Antipsychotic treatment monitoring method (Machine-translation by Google Translate, not legally bind

专利摘要:
Method of monitoring antipsychotic treatment. The present invention relates to a method of monitoring antipsychotic treatment and/or indication of response to it in a subject diagnosed with psychosis comprising at least the detection and/or quantification of the expression of the rpph1 gene. It also refers to the use of expression of the rpph1 gene as a biomarker for the same purpose. In addition, it also relates to a kit for the detection of the expression of the rpph1 gene and the use thereof for the purposes described. (Machine-translation by Google Translate, not legally binding)
公开号:ES2562684A1
申请号:ES201431188
申请日:2014-08-04
公开日:2016-03-07
发明作者:Jesus Vicente SAINZ MAZA；Benedicto CRESPO FACORRO
申请人:Consejo Superior de Investigaciones Cientificas CSIC；Universidad de Cantabria；Fundacion Instituto de Investigacion Marques de Valdecilla；
IPC主号:

专利说明:

DESCRIPTION

Antipsychotic treatment monitoring method.

The present invention relates to a method for monitoring an antipsychotic treatment in a subject diagnosed with psychosis comprising the detection and / or quantification of the expression of the RPPH1 gene. Therefore, the present invention could be framed in the field of medicine.
image 1
image2
image3
STATE OF THE TECHNIQUE
 10
Psychotic diseases, also called psychotic disorders, have common pathological and symptomatic features, with psychosis. These diseases include schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol or drug withdrawal syndrome, with schizophrenia considered as representative of this group. fifteen

Schizophrenia is a serious mental illness characterized by positive (hallucinations, delusions, behavioral alterations) and negative symptoms (flattened affection, alogia, anergy, associability), and cognitive malfunction already from the initial stages of the disease (Pelayo-Terán JM et al. EarlyInterv. Psychiatry 2008 2: 178-187). In addition to this obvious psychopathological disparity with psychotic, affective, cognitive symptoms, etc., all these manifestations are associated with very negative effects on the functioning and personality of the affected individual. The onset of symptoms normally occurs in young adulthood, with a lifetime prevalence of around 0.3-0.7%. (van Os J et al. Lancet 2009 374 (9690): 635-45; van Os J et al., Psychol. Med. 2009 Feb; 39 (2): 179-95). 25 Generally, the first symptoms of the disease occur in adolescence or early adulthood, and rarely in children; The age of presentation has been calculated between 15 and 35 years (50% below 25 years), being infrequent after 40 years. The incidence of schizophrenia is slightly higher in men than in women (1.6: 1). A considerable number of patients present a significant degree of disability during the first 30 years of disease progression. The life expectancy of people with the disease is reduced by an average of 10 years.

Although the symptoms and development of schizophrenia are variable, in general, affected people usually have additional morbid conditions such as major depression and anxiety disorders. In addition to all this, being a chronic disease leads to a significant deterioration in the patient's quality of life and by extension also to the families of the affected people. In this way the attention to this pathology is considered of maximum relevance.
 40
Historically, the role of various factors (genetic, biological and environmental) as causing or precipitating schizophrenia has been pursued; but no theory has obtained full acceptance, so that the current hypotheses defend the existence of multifactorial etiopathogenic mechanisms. Genetics, environmental factors, neurobiology, and psychological and social processes are factors that seem to necessarily influence the onset of the disease. Epidemiological and genetic studies have shown that a combination of genetic and environmental factors contributes to the onset and development of schizophrenia. According to studies conducted in pairs of twins, there is a complex transmission with a strong hereditary component estimated at between 80% -85% (Tandon R et al. Schizophr. Res. 2008 102 (1-3): 1-18; Cardno AG et al. Arch. Gen. Psychiatry 50 1999 Feb; 56 (2): 162-8). A polygenic model, with an indefinite number of genes with additive effect, has been proposed to explain the genetic component in the development of the disease.
Given the absence of specific defined markers, the diagnosis is made by observing the patient's behavior and the description that the patient himself makes of his experiences. Treatment in the early stages of the disease is crucial to improve the prognosis of the disease. Currently available antipsychotic drugs (with a main action of blocking dopaminergic receptors) improve the 5 positive symptoms (hallucinations, delusions, behavioral alterations) but have a very limited effect on the negative symptoms (flattened affection, abulia, anergia, sociality, etc.) and cognitive deficits (attention deficits, working memory, visual memory) that patients suffer. Although the medication decreases or improves positive symptoms, only 50-60% of patients have marked improvement (responders) (Crespo-Facorro 10 B et al. Psychopharmacology 2012 Jan; 219 (1): 225-33) . An early onset of the disease, problems in adapting the individual prior to the onset of the disease, as well as a delay in the use of effective treatment seems to be related to a worse response to treatment (Marshall M et al. Arch. Gen. Psychiatry. 2005 Sep; 62 (9): 975-83; Crespo-Facorro B et al. J. Psychiatr. Res. 2007 Oct; 41 (8): 659-66). The characterization of the predictive factors 15 of an adequate response to pharmacological treatment is one of the important areas for the research and treatment of schizophrenia. Determining, before treatment, the probability of obtaining a favorable response to neuroleptic (antipsychotic) treatment would help in clinical practice to select appropriate treatments and improve prognosis. However, there are still no clear biological indicators (biomarkers) that allow physicians to predict the individual patient's response to antipsychotic drugs. The reasons for the therapeutic success or failure of antipsychotic drugs are not clearly established, although it is postulated that the variability of certain genetic factors helps determine the response that an individual will have to antipsychotic treatment. 25

