Pharmacogenetics of Antipsychotics

Abstract

Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods:We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses.Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion:First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. W W W La pharmacogénétique des antipsychotiquesObjectif : Au cours des dernières décennies, des efforts croissants ont été déployés dans des études visant à percer l'influence des facteurs génétiques sur le dosage des antipsychotiques (AP), la réponse au traitement, et la survenue d'effets indésirables. Ces études voulaient améliorer les soins cliniques en prédisant le résultat du traitement par AP, et en donnant lieu ainsi à des stratégies de traitement individualisées. Nous présentons les résultats les plus importants obtenus par des études tant de gènes candidats que d'association pangénomique, notamment les facteurs pharmacocinétiques et pharmacodynamiques. Méthodes :Nous avons passé en revue les études sur la pharmacogénétique de la réponse aux AP et des effets indésirables publiées dans PubMed jusqu'au début de 2012. Vu le nombre élevé d'études publiées, notre revue a mis l'accent sur les résultats qui ont été reproduits dans des études indépendantes ou qui sont soutenus par des méta-analyses.

The Impact of Drug and Gene Interaction on the Antipsychotic Medication for Schizophrenia

“…The major enzymes that have been identified from the CYP family include CYP1A2, CYP2D6, CYP3A4 and CYP2C19. These enzymes are coded by highly polymorphic genes [11]. For instance, CYP2D6 contains over 60 alleles and 130 genetic variations due to combinations of single nucleotide polymorphisms (SNPs) and copy number variations.…”

Recent Advances in Application of Pharmacogenomics for Biotherapeutics

“…Furthermore, variations affecting therapeutic outcomes of these drugs are in genes required for their absorption, distribution, metabolism, or excretion. Thus, most of the early targets of this search for variations for Phase I enzymes (32)(33)(34)(35) or Phase II enzymes (36,37) transporters (36,(38)(39)(40)(41)(42)(43)(44) and receptors (45-53). However, there is a small but significant number of examples of application of PGx to BTs (Table II).…”

Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms

“…Изуче-ние антипсихотикиндуцированных экстрапирамидных расстройств крайне важно, так как они могут ухудшать качество жизни пациента, приводить к инвалидизации и низкой приверженности к лечению вплоть до отказа от него и соответственно к рецидиву заболевания [14]. Риск развития нейролептических побочных эффектов экстра-пирамидного спектра, естественно, не относится только к шизофрении, он возможен при лечении антипсихотика-ми и других заболеваний (расстройства шизофреническо-го спектра и обcессивно-компульсивные, нарушения по-ведения при деменции) [15].…”