Desipramine

Desipramine, marketed under the brand name Norpramin, is a tricyclic antidepressant (TCA) commonly prescribed for major depressive disorder.

It is primarily indicated for the treatment of depression and may also be used off-label for neuropathic pain and attention-deficit/hyperactivity disorder. Desipramine works by inhibiting the reuptake of the neurotransmitter norepinephrine (noradrenaline) in the brain, increasing its availability in synaptic clefts.

By blocking the norepinephrine transporter, desipramine enhances noradrenergic neurotransmission, which helps improve mood and reduce depressive symptoms over time.

The primary gene affecting desipramine pharmacokinetics is CYP2D6. CYP2D6 encodes the liver enzyme cytochrome P450 2D6, which is responsible for the oxidative metabolism of desipramine into less active or inactive compounds.

Variations in CYP2D6 can lead to different enzyme activity levels: reduced function alleles slow drug clearance, while multiple copies of functional alleles accelerate it. These differences directly impact desipramine plasma concentrations and can influence both efficacy and risk of side effects.

Genetic variations in CYP2D6 categorize individuals as ultrarapid, normal, intermediate, or poor metabolizers of desipramine. Ultrarapid metabolizers clear the drug quickly, risking subtherapeutic levels and treatment failure, whereas poor metabolizers clear it slowly, increasing the likelihood of elevated concentrations and adverse effects. Intermediate metabolizers exhibit moderately reduced activity, and normal metabolizers generally experience expected drug exposure. When genotype information is indeterminate or unavailable, standard dosing and clinical monitoring are recommended.

Ultrarapid Metabolizer

• Effect: Lower desipramine levels due to accelerated metabolism.
• Clinical consequence: Increased risk of treatment failure or inadequate response.
• Side effects: Uncommon; may experience minimal side effects because of reduced drug exposure.

Normal Metabolizer

• Effect: Expected desipramine levels and metabolism.
• Clinical consequence: Standard therapeutic benefit anticipated.
• Side effects: Typical TCA side effects (e.g., dry mouth, drowsiness) with moderate frequency.

Intermediate Metabolizer

• Effect: Moderately elevated desipramine levels due to reduced metabolism.
• Clinical consequence: Increased risk of dose-related side effects.
• Side effects: Mild to moderate anticholinergic effects (e.g., dry mouth, constipation) occurring occasionally.

Poor Metabolizer

• Effect: Significantly elevated desipramine levels due to greatly reduced metabolism.
• Clinical consequence: High risk of toxicity and adverse effects.
• Side effects: Severe anticholinergic effects (e.g., urinary retention, blurred vision), orthostatic hypotension; high frequency without dose adjustment.

Indeterminate/Not Available

• Effect: Unknown impact on desipramine levels.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Unknown; monitor for typical TCA adverse effects.

CYP2D6 Dosing Guideline

Examples of alternative antidepressants not primarily metabolized by CYP2D6 include selective serotonin reuptake inhibitors (SSRIs) like sertraline or citalopram, and atypical agents such as mirtazapine. These are provided as examples from CPIC guidelines and do not constitute medical advice.

• CPIC – Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19