Pharmacogenomic protocols in CNS disorders and dementia

Abstract

The application of genomic procedures as diagnostic and therapeutic tools is a major challenge for the coming decades. Pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. About 25% of the 100 most prescribed drugs in the USA and the EU are psychotropic drugs, currently used in dementia. Approximately 60-80% of CNS drugs are metabolized via enzymes of the CYP gene superfamily; 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 57.76% of patients with Alzheimer's disease are extensive metabolisers (EMs) for CYP2D6 enzymes, 31.06% are intermediate metabolisers (IMs), 5.28% are poor metabolisers (PMs), and 5.90% are ultrarapid metabolisers (UMs); 73.71% are CYP2C19-EMs, 25.12% IMs, and 1.16% PMs; 60.87% are CYP2C9-EMs, 34.16% IMs, and 4.97% PMs; 82.75% are CYP3A4/5-EMs, 15.88% IMs, and 1.37% UMs. A trigenic cluster integrating CYP2D6+CYP2C19+CYP2C9 polymorphic variants yields 82 different haplotype-like profiles, representing 36 different pharmacogenetic phenotypes in which only 26.51% of patients show a pure 3EM phenotype. These data clearly indicate that the incorporation of pharmacogenomic protocols to dementia research and clinical trials can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improve drug efficacy and safety.