Regarding the variability of the clinical response to treatment with antipsychotic drugs, several studies have confirmed the importance of functional mutations detected in CYP metabolic enzymes (Ingelman-Sundberg M et al. Pharmacogenetics 2000 Feb; 10 (1): 91- 3; Nebert DW et al. Pharmacology 2000 Sep; 61 (3): 124-35) and in genes related to dopaminergic and serotonergic neurotransmission (Zhang JP et al. Expert Opinion. Drug Metab. Toxicol. 2011 Jan; 7 ( 1): 9-37). Some of these mutations have been associated with the development of side effects and it has been suggested that it can be used to adjust the therapeutic doses of antipsychotic and anti-depressant drugs. Research that studies genes related to neurotransmitter pathways, traditionally involved with the disease, have not provided much progress in explaining the variability observed in the response to treatment with antipsychotic drugs. Other genes and / or other genetic and genomic factors, which have not yet been characterized, may contribute to the disease and the response to drugs. In order to be able to select the most appropriate antipsychotic medication for each patient, and to generate new and more effective therapies, it is necessary to identify the genomic components today unknown.

Alterations in gene expression and regulation can explain the processes through which the disease passes, the mechanisms of action of the treatments and the results obtained with the treatment. These alterations are not detectable through classic studies of linkage and genetic association. The use of techniques (large-scale sequencing) to measure differences in gene expression with great precision can help discern changes that reflect biochemical alterations or other mechanisms that cause disease pathology (Konradi C. Brarain Res. Rev. 2005 Dec 1; 50 (1): 142-55).
 fifty
Post-mortem studies of gene expression obtained in the brains of patients with schizophrenia are affected by the variation in ribonucleic acid (RNA) levels depending on the drug used and the sample collection time after death. However, a viable alternative is the analysis of RNA levels in the
lymphocytes, free of the variability observed in post-mortem studies (Czermak C et al. J. Neuroimmunol. 2004 May; 150 (1-2): 145-9). Other studies have shown that the level of expression of genes encoding neurotransmitter receptors and other proteins is similar in peripheral blood lymphocytes and in the central nervous system (Gladkevich A et al. Prog. Neuropsychopharmacol. Biol. Psychiatry 2004 May; 28 (3): 559-76; Glatt SJ et al. 2005 5 Proc. Natl. Acad. Sci. USA 2005 Oct 25; 102 (43): 15533-8). Confirming this alternative, a recent study in peripheral blood lymphocytes showed that dopamine 3 (D3) receptor RNA levels are higher in patients with schizophrenia than in control subjects, and the use of this measure has been suggested as a diagnostic marker of the disease (Ilani T et al. Proc. Natl. Acad. Sci. USA 2001 98 (2): 625-8; van der Weide J et al. Pharmacogenetics 10 2003 13 (3): 169-72). In a study of 13 untreated patients, these showed increased levels of expression of the gene coding for the dopamine 2 receptor (D2) and modulation of the genes coding for the potassium channels (Zvara A et al. Dis. Markers 2005; 21 ( 2): 61-9). Another work that analyzed 5 families affected by the disease and 9 controls using microarrays for 1128 genes expressed in the brain, revealed that the expression of several 15 neuropeptide receptors and regulatory proteins was altered in patients (Vawter MP et al. Schizophr. Res 2002 Nov 1; 58 (1): 11-20). A reduction in the expression of the 7-acetylcholine receptor (CHRNA7) was observed in lymphocytes of patients compared to the levels measured in the control subjects (Perl O et al. FASEB J. 2003 Oct; 17 (13): 1948-50) . These and other studies use microarrays to characterize the expression in schizophrenia, but the limitation 20 of the microarrays is their poor reproducibility, which has led to their replacement by massive sequencing for the analysis of gene expression in schizophrenia.

A method is therefore necessary for the monitoring of antipsychotic treatments as well as for the prediction of the clinical response to said treatment in 25 individuals with psychosis.
DESCRIPTION OF THE INVENTION

In the present invention a method for the monitoring of antipsychotic treatments is described as well as to indicate the clinical response to said treatment in individuals with psychosis.

This invention identifies new genetic markers that are useful for monitoring an antipsychotic treatment and / or indicate the favorable or not response to the treatment of patients with psychosis, including patients with schizophrenia. In the present invention, genes with significant differential expression are identified between individuals with psychosis and control individuals and also between individuals with psychoses treated and not treated with antipsychotics (cases / controls; medicated / non-medicated). Genes have been identified, among which RPPH1 stands out, whose expression is altered due to the effects of antipsychotic drugs. For this, large-scale sequencing of messenger RNA (mRNA) has been used from clinical samples sub-divided into different categories: “group 1: healthy controls; group 2: patients with disease without medication (they have never received any antipsychotic treatment) and group 3: those same patients in group 2 after three months of treatment and with changes in their clinical symptomatology. The differential expression profiles performed have allowed characterizing new genes involved in the therapeutic action of antipsychotics that have not been detected using other methods, such as genomic association. Among the genes that demonstrate its usefulness for the monitoring of antipsychotic treatments as well as to indicate the clinical response to such treatment in individuals with psychosis is the RPPH1 gene and also the combination of this with any of the 50 genes ALPL, CRISP3, ABCA13 , CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.

Therefore, a first aspect of the present invention relates to a method of obtaining useful data for the monitoring of an antipsychotic treatment in a subject diagnosed with psychosis comprising the detection and / or quantification of the expression of the RPPH1 gene in a isolated biological sample from said subject before and after the administration of the antipsychotic treatment and / or to indicate the favorable clinical response or not to an antipsychotic treatment. Hereinafter we will refer to this as the "first method of the invention".

