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Atomoxetine

Psychostimulants

Drug Overview

Atomoxetine (brand name Strattera) is a non-stimulant medication approved for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults.

It is used to manage core ADHD symptoms such as inattention, hyperactivity, and impulsivity when stimulant medications are not suitable or have been ineffective.

Atomoxetine works by selectively inhibiting the presynaptic norepinephrine transporter in the central nervous system, increasing extracellular norepinephrine levels and improving neuronal signaling associated with attention and impulse control.

Relevant Genes and Their Roles

The primary gene affecting atomoxetine response is CYP2D6. CYP2D6 encodes an enzyme in the liver responsible for metabolizing atomoxetine into inactive compounds. Variations in this gene alter the speed at which the drug is cleared from the body.

Genetic variants of CYP2D6 define metabolizer phenotypes—poor, intermediate, normal, and ultrarapid—that determine enzyme activity levels. Metabolizer status influences both drug efficacy and risk of side effects by modulating atomoxetine exposure.

Impact of Genetics on Drug Response

CYP2D6 metabolizer status influences atomoxetine exposure: ultrarapid metabolizers clear the drug quickly and may not achieve therapeutic levels, while poor metabolizers clear it slowly and may have higher drug concentrations, increasing both efficacy and risk of side effects. Intermediate and normal metabolizers exhibit intermediate exposures, with corresponding clinical effects and dosing considerations.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect on drug levels: Significantly increased clearance of atomoxetine, leading to lower blood levels.
  • Clinical consequence: Reduced efficacy; subtherapeutic response at standard doses.
  • Side effects: Generally fewer side effects due to low exposure; efficacy may be inadequate.

Normal Metabolizer

  • Effect on drug levels: Expected clearance and blood levels within the typical therapeutic range.
  • Clinical consequence: Standard efficacy and tolerability at recommended doses.
  • Side effects: Common side effects such as gastrointestinal upset and insomnia; generally mild to moderate and infrequent.

Intermediate Metabolizer

  • Effect on drug levels: Slower clearance than normal, resulting in moderately increased blood levels.
  • Clinical consequence: Potential for increased response and slight increase in risk of side effects.
  • Side effects: Similar to normal metabolizers but may experience mild to moderate side effects more frequently (e.g., dry mouth, dizziness).

Poor Metabolizer

  • Effect on drug levels: Markedly reduced clearance, causing high blood levels of atomoxetine.
  • Clinical consequence: Enhanced efficacy but increased risk of adverse effects; may require lower doses.
  • Side effects: Higher likelihood of adverse reactions such as increased heart rate, elevated blood pressure, and significant insomnia; severity can be moderate to severe.

Indeterminate/Not Available

  • Effect on drug levels: Unknown.
  • Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
  • Side effects: Cannot be predicted based on genotype; monitor clinically.

Dosing Guidelines

The following dosing guidelines are based on the available guidelines for CYP2D6 genotype from the Clinical Pharmacogenetics Implementation Consortium (CPIC).

CYP2D6 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer Your body clears this medicine very quickly, so you may need a higher dose to get the right effect. Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml. Dosages greater than 100 mg/day may be needed to achieve target concentrations.
Normal Metabolizer You may need a higher dose or monitoring if the medication isn’t working well. Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml. Dosages greater than 100 mg/day may be needed to achieve target concentrations.
Intermediate Metabolizer Your body processes this drug more slowly, so you may need lower doses or careful adjustments. Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks, consider obtaining a plasma concentration 2–4 hours after dosing. If concentration is <200 ng/ml, consider a proportional dose increase to approach 400 ng/ml. If unacceptable side effects are present at any time, consider a reduction in dose.
Poor Metabolizer Your body processes this drug very slowly, so you may need a lower dose and close monitoring to avoid side effects. Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks, consider obtaining a plasma concentration 2–4 hours after dosing. If concentration is <200 ng/ml, consider a proportional dose increase to approach 400 ng/ml. If unacceptable side effects are present at any time, consider a reduction in dose.
Indeterminate / Not available Unknown impact Initiate therapy with recommended starting dose.

Alternative Treatment Options

The CPIC and FDA guidelines do not specify alternative drugs for atomoxetine based on CYP2D6 genotype. As examples used in clinical practice, other ADHD treatments such as methylphenidate or amphetamine-based stimulants may be considered depending on individual response and tolerability. This information is provided for illustration and should not be taken as specific medical advice.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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