Aripiprazole is an atypical or second generation antipsychotic drug (SGA) that has been approved by the FDA in the last decade for the treatment of schizophrenia, for the treatment of acute manic phase and mixed episodes associated with bipolar disorder and for the treatment of Tourette's syndrome. It is also sometimes prescribed to treat clinical depression.

Aripiprazole has a long-term efficacy greater than other antipsychotics in addition to presenting minor relapses. Furthermore, there is no evidence to associate prolongation of the cardiac QT interval with aripiprazole intake, as is true for many of the antipsychotics on the market.

Aripiprazole offers the same efficacy as haloperidol (which was one of the first drugs with a good clinical response that was used in the 20th century for the treatment of mental disorders) but is more effective in relieving negative symptoms such as social isolation and causes fewer extrapyramidal side effects than other SGA and FGA (first generation antipsychotics).

Among the pharmacokinetic markers, the phenotypic and phenotypic status of CYP2D6 has a clear clinical impact on the doses to be prescribed for antipsychotics such as aripiprazole, iloperidone, paliperidone and risperidone (all second generation or atypical).

Cytochrome CYP2D6 metabolism is the major route of metabolism of these antipsychotics and numerous clinical studies have shown that genetic variations in CYP2D6 have a marked effect on the bioavailability and toxicity of these drugs.

Cytochrome CYP2D6 activity varies considerably within a population and includes individuals who are ultrafast metabolizers (UM), extensive or normal metabolizers (EM), intermediate metabolizers (IM) and poor or slow metabolizers (PM). Individuals PM and UM have a metabolic rate that varies between 5 and 15 times of the metabolizers EMs and this is reflected in the blood concentrations of the antipsychotic. The implication of being an intermediate metabolizer is more difficult to determine and varies poorly depending on the individual cases since there is a clear overlap between intermediate and extensive metabolizing individuals. For drugs whose plasma clearance depends primarily on CYP2D6 activity, such as aripiprazole, large differences are observed in the "area under the curve" or AUC (which is a pharmacokinetic parameter to quantify blood concentration over time) and in the clearance between EM (extensive or normal metabolizers) and PM (poor metabolizers) individuals.

The implications of the genotype and metabolic status of CYP2D6 during long-term antipsychotic therapy are clinically relevant as they should guide dose adjustment of the drug to minimize the risk of drug concentration-dependent side effects.

In addition, there is considerable variability in the distribution of different allelic variants or polymorphisms among different ethnic groups, resulting in a variable proportion of PM, IM, EM or UM individuals between populations. There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population. To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard. For drugs with CYP2D6 as the major contributor to clearance (>60%), large differences in the area under the plasma concentration-time curve (AUC, a pharmacokinetic measure of drug bloodstream concentration) or oral clearance were observed between EMs and PMs.

The different polymorphic variants or alleles of CYP2D6 are classified in the following groups according to their functionality: Alleles resulting in partial activity; alleles resulting in loss of activity (LoF, Loss of Function alleles or null alleles), alleles with normal activity and alleles with increased activity (GoF, Gain of Functiona alleles or ultrarapid alleles).

The null or inactive (LoF) alleles are called CYP2D6 *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16,*18, *19, *20, *21, *38, *40, *42, *44, *56 and *62.

In tellmeGen we give information about the genotype status of the CYP2D6*3, *4, *5, *12 and *56, since they are the most frequent in different ethnicities. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among these null alleles, *3, *4, *5 and *6 account for ~97% of all alleles causing the PM phenotype in Caucasians. CYP2D6* 5 is a deletion of the entire CYP2D6 gene and for this reason with the SNP array technology that we use in tellmeGen we are not able to study it and a sequenciation of the gen must be done.

There are allelles with partial or residual functions (CYP2D6*9, *10, *14, *17, *18, *29, *41, *47, *49, *50, *51, *54, *55 and *57), which are not totally inactive but have a diminished activity. In tellmeGen we study the genotype status of CYP2D6*9, *10, *29 and *41 alleles. Individuals with one copy of a partially functional allele and a copy of an inactive allele will be intermediate metabolizers (IM). On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the ultra metabolizer (UM) phenotype. Marked decreases in plasma drug concentration have been observed in UMs with several antipsychotics and antidepressants.

Poor metabolising patients, PM, who are prescribed ariprazole have a 60% higher drug exposure than normal and extensive metabolizers (EM), and the clearance time of the drug in the body is significantly increased, the patient develops more marked side effects and a failure to respond to medication, so from the American and European dosing guidelines it is recommended a reduction of 50% of the dose in oral intake and 75% of the dose in injection intramuscularly in these individuals. The reduction in dosage according to the metabolizing status of the patients, although it is a common practice in most antipsychotics, is still stricter for aripiprazole and zuclopenthixol. In addition, the psychiatric professional must consider that part of aripiprazole is also metabolised by CYP3A4, so if the patient, whether or not PM, is taking another psychiatric drug in combination that is a CYP3A4 inhibitor, such as fluoxetine (antidepressant), paroxetine (antidepressant), duloxetine (antidepressant), bupropion (antidepressant), thioridazine (antipsychotic and anxiolytic), must take doses of aripiprazole between 50-75% below the standard dose, and if the individual is also PM greater monitoring of the dose and even a change in medication should be considered. In those patients who, on the contrary, are UM, the medical professional must carry out an extensive monitoring of the therapy to avoid an excessive clearance of the drug in the bloodstream.

It is important to emphasize that deficiency in the metabolising capacity of CYP2D6 can occur due to genetic causes or due to the concomitant administration of CYP2D6 inhibitors (an environmental factor). The second phenomenon is called phenoconversion because it may occur that the individual is genetically normal for CYP2D6 function but behaves like a poor metabolizer.

The best clinical practice should always combine therapeutic monitoring or TDM ("therapeutc drug monitoring") by biochemical analysis and genotyping of patients.

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