RU2821045C1 - Method for selecting therapeutic approach in patients with schizophrenia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to psychiatry and can be used to select a therapeutic approach to patients with schizophrenia. Individual selection and dosing of drugs for a specific patient is carried out based on data of a multivariate genetic test. Pharmacogenetic testing is carried out by means of microchips. Cumulative risk of developing antipsychotic-induced adverse reactions due to efflux disturbance of antipsychotics of 1^st, 2^nd and 3^rd generations, given in table 1, through blood-brain barrier and membrane of neurons is estimated by antipsychotic transporter proteins P-glycoprotein, Breast Cancer Resistance Protein, Multidrug Resistance-Associated Protein 1, encoded by genes ABCB1, ABCG2, ABCC1 respectively. For this purpose, by testing 26 low-functional and non-functional allelic variants of genes ABCB1, ABCG2, ABCC1, presented in table 2, patient’s genotype, information on genetically determined transport of antipsychotics is determined according to table 3. Patients are divided into three types: slow conveyors, intermediate conveyors, common conveyors. Based on the test results, a list of antipsychotics is obtained, divided into four categories: “Use as directed” in homozygous carriage of full-functional allelic variants of genes in a patient; “Use with caution” in case of heterozygous carriage of low-functional allelic variants of genes; “Use with increased care and with more frequent monitoring” in case of homozygous carriage of low-functional allelic variants of genes; “Do not use” in non-functional allelic variants in a patient with homozygous carriage. Slow transporter type patients take the selected antipsychotic in the starting and target dose by at least 50% and lower than the average therapeutic dose. Patients with the intermediate transporter type take the selected antipsychotic in the starting and target dose not less than 25 % lower than the recommended average therapeutic dose. Patients with the common transporter type take the selected antipsychotic in the average therapeutic single and daily doses according to the current instructions for the given medicinal agent.

EFFECT: method provides the possibility of increasing the effectiveness of choosing a therapeutic approach in patients with mental disorders by creating a personalized strategy for selecting an antipsychotic before starting the therapy, dosage regimen, dose escalation rate and possibility of combination with other antipsychotics.

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Description

The invention relates to the field of psychiatry and related specialties (psychotherapy, addiction medicine, neurology and clinical pharmacology) and can be used for the treatment of mental disorders, including schizophrenia.

Schizophrenia is one of the most serious and socially significant mental disorders, the prevalence of which reaches millions of cases in the world. To treat mental disorders, including schizophrenia, medications - antipsychotics - are usually used.

Despite the generation of new antipsychotics, the problem of antipsychotic-induced adverse reactions has not been solved to date, and the accumulated experience in the targeted prevention of antipsychotic-induced adverse reactions allows us to assert that most of them can be prevented or their consequences can be significantly reduced.

This problem leads to: a decrease in the quality of life of patients; to reduce the adherence of patients with mental disorders to chronic therapy with antipsychotics; to the development of pseudo-resistance of mental disorders to prescribed antipsychotics; to the progression of the disease.

The study of the mechanisms of development of antipsychotic-induced adverse reactions is based on changes in their metabolism and transport, depending on the following risk factors for adverse reactions of psychopharmacotherapy:

- from modifiable factors (choice of antipsychotic, its dose, dosage regimen, taking into account comorbid conditions, etc.);

- from non-modifiable factors (gender, age of patients, genetic predisposition).

The study of genetic predisposition to the development of antipsychotic-induced adverse reactions is based on association genetic studies and genome-wide studies of single-nucleotide variants and polymorphisms of candidate genes involved in the metabolism, transport, cumulation, excretion of antipsychotics and their active metabolites.

There is a known method for optimizing and individualizing the selection and dosing of drugs, including data from a multigene multivariate genetic test, which takes into account the characteristics of the genotype, phenotype, as well as information about the metabolism of the drug (see US patent No. 8589175, IPC G06Q 50/00, G16H 10/60 , 2013).

This test (GeneSight Psychotropic test) was developed by a group of scientists at the Mason Clinic (USA). The analysis is carried out for 59 allelic variants of 8 genes - CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP2B6, CYP2D6, HTR2A and SLC6A4.

