11 Pharmacogenomics Effect of drug metabolizing enzymes on antidepressant drugs CYP2D6

Pharmacogenomics and Antidepressants

Overview of Pharmacogenomics

• Focuses on how drug metabolizing enzymes affect antidepressant effectiveness.

• Key enzymes: CYP2D6 and CYP2C19.

• Crystal structure studies of CYP2D6 (Rowland et al., 2006).

Objectives and Importance

• Understanding CYP2D6 polymorphisms and their clinical impacts on antidepressants.

• Enhance knowledge on pharmacogenomics and antidepressant drugs (CYP2D6, CYP2C19).

Clinical Efficacy of Antidepressants

• Randomized controlled trials indicate:

  • Only 35-45% of patients return to premorbid functioning after 6-8 weeks of standard antidepressant doses (Kirchheiner et al., 2004).

CYP2D6 and Antidepressant Dosing

• Recommended dosing considers population and subpopulation differences:

  • 7-10% Caucasians are poor metabolizers, 40% are intermediate, and 50% are extensive metabolizers.

  • Average dose calculations:

    • Formula: Dave = 0.1DPM + 0.4DIM + 0.5DEM.

Sites of Action for Antidepressants

• Tricyclic antidepressants (TCAs) and their mechanisms, focusing on NET and SERT activities:

  • Examples: imipramine, desipramine, amitriptyline, nortriptyline.

Metabolism of Tricyclic Antidepressants

• Key metabolic pathways in the liver include:

  • N-demethylation and ring hydroxylation processes retaining biological activity.

Genetic Variability in CYP Enzymes

Metabolizer Classifications

• Ultrarapid Metabolizers (UM): > 2 active genes.

• Extensive Metabolizers (EM): 2 functional genes.

• Intermediate Metabolizers (IM): One functional and one defective allele.

• Poor Metabolizers (PM): No functional enzymes (defects or deletions).

CYP2D6 Genetic Polymorphisms

• Various mutations affect enzyme activity:

  • *1 (Wild-type): Normal activity.

  • *3, *4, *5 (Inactive): Variable frequencies in populations.

  • *2xn (Increased activity): Gene duplications observed.

CYP2C19 and its Role in Antidepressants

• Catalyzes selective 4-hydroxylation of S-mephenytoin.

• Polymorphisms include:

  • *2A and *3A: Resulting in no enzyme activity (poor metabolizers).

Population Data on CYP2C19

• Poor metabolizer frequencies:

  • 13-23% in Asian populations.

  • 2-5% in Caucasians.

Other Factors Influencing Antidepressant Response

• Variability may arise from:

  • 5-HT receptors.

  • NET (SLC6A2) and adrenergic receptors.

• Limited available information on these influences.