"Monitoring of a treatment" means the indication of whether the patient is properly medicated with said treatment; i.e. who is following the prescribed medication properly (abandonment of treatment is common in these patients). 10

It is understood by "indication of the clinical response" to determine whether the antipsychotic treatment has a favorable response or not, that is, that it manages to improve or decrease the symptoms of the disease or not.
 fifteen
RPPH1 is understood as the gene known by its identification number 85495 (NCBI Gene ID) (Ribonuclease P RNA Component H1).

“Treatment” means the set of means used to cure or relieve a disease. "Antipsychotic treatment" means the measures known by the expert in the field taken to alleviate psychosis, preferably the administration of antipsychotic drugs, such as, but not limited to, clozapine (Clorazil®), risperidone (Risperdal®) , olanzapine (Zyprexa®), quetiapine (Seroquel®), ziprasidone (Geodon®), aripiprazole (Abilify®), paliperidone (Invega®), asenapine, iloperidone (Zomaril®), zotepine, amisulpride, chlorpromazine (Larorapine®) ), fluphenazine (Prolixin®), haloperidol 25 (Aldol®, Serenace®), loxapine (Loxapac®, Loxitane®), perfenazine, pimozide (Orap®) and zuclopenthixol (Clopixol®).

In the present invention the term "subject", "individual" and "patient" are used interchangeably. Preferably the subject is a human. 30

“Psychosis” is understood as any psychopathological condition in which symptoms such as hallucinations, delusions and behavioral alterations appear that are associated with an alteration of the reality judgment and without any alteration of the level of consciousness.
 35
The term "biological sample" in the present invention refers to any sample that makes it possible to detect and / or quantify the expression of the gene or genes of the individual from which said sample has been obtained, and includes, but is not limited to, any of the biological fluids of an individual, obtained by any method known to a person skilled in the art that serves this purpose. The biological sample comprises RNA and / or protein, preferably messenger RNA. The biological sample could be, for example, but not limited to, a sample of fluid, such as blood, plasma, serum, saliva, urine, synovial fluid or lymph. It can also be a tissue sample. The biological sample can also come from routine extractions in analyzes that can be performed periodically to patients. The biological sample in the present invention can be fresh, frozen, fixed, or fixed and embedded in paraffin.

In a preferred embodiment of the first aspect of the invention, the method further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4 , 50 OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof. Preferably the genes are ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.

The following genes are those known to the person skilled in the art: ALPL (alkaline phosphatase, liver / bone / kidney, referred to the identification number gene or geneID 249), CRISP3 (cysteine-rich secretory protein 3, geneID 10321), ABCA13 (ATP-binding cassette, sub-family A (ABC1), member 13, geneID 154664), CEACAM8 (carcinoembryonic antigen-5 related cell adhesion molecule 8, geneID 1088), MMP8 (matrix metallopeptidase 8 (neutrophil collagenase), geneID 4317) , OLFM4 (olfactomedin 4, geneID 10562), OLR1 (oxidized low density lipoprotein (lectin-like) receptor 1, geneID 4973), LTF (lactotransferrin, geneID 4057), GPER (G protein-coupled estrogen receptor 1, geneID 2852), MIR3198 (microRNA 3198-1, geneID 100423025), ADAMTS2 (ADAM metallopeptidase with thrombospondin type 1 motif, 2, 10 geneID 9509), UNC45B (unc-45 homolog B (C. elegans), geneID 146862), CD177 (CD177 molecule, geneID 57126) RFX2 (regulatory factor X, 2 (influences HLA class II expression), geneID 5990), CNTNAP3 (contact tin associated protein-like 3, geneID 79937), and ENTPD2 (ectonucleoside triphosphate diphosphohydrolase 2, geneID 954). Where the identification numbers (or geneID) are those of the NCBI database (National Center for 15 Biotechnology Information).
In a more preferred embodiment of the first aspect of the invention the method further comprises the detection and / or quantification of the expression of the ALPL gene. In an even more preferred embodiment, the method further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CRISP3, 20 ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198, or any combination thereof. Preferably, the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.

In another more preferred embodiment of the first aspect of the invention, the method further comprises the detection and / or quantification of ADAMTS2 gene expression. In an even more preferred embodiment, the method further comprises the detection and / or quantification of the expression of the UNC45B gene. In another even more preferred embodiment, the method further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 or any combination thereof. Preferably the genes are CD177, RFX2, CNTNAP3 and ENTPD2.

A second aspect of the present invention relates to an in vitro method for the monitoring of an antipsychotic treatment and / or the indication of the clinical response to an antipsychotic treatment in a subject diagnosed with psychosis comprising:

to. detecting and / or quantifying the levels of an RPPH1 gene expression product in an isolated biological sample from said subject before the administration of the treatment;
b. detecting and / or quantifying the level of the gene expression product described in step 40 (a) in an isolated biological sample from the same subject after treatment administration;
C. compare the levels obtained in steps (a) and (b);
d. Associate a significant decrease in the expression of the RPPH1 gene with the adequate follow-up of the antipsychotic treatment and / or with a favorable response to it.

Hereinafter we will refer to this as the "second method of the invention".

The term "in vitro" refers to the method of the invention being performed outside the body of the subject.

The levels of the expression product in the present invention may be previously normalized.

"Favorable response" means the significant reduction, for example of 40%, of the symptoms of the patient's psychosis according to the Brief Phsychiatric Rating Scale (BPRS) scale (Overall, JE and Gorham, DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: 799-812). 5

"After the administration of the treatment" is understood at a time considered by the person skilled in the art as necessary for the treatment to be considered effective, for example after several months of treatment, preferably three months.
 10
In a preferred embodiment of the second aspect of the invention the method further comprises the detection and / or quantification of the expression in step (a) and in step (b) is at least one of the genes that are selected from the list that It includes: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof; preferably the 15 genes are ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; and where in step (d) a significant decrease in the expression of RPPH1 and a significant decrease in the expression of ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and / or ENTPD2 are associated; and / or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, 20 MMP8, OLFM4, OLR1 and / or LTF, or any combination thereof, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment. Preferably in step (d) a significant decrease in the expression of RPPH1, ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2 is associated; and a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.