The attending physician is provided with information already analyzed by the program based on the patient’s genotyping results. The report contains a list of antipsychotics and antidepressants divided into 3 categories: “use as directed,” “use with caution,” and “use with increased caution and more frequent monitoring.” The doctor also receives additional information that helps make decisions about prescribing or withdrawing the drug for a particular patient.

Thus, this algorithm allows you to make a decision on prescribing antipsychotics without the involvement of a clinical pharmacologist.

The disadvantages of this method are:

- inability to study single-nucleotide variants/polymorphisms of genes encoding antipsychotic transporter proteins;

- the use of only one or two single-nucleotide variants/polymorphisms assessed by PCR diagnostics, which does not allow to give a general picture of changes in the transport of antipsychotics across the neuronal membrane and the blood-brain barrier;

- lack of assessment of the cumulative effect of the studied single nucleotide variants/polymorphisms of several genes encoding antipsychotic transporter proteins;

- inability to fully characterize the genetically determined changes in the functional activity of this transporter protein and its expression level.

The closest in technical essence to the claimed solution is an assessment method using reports on neuropsychiatric studies, including data on genetic information that is specific to a patient with mental disorders (see patent No. US 8706526, IPC G06F19/00, G06Q50/22, G16H10 /60, 2014).

This Genecept Assay test was developed in the USA. The study is carried out on allelic variants in 20 genes, including 5HT2C, MC4R, DRD2, COMT and genes of the cytochrome p450 system.

The conclusion is provided in the form of a detailed table with recommendations for prescribing medications for a particular patient.

The disadvantages of this method are:

- absence of genes encoding antipsychotic transporter proteins in the test;

- the impossibility of assessing the risk of changes in the transport of antipsychotics across the neuronal membrane and the blood-brain barrier;

- the impossibility of assessing genetically determined changes in the functional activity of antipsychotic transporter proteins and their expression level.

The technical result of the proposed solution is to increase the effectiveness of the choice of treatment tactics for patients with mental disorders by creating, before the start of therapy, a personalized strategy for choosing an antipsychotic, its dosage regimen, the rate of dose increase and the possibility of combination with other antipsychotics.

To achieve the specified technical result in the method for selecting treatment tactics for patients with schizophrenia, including individual selection and dosing of drugs for a specific patient, based on data from a multivariate genetic test, according to the invention, pharmacogenetic testing is carried out using microchips, while the cumulative risk of developing antipsychotic-induced adverse reactions is assessed. reactions due to disruption of the efflux of antipsychotics of the 1st, 2nd and 3rd generations, shown in Table 1, through the blood-brain barrier and neuronal membrane through the antipsychotic transporter proteins P-glycoprotein, Breast Cancer Resistance Protein, Multidrug Resistance-Associated Protein 1, encoded by the ABCB1, ABCG2 genes , ABCS1, respectively; for this purpose, by testing 26 low-functional and non-functional allelic variants of the genes: ABCB1, ABCG2, ABCC1, presented in Table 2, the characteristics of the patients’ genotype, information on the genetically determined transport of antipsychotics are determined in accordance with Table 3, and patients are divided into three types: slow transporters , intermediate transporters, common transporters, and also based on the test results, a list of antipsychotics is obtained, divided into four categories: “use as directed” in case of homozygous carriage of fully functional allelic gene variants in the patient; “use with caution” in heterozygous carriage of low-functional allelic gene variants; “use with increased caution and with more frequent monitoring” in case of homozygous carriage of low-functional allelic gene variants; “do not use” in case of homozygous carriage of non-functional allelic gene variants in the patient.

According to the invention, patients with the “slow transporter” type take the selected antipsychotic at a starting and target dose of at least 50% or lower compared to the average therapeutic dose.

According to the invention, patients with the intermediate transporter type take the selected antipsychotic at a starting and target dose of at least 25% lower than the recommended average therapeutic dose.

According to the invention, patients with the “common transporter” type take the selected antipsychotic in average therapeutic single and daily doses, according to the current instructions for this drug.

