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Clozapine is quite effective to treat schizophrenia, but its use is complicated by several factors.

This review of the literature sought to describe the main pharmacogenetic studies of clozapine and the genes that potentially influence response to treatment with this medication in schizophrenics. We searched the PubMed database for studies published in English in the last psicofarmafos years using keywords related to the topic.

Our search yielded studies that met the search and selection criteria. Of these, 21 review articles were excluded. The studies included for analysis showed controversial results. Therefore, efforts to identify key gene mechanisms that will be useful in predicting clozapine response and side effects have not been fully successful.

Psicof rmacos 2 Trabalhos Acadêmicos – Serviço

Further studies with new analysis approaches and larger sample sizes are still required. Schizophrenia is an oft-devastating neuropsychiatric illness with a lifetime prevalence of 0. Schizophrenia is a complex and highly heritable disorder with a significant impact on public health. Clozapine is an antipsychotic drug widely used in the treatment of schizophrenia. It is more effective than traditional antipsychotics for patients with poor response or resistance to treatment.

The variability of response to clozapine treatment in schizophrenia patients has a marked impact on clinical practice. The effect of psychopharmacological treatment depends on many factors that influence response. The heterogeneity of response is partly attributable to physiological and environmental factors affecting individuals, including age, sex, ethnicity, liver and kidney function, diet, co-medication, severity and type of illness, and alcohol and tobacco use.

In a study of monozygotic twins, Vojvoda et al. Symptom improvement following clozapine treatment showed strong concordance in monozygotic twin pairs. Two case reports of agranulocytosis induced by clozapine in monozygotic twins with schizophrenia provided evidence for a genetic basis of this adverse event. Pharmacogenetics is the study of the influence of genetic variants on response to medications and adverse effects, as well as the consequent understanding of how genes interact to determine individual variability in this response.

The goal of pharmacogenetics is to find polymorphisms in genes encoding proteins and enzymes involved in the transport, metabolism, and action of drugs, enabling knowledge of the applicability of a particular drug and increasing its effectiveness. The detection of individual genetic differences in the response to clozapine may provide new strategies for the treatment of major psychoses such as schizophrenia. The application of pharmacogenetic data has been analyzed in several studies investigating the impact of genetic polymorphisms on adverse effects and response to treatment with clozapine.

The objective of the present literature review was to discuss the main results of these studies. We searched the PubMed database for scientific articles published in English in the last 20 years about the use of clozapine to treat schizophrenia.

The last search was performed on October 11, The following keywords were used in the search: Combinations of these keywords with schizophrenia, pharmacogenetic, pharmacogenomic, side effects, adverse effects, genotype, and allele were also used.

Further searches were conducted based on the list of references of the selected articles and included in this review when relevant.

The articles were selected according to the following criteria: Studies containing no information about the type of antipsychotics were not included. One hundred and forty-five articles met the search and selection criteria. To supplement the data of the remaining studies, six meta-analyses were also assessed.

The articles were divided according to their focus: Table 1 summarizes significant results regarding response to treatment. Table 2 shows findings related to adverse effects. Nevertheless, these results are uncertain and should be considered cautiously, since several studies did not report the same associations. See text for supplementary information about other nonsignificant studies concerning these genes. See text for complementary information about other nonsignificant studies concerning these genes.


II Neurological, cardiovascular, gastrointestinal, hematological, behavioral, and musculoskeletal adverse reactions. Most drugs used in clinical practice that act on the central nervous system CNS are extensively metabolized in the liver by enzymes of the cytochrome P CYP system. Variations in genes coding for CYP enzymes can result in absent, deficient, or increased activity.

However, van der Weide et al. The cytochrome P, family 2, subfamily D, polypeptide 6 gene CYP2D6 is highly polymorphic, and more than 90 allelic variants and subvariants have been described.

Caballo 6 8 psicofarmacos

Since clozapine is metabolized minimally by this enzyme, 92 more studies on clozapine metabolism would be helpful. However, variations in metabolizing enzymes cannot be fully responsible for the heterogeneity observed in the response of an individual to treatment.

The pharmacological effects of the medication are not typically monogenic traits; moreover, they are determined by the interposition of several genes psicofaemacos proteins involved in multiple pathways that determine the osicofarmacos and effects of drugs in addition to their metabolism.

Since clozapine is a high-affinity antagonist of dopamine receptors, initial studies focused on the relationship between the dopamine D4 receptor gene DRD4 and the response to clozapine. However, most studies were unable to detect this significant association. The dopamine D3 receptor gene DRD3 is important because antipsychotics show high affinity for this receptor, especially in the mesolimbic system.

Another obvious candidate for pharmacogenetic studies is DRD2because clozapine has an affinity for this receptor. Positive results were found by Malhotra et al. Recently, Xu et al. Of the seven subtypes of serotonin receptors 5-HT5-HT2 subtypes are the strongest targets of atypical antipsychotic drugs. These results were subsequently replicated by Yu et al. Unclear results were observed for HTR3A.

They found that individuals homozygous for the short allele tended to show a poor response to treatment with clozapine. Two previous studies did not find a significant relationship.