In another preferred embodiment of the second aspect of the invention the method further comprises the detection and / or quantification in step (a) and in step (b) of the expression of the ALPL gene; and in step (d) the association of a significant decrease in the expression of 30 ALPL with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment. In an even more preferred embodiment, the method further comprises the detection and / or quantification in step (a) and in step (b) of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198, or any combination thereof; and in step (d) a significant decrease in the expression of GPER, MIR3198, is associated; or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 or LTF, or any combination thereof, with treatment follow-up and / or a favorable response to antipsychotic treatment. Preferably the detection and / or quantification in step (a) and in step (b) is of the genes CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198; and in step (d) a significant decrease in the expression of GPER and MIR3198 is associated; or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.
 Four. Five
In another preferred embodiment of the second aspect of the invention, the method further comprises the detection and / or quantification in step (a) and in step (b) of ADAMTS2 gene expression; and in step (d) the association of a significant decrease in ADAMTS2 expression with treatment follow-up and / or a favorable response to antipsychotic treatment. In an even more preferred embodiment, the method further comprises detection 50 and / or quantification in step (a) and in step (b) of the level of expression of the UNC45B gene; and in step (d) the association of a significant decrease in the expression of UNC45B with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment. More preferably it also comprises the detection and / or quantification in step (a) and in the stage
(b) of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 or any combination thereof; and in step (d) the association of a significant decrease in the expression of the CD177, RFX2, CNTNAP3 and ENTPD2 genes, or any combination thereof, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment. Even more preferably, the detection and / or quantification in step (a) and in step (b) is of the CD177, RFX2, CNTNAP3 and ENTPD2 genes; and in step (d) a significant decrease in the expression of CD177, RFX2, CNTNAP3 and ENTPD2 is associated with treatment follow-up and / or a favorable response to antipsychotic treatment.
The detection and / or quantification in the present invention can be carried out by any technique known to the person skilled in the art, for example by sequencing, amplification by polymerase chain reaction (PCR), microarray or SAGE. Detection can be carried out using primers and / or probes.

For this reason, in an even more preferred embodiment of the first, second and third aspects of the invention, detection and / or quantification is carried out by sequencing, PCR, microarray or by serial analysis of gene expression (SAGE).

The term "sequencing," as used herein, refers to the determination of the nucleotides of a template nucleic acid and its order. Conditions in which sequencing is performed generally include (a) contacting a template nucleic acid with a polymerase in a mixture that further comprises a primer, a bivalent cation (eg, Mg2 +), and nucleotides, generally, dNTPs and at least one ddNTP (dideoxynucleotide diphosphate), and (b) subjecting said mixture to a temperature sufficient for the polymerase to initiate the incorporation of the nucleotides into the primer by complementing the bases with the template nucleic acid, and giving rise to a population of complementary DNA molecules of different sizes. The separation of said population from complementary DNA molecules, generally, by electrophoresis, allows the nucleotide sequence to be determined.
 30
The term "amplification", as used herein, refers to the increase in the number of copies of a template nucleic acid. Conditions under which amplification is performed generally include (a) contacting a template nucleic acid with a polymerase in a mixture that further comprises at least one primer (usually two primers), a bivalent cation (eg, Mg2 +) , and nucleotides, generally, dNTPs, and 35 (b) subjecting said mixture to a temperature sufficient for the polymerase to initiate the incorporation of the nucleotides into the primer by complementing bases with the template nucleic acid, and giving rise to a population of molecules of complementary DNA generally of the same size.
 40
The PCR can also be quantitative real-time PCR.
The term "template nucleic acid" or "template", as used herein, refers to a single or double stranded nucleic acid molecule that is to be amplified or sequenced.
 Four. Five
The term "primer" (also called "first" or "oligo"), as used herein, refers to an oligonucleotide capable of acting as a starting point for DNA synthesis when hybridized with the template nucleic acid. Preferably, the primer is a deoxyribose oligonucleotide. Primers can be prepared by any suitable method, including, but not limited to, cloning and restriction of appropriate sequences and direct chemical synthesis. The primers can be designed to hybridize with specific nucleotide sequences in the template nucleic acid (specific primers) or can be synthesized at random (arbitrary primers).

According to the present invention a "primer" can be labeled or labeled by techniques well known in the state of the art. Detectable labels include, for example, radioactive isotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels or enzymatic labels.
 5
The term "microarray" (or "chip") in the present invention refers to a solid support to which the RNA or protein is bound for gene expression analysis by hybridization with probes or antibody detection.

The term "SAGE" refers to the detection and quantification of gene expression by RNA measurement. In the present invention, the SAGE variants known to those skilled in the art can be used, such as, for example, SuperSAGE, MicroSAGE and LongSAGE.

A third aspect of the present invention relates to the use of the expression of the RPPH1 15 gene as a biomarker for monitoring an antipsychotic treatment and / or the indication of the clinical response to said antipsychotic treatment in a subject diagnosed with psychosis.

A preferred embodiment of the third aspect of the invention further comprises the use of the expression of at least one of the genes that are selected from the list comprising: ALPL, 20 CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER , MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof. Preferably the genes are RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.
 25
Another preferred embodiment of the third aspect of the invention further comprises the use of ALPL gene expression. More preferably it also includes the use of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198 or any combination thereof; preferably the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, 30 GPER and MIR3198.

Another preferred embodiment of the third aspect of the invention further comprises the use of ADAMTS2 gene expression. More preferably it also comprises the use of the expression of the UNC45B gene. Even more preferably it also includes the use of the expression at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof; preferably from CD177, RFX2, CNTNAP3 and ENTPD2.

