Nortriptyline

Nortriptyline (brand name Pamelor) is a tricyclic antidepressant that has been used for decades to manage mood disorders. It is available in oral formulations and is typically prescribed under close medical supervision.

This medication is indicated primarily for the treatment of major depressive disorder. It may also be used off-label for chronic pain syndromes, migraine prophylaxis, and certain anxiety disorders. Its efficacy in these conditions is tied to its ability to modulate neurotransmitter levels.

Nortriptyline works by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin in the central nervous system. By blocking their reabsorption into presynaptic nerve terminals, nortriptyline increases the availability of these mood-regulating chemicals in the brain, which helps improve mood and reduce pain signals.

The primary gene affecting nortriptyline response is CYP2D6, a member of the cytochrome P450 family involved in drug metabolism. CYP2D6 converts nortriptyline into less active metabolites through demethylation and hydroxylation. Individuals inherit different versions of this gene, leading to variable enzyme activity.

Genetic variants in CYP2D6 define metabolizer categories—ranging from ultrarapid to poor—that influence how quickly nortriptyline is broken down. A “metabolizer” is simply how effectively your body processes a drug; for example, a poor metabolizer processes drugs slowly, leading to higher blood levels and increased risk of side effects.

Individuals with ultrarapid or rapid CYP2D6 activity clear nortriptyline too quickly, reducing its clinical effect. Normal metabolizers achieve expected blood levels and response. Intermediate and poor metabolizers have slower clearance, which raises plasma concentrations and heightens side effect risk. When genotype is indeterminate or not available, standard dosing with clinical monitoring is advised.

Ultrarapid Metabolizer

• Effect on drug levels: Decreased plasma concentrations due to rapid clearance.
• Clinical consequence: Increased risk of treatment failure and lack of efficacy.
• Side effects: Typically fewer adverse effects, but at the cost of insufficient symptom relief.

Normal Metabolizer

• Effect on drug levels: Plasma concentrations within expected therapeutic range.
• Clinical consequence: Likely to achieve intended antidepressant effect.
• Side effects: Standard side effect profile (dry mouth, dizziness) at usual frequency and severity.

Intermediate Metabolizer

• Effect on drug levels: Moderately increased plasma concentrations.
• Clinical consequence: Higher likelihood of side effects at standard doses.
• Side effects: Increased risk of anticholinergic and cardiovascular adverse events, generally mild to moderate.

Poor Metabolizer

• Effect on drug levels: Markedly elevated plasma concentrations due to slow clearance.
• Clinical consequence: High probability of dose-related side effects and toxicity.
• Side effects: Severe anticholinergic effects (e.g., dry mouth, blurred vision), cardiotoxicity; risk frequency is high.

Indeterminate/Not Available

• Effect on drug levels: Unknown impact due to insufficient or missing genetic data.
• Clinical consequence: No specific guidance; standard dosing is recommended.
• Side effects: Unknown; monitor clinically as with standard prescribing.

CYP2D6 Dosing Guidelines

When CYP2D6-related dosing is problematic or risk of failure is high, guidelines suggest considering antidepressants not primarily metabolized by CYP2D6. Examples include selective serotonin reuptake inhibitors (SSRIs) such as sertraline or escitalopram, serotonin–norepinephrine reuptake inhibitors (SNRIs) like venlafaxine, or other classes such as mirtazapine. These options serve as examples only and are not a substitute for professional judgment.

• CPIC – Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19