engleski

Pharmacogenomics in psychiatry

Pharmacogenomics investigations in psychiatry attempt to define the impact that genetic polymorphisms have on positive and adverse reactions to psychotropic drugs. Candidate pharmacokinetics’ genes are these of drug– metabolizing enzymes and membrane drug transporters, while on pharmacodynamics’ part these are genes encoding drug targets: elements of neurotransmitter pathways such as transporters and receptors. The most important enzymes involved in the metabolism of psychotropic drugs are CYP2D6, CYP2C19, CYP1A2 and CYP3A4. P-glycoprotein, coded by polymorphic MDR1/ABCB1 is recognized to be important in regulating access of therapeutic agents to the brain and other tissues, and thus has pharmacogenetic relevance. At pharmacodynamic level, polymorphic serotonin transporter (SERT), as the main target of many antidepressant drugs, could also be an attractive candidate for psychopharmacotherapy outcome assessments. Lot of research have been undertaken to provide a better understanding of the genetic factors involved in weight gain and metabolic disturbances associated with second generation antipsychotics treatment. Notwithstanding the large effects of pharmacogenetic polymorphisms on the kinetics of psychotropic drugs, individual response is still poorly characterized due to insufficient knowledge of pharmacodynamics mechanisms. Genetics is only one of many variables (environmental, personal) adding to the complexity of drug response. For some drugs, genetics may be extremely important in most patients, while in others it may be irrelevant when compared with environmental factors. Genetic testing may be crucial for understanding some rare (“outliers”) patients’ drug response. In psychiatry, two types of pharmacogenetic tests are ready for clinical practice: CYP2D6 and CYP2C19 testing for some antidepressants and antipsychotics, mostly for dosing, and HLA testing to rule out carbamazepine for some Asian patients. Other tests offered to psychiatrists in the US and in few European countries for genotyping of multiple CYPs and pharmacodynamic genes have limited data on clinical validity/utility. As therapeutic drug monitoring (TDM) identifies phenoconversion due to inhibitors/inducers, it is crucial to conjointly implement TDM and pharmacogenetic testing in order to advance personalized dosing. Educating health professionals in how to use pharmacogenetic tests for drug selection/dosing in the context of other factors such as environmental and personal factors and pharmacological mechanisms is important task, due to limited pharmacological training in medical schools.

psychotropic drugs; metabolic enzymes; CYP2D6; CYP2C19; SERT

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