The inventive method solves the problem of assessing the cumulative risk of developing antipsychotic-induced adverse reactions by disrupting the efflux of antipsychotics of 1st, 2nd and 3rd generations through the blood-brain barrier and neuronal membrane through antipsychotic transporter proteins P-glycoprotein, Breast Cancer Resistance Protein, Multidrug Resistance-Associated Protein 1 .

Non-functional and low-functional single nucleotide variants and polymorphisms of genes encoding antipsychotic transport proteins across the blood-brain barrier and neuronal membrane are associated with a significant decrease in the functional activity and/or expression of these transport proteins involved in the efflux of antipsychotics across the blood-brain barrier.

Genes encoding transporter proteins consist of exons (coding regions of the gene) and introns (non-coding regions of the gene).

On the one hand, single-nucleotide variants/polymorphisms located in exons predominantly affect the functional activity of the transporter protein, leading to its decrease (risk of developing undesirable side reactions) or increase (risk of therapeutic resistance).

On the other hand, single nucleotide variants/polymorphisms located in the intronic or promoter region cause, to a large extent, changes in the expression of the transporter protein, including a decrease (risk of adverse reactions) and increase (risk of therapeutic resistance) in the expression of the transporter protein.

The use of only one or two single-nucleotide variants/polymorphisms located only in the coding part of the gene for pharmacogenetic testing, which is possible as a result of PCR diagnostics or whole exome sequencing, cannot provide a general picture of changes in the transport of antipsychotics across the neuronal membrane and the blood-brain barrier.

Experiments have shown that only an assessment of the cumulative effect of the studied single-nucleotide variants of genes encoding transporter proteins can adequately help to understand the changes that have occurred in the functional activity of these transporter proteins and the level of their expression in the brain.

Therefore, to solve this problem, it is important and necessary to develop a personalized selection strategy: antipsychotic; dosage regimens; the rate of dose increase and the possibility of combination with other antipsychotics if polytherapy for mental disorders is necessary or in cases where additional prescription of drugs from another pharmacological group is necessary (in particular, antidepressants, mood stabilizers, etc.).

For example, the transporter protein glycoprotein P (P-gp) is involved in the transport of not only antipsychotics, but also antidepressants: imipramine, escitalopram, amitriptyline, paroxetine, venlafaxine and citalopram; mood stabilizers: lamotrigine, which can be prescribed to patients with mental disorders as additional therapy to antipsychotics that are transported by the same transporter proteins.

The inventive method allows for the assessment of the cumulative genetic risk of changes in the transport of antipsychotics through the blood-brain barrier and neuronal membrane, performing pharmacogenetic testing via microarrays using a new pharmacogenetic panel “Transporter proteins (RT) - antipsychotic (AR) - pharmacogenetic test (PGx)” or “PTAP -PGx").

Membrane transport protein (transport protein) is a membrane protein that is involved in the movement of ions, small molecules and macromolecules, such as other protein or drugs (including antipsychotics) and other xenobiotics, across a biological membrane.

The leading transport proteins of antipsychotics across the blood-brain barrier are P-glycoprotein (P-gp), or multidrug resistance protein 1 (MDR1-Multidrug Resistance Protein 1); BCRP - “Breast Cancer Resistance Protein”; MRP1 is a protein associated with multidrug resistance (Multidrug Resistance-Associated Protein 1) (presented in Table 1, Fig. 1).

Depending on the functional activity of these proteins, 4 groups of patients with mental disorders can be distinguished: slow transporters; intermediate conveyors; common transporters; ultra-fast conveyors.

Slow transporters are patients in whom transport proteins have significantly reduced functional activity, resulting in a significantly reduced rate of efflux of certain drugs, particularly antipsychotics.

Typically, patients with this phenotype are homozygous for a non-functional or low-functional single nucleotide variant/polymorphism of the gene/genes encoding one or more transporter proteins.

Accordingly, in these patients, antipsychotics accumulate in the brain at high concentrations, leading to a significant risk of developing serious antipsychotic-induced adverse reactions.

