The impact of Cytochrome P450‐2D6 genotype on the use and interpretation of therapeutic drug monitoring in long‐stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice

Abstract

SUMMARYPurpose This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. Methods The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. Results For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to ). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. Conclusions CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.

Roles of polymorphic enzymes CYP2D6 and CYP2C19 for in vitro metabolism of amitriptyline at therapeutic and toxic levels

“…Poor metabolizer (PM) status with respect to CYP2D6 (CYP2D6 PM) has been associated with increased plasma concentrations of antidepressants as compared with extensive metabolizers (EM) [5]. For the tricyclic antidepressant amitriptyline, Mellstrom et al [7] found that the amitriptyline clearance is correlated with a debrisoquine/4-OH-debrisoquine ratio (indicating CYP2D6 metabolizer status) in a single-dose study.…”

“…There has been considerable focus on the role of the polymorphic cytochrome P450 (CYP) enzymes CYP2D6 and CYP2C19 for the metabolism of important drug classes such as antidepressants and antipsychotics [1][2][3][4][5][6]. Poor metabolizer (PM) status with respect to CYP2D6 (CYP2D6 PM) has been associated with increased plasma concentrations of antidepressants as compared with extensive metabolizers (EM) [5].…”

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

“…Due to absent CYP2D6-mediated metabolism, PMs have higher plasma concentrations of antidepressants metabolized by CYP2D6 than EMs [8] and are therefore more likely to suffer from dose-dependent adverse drug reactions (ADRs). Especially in patients taking TCAs, PMs may experience cardiotoxicity and other severe ADRs, because TCAs have a narrow therapeutic range.…”

Can the genotype or phenotype of two polymorphic drug metabolising cytochrome P450-enzymes identify oral lichenoid drug eruptions?

“…Likewise, we found that the patients with one fully functional allele and a PM‐allele had a statistically significant higher MR vs. patients with two fully functional alleles for both sparteine and mephenytoin. The clinical relevance of differentiating among CYP IM‐genotypes and CYP EM‐genotypes may be relevant when the patient is chronically medicated because of possible drug accumulation (43). There were no statistical differences between the CYP‐genotype or ‐phenotype subgroups in the distribution of systemic diseases/medical conditions and exposure to drugs and polypharmacy.…”