Amitriptyline or Not, That Is the Question: Pharmacogenetic Testing of CYP2D6 and CYP2C19 Identifies Patients with Low or High Risk for Side Effects in Amitriptyline Therapy

Abstract

Background: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. Methods: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. Results: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >5; area under the curve, 0.733; P ‫؍‬ 0.008). Carriers of two functional CYP2D6 alleles had a

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

“…Accordingly, no significant differences in response rates were found for the different CYP2D6 metabolizer groups in previous studies. 25,26 CYP2D6-medicated IMs showed also less response than IMs treated with other drugs after 4 weeks of treatment (3/ 42, 7% vs 21/84, 25%, P ¼ 0.017). The lower response may be due to the higher adverse effects frequency of IMs under CYP2D6 medication.…”

“…Similarly, no correlation between drug concentrations or genotypes and therapeutic response of amitriptyline-treated patients was found previously, though a correlation with side effects was observed. 26 This implies that dose reduction due to side effects as proposed for IMs does not interfere with the efficacy of treatment.…”

“…The associations found should be replicated in larger, more controlled settings. Additional monitoring of drug concentrations as the link between CYP2D6 metabolic status and clinical response as exemplified in a previous study on amitriptyline 26 would be useful.…”

Psicofarmacogenética

“…Outros estudos subseqüentes definiram que o número de cópias do gene determinaria a dose individualmente dos inibidores da recaptação de serotonina e ainda relacionando o nú-mero de cópias com a presença de efeitos cardiovasculares e toxicidade 10,11 .…”

Pharmacogenetics as Personalized Medicine: Association Investigation of SOD2 Rs4880, CYP2C19 Rs4244285 and FCGR2A Rs1801274 Polymorphisms with Breast Cancer Population in Iraqi Women

“…Pharmacogenetics has been defined as the science of pharmacological response and its modification by hereditary influence; the subjects of interest relate both to efficacy (therapeutic effectiveness) and toxicity (production of side effects or unwanted effects) [8]. Dealing with the genetic basis which underlies variable drug response in individual patients, it develops an individualized approach to the therapy, where optimally effective drugs are matched to a patient's unique genetic profile [9].…”