Genetic Variation

Ultrarapid/Rapid Metabolizer

Effect on drug levels: Increased clearance leads to lower blood concentrations.
Clinical consequence: Higher chance of treatment failure due to sub-therapeutic levels.
Side effects: Generally fewer side effects; efficacy may be reduced.

Normal Metabolizer

Effect on drug levels: Expected, standard pharmacokinetics.
Clinical consequence: Typical therapeutic response.
Side effects: Side effect risk as described in standard prescribing information.

Intermediate Metabolizer

Effect on drug levels: Moderately reduced clearance, higher than normal concentrations.
Clinical consequence: Increased probability of side effects.
Side effects: Mild to moderate side effects may be more frequent.

Poor Metabolizer

Effect on drug levels: Greatly reduced clearance, significantly higher concentrations.
Clinical consequence: High risk of adverse effects or toxicity.
Side effects: More severe side effects (e.g., anticholinergic effects, sedation) may occur frequently.

Indeterminate/Not Available

Effect: Unknown
Clinical consequence: No specific guidance; follow standard dosing with monitoring.

Dosing Guidelines

CYP2D6 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Lower plasma concentrations may lead to treatment failure.	Avoid tricyclic use; consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider higher target dose and use therapeutic drug monitoring.
Normal Metabolizer	Expected metabolism and therapeutic response.	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Higher plasma concentrations may increase side effect risk.	Consider a 25% reduction of recommended starting dose and use therapeutic drug monitoring.
Poor Metabolizer	Markedly increased risk of side effects due to high plasma levels.	Avoid tricyclic use; consider alternative drug. If a TCA is warranted, consider 50% dose reduction and use therapeutic drug monitoring.
Indeterminate/Not available	Unknown impact	Initiate standard starting dose with clinical monitoring.

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Lower active drug levels; possible reduced efficacy or altered side effects.	Avoid tertiary amine use; consider alternative drugs not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If a tertiary amine is warranted, use therapeutic drug monitoring.
Rapid Metabolizer	Lower active drug levels; possible reduced efficacy or altered side effects.	Avoid tertiary amine use; consider alternative drugs not metabolized by CYP2C19. If a tertiary amine is warranted, use therapeutic drug monitoring.
Normal Metabolizer	Expected metabolism and therapeutic response.	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Moderately reduced metabolism; slight increase in drug levels.	Initiate therapy with recommended starting dose.
Poor Metabolizer	Higher drug levels may increase side effect risk.	Avoid tertiary amine use; consider alternative drugs not metabolized by CYP2C19. For tertiary amines, consider 50% dose reduction and use therapeutic drug monitoring.
Likely Intermediate Metabolizer	Moderately reduced metabolism; slight increase in drug levels.	Initiate therapy with recommended starting dose.
Likely Poor Metabolizer	Higher drug levels may increase side effect risk.	Avoid tertiary amine use; consider alternative drugs not metabolized by CYP2C19. For tertiary amines, consider 50% dose reduction and use therapeutic drug monitoring.
Indeterminate/Not available	Unknown impact	Initiate standard starting dose with clinical monitoring.

Alternative Treatment Options

Examples of alternative treatments from guidelines include TCAs not extensively metabolized by these enzymes, such as nortriptyline or desipramine, or choosing non-TCA antidepressants. These are guideline examples only and not specific medical advice.

Sources and References

CPIC – Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19