Therefore, for patients with this pharmacogenetic profile, it is advisable not to use or replace the prescribed antipsychotic, or a careful dose selection of this antipsychotic should be carried out under the control of therapeutic drug monitoring of the level of its active metabolites in the blood, since intravital studies of the level of antipsychotics or their active metabolites in the brain are technically difficult and are carried out only under experimental conditions.

With this phenotype, the starting and target dose of this antipsychotic should be at least 50% or lower compared to the average therapeutic dose (according to the instructions for the drug).

Transporter intermediates are patients whose transport proteins have moderately reduced functional activity, resulting in a reduced rate of antipsychotic efflux.

Typically, patients with this phenotype are heterozygotes for a nonfunctional or low-functional variant of the genes encoding transporter proteins.

In such patients, the synthesis of a “defective” transporter protein or a moderate decrease in the synthesis of a normal transporter protein occurs, as a result of which the functional activity of the transporter protein and the efficiency of efflux of the antipsychotic across the blood-brain barrier and neuronal membrane are reduced.

Accordingly, in intermediate metabolizers, antipsychotics accumulate at the level of brain neurons, leading to a moderate increase in the risk of antipsychotic-induced adverse reactions.

Therefore, for patients with this pharmacogenetic profile, careful selection of the antipsychotic dose should be carried out, and its single and daily doses should be approximately 25% less than the recommended average therapeutic dose (according to the instructions for the drug).

Common transporters are patients in whom the transport proteins have normal functional activity, resulting in a preserved (average) rate of antipsychotic efflux.

Patients who have this type of transporter protein are homozygous for the fully functional (normal) variant of the gene/genes encoding this protein/proteins.

Accordingly, in these patients the risk of developing antipsychotic-induced adverse reactions is the population average (minimal).

Antipsychotics, the efflux of which is carried out through a fully functional transporter protein, are prescribed in average therapeutic single and daily doses, according to the current instructions for this drug.

The tactics of a psychiatrist in carriers of alleles of non-functional or low-functional variants of genes encoding proteins transporting antipsychotics through the blood-brain barrier and neuronal membrane should be based on a cumulative assessment of carriage of as many previously studied non-functional variants of genes encoding proteins transporting antipsychotics 1, 2 and 3 generations.

Such a cumulative assessment of the genetic risk of changes in the transport of antipsychotics and the development of antipsychotic-induced adverse reactions significantly modifies and significantly improves the currently existing personalized strategy of psychopharmacotherapy and explains the importance of the development of pharmacogenetic panels and their use in real clinical psychiatric practice.

From the above it follows that the introduced distinctive features influence the specified technical result and are in a cause-and-effect relationship with it.

The method is illustrated in the drawings, where in FIG. 1 shows Table 1 “Transporter proteins of antipsychotics and their substrates”; in fig. 2 shows Table 2 “Panel of non-functional and low-functional single nucleotide variants of genes encoding antipsychotic transporter proteins”; in fig. 3 shows Table 3 “Pharmacogenetic Panel”; in fig. 4 shows pharmacogenetic testing of the patient, example 1; in fig. 5 shows pharmacogenetic testing of the patient, example 2; in fig. 6 shows pharmacogenetic testing of the patient, example 3.

The method is carried out as follows.

First, biological material is collected (venous blood or buccal epithelium). The sample is then genetically analyzed.

When implementing this method, the cumulative genetic risk is assessed through pharmacogenetic testing (a new pharmacogenetic panel designed for microarray technology), that is, a multigene multivariate genetic test is performed.

Pharmacogenetic testing identifies genetic polymorphisms of candidate genes to assess the cumulative risk of antipsychotic-induced adverse reactions in patients with mental disorders. In this case, microarray technology is used, which makes it possible to simultaneously identify several thousand different single-nucleotide variants/polymorphisms of candidate genes.

The method takes into account the genotype characteristics of these patients, as well as the information obtained about genetically determined changes in the transport of antipsychotics through the blood-brain barrier and neuronal membrane.

