Abstract
Antipsychotic drugs are the neuroleptics currently used in the treatment of schizophrenia (SCZ) and psychotic disorders. SCZ has a heritability estimated at 70% - 90%; and pharmacogenomics accounts for 60% - 90% variability in the pharmacokinetics and pharmacodynamics of psychotropic drugs. Personalized therapeutics based on individual genomic profiles in SCZ entails the characterization of 5 types of gene clusters and their related metabolomic profiles: 1) genes associated with disease pathogenesis; 2) genes associated with the mechanism of action of drugs; 3) genes associated with drug metabolism (phase I and II reactions); 4) genes associated with drug transporters; and 5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single-nucleotide polymorphisms in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4. About 10% - 20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6 + CYP2C19 + CYP2C9 genes. Efficacy and safety issues in the pharmacological treatment of SCZ are directly linked to genetic clusters involved in the pharmacogenomics of antipsychotic drugs and also to environmental factors. Consequently, the incorporation of pharmacogenomic procedures both to drugs under development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system disorders.
Highlights
Central nervous system (CNS) disorders are the third greatest problem of health in developed countries, representing 10% - 15% of deaths after cardiovascular disorders (25%) and cancer (20%)
Personalized therapeutics based on individual genomic profiles in SCZ entails the characterization of 5 types of gene clusters and their related metabolomic profiles: 1) genes associated with disease pathogenesis; 2) genes associated with the mechanism of action of drugs; 3) genes associated with drug metabolism; 4) genes associated with drug transporters; and 5) pleiotropic genes involved in multifaceted cascades and metabolic reactions
The genes involved in the pharmacogenomic response to drugs in CNS disorders may fall into five major categories: 1) genes associated with CNS pathogenesis; 2) genes associated with the mechanism of action of drugs; 3) genes associated with drug metabolism; 4) genes associated with drug transporters; and 5) pleiotropic genes involved in multifaceted cascades and metabolic reactions [2]
Summary
Central nervous system (CNS) disorders are the third greatest problem of health in developed countries, representing 10% - 15% of deaths after cardiovascular disorders (25%) and cancer (20%). Potential reasons to explain this historical setback might be that: 1) the molecular pathology of brain disorders is still poorly understood; 2) drug targets are inappropriate, not fitting into the real etiology of the disease; 3) most treatments are symptomatic, but not anti-pathogenic; 4) the genetic component of CNS disorders is poorly defined; and 5) the understanding of genome-drug interactions is very limited [2,4,5,6]. A growing body of fresh knowledge on the pathogenesis of CNS disorders, together with data on neurogenomics and pharmacogenomics, is emerging in recent times The incorporation of this new armamentarium of molecular pathology and genomic medicine to daily medical practice, together with educational programs for the correct use of drugs, must help to: 1) understand brain pathogenesis; 2) establish an early diagnosis; and 3) optimize therapeutics either as a preventive strategy or as a formal symptomatic treatment [2,5,6,13,14]. Have demonstrated that the efficacy and safety of antipsychotics are closely related to the pharmacogenomic profiles of schizophrenic patients [1,17,22]
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