Imipramine Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Imipramine (brand name Tofranil) is a tricyclic antidepressant (TCA) that has been used for decades to manage mood disorders. It is classified as a tertiary amine TCA and is available in oral tablet form.

Imipramine is primarily indicated for the treatment of major depressive disorder. It is also used off-label for conditions such as nocturnal enuresis in children and certain types of neuropathic pain.

The drug works by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine in the central nervous system, thereby increasing their availability and improving mood and emotional balance.

Relevant Genes and Their Roles

Two key liver enzymes—CYP2D6 and CYP2C19—are responsible for metabolizing imipramine. CYP2D6 converts imipramine into less active compounds, while CYP2C19 contributes to the dealkylation of tertiary amines into secondary amines.

Variants in these genes can alter enzyme activity: “ultrarapid” or “rapid” alleles can speed up drug clearance, lowering therapeutic levels, whereas “intermediate” or “poor” alleles slow metabolism, leading to higher plasma concentrations and a greater risk of side effects.

Impact of Genetics on Drug Response

Patients with ultrarapid or rapid metabolizer status may clear imipramine too quickly, risking treatment failure. Normal metabolizers generally achieve expected drug levels and response. Intermediate and poor metabolizers have reduced clearance, resulting in higher blood levels and an increased chance of adverse effects such as anticholinergic symptoms and cardiovascular events.

Expected Clinical Effects of Genetic Variation

Ultrarapid/Rapid Metabolizer

Effect on drug levels: Lower than expected plasma concentrations
Clinical consequence: Increased risk of therapeutic failure and inadequate symptom control
Side effects: Fewer side effects, though treatment may be ineffective (mild severity, infrequent)

Normal Metabolizer

Effect on drug levels: Typical plasma concentrations
Clinical consequence: Expected therapeutic effect at standard dosing
Side effects: Standard TCA side effect profile (anticholinergic, cardiovascular; moderate frequency)

Intermediate Metabolizer

Effect on drug levels: Moderately increased plasma concentrations
Clinical consequence: Elevated risk of side effects without increased efficacy
Side effects: Anticholinergic (dry mouth, constipation), cardiovascular (orthostatic hypotension); moderate severity, occasional

Poor Metabolizer

Effect on drug levels: Significantly increased plasma concentrations
Clinical consequence: High risk of adverse reactions at standard doses
Side effects: Severe anticholinergic and cardiac effects (e.g., arrhythmias); high severity, common

Indeterminate/Not Available

Effect: Unknown
Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
Side effects: Unpredictable; monitor closely for efficacy and toxicity

Dosing Guidelines

The following dosing guidelines are based on the CPIC guideline for tricyclic antidepressants in relation to CYP2D6 and CYP2C19 genotypes.

CYP2D6 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Lower plasma levels; risk of treatment failure	Avoid TCAs due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If TCA is warranted, titrate to a higher dose and use therapeutic drug monitoring.
Normal Metabolizer	Normal metabolism and expected drug levels	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Moderately increased drug levels; higher side-effect risk	Consider a 25% reduction of the recommended starting dose. Use therapeutic drug monitoring to guide adjustments.
Poor Metabolizer	Significantly increased drug levels; high side-effect risk	Avoid TCAs due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If TCA is warranted, consider 50% dose reduction and use therapeutic drug monitoring.
Indeterminate	Unknown impact	Initiate therapy with recommended starting dose.
Not available	Unknown impact	Initiate therapy with recommended starting dose.

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Lower levels of tertiary amines; potential sub-optimal response	Avoid tertiary amines; consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If tertiary amine is necessary, use therapeutic drug monitoring.
Rapid Metabolizer	Lower levels of tertiary amines; potential sub-optimal response	Avoid tertiary amines; consider alternative drug not metabolized by CYP2C19. If tertiary amine is necessary, use therapeutic drug monitoring.
Normal Metabolizer	Normal metabolism and expected drug levels	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Moderately reduced metabolism; slight increase in drug levels	Initiate therapy with recommended starting dose.
Poor Metabolizer	Significantly reduced metabolism; higher drug levels	Avoid tertiary amines; consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). For tertiary amines, consider 50% dose reduction and use therapeutic drug monitoring.
Likely Intermediate Metabolizer	Reduced metabolism; slight increase in drug levels	Initiate therapy with recommended starting dose.
Likely Poor Metabolizer	Greatly reduced metabolism; higher drug levels	Avoid tertiary amines; consider alternative drug not metabolized by CYP2C19. For tertiary amines, consider 50% dose reduction and use therapeutic drug monitoring.
Indeterminate	Unknown impact	Initiate therapy with recommended starting dose.
Not available	Unknown impact	Initiate therapy with recommended starting dose.

Alternative Treatment Options

Based on the CPIC guideline, patients who require alternatives to imipramine may consider secondary amine TCAs such as nortriptyline or desipramine, which rely less on CYP2C19. Other antidepressant classes (e.g., SSRIs, SNRIs) may also be appropriate. These examples are for informational purposes only.

Sources and References

CPIC – Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19