In an even more preferred embodiment of the first, second and third aspects of the invention, psychosis is caused by at least one of the diseases selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and syndrome. Withdrawal from alcohol or drugs. Preferably the disease is schizophrenia.

"Schizophrenia" is understood to be that disease in which there is a 45 sensory and perceptual disorder that lasts more than six months without other psychopathological alterations (affective and level of consciousness) associated with the appearance of the picture. Its duration must be at least six months (according to the American Psychiatric Association, DSM-V).
 fifty
The terms "bipolar disorder," "depression," "alcoholism," "drug addiction," "withdrawal syndrome" are those known to those skilled in the art.

In another even more preferred embodiment of the first, second and third aspects of the invention, the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, Chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, pimozide and zuclopenthixol. 5

In another even more preferred embodiment of the first, second and third aspect of the invention the expression is of RNA and / or protein. The RNA can be messenger RNA (mRNA) or a microRNA.

The present invention also relates to the use of the expression of the genes described in the present invention (RPPH1; RPPH1 and at least ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B , CD177, RFX2, CNTNAP3 or ENTPD2, or any combination thereof; RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3; and ALPL; RPPH1, ALPL and at least CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 or ENTPD2, or any combination thereof; RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; RPPH1 and ADAMTS2; RPPH1, ADAMTS2 and UNC45B; RPPH1, ADAM1, CDPHTS, ADAM1, CDAMTS RFX2, CNTNAP3 or ENTPD2, or any combination thereof; RPPH1, 20 ADAMTS2 and UNC45B; RPPH1, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2) for the evaluation of the degree of effectiveness and tolerability of antipsychotic drugs. The evaluation can be performed in vitro, ex vivo or in experimental animals.

A fourth aspect of the present invention relates to a kit comprising primers, probes 25 or specific antibodies for the detection and / or quantification of the expression of the RPPH1 gene.

In a preferred embodiment of the fourth aspect of the invention, the kit further comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, 30 ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof. Preferably the kit comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of the RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177 genes , RFX2, CNTNAP3 and ENTPD2. 35

In another preferred embodiment of the fourth aspect of the invention, the kit further comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of the ALPL gene. In an even more preferred embodiment, it also comprises primers, probes or antibodies specific for the detection and / or quantification of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198 or any combination thereof; preferably from CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.

In another preferred embodiment of the fourth aspect of the invention, the kit further comprises 45 primers, probes or antibodies specific for the detection and / or quantification of ADAMTS2 gene expression. In an even more preferred embodiment, it also comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of the UNC45B gene. More preferably, the kit also comprises specific primers, probes or antibodies for the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2, or any of its combinations; preferably the genes are CD177, RFX2, CNTNAP3 and ENTPD2.

In a more preferred embodiment of the fourth aspect of the invention, the kit consists of specific primers, probes or antibodies for the detection and / or quantification of the expression of the genes and combinations described previously.

A fifth aspect of the present invention relates to the use of the kit of the fourth aspect of the invention for the monitoring of an antipsychotic treatment and / or the indication of the clinical response favorable or not to an antipsychotic treatment in a subject diagnosed with psychosis.

In a preferred embodiment of the fifth aspect of the invention, psychosis is caused by at least one of the diseases that are selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol or drug withdrawal syndrome. Preferably the disease is schizophrenia.
In another preferred embodiment of the fifth aspect of the invention, the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, chlorpromazine, fluphenazine, fluphenazine loxapine, perphenazine, pimozide and zuclopenthixol.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For the experts in the field, other objects, advantages and characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration and are not intended to be limiting of the present invention.
 25 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Graph representing the level of expression, obtained by massive sequencing of the transcritptoma, of ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B. The level of expression of the untreated cases "1" was obtained in our previous study of a group of 30 36 patients with schizophrenia, the levels of the untreated cases "2" correspond to the subsequent study with the data of 22 of the patients previously treated

EXAMPLES
 35
The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the invention.

Example 1. Differential expression in 22 patients with unmedicated schizophrenia (have never previously received treatment) and medicated (those same patients after being in treatment for three months).

In a previous study (Sainz J et al. Mol. Psychiatry. 2013 Oct; 18 (10): 1056-7) differential expression was described between 36 schizophrenia patients (never undergoing treatment) and 40 healthy controls. 200 genes were characterized with significant differential expression between the 45 schizophrenia patients and the controls. These genes are significantly enriched in seven biological processes categorized in Gene Ontology including protein processing, innate immune response, acute inflammatory response and wound response. However, in this work there is no reference to which genes are useful for the follow-up of an antipsychotic treatment or indicate whether the patient is responding to an antipsychotic treatment.

In the present invention, the transcriptome of 22 of the 36 schizophrenia patients analyzed in said previous study before and after antipsychotic medication was analyzed.

Expression analysis by massive RNA sequencing in blood samples of the 22,278 genes (RefSeqs) analyzed revealed that 17 genes had a statistically significant differential expression (PadjValue <0.05, DESEQ statistical analysis) after correcting by multiple tests (table one). The P values, after correcting for the number of tests 5 performed, range from 0.035 to 6.20E-40.

In ten of these genes the expression is decreased in medicated patients while in the remaining seven genes it is increased [see table 1 columns baseMeanA (unmedicated) and baseMeanB (medicated)]. The decreased expression genes are the genes: RPPH1, ALPL, 10 GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; while the genes whose expression is increased are the genes: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF. Six genes of these 17 genes have significantly greater expression in schizophrenics than in control individuals according to the publication of Sainz J et al. 2013 Mol Psychiatry 18: 1056-1057 (ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2), and 15 these 6 genes also have a significantly lower expression after medicating than before medicating. Table 2 and 3 provide the individualized expression per patient.