Based on the results of the pharmacogenetic test, patients are divided into 3 types (slow transporters, intermediate transporters, common transporters) by testing 26 low-functional and non-functional variants of the ABCB1, ABCG2, ABCC1 genes involved in the transport of 1st, 2nd and 3rd generation antipsychotics.

Table 1 shows that the P-gp transporter protein is involved in the transport of the following antipsychotics: 1st generation - chlorpromazine, trifluoperazine, amisulpride; 2 generations - clozapine, olanzapine, quetiapine, risperidone, paliperidone; 3 generations - aripiprazole; and BCRP: 1st generation - haloperidol, chlorpromazine; 2 generations - clozapine, olanzapine, quetiapine, risperidone, paliperidone; 3 generations - aripiprazole; Currently, there is information about the participation of MRP 1 in the transport of clozapine.

Table 2, fig. 2 demonstrates that the developed test system searches for 5 single-nucleotide variants/polymorphisms of the ABCB1 gene, 20 single-nucleotide variants/polymorphisms of the ABCG2 gene and 1 single-nucleotide variant of the ABCC1 gene.

The risk of a genetically determined decrease in the functional activity and efflux of antipsychotics through the blood-brain barrier and the membrane of neurons of the targets of these antipsychotics is assessed most fully (taking into account the available results of genetic and clinical studies).

The genetically determined risk of developing the above phenotypes is assessed on the basis of homozygous or heterozygous carriage of full-functional (normal variant), low-functional (medium-risk group) and non-functional (high-risk group) single nucleotide variants/polymorphisms of genes encoding antipsychotic transporter proteins, which is presented in Table 3 , in Fig 3.

Based on the assessment data, individual treatment tactics for a particular patient are selected.

If it is determined that the patient has a “slow transporter” type, it is recommended not to use or replace a previously prescribed antipsychotic, or to carefully select the dose of this antipsychotic under the supervision of therapeutic drug monitoring of the level of its active metabolites in the blood.

In this case, the starting and target dose of this antipsychotic should be at least 50% or lower compared to the average therapeutic dose (according to the instructions for the drug).

If it is determined that the patient has the “intermediate transporter” type, then it is recommended to carefully select the dose of the antipsychotic, and its single and daily doses should be approximately 25% lower than the recommended average therapeutic dose (according to the instructions for the drug).

If it is determined that the patient has the “common transporter” type, then it is recommended to prescribe an antipsychotic in average therapeutic single and daily doses, according to the current instructions for this drug.

Thus, this method cumulatively (comprehensively) evaluates the contribution of a wide range of non-functional and low-functional variants of the above genes of antipsychotic transport proteins of 1st, 2nd and 3rd generations through the blood-brain barrier and neuronal membrane.

The attending psychiatrist is provided with information based on the results of pharmacogenetic testing that has already been analyzed by a clinical pharmacologist. The conclusion contains a list of antipsychotics, divided into 4 categories: “use as intended” (homozygous carriage of fully functional allelic gene variants); “use with caution” (heterozygous carriage of low-functional allelic gene variants); “use with increased caution and with more frequent therapeutic drug monitoring” (homozygous carriage of low-functional and heterozygous carriage of non-functional allelic variants of genes); “do not use” (homozygous carriage of non-functional allelic gene variants).

The attending physician (psychiatrist) can discuss with the patient the results of choosing an antipsychotic or adjusting its dose, as well as the need and timing of therapeutic drug monitoring of the level of the antipsychotic in the blood serum at the next visit.

The method is illustrated by the following examples.

Example 1

Patient M., 32 years old, suffering from schizophrenia since the age of 28, was admitted to the clinic due to the lack of a therapeutic response to antipsychotics for several years after the onset of schizophrenia.

There was an increase in hallucinatory-delusional symptoms, as well as the development of antipsychotic-induced adverse reactions during treatment with various antipsychotics, as well as their combination.

First, biological material was collected, then a genetic analysis of the sample was carried out.

The risk of a genetically determined decrease in the efflux of antipsychotics through the blood-brain barrier and the membrane of neurons of the targets of these antipsychotics was assessed.

