Sertraline Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Sertraline (brand name Zoloft) is a prescription medication in the selective serotonin reuptake inhibitor (SSRI) class. It is commonly prescribed for a variety of mood and anxiety disorders.

Sertraline is approved to treat major depressive disorder, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social anxiety disorder, and premenstrual dysphoric disorder (PMDD). It helps improve mood, sleep, appetite, and energy level while decreasing nervousness.

As an SSRI, sertraline works by blocking the reuptake of serotonin, a neurotransmitter, in the brain. This increases serotonin levels in the synaptic cleft and enhances communication between nerve cells, supporting improved mood and reduced anxiety.

Relevant Genes and Their Roles

Two liver enzymes, CYP2C19 and CYP2B6, play key roles in the metabolism of sertraline. CYP2C19 is primarily responsible for converting sertraline into less active compounds, while CYP2B6 also contributes to its metabolic breakdown. Both belong to the cytochrome P450 family of enzymes, which process many drugs.

Genetic variations in these enzymes can speed up or slow down sertraline clearance. People with faster versions (ultrarapid or rapid metabolizers) may have lower drug levels, potentially reducing effectiveness. Those with slower versions (intermediate or poor metabolizers) can have higher drug levels, increasing the risk of side effects. Understanding these differences can guide safer and more effective dosing.

Impact of Genetics on Drug Response

Depending on their CYP2C19 and CYP2B6 metabolizer status, patients may process sertraline more quickly or slowly than average. Ultrarapid and rapid metabolizers clear the drug faster, which may lead to subtherapeutic concentrations and reduced benefit. Intermediate and poor metabolizers clear the drug more slowly, increasing exposure and the potential for adverse effects. Knowing a patient’s metabolizer phenotype helps tailor dosing or consider alternative therapies.

Expected Clinical Effects of Genetic Variation

Ultrarapid/Rapid Metabolizer

Effect on drug levels: Lower than expected plasma concentrations
Clinical consequence: Possible reduced treatment efficacy
Side effects: Generally fewer or milder side effects due to lower exposure

Normal Metabolizer

Effect on drug levels: Expected therapeutic concentrations
Clinical consequence: Standard efficacy and safety profile
Side effects: Typical side effect frequency and severity as described in the drug label

Intermediate Metabolizer

Effect on drug levels: Moderately higher plasma concentrations
Clinical consequence: Potential for improved efficacy but increased side effect risk
Side effects: Mild to moderate side effects (e.g., nausea, headache) more likely

Poor Metabolizer

Effect on drug levels: Significantly elevated plasma concentrations
Clinical consequence: Higher risk of adverse effects and toxicity
Side effects: More severe side effects (e.g., increased anxiety, insomnia, gastrointestinal issues)

Indeterminate/Not Available

Effect on drug levels: Unknown
Clinical consequence: No specific guidance; follow standard dosing
Side effects: Monitor clinically for any unexpected reactions

Dosing Guidelines

The following dosing guidelines are based on CPIC recommendations for sertraline and take into account CYP2C19 and CYP2B6 metabolizer status.

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Your body processes this drug slightly faster than average, but no dose change is needed.	Initiate therapy with recommended starting dose.
Rapid Metabolizer	Your body processes this drug slightly faster than average, but no dose change is needed.	Initiate therapy with recommended starting dose.
Normal Metabolizer	You can use the normal recommended dose for this medication.	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Your body processes this drug more slowly, so doctors may adjust the dose more carefully.	Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.
Likely Intermediate Metabolizer	Your body processes this drug more slowly, so doctors may adjust the dose more carefully.	Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.
Poor Metabolizer	Your body processes this drug much more slowly, so you may need a lower dose to avoid side effects.	Consider a lower starting dose, slower titration, and 50% reduction of maintenance dose or select an alternative not predominantly metabolized by CYP2C19.
Likely Poor Metabolizer	Your body processes this drug much more slowly, so you may need a lower dose to avoid side effects.	Consider a lower starting dose, slower titration, and 50% reduction of maintenance dose or select an alternative not predominantly metabolized by CYP2C19.
Indeterminate	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.
Not available	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.

CYP2B6 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Your body processes this drug a bit faster, but no dose change is usually needed.	Initiate therapy with recommended starting dose.
Rapid Metabolizer	Your body processes this drug a bit faster, but no dose change is usually needed.	Initiate therapy with recommended starting dose.
Normal Metabolizer	You can use the normal recommended dose for this medication.	Initiate therapy with recommended starting dose.
Intermediate Metabolizer	Your body processes this drug more slowly, so your doctor may adjust the dose more carefully.	Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose.
Poor Metabolizer	Your body processes this drug much more slowly, so you may need a lower dose to avoid side effects.	Consider a lower starting dose, slower titration, and 25% reduction of maintenance dose or select an alternative not predominantly metabolized by CYP2B6.
Indeterminate	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.

Alternative Treatment Options

For patients who are poor metabolizers of CYP2C19 or CYP2B6, CPIC guidelines suggest considering an antidepressant not primarily metabolized by these enzymes. Examples may include fluoxetine or paroxetine for CYP2C19 poor metabolizers, and bupropion or mirtazapine for CYP2B6 poor metabolizers. These are provided as examples from guidelines, not as direct medical advice.

Sources and References

CPIC – CPIC Guideline for SSRI and SNRI Antidepressants