CYP1A2 expression rather than genotype is associated with olanzapine concentration in psychiatric patients

Fekete, Ferenc; Menus, Ádám; Tóth, Katalin; Kiss, Ádám Ferenc; Minus, Annamária; Sirok, Dávid; Belič, Aleš; Póti, Ádám; Csukly, Gábor; Monostory, Katalin

doi:10.1038/s41598-023-45752-6

Cited by 5 publications

(1 citation statement)

References 82 publications

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“…As not all studies were significant or concordant, these results should also be taken with caution. Since CYP1A2 is the main metabolic enzyme involved in olanzapine metabolism and our patient was homozygous for the CYP1A2 *1F polymorphism, it is more likely that the response to olanzapine treatment or the need for higher doses is related to this polymorphism, which is located in the promoter region of CYP1A2 gene and increases the inducibility of the gene and thus its expression ( 41 ). This leads to increased olanzapine metabolism and a poorer response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Case report: Avoiding intolerance to antipsychotics through a personalized treatment approach based on pharmacogenetics

Korošec Hudnik,

Blagus,

Redenšek Trampuž

et al. 2024

Front. Psychiatry

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IntroductionThe standard approach to treatment in psychiatry is known as “treatment as usual” (TAU), in which the same types of treatment are administered to a group of patients. TAU often requires numerous dose adjustments and medication changes due to ineffectiveness and/or the occurrence of adverse drug reactions (ADRs). This process is not only time-consuming but also costly. Antipsychotic medications are commonly used to treat various psychiatric disorders such as schizophrenia and mood disorders. Some of the inter-individual differences in efficacy and ADRs observed in psychopharmacotherapy can be explained by genetic variability in the pharmacokinetics and pharmacodynamics of antipsychotics. A better understanding of (in)efficacy and possible ADRs can be achieved by pharmacogenetic analysis of genes involved in the metabolism of antipsychotics. Most psychotropic drugs are metabolized by genetically variable CYP2D6, CYP1A2, CYP3A4, and CYP2C19 enzymes. To demonstrate the utility of pharmacogenetic testing for tailoring antipsychotic treatment, in this paper, we present the case of a patient in whom a pharmacogenetic approach remarkably altered an otherwise intolerant or ineffective conventional TAU with antipsychotics.MethodsIn this case report, we present a 60-year-old patient with psychotic symptoms who suffered from severe extrapyramidal symptoms and a malignant neuroleptic syndrome during treatment with risperidone, fluphenazine, aripiprazole, brexpiprazole, and olanzapine. Therefore, we performed a pharmacogenetic analysis by genotyping common functional variants in genes involved in the pharmacokinetic pathways of prescribed antipsychotics, namely, CYP2D6, CYP3A4, CYP3A5, CYP1A2, ABCB1, and ABCG2. Treatment recommendations for drug–gene pairs were made according to available evidence-based pharmacogenetic recommendations from the Dutch Pharmacogenetics Working Group (DPWG) or Clinical Pharmacogenetics Implementation Consortium (CPIC).ResultsPharmacogenetic testing revealed a specific metabolic profile and pharmacokinetic phenotype of the patient, which in retrospect provided possible explanations for the observed ADRs. Based on the pharmacogenetic results, the choice of an effective and safe medication proved to be much easier. The psychotic symptoms disappeared after treatment, while the negative symptoms persisted to a lesser extent.ConclusionWith the case presented, we have shown that taking into account the pharmacogenetic characteristics of the patient can explain the response to antipsychotic treatment and associated side effects. In addition, pharmacogenetic testing enabled an informed choice of the most appropriate drug and optimal dose adjustment. This approach makes it possible to avoid or minimize potentially serious dose-related ADRs and treatment ineffectiveness. However, due to the complexity of psychopathology and the polypharmacy used in this field, it is of great importance to conduct further pharmacokinetic and pharmacogenetic studies to better assess gene–drug and gene–gene–drug interactions.

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Section: Discussionmentioning

confidence: 99%

Case report: Avoiding intolerance to antipsychotics through a personalized treatment approach based on pharmacogenetics

Korošec Hudnik,

Blagus,

Redenšek Trampuž

et al. 2024

Front. Psychiatry

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Clinical effects of CYP2D6 phenoconversion in patients with psychosis

De Brabander,

Breddels,

van Amelsvoort

et al. 2024

J Psychopharmacol

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Background: Pharmacogenetics is considered a promising avenue for improving treatment outcomes, yet evidence arguing for the use of pharmacogenetics in the treatment of psychotic disorders is mixed and clinical usefulness is under debate. Many patients with psychosis use multiple medications, which can alter the metabolic capacity of CYP enzymes, a process called phenoconversion. In clinical studies, treatment outcomes of drugs for psychosis management may have been influenced by phenoconversion. Aim: Here we evaluate the impact and predictive value of CYP2D6 phenoconversion in patients with psychotic disorders under pharmacological treatment. Method: Phenoconversion-corrected phenotype was determined by accounting for inhibitor strength. Phenoconversion-corrected and genotype-predicted phenotypes were compared in association with side effects, subjective well-being and symptom severity. Results: Phenoconversion led to a large increase in poor metabolizers (PMs; 17–82, 16% of sample), due to concomitant use of the serotonin reuptake inhibitors fluoxetine and paroxetine. Neither CYP2D6-predicted nor phenoconversion-corrected phenotype was robustly associated with outcome measures. Risperidone, however, was most affected by the CYP2D6 genotype. Conclusion: Polypharmacy and phenoconversion were prevalent and accounted for a significant increase in PMs. CYP2D6 may play a limited role in side effects, symptoms and well-being measures. However, due to the high frequency of occurrence, phenoconversion should be considered in future clinical trials.

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Tug of war between clozapine and CYP450 inducers: A case report

Taneja,

Leontieva

2024

SAGE Open Medical Case Reports

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The management of schizoaffective disorder bipolar type often involves a combination of pharmacotherapy and psychotherapy. Clozapine, an effective antipsychotic for treatment-resistant schizophrenia, and oxcarbazepine, a mood stabilizer, is a commonly prescribed medication. We present a case report of a 56-year-old male with schizoaffective disorder bipolar type who experienced subtherapeutic clozapine levels despite dose adjustments, leading to deteriorating symptoms. Oxcarbazepine, a weak CYP450 inducer, likely contributed to the subtherapeutic levels. Additionally, the pharmacogenetic analysis revealed a CYP1A2 *1F/*1F genotype, indicating normal activity with a potential for decreased serum levels and adverse events in the presence of inducers. The patient was eventually stabilized on a regimen of lithium, paliperidone, and quetiapine, avoiding oxcarbazepine. This case highlights the importance of considering individual patient factors, including pharmacogenetics when managing treatment-resistant patients. Monitoring serum clozapine levels and assessing enzyme activity before initiating therapy may help optimize treatment outcomes and minimize adverse events.

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CYP1A2 expression rather than genotype is associated with olanzapine concentration in psychiatric patients

Cited by 5 publications

References 82 publications

Case report: Avoiding intolerance to antipsychotics through a personalized treatment approach based on pharmacogenetics

Case report: Avoiding intolerance to antipsychotics through a personalized treatment approach based on pharmacogenetics

Clinical effects of CYP2D6 phenoconversion in patients with psychosis

Tug of war between clozapine and CYP450 inducers: A case report

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