The research data are presented in Table 4, Fig. 4.

It was found that the patient is a homozygous carrier of low-functional allelic variants of the ABCB1 and ABCG2 genes, which caused a significant decrease in the functional activity of transporter proteins, a significant decrease in the efflux of antipsychotics taken through the blood-brain barrier and the membrane of target neurons, their accumulation (cumulation) in the brain and the development of antipsychotic-induced adverse reactions even when using initial (starting) doses of several antipsychotics, as well as their increase with a further increase in the dose of antipsychotics taken.

The lack of a pharmacogenetic panel, as well as the inability to conduct pharmacogenetic testing before prescribing antipsychotics to a patient with schizophrenia, led to a long history (more than 3 years) of antipsychotic-induced adverse reactions and pseudo-resistance to previously used antipsychotics (when using a wide range of antipsychotics in monotherapy and in polytherapy, including: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, chlorpromazine (transport involving low-functional transporter proteins P-gp and BCRP); haloperidol (transport involving low-functional transporter protein BCRP); transporter protein P-gp).

Pharmacogenetic testing was carried out, which revealed:

1. The functional activity of the P-gp transporter protein (responsible for the transport of the following antipsychotics: clozapine, olanzapine, quetiapine, risperidone, paliperidone, aripiprazole, amisulpride, chlorpromazine, sulpiride, trifluoperazine) is significantly reduced (detected: homozygous carriage of the low-functional allele T variant rs1045642 ( C3435T) and homozygous carriage of the low-functional T allele of variant rs1128503 (C1236T) of the ABCB1 (MDR1) gene, encoding the activity of the P glycoprotein (P-gp).

2. The functional activity of the BCRP transporter protein (responsible for the transport of the following antipsychotics: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, chlorpromazine, haloperidol, sulpiride) is significantly reduced (found: homozygous carriage of the low-functional allele A of variant rs2231142 (C421A), heterozygous carriage of the low-functional allele C of variant rs192169063 (T1465C), heterozygous carriage of the low-functional allele T of variant rs72552713 (C376T), heterozygous carriage of the low-functional allele C of variant rs1061018 (T623C), heterozygous carriage of the low-functional allele G of variant rs750568956 ( T1574G), heterozygous carriage of the low-functional allele A of variant rs372192400 (G88131153A) of the ABCG2 gene, encoding the activity of the BCRP transporter protein).

3. The functional activity of the MRP1 transporter protein (responsible for the transport of the following antipsychotics: clozapine) is preserved.

Thus, pharmacogenetic testing of the functional activity of transporter proteins made it possible to explain the development of antipsychotic-induced reactions and pseudo-resistance to previously used antipsychotics in this patient.

The cumulative genetic risk of decreased drug transport, including antipsychotics, involving the transporter proteins P-gp and BCRP in the patient is assessed as high.

Considering that the functional activity of two of the three transporter proteins under study, which ensure the transport of psychotropic drugs across the blood-brain barrier and the membrane of target cells of a wide range of antipsychotics, is significantly reduced, the phenotype of this patient is a “slow transporter”.

Recommended:

Use the following antipsychotics with increased caution and with more frequent therapeutic drug monitoring: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, chlorpromazine, trifluoperazine, haloperidol, sulpiride, amisulpride.

The starting and target dose of these antipsychotics should be at least 50% or lower compared to the average therapeutic dose (according to the instructions for the drug).

The drug of choice for this patient was the antipsychotic cariprazine, whose transport across the blood-brain barrier does not involve the above transporter proteins.

There was a positive clinical effect after correction of therapy in the form of a reduction in hallucinatory-delusional symptoms and a reduction in the patient’s previously existing antipsychotic-induced adverse reactions.

Example 2

Patient P., 24 years old, was admitted to the clinic in an acute psychotic state. According to relatives, hallucinatory-paranoid symptoms increase over the course of 5 months. He had not previously sought medical help and had not received antipsychotic therapy.

Pharmacogenetic testing was performed before prescribing antipsychotic therapy.

First, biological material was collected, then a genetic analysis of the sample was carried out.

