Kronik Psikiyatrik Hastalıklarda Farmakogenetik
Özet
Farmakogenetik (PGt) ve farmakogenomik (PGx), genetik çeşitliliğin ilaçların güvenliği, etkinliği, doz optimizasyonu ve yan etkileri üzerindeki etkisini inceleyen, kişiselleştirilmiş tedavinin gelişiminde önemli rol oynayan bilim dallarıdır. İnsan Genom Projesi ve genom çapında ilişkilendirme çalışmaları (GWAS) sayesinde bu alandaki araştırmalar tek genlerden tüm genom düzeyine hızla evrilmiştir. Genetik çeşitliliğin en yaygın kaynağı tek nükleotid polimorfizmleridir (SNP). İlaç metabolizasyonunun, özellikle faz-I oksidasyon reaksiyonlarının yaklaşık %80'inde karaciğerdeki sitokrom P450 (CYP450) enzim ailesi görev alır. Bu genlerdeki polimorfizmler enzim aktivitesini değiştirerek zayıf (PM), orta düzey (IM), normal (EM) ve hızlı (UM) metabolizör fenotiplerini oluşturur; bu durum ilaç-gen etkileşimi yoluyla kişilerin ilaca verdiği yanıtı doğrudan etkiler. Psikiyatride advers olaylar, tedavi yanıtsızlığı ve çoklu ilaç kullanımı sık görülmekte olup, psikotropların metabolizması en çok yüksek oranda polimorfizm gösteren CYP2D6 ve CYP2C19 izoformları ile ilişkilidir. Ayrıca ilaç-ilaç ve çevresel faktörler (yaş, hastalıklar, sigara/nikotin kullanımı, diyet) de enzim aktivitesini etkiler. Günümüzde klinik pratikte CPIC, DPWG ve FDA gibi kuruluşlar, başta antidepresanlar, antipsikotikler ve ciddi kutanöz advers reaksiyon riski taşıyan duygudurum dengeleyicileri (HLA alelleri) için farmakogenetik dozaj ve tedavi kılavuzları yayımlamaktadır. Ancak test maliyetleri, standardizasyon eksikliği ve kanıtlardaki çelişkiler nedeniyle bu testlerin psikiyatride rutin kullanımı henüz sınırlıdır.
Pharmacogenetics (PGt) and pharmacogenomics (PGx) are scientific disciplines that investigate the impact of genetic diversity on drug safety, efficacy, dose optimization, and side effects, playing a crucial role in the development of personalized treatment. Thanks to the Human Genome Project and genome-wide association studies (GWAS), research in this field has rapidly evolved from single genes to the whole genome level. The most common source of genetic variation is single nucleotide polymorphisms (SNPs). The cytochrome P450 (CYP450) enzyme family in the liver is responsible for drug metabolism, particularly for approximately 80% of phase-I oxidation reactions. Polymorphisms in these genes alter enzyme activity, leading to poor (PM), intermediate (IM), normal (EM), and ultra-rapid (UM) metabolizer phenotypes, which directly affect individual drug responses through drug-gene interactions. Adverse events, treatment non-response, and polypharmacy are frequently encountered in psychiatry, and the metabolism of psychotropics is mostly associated with the highly polymorphic CYP2D6 and CYP2C19 isoforms. Additionally, drug-drug and environmental factors (age, diseases, smoking/nicotine use, diet) affect enzyme activity. Currently, organizations such as CPIC, DPWG, and FDA publish pharmacogenetic dosing and treatment guidelines, especially for antidepressants, antipsychotics, and mood stabilizers (HLA alleles) carrying risks for severe cutaneous adverse reactions. However, due to test costs, lack of standardization, and conflicting findings in evidence, the routine use of these tests in psychiatry is still limited.
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