Example 2. Genes with differential expression in schizophrenia patients and modulated by antipsychotics

Of the 17 genes identified with differential expression (see example 1, table 1) and comparing it with the genes identified with schizophrenia in Sainz J et al. 2013, eleven of them are not previously related to the diagnosis of schizophrenia: RPPH1, ALPL, GPER, CEACAM8, OLR1, LTF, OLFM4, CRISP3, ABCA13, MMP8 and MIR3198 (table 2), therefore, in light of the results found, said expression is moderated by the presence of antipsychotic drugs in the body. Since antipsychotic drugs are common to the treatment of various types of psychosis, the regulation of these genes is a reliable indicator of the correct monitoring of treatment by individuals; Adherence to this medication follow-up is one of the biggest problems in these patients, so these markers are useful to better control their evolution (Table 2).





































The other six genes (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2, UNC45B) with differential expression are common with the document by Sainz J et al. 2013 among non-medicated / medicated schizophrenics, they also have differential expression in non-medicated schizophrenics / healthy controls. Specifically, in patients six of the genes that have altered expression in schizophrenia, their expression is reverted back to 5 levels of expression of control subjects, when they take antipsychotic medication (Table 3). These 6 genes have higher expression in patients without schizophrenia without medicating and when they are medicated with antipsychotics the expression is decreased to the level of healthy controls and in addition their expression is altered in individuals with schizophrenia (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 , UNC45B). These 6 genes related to schizophrenia 10 represent a fraction (35.29%) of the total antipsychotic modulated genes of the significantly higher total than expected (Chi Test; P Value = 1,18971E-50).





















































There is a great ignorance of what causes a psychotic outbreak in a patient, and in certain cases the remission of the psychotic outbreak is carried out without pharmacological intervention. Schizophrenia is considered as a combination of genetic variants that in each individual case causes the disease uniquely. That is why the analysis of the values of the genes with differential expression characteristic of schizophrenia (table 3) must be accompanied by 5 the assessment of the genes altered by the medication (table 2) in order to better identify the patient's adherence to the treatment . In this sense, the genes in table 2 that best identify the patients who follow the treatment are RPPH1 and ALPL (with 81% of the patients identified with these genes). The combination of ALPL with any of the genes identified in Table 3 (ie ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B) is the least informative since there is at least one patient (identified as 511) that would only have higher values before the medication later in one of the genes (UNC45B) and not in the others, when said decrease caused by the treatment is key in all these genes: RPPH1, ALPL, ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B (Table 1); therefore the combination ALPL, ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B could underrepresent the follow-up of the treatment and its effects on the progress of the schizophrenic patient. The RRPH1 combination together with the genes identified in Table 3 (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B), however, does identify at least two genes whose expression decreases with treatment, improving the information obtained with the combination mentioned above. ; In addition, the RPPH1 pval is less than the ALPL (see table 1, pval RRPH1 = 3.45E-07 vspval ALPL = 1.85E-06), which indicates that the differential expression of RPPH1 before and after the medication is statistically more significant than the expression difference of ALPL.

Therefore, the present invention demonstrates the utility of the expression of the RPPH1 25 gene for the monitoring of an antipsychotic treatment and / or for knowing the clinical response to an antipsychotic treatment, as well as that of its combination with the expression of the genes described in the present invention for the same purpose.

Example 3. Genes with reversed expression by antipsychotics 30

The six common genes in the case / control and medicated / non-medicated differential expression lists are significantly overexpressed in schizophrenia patients and the medication decreases the expression to expression levels of the individual unaffected by schizophrenia (Table 4) ( Figure 1). 35

Table 4. Genes with expression reversed by medication.
 Gen  baseMean Controls BaseMean No med BaseMean No med2 baseMeanMed
 ADAMTS2  4.40 45.83 43.98 4.47
 UNC45B  132.73 336.93 446.90 160.05
 CD177  87.52 170.70 186.74 69.43
 ENTPD2  18.76 35.71 37.19 22.02
 CNTNAP3  161.69 304.89 301.04 166.32
 RFX2  370.65 642.28 692.31 364.88
BaseMean is the average expression of the individuals in the group. BaseMean No med is the mean expression in non-medicated individuals in the case / control study. BaseMean No med2 is the mean expression in non-medicated individuals in the medicated / non-medicated study. BaseMeanMed is the mean expression in medicated individuals

Example 4. Enrichment in Gene Ontology categories

To determine the biological processes, the molecular function and the cellular location of the genes with differential expression found in the present invention, the data from the Gene Ontology repository, known by the person skilled in the art, was used by means of the suite tool 5 FatiGO Babelomics computing. Of the 17 genes with differential expression between medicated and non-medicated, four of them (ENTPD2, MMP8, ADAMTS2, CRISP3) locate in the categories "extracellular matrix" and "proteinaceous extracellular matrix". The fraction of genes in both categories represents 23.53% of the total that compared with the expected fractions, 1.49% and 1.59%, shows a significant enrichment of genes in these 10 categories, related to inter-cellular communication , after correcting for the multiple analyzes performed (Padj value = 0.01541).

