Pharmacogenomic Biomarkers in Neuropsychiatry: The Path to Personalized Medicine in Mental Disorders

Neuropsychiatric disorders and dementia represent a major cause of disability and high cost in developed societies. Most disorders of the central nervous system (CNS) share some common features, such as a genomic background in which hundreds of genes might be involved, genome-environment interactions, complex pathogenic pathways, poor therapeutic outcomes, and chronic disability. Recent advances in genomic medicine can contribute to accelerate our understanding on the pathogenesis of CNS disorders, improve diagnostic accuracy with the introduction of novel biomarkers, and personalize therapeutics with the incorporation of pharmacogenetic and pharmacogenomic procedures to drug development and clinical practice. The pharmacological treatment of CNS disorders, in general, accounts for 10–20% of direct costs, and less than 30–40% of the patients are moderate responders to conventional drugs, some of which may cause important adverse drugs reactions (ADRs). Pharmacogenetic and pharmacogenomic factors may account for 60–90% of drug variability in drug disposition and pharmacodynamics. 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 10–20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism of many psychotropic agents. Other 100 genes participate in the efficacy and safety of psychotropic drugs. The incorporation of pharmacogenetic/ pharmacogenomic protocols to CNS research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety. To achieve this goal several measures have to be taken, including: (a) educate physicians and the public on the use of genetic/ genomic screening in the daily clinical practice; (b) standardize genetic testing for major categories of drugs; (c) validate pharmacogenetic and pharmacogenomic procedures according to drug category and pathology; (d) regulate ethical, social, and economic issues; and (e) incorporate pharmacogenetic and pharmacogenomic procedures to both drugs in development and drugs in the market to optimize therapeutics.