The risk of a genetically determined decrease in the efflux of antipsychotics through the blood-brain barrier and the membrane of neurons of the targets of these antipsychotics was assessed.

The research data are presented in Table 5, Fig. 5.

Pharmacogenetic testing revealed:

1. The functional activity of the P-gp transporter protein (responsible for the transport of the following antipsychotics: clozapine, olanzapine, quetiapine, risperidone, paliperidone, aripiprazole, amisulpride, chlorpromazine, sulpiride, trifluoperazine) is significantly reduced (detected: homozygous carriage of the low-functional allele T variant rs1128503 ( C1236T), heterozygous carriage of the low-functional allele G of variant rs9282564 (A61G), heterozygous carriage of the low-functional allele T of variant rs1045642 (C3435T) of the ABCB1 (MDR1) gene, encoding the activity of glycoprotein P (P-gp).

2. The functional activity of the BCRP transporter protein (responsible for the transport of the following antipsychotics: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, chlorpromazine, haloperidol, sulpiride) is preserved.

3. The functional activity of the MRP1 transporter protein (responsible for the transport of the following antipsychotics: clozapine) is slightly reduced (heterozygous carriage of the low-functional allele A of the rs212090 (T16142147A) gene ABCC1 encoding the MRP1 protein was detected).

As a result, the cumulative genetic risk of decreased drug transport (antipsychotics) involving the P-gp, BCRP, and MRP1 transporter proteins in this patient is assessed as average.

Considering that the functional activity of one of the three transporter proteins under study, which ensure the transport of psychotropic drugs across the blood-brain barrier and the membrane of target cells of a wide range of antipsychotics, is significantly reduced, and the other is slightly reduced, the pharmacogenetic phenotype of this patient is an “intermediate transporter”.

Recommended:

1. Use the following antipsychotics with increased caution and with more frequent therapeutic drug monitoring: trifluoperazine, amisulpride.

The starting and target dose of these antipsychotics should be at least 50% or lower compared to the average therapeutic dose (according to the instructions for the drug).

2. Use the following antipsychotics with caution: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, chlorpromazine, sulpiride.

The starting and target dose of these antipsychotics should be at least 25% or lower compared to the average therapeutic dose (according to the instructions for the drug).

3. Use the following antipsychotics as prescribed: haloperidol (according to the instructions for the drug).

The drug of choice for this patient was the antipsychotic haloperidol, the transport of which through the blood-brain barrier involves the transporter protein BCRP, the functionality of which is fully preserved.

There was a positive effect of therapy in the form of a reduction in hallucinatory-delusional symptoms without the development of pronounced antipsychotic-induced adverse reactions.

Example 3

Patient A., 18 years old, was brought to the clinic by her mother. According to the mother, the grandmother suffered from schizophrenia. The patient has been extremely concerned about her appearance for many years, but over the past few months she has been expressing thoughts about “being controlled by the body.” She had not previously sought medical help or received therapy.

Pharmacogenetic testing was performed before prescribing antipsychotic therapy.

First, biological material was collected, then a genetic analysis of the sample was carried out.

The risk of a genetically determined decrease in the functional activity of transporter proteins and disruption of the efflux of antipsychotics through the blood-brain barrier and the membrane of neurons of the targets of these antipsychotics was assessed.

The research data are presented in Table 6, Fig. 6.

Pharmacogenetic testing revealed:

1. The functional activity of the P-gp transporter protein (responsible for the transport of the following antipsychotics: clozapine, olanzapine, quetiapine, risperidone, paliperidone, aripiprazole, amisulpride, chlorpromazine, sulpiride, trifluoperazine) is slightly reduced (heterozygous carriage of the low-functional allele T variant rs1045642 was found ( C3435T) and heterozygous carriage of the low-functional allele T of the rs1128503 (C1236T) gene ABCB1 (MDR1), encoding the activity of the P glycoprotein (P-gp);

2. The functional activity of the BCRP transporter protein (responsible for the transport of the following antipsychotics: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, chlorpromazine, haloperidol, sulpiride) is slightly reduced (heterozygous carriage of the low-functional allele C variant rs192169063 (T1465C) was detected, new carriage of the low-functional allele T of variant rs72552713 (C376T), heterozygous carriage of the low-functional allele C of variant rs1061018 (T623C), heterozygous carriage of the low-functional allele G of variant rs750568956 (T1574G) of the ABCG2 gene, encoding the activity of the BCRP transporter protein);

3. The functional activity of the MRP1 transporter protein (responsible for the transport of the following antipsychotics: clozapine) is preserved.

