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The response of individual patients to the same drug given in the same dose varies considerably. Many patients will experience the desired drug effect, others may experience no effects, yet others may suffer from well-known adverse drug reactions, and very rarely individual patients will die from severe side effects. Phenotyping The rapid advances in pharmacogenetic knowledge and genotyping methodology however provide a basis and challenge for clinical studies on the role and usefulness of pharmacogenetic testing in clinical psychiatry. Using modern DNA amplification techniques, genotyping allows characterization of many significant CYP genes with only a single venous blood sample. However, genotyping is only clinically relevant to the degree with which it predicts phenotype. Consequently, the optimal method of describing real-time enzyme activity is phenotyping, where metabolism of a carefully selected probe compound is used to estimate the activity of one or more of the enzymes involved in its metabolism. Although it is often more cumbersome than genotyping, phenotyping provides the most clinically relevant information because it is a reşection of the combined effects of genetic, environmental, and endogenous factors on CYP activity. Several potential phenotyping probes have been proposed for most CYP enzymes, each with unique advantages and disadvantages. The pharmacogenetic tools available are phenotyping, i.e. measurement of a specific enzyme activity by use of a probe drug, and genotyping, analysis of functionally important mutations in the gene coding for the specific enzyme. * Numerous CYP enzymes involved in the metabolic processing of psychotropic medications have genetic variants or polymorphisms. These polymorphisms result in a wide range of metabolic capacity across patients, and can substantially alter the metabolism of specific drugs in certain patients. A genetically poor metabolizer who was not exposed to a CYP inhibitor would have the same phenotype for metabolism as that of a regular metabolizer who was taking a CYP inhibitor. Interestingly, in a poor metabolizer, the effects of a CYP inhibitor would be less important as the enzyme is already deficient. Clinical studies have shown that in patients with CYP 2D6 polymorphism, treatment with the atypical antipsychotic risperidone is associated with an 3-fold risk of adverse effects because of the inability to metabolize the drug adequately in poor metabolizers. * Alternatively, a genetically “super” metabolizer (due to gene amplification) who was not exposed to a CYP inducer would exhibit the same phenotype as a regular metabolizer administered a CYP inducer; thus, administration of a CYP inducer to a genetically extensive metabolizer would result in particularly rapid removal of substrate drugs from the system. For many of the phenotypes (e.g., poor, intermediate, wild-type-extensive, and super metabolizer), there is a wide range of capacities due to heterozygous alleles. For some there are commercial tests available to determine genotype. CYP2D6 phenotyping CYP2D6 plays a pivot role in metabolism of xenobiotics, especially psychotropic drugs. Predicting its metabolic activity in patients may help to personalize pharmacotherapy. Eight-hour urinary ratio of dextromethorphan/dextrorphan molar concentrations serves as a measure of CYP2D6 activity with 0.3 as a cut-off value separating poor and extensive metabolizers. Unfortunately, collecting of urine for 8 hours may be difficult in psychiatric patients. The assessment of dextromethorphan/dextrorphan molar concentrations in serum is less used since correlation with urine dextromethorphan/dextrorphan molar concentrations and cut-off value in serum is not well established Previous studies showed that metoprolol can be used as the CYP2D6 probe for determining the polymorphism of CYP2D6. Debrisoquine hydroxylation polymorphism is by far the most thoroughly studied polymorphism genetic hydroxylation phenotype has been the most used test in humans to evaluate CYP2D6 activity. Two debrisoquine hydroxylation phenotypes have been described: poor and extensive metabolizers. A group with a very low debrisoquine metabolic ratio within the extensive metabolizers, named ultra rapid metabolizers, have also been distinguished. This CYP2D6 variability can be for a large part alternatively determined by genotyping, which appears to be of clinical importance given CYP2D6 involvement in the metabolism of a large number of commonly prescribed drugs. CYP2D6 pharmacogenetics may then become a useful tool to predict drug-related side effects, interactions or therapeutic failures of the CYP2D6 drug-metabolizing *CYP1A2 phenotyping Caffeine (1,3,7-trimethylxanthine [137X]) is one of the most commonly ingested compounds throughout the world. The metabolic pathways of caffeine are complex but involve the formation of three principal metabolites: theobromine (3,7-dimethyl xanthine [37X]), theophylline (1,3-dimethylxanthine [13X]), and paraxanthine (1,7-dimethylxanthine [17X]). Each of these metabolites is primarily formed by cytochrome CYP 1A2. Caffeine has become popular as a metabolic probe for CYP1A2 activity in humans. It is one of the major P450 cytochromes in the liver and accounts for 15% of the total P450 content. If a CYP1A2 phenotyping needed, subjects were asked to comply with a diet free of caffeine, ethanol, and grapefruit juice/products for 48 h, and come to the hospital for an overnight stay of approximately 12 h prior to the initiation of the sample taking. After eating a standardized breakfast, subjects received 200 mg of caffeine. Immediately after caffeine administration, subjects began to collect their urine and continued to do so over the next 8 h. CYP2C9 phenotyping Despite the few reports to the contrary, significant evidence supports the use of tolbutamide as a selective in-vivo CYP2C9 probe. Isolated reports also support the use of the 6 h DPH/HPPH ratio, but more clinical data are required before recommending it’s widespread use. Concerns over the extremely narrow therapeutic index and possible need for steady-state sampling will have to be addressed prior to more widely applied use of warfarin as a CYP2C9 probe. Alternately, the use of warfarin as a probe may be limited to those requiring warfarin therapy for a medical indication. The metabolic pathways of losartan and its metabolite need to be further elucidated prior to its use for CYP2C9 phenotyping. CYP3A4 phenotyping Several methods of phenotyping CYP3A activity have been proposed, and identification of the ideal probe has been difficult. The most widely accepted and tested CYP3A probes are erythromycin and midazolam. However, in their current form, neither phenotyping procedure is ideal. Cocktail approach Marker or probe drugs have been widely used for phenotyping various individual cytochrome P450 (CYP) activities, and this approach has been widely used in many clinical investigations in the field of drug metabolism and pharmacogenetics. A practical limitation of such phenotyping has been the inability to test the activity of several enzymes simultaneously, because a separate probe drug is generally required for each enzyme. As a result, attempts have been made to permit concurrent administration of probes so that multiple enzymes can be tested at once. Thus the cocktail approach was developed, involving the administration of multiple probe drugs simultaneously and the measurement of plasma kinetics and/or urinary excretion of unchanged parent compound and metabolites. Genetic polymorphisms have been described for most drug-metabolizing enzymes, including CYP2C19 and CYP2D6, that give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. The functional importance of genomic variability in CYP1A2, CYP2E1, and CYP3A remains unclear, but it was found that genetic polymorphisms of CYP1A2 were related to the inducibility of CYP1A2 in vivo. CYP3A accounts for up to 25% of the total CYP present in adult human liver and is the major CYP present in the human intestine. The importance of the CYP3A enzymes is most established with respect to the metabolism of xenobiotics and medications. CYP2E1 has received much attention because of its ability to bioactivate a number of potentially harmful compounds, including some toxins and carcinogens. Therefore phenotyping individuals with respect to CYP3A, CYP1A2, CYP2C19, CYP2E1, and CYP2D6 activities is of clinical relevance. *complications that should be avoided in a cocktail approach are mutual interactions between the probe drugs, low doses need to be used. Another consideration is that several drugs and metabolites must be analyzed in the same biologic sample, which requires an appropriate degree of selectivity and sensitivity of the analytic methods.