Venlafaxine

Venlafaxine, marketed under brand names Effexor and Effexor XR, is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant.

It is commonly prescribed for major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder.

Venlafaxine works by inhibiting the reuptake of serotonin and norepinephrine in the brain, increasing their availability in synaptic clefts and helping to improve mood and reduce anxiety.

The primary gene affecting venlafaxine metabolism is CYP2D6, a liver enzyme responsible for converting venlafaxine to its active metabolite O-desmethylvenlafaxine (desvenlafaxine).

Variations in CYP2D6 can alter enzyme activity, leading to differences in how quickly individuals convert venlafaxine into its active form. Metabolizer status ranges from poor to ultrarapid, affecting drug effectiveness and the risk of side effects.

Genetic variations in CYP2D6 result in distinct metabolizer phenotypes—ultrarapid, normal, intermediate, and poor—that influence venlafaxine and desvenlafaxine levels. Ultrarapid metabolizers may clear the drug too quickly, reducing efficacy, while poor metabolizers may have higher venlafaxine and lower active metabolite concentrations, potentially leading to increased side effects or altered therapeutic response.

Genotype-based metabolizer status for CYP2D6 can affect clinical outcomes with venlafaxine:

Ultrarapid Metabolizer

• Effect on drug levels: Faster conversion to active metabolite, potentially lower venlafaxine and higher desvenlafaxine levels.
• Clinical consequence: Efficacy impact unclear; may require monitoring for reduced therapeutic effect.
• Side effects: Insufficient evidence; no specific side effects established.

Normal Metabolizer

• Effect on drug levels: Balanced conversion; standard venlafaxine and desvenlafaxine levels.
• Clinical consequence: Typical therapeutic response at standard doses.
• Side effects: Standard adverse effect profile; common side effects include nausea, headache, and insomnia.

Intermediate Metabolizer

• Effect on drug levels: Slower conversion; slightly higher venlafaxine and lower desvenlafaxine levels.
• Clinical consequence: Likely similar efficacy to normal metabolizers but monitor for reduced effect.
• Side effects: No established increase; follow standard side effect monitoring.

Poor Metabolizer

• Effect on drug levels: Significantly reduced conversion; higher venlafaxine and lower desvenlafaxine levels.
• Clinical consequence: Increased risk of adverse effects and potentially reduced efficacy.
• Side effects: Higher risk of SNRI side effects such as hypertension, sweating, and dizziness; severity may be increased.

Indeterminate/Not Available

• Effect on drug levels: Unknown.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Not established; follow usual monitoring.

CYP2D6 Dosing Guideline

Examples of alternative antidepressants not primarily metabolized by CYP2D6 include sertraline and citalopram. These are suggestions from CPIC guidelines for informational purposes only; consult a healthcare professional for personalized recommendations.

• CPIC – Guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19
• FDA – Table of Pharmacogenetic Associations