The cumulative genetic risk of decreased transport of drugs (antipsychotics) involving the transporter proteins P-gp, BCRP, MRP1 in this patient is assessed as low.

Considering that the functional activity of two of the three studied transporter proteins, which ensure the transport of psychotropic drugs through the blood-brain barrier and the membrane of target cells of a wide range of antipsychotics, is slightly reduced, and the third is preserved in full, the pharmacogenetic phenotype of this patient is “common transporter” .

Recommended:

Use the following antipsychotics as prescribed: clozapine, olanzapine, quetiapine, risperidone, paliperidone, aripiprazole, amisulpride, chlorpromazine, sulpiride, trifluoperazine, haloperidol (according to the instructions for the drug).

Thus, given that this patient has a common transporter phenotype, it was possible to safely use antipsychotics for the treatment of schizophrenia spectrum disorder.

During dynamic observation, the patient achieved pharmaco-induced remission of the mental disorder without the development of adverse reactions for three months.

Thus, the proposed method, based on pharmacogenetic testing of the functional activity of transporter proteins and the rate of efflux of antipsychotics through the blood-brain barrier and the membrane of the target neurons of their action, allows for a personalized strategy for choosing an antipsychotic, its dosage regimen, the rate of dose increase, and the possibility of combination with others before the start of therapy. antipsychotics if polytherapy for mental disorders is necessary or in cases where additional prescription of drugs from another pharmacological group is necessary to reduce the risk of adverse reactions in a particular patient.

Claims (4)

1. A method for selecting treatment tactics for patients with schizophrenia, including individual selection and dosing of medications for a specific patient, based on data from a multivariate genetic test, characterized in that pharmacogenetic testing is carried out using microchips, while the cumulative risk of developing antipsychotic-induced adverse reactions is assessed by disturbances in the efflux of antipsychotics of the 1st, 2nd and 3rd generations, shown in Table 1, through the blood-brain barrier and neuronal membrane through the antipsychotic transporter proteins P-glycoprotein, Breast Cancer Resistance Protein, Multidrug Resistance-Associated Protein 1, encoded by the ABCB1, ABCG2, ABCC1 genes, respectively ; for this purpose, by testing 26 low-functional and non-functional allelic variants of the ABCB1, ABCG2, ABCC1 genes presented in Table 2, the characteristics of the patients’ genotype, information on genetically determined transport of antipsychotics are determined in accordance with Table 3, and patients are divided into three types: slow transporters, intermediate transporters, common transporters, and also based on testing results, a list of antipsychotics is obtained, divided into four categories: “use as directed” in case of homozygous carriage of fully functional allelic gene variants in the patient; “use with caution” in heterozygous carriage of low-functional allelic gene variants; “use with increased caution and with more frequent monitoring” in case of homozygous carriage of low-functional allelic gene variants; “do not use” in case of homozygous carriage of non-functional allelic gene variants in the patient. 2. The method for choosing treatment tactics for patients with schizophrenia according to claim 1, characterized in that patients with the “slow transporter” type take the selected antipsychotic in the starting and target dose of at least 50% and lower compared to the average therapeutic dose. 3. A method for choosing treatment tactics for patients with schizophrenia according to claim 1, characterized in that patients with the “intermediate transporter” type take the selected antipsychotic at a starting and target dose of at least 25% lower than the recommended average therapeutic dose. 4. The method of choosing treatment tactics for patients with schizophrenia according to claim 1, characterized in that patients with the “common transporter” type take the selected antipsychotic in an average therapeutic single and daily dose, according to the current instructions for this drug.

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