Example 5. Functions and relationship with disease of genes with differential expression
 fifteen
Analyzing the “Genome Wide Association Studies Catalog” (GWAS, as of January 18, 2013) we found that 6 of the 17 genes found in the medicated / non-medicated analysis (LTF, OLFM4, ADAMTS2, RFX2, ALPL, ABCA13) have been associated to 17 traits / diseases that include schizophrenia and bipolar disorder (OLFM4 and RFX2; these genes appear in the GWAS catalog associated with schizophrenia in the “mapped” category, but not in the “reported” category), time of deficit onset of attention with hyperactivity (ADAMTS2), ischemia (OLFM4, ADAMTS2), response to amphetamines (ABCA13), AIDS (LTF) and immune response to anthrax vaccine (OLFM4), among others (Troyer JL et al. J. Infect. Dis. 2011 203: 1491-502; Lasky-Su J et al. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2008 147B: 1355-8; Wang KS et al. Schizophr. Res. 2010 124: 192 -9; Pajewski NM et al. Vaccine 25 2012 30: 4778-84; Hart AB et al. PLoS One. 2012 7 (8): e42646; Matarín M et al. Lancet Neurol. 2007 6: 414-20; Arning A et al. Blood. 2012 120: 5231-6) but its relationship with antipsychotic drugs or with the treatment of schizophrenia had never been described before. Therefore, they are new genes and new biological pathways that are altered in psychotic diseases and that are reversed by treatment. 30

The GWAS catalog includes associations to traits / diseases for 4,828 genes of the 22,278 we have analyzed in our expression studies, or a fraction equivalent to 21.67% of the total. The fraction of genes with differential expression noted in GWAS is somewhat higher (35.29%), therefore we observe an enrichment, although not significant, of genes associated with diseases in genes whose expression is modulated by antipsychotics.

According to the scientific literature deposited in the GeneRIF repository of the National Center for Biotechnology Information (NCBI), ABCA13 has been related to schizophrenia (although it has not been related to the therapeutic effect of antipsychotic drugs), bipolar disorder and depression ( Knight HM et al. Am. J. Hum. Genet. 200985 (6): 833-46) and the LTF and OLR1 genes with the immune system in several studies (Guillen C et al. J Immunol. 2002 168 (8): 3950-7; Huang D et al. J. Cardiovasc. Pharmacol. 2012 60: 133-9), LTF with wound response (Engelmayer J et al. J. Surg. Res. 2008 149 (2): 278-86 ), and ALPL, GPER, LTF, MMP8, OLR1 and CRISP3 have been related to the inflammatory response in several studies 45 (Filipowicz R et al. Clin. J. Am. Soc. Nephrol. 2013 8 (1): 26-32 ; Chakrabarti S et al. PLoS One. 2012 7 (12): e52357; Weinberg AD et al. Immunol Rev. 2011 244 (1): 218-31; Quintero PA et al. J. Immunol. 2010 184 (3): 1575-88; Lubrano V et al. Lipids. 2008 43 (10): 945-5 0; Plager DA et al. PLoS One. 2010 5 (7): e11450). That is, 6 of the 17 genes with differential expression in the differential expression analysis between medicated / non-medicated are related to the immune system, the inflammatory system and the wound response. This represents 35.29% of the genes modulated by the antipsychotics while the fraction of human genes related to these categories in GeneRIF is 19.78% (3,083 genes of the 15,589 human genes noted) is shown by an enrichment in genes of defense systems e
inflammation modulated by antipsychotics, which implies a relationship of these immune response genes also in schizophrenia.

MATERIALS AND METHODS
 5
Study design
The data of the present investigation were obtained from a three-year continuous and longitudinal epidemiological intervention program of a first episode of psychosis (PAFIP) that was carried out in the outpatient clinic and the hospitalization unit of Marqués University Hospital of Valdecilla, (Santander, Spain). Complying with international standards of research ethics 10, this program was approved by the local institutional review board. Patients who met the inclusion criteria and their families in writing informed consent to be included in the PAFIP.

The patients recruited in this study were obtained from a consecutive sample of 15 non-affective psychotic patients enrolled in the first episode of psychosis program (PAFIP) from May 2010 to May 2012. Patients had to meet the following criteria: 1) Age 15-60 years, 2) live in the catchment area, 3) that was your first episode of psychosis 4) have never been treated with antipsychotic medications, 5) meet the DSM-IV criteria for short-term psychosis, schizophreniform disorder, schizophrenia, or schizoaffective disorder, 6) who have understood the nature of the study and signed an informed consent document.

Patients were excluded for any of the following reasons: 1) meet the DSM-IV criteria for drug dependence, 2) meet the DSM-IV criteria for mental retardation, 3) have a serious illness. The diagnoses were confirmed according to the DSM-IV criteria, using the Structured Clinical Interview for the DSM-IV (SCID-I) (First, MB et al. (2001) Structured Clinical Interview for Dsm-Iv-Tr Axis I Disorders-Non -Patient Edition, Biometrics Research Department: New York) by an expert psychiatrist after 6 months of the first contact. 30

Additionally, a group of healthy people (N = 40) were also analyzed to serve as a control group. Healthy people had no history of psychiatric disease (including the absence of drug dependence), neurological or general medical: They did not receive any pharmacological treatment on a regular basis as shown in the abbreviated version of the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen NC, et al. The Comprehensive Assessment of Symptoms and History (CASH) an instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992; 49: 615–623). The absence of a family history of psychosis among first-degree relatives was also evaluated by medical history and family interview. After a detailed description of the protocol, the 40 healthy controls gave their written consent to participate in the study according to international ethical standards. The demographic and clinical characteristics of the patients and controls are shown in Table 5.

