Although several factors, such as age, gender, body fat, alcohol intake, and nicotine consumption, account for the patient-topatient differences, there is increasing evidence that genetic factors also underlie the differences in psych opharmacological drug response.114,115 This hypothesis is further supported by observations of comparable responses to antidepressant therapy among relatives.116 Thus, the concept of pharmacogenetics as originally defined by Vogel 1959,117 which means heritable differences in metabolism and activity of exogenous agents, might help unravel the variability in Inhibitors,research,lifescience,medical drug response

and metabolism. Relevant genetic polymorphisms are found in drugmetabolizing enzymes, neurotransmitter Inhibitors,research,lifescience,medical receptors, and transport proteins. These variants result in no effect or in a change in the rate of metabolism, as well as in these altered protein binding and/or function.118 Accordingly, most studies focus on the cytochrome P-450 isoenzymes (CYP), neurotransmitter receptors, and selective transporters, following the hypotheses Inhibitors,research,lifescience,medical of pathophysiological and drug action mechanisms. However, newer concepts such as the drug’s site of action, the signal transduction cascade,

or neuropeptides are also gaining importance in this field of research. Metabolizing enzymes have long been recognized as a major source of pharmacokinetic variability, since they influence the interindividual variation in elimination rates, steady-state concentrations, and biotransformation. More than 30 isoforms of the cytochrome P-450 isoenzymes Inhibitors,research,lifescience,medical are known today, but few have clinical significance in psychiatry: CYP3A, CYP2D6, CYP2C19, and CYP2C9.118 Different drugs are metabolized by different enzymes and variants in these genes can lead to three possible phenotypes: poor metabolizers (PM), normal metabolizers (NM), and extensive metabolizers (EM). About 7% of Caucasians, 1% of Asians, and 7% to 8% of Africans are classified as PM, who might exhibit

increased concentrations Inhibitors,research,lifescience,medical of metabolized drugs at conventional doses.119 Genotyping of metabolizing enzymes might have clinical implications, as combinations of drugs that are metabolized by one enzyme may lead to dangerous pharmacokinetic interactions, particularly in Dacomitinib PMs.120 Thus, the knowledge of an individual’s metabolic rate will help adjust therapeutic doses or combinations accordingly. The genetic basis of pharmacodynamic variability is becoming a focus of future research. Interesting directions include variants in genes that regulate monoamine uptake, the function of receptors, or the events of the signal transduction cascade.30 Although many investigations have shown that genetic variations in target proteins influence their interaction with psychotropic drugs, these results are still inconclusive and far from the original concept of tailoring the drug regimen to an individual’s predisposition and predicting a patient’s response to therapeutic agents.