Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants

Br J Clin Pharmacol. 2008 Apr;65(4):558-64. doi: 10.1111/j.1365-2125.2007.03052.x. Epub 2007 Dec 7.


What is already known about this subject: * Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. * Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients.

What this study adds: * This large population-based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6*4 polymorphism on intolerability of antidepressants. * The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs). * Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy.

Aims: To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy.

Methods: The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses.

Results: In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02).

Conclusions: The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.

MeSH terms

  • Aged
  • Amitriptyline / administration & dosage
  • Amitriptyline / pharmacokinetics*
  • Antidepressive Agents, Tricyclic / administration & dosage
  • Antidepressive Agents, Tricyclic / pharmacokinetics*
  • Body Weight / drug effects
  • Cohort Studies
  • Cytochrome P-450 CYP2D6 / drug effects
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Drug Administration Schedule
  • Drug Monitoring*
  • Female
  • Genotype
  • Humans
  • Male
  • Netherlands
  • Polymorphism, Genetic / drug effects*
  • Polymorphism, Genetic / genetics
  • Treatment Outcome
  • Treatment Refusal / psychology


  • Antidepressive Agents, Tricyclic
  • Amitriptyline
  • Cytochrome P-450 CYP2D6