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.

PURPOSE: 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 EMs (0.56 (95%CI: 0.26-0.74)). 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.

Polymorphic drug metabolism (CYP2D6) and utilisation of psychotropic drugs in hospitalised psychiatric patients: a retrospective study.

AIM: The aim of the current retrospective study was to assess the influence of polymorphic drug metabolism as assessed by genotyping, on the on the utilisation of psychotropic drugs in hospitalised psychiatric patients. The utilisation of psychotropic drugs was assessed using pharmacy records with emphasis on the number of prescriptions and prescriptions for possible side effects. METHODS: CYP2D6 genotype was assessed in 241 psychiatric patients by investigation for the five most common allelic variants ( CYP2D6*3, *4, *6, *7, *8) and the presence of gene duplication using allele-specific polymerase chain reaction. Data concerning the pharmacotherapy of the patients were retrieved from the pharmacy information system. Data was analysed on differences observed in pharmacy records concerning the different metabolic classes: ultra rapid metabolisers (UMs), extensive metabolisers (EMs) and poor metabolisers (PMs). RESULTS: For CYP2D6, 2.5% was UM (95% CI: 0.5-4.5%, n=6) and 8.3% was PM (95% CI: 4.8-11.8%, n=20). Drugs metabolised by CYP2D6 were less frequently prescribed in PMs than EMs (21.1% vs 33.6%, P=0.023). The average duration of prescriptions was significantly lower in PMs than EMs (54 days vs 106 days, P=0.010). Between UMs and EMs, no significant differences were found, although a similar tendency was observed. With regard to dose, no consistent differences were observed between the CYP2D6 genotype classes. Drugs against Parkinsonian-like side effects were given twice as frequently in PMs as EMs (6.9% vs 3.4%, P=0.045). CONCLUSIONS: Patients with impaired CYP2D6 metabolism received fewer CYP2D6 drugs. PMs were more prone to Parkinsonian-like side effects as evidenced by more prescriptions for drugs combating these side effects. Dose titrations were not often used to compensate for genetic polymorphisms. Pharmacy records might be a useful tool to detect differences related to polymorphic metabolism.