This finding constituted a great potential for pharmacogenetic studies as a key for future improvement and individualization of clinical treatment of patients with schizophrenia. However, these results have not been replicated with the same approach so far, and the pharmacogenetic test designed for use in clinical practice is no longer available on the market.

Since catecholamine receptors are G-protein-coupled GPCRs and antipsychotics exert their effects by competitive antagonism of postsynaptic GPCRs, this protein may have an important influence on the function of dopaminergic and serotoninergic systems. This result was corroborated by the study conducted by Kohlrausch et al. Studies involving other genes with significant associations include variants in the following genes: The tumor necrosis factor gene TNF showed significant 49 and nonsignificant results.

As these studies are mostly unique, confirmation of the results is necessary. There is strong evidence that the serotonergic 5-HT system plays a role in the regulation of feeding behavior; thus, clozapine-induced weight gain could be explained by dysfunction of this neurotransmitter.

A recent meta-analysis of schizophrenia individuals suggested that the C allele is associated with weight gain. Agranulocytosis is a serious adverse effect associated with clozapine.

Some studies showed strong associations between polymorphisms in psicofaracos of the major histocompatibility complex HLA and the occurrence of this adverse effect. A study conducted with a Brazilian population sample evaluated the influence psicofadmacos GNB3 polymorphisms and the occurrence of tonic-clonic seizures due to clozapine treatment.

Genome-wide association studies GWASsa powerful method for the large-scale analysis of genotype-phenotype relationships, are currently the method of choice for dissecting the genetic basis psicofxrmacos complex traits. Pskcofarmacos studies of antipsychotic response and adverse effects have been published, partly due to the need for large cordloli to achieve truly significant results.

One of these studies 75 examined 12 indicators of metabolic side effects of antipsychotics and found a polymorphism in the protein kinase type II beta gene PRKAR2B mediating effects of clozapine on triglyceride levels.


The authors found one polymorphism rs located approximately kb downstream from MC4R previously identified as a candidate for weight-related phenotypesimplicating MC4R in extreme SGA-induced weight gain and related metabolic disturbances, including in the clozapine-treated sample. More intriguing is psicofarmaacos most candidate genes that were previously found to be associated with individual response to treatment, or adverse effects of clozapine Tables 1 and 2did not show statistical significance in these studies.

As GWASs are exploratory, they should be replicated in independent samples. The study of pharmacogenetics in schizophrenia had its milestone in the work of Arranz et al. Since then, few studies have been carried out with this approach. Studies with individual candidate genes have been more frequent in recent years, and GWASs are the real promise.

Most of the reviewed articles were individual association studies. This approach has minimal practical value, since most antipsychotics have multiple targets, and it would be unlikely for only one of these targets to be responsible for all variability in treatment response.

Association studies psjcofarmacos the most appropriate strategy for pharmacogenetic research. In addition to type I and II statistical errors, the difficulty lies mainly in the standardization of clinical samples in relation to an appropriate number of individuals and detailed clinical information about symptom improvement and development of adverse effects.

The complexity of genetic factors implicated in psychiatric illness and response to medication is also ppsicofarmacos complicating factor. Other difficulties include incomplete knowledge of the psicofarmacox of schizophrenia, the complexity of brain function, and the influence of nongenetic factors, including age, diet, environmental exposures and interactions, comorbidities, and drug interactions.

The dynamics of epigenetic events can also be responsible for the variations observed in the clinical response to antipsychotics. In most meta-analyses, the heterogeneity of the antipsychotic drugs used in psicofaramcos analyzed studies limits the possibility of examining the association of candidate genes with any specific drug. In the psicofamracos of schizophrenia, meta-analyses support the involvement of DRD2 and DRD3 in treatment response and HTR2C in weight gainbut simultaneously indicate that the establishment of pharmacogenetics associations in clinical psychiatry requires much larger sample sizes.

Population stratification in case-control studies causes most false-positive associations, because genetic differences between ethnic groups often lead to differences in treatment response. Additionally, non-publication of negative findings also generates a problem in terms of replication of results.

Despite continuous advances toward revealing the genetic basis of many complex traits using GWASs, a major proportion of genetic variance remains unexplained. A large number of disorders have been studied by GWASs, contributing to the detection of many previously undetected loci.

For example, Franke et al. However, psicofagmacos GWASs have achieved limited success in explaining a considerable proportion of genetic variance of complex traits. In addition, psiocfarmacos such contributions is difficult when the predisposing allele is rare or the sample size is not sufficiently large.

The CATIE study and a double-blind study investigating dose of antipsychotics, controlled for confounding variables in psicpfarmacos practice, indicated that variations in metabolizing enzymes play a small role in determining the clinical response to antipsychotics.

However, combining assessment of these pharmacokinetic factors with analysis of pharmacodynamic markers, each conferring moderate effects, may be a more valid approach, possibly improving cost-effectiveness in clinical practice. Substantial advances in knowledge of the gene-response connection have been made, and pharmacogenomics approaches have become increasingly popular. With advances in sequencing technologies and bioinformatics, new dimensions in the search for multiple cordiioli and how their expression affects response to medication are being generated.

However, clinical and pharmacogenomic knowledge has not advanced as rapidly as technology, and no application has been developed yet regarding the management of schizophrenia treatment and drug development.