Table 5. Sociodemographic and clinical characteristics of the patients and controls studied in the case / control analysis.
 features  Total (N = 76) Patients (N = 36) Controls (N = 40)
 Mean SD Mean SD Mean SD F (df = 1) p
 Admission age, years  31.4 9.1 29.7 9.7 33 8.3 2,562 0,114
 Start age psychosis, year        29.1 9.6 -
 Disease duration, m        8 10.4 -
 Duration psychosis, m        5.6 9.2 -

 Diagnosis  N% N% N% χ ^ 2 (df = 1) p
 Schizophrenia        5 16.1 -
 Other diagnoses spectrum schizophrenia        26 83.9 -
 Trast. Brief psychotic        9 29 -
 Trast. Not specified psychotic        1 3.2 -
 Trast. Schizophreniform        14 45.2 -
 Trast. schizoaffective        1 3.2 -
 Trast. delirious        1 3.2 -
 Sex (male)  40 52.6 19 52.8 21 52.5 0.001 0.981
 Caucasian (yes)  73 96.1 33 91.7 40 100.0 3,470 0.062
 Educational level (elementary)  29 40.8 14 45.2 15 37.5 0.424 0.515
 Use Tobacco (yes)  46 60.5 21 58.3 25 62.5 0.138 0.711
 Cannabis use (yes)  28 36.8 15 41.7 13 32.5 0.684 0.408
 Use Alcohol (yes)  54 71.1 22 61.1 32 80 3,287 0.07
 Other drugs (yes)  11 14.5 7 19.4 4 10 1,365 0.243
Trast disorder Mean, average. SD, standard deviation. M, months. F (df = 1), statistical analysis and degrees of freedom.
 5

At baseline (initial time) of obtaining blood samples, the analyzed patients had not previously received any dose of antipsychotic treatment, although certain concomitant medications (lormetazepam and clonazepam) were allowed for the treatment of agitation, anxiety and / or insomnia 10

The antipsychotic drugs (risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) with which patients were treated are second generation antipsychotics that are characterized by having a common action of antagonism at the level of 5-HT2 and D2 receptors and represent the Most of the second generation antipsychotics that are currently used. A relatively potent action of serotonin 5-HT2A receptor antagonism associated with a milder antagonism of D2 dopamine receptors is the common central feature of second generation antipsychotics. The only one of those drugs used that has a differentiated action is aripiprazole that has an associated action of partial agonist of the high affinity D2 dopamine receptors. (Schwartz 20 TL and Stahl SM CNS Neurosci. Ther. 2011 17 (2): 110-7).

Gravity scales “Clinical Global Impression (CGI) scale” (Guy W (1976) ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare publication ADM 76338. Washington, DC: National Institute of Mental Health; 217– 222), “Brief Psychiatric Rating Scale” (BPRS), (Overall, JE and Gorham, DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: 799-812), “Scale for the Assessment of Positive 5 symptoms” ( SAPS), “Scale for the Assessment of Negative symptoms” (SANS) (Andreasen, NC (1983) Scale for the Assessment of Negative Symptoms (Sans). University of Iowa: Iowa City .; Andreasen, NC (1984) Scale for the Assessment of Positive Symptoms (Saps), University of Iowa: Iowa City, “Calgary Depression Scale for Schizophrenia” (CDSS) (Addington, D., Addington, J., and Maticka-Tyndale, E. (1993) Assessing Depression in Schizophrenia : The 10 Calgary Depression Scale. Br J Psychiatry Suppl: 39-44.) And “Young Mania Rating Scale (YMRS) ”(Young, R.C., Biggs, J.T., Ziegler, V.E., and Meyer, D.A. (1978) A Rating Scale for Mania: Reliability, Validity and Sensitivity. Br J Psychiatry 133: 429-435) were used to evaluate clinical symptomatology. The same psychiatrist (Benedicto Crespo Facorro) completed all clinical evaluations to ensure the reliability of clinical evaluations. The severity of psychopathology at the beginning of the study is shown in Table 6.

Table 6. Psychopathology of the 22 medicated patients, used in the medicated / non-medicated study, at the baseline and at three months and description of the changes in the severity of the symptoms. twenty
 Total Change Protocol
 (N = 22) (N = 13) (N = 9) F
 Variable  Mean SD Mean SD Mean SD df = 1.21 p
 CGI
 Basal  6.0 0.8 5.7 0.9 6.3 0.5 4.058 0.058
 3 months  2.3 1.1 2.5 1.1 2.1 1.2 0.500 0.488
 Change at 3 months from baseline  -3.6 1.6 -3.2 1.7 -4.2 1.4 2,097 0.163
 Change at 3 months from baseline        -3.7 0.3 -3.6 0.4 0.005 0.945
 BPRS
 Basal  53.0 9.1 51.7 8.8 54.9 9.7 0.643 0.432
 3 months  28.7 3.9 29.5 4.4 27.4 2.7 1,579 0.223
 Change at 3 months from baseline  -24.3 10.2 -22.2 10.0 -27.4 10.1 1,472 0.239
 Change at 3 months from baseline        -23.5 1.1 -25.5 1.3 1,406 0.250
 SANS
 Basal  5.8 5.7 5.8 6.5 5.8 4.6 0.000 0.997
 3 months  4.0 3.7 3.4 3.0 4.9 4.5 0.879 0.360
 Change at 3 months from baseline  -1.8 6.9 -2.4 7.6 -0.9 6.0 0.244 0.626
 Change at 3 months from baseline       -2.4 1.1 -0.9 1.3 0.835 0.372
 SAPS
 Basal  12.0 3.6 11.8 3.5 12.3 3.8 0.094 0.762
 3 months  0.4 1.0 0.4 1.0 0.3 1.0 0.015 0.905
 Change at 3 months from baseline  -11.7 3.9 -11.5 4.1 -12.0 3.8 0.098 0.758
 3 month change        -11.7 0.3 -11.7 0.3 0.004 0.953
 Total Change Protocol
 (N = 22) (N = 13) (N = 9) F
 Variable  Mean SD Mean SD Mean SD df = 1.21 p
 from basal
 Positive dimension
 Basal  6.3 2.4 5.8 1.9 7.0 2.9 1.461 0.241
 3 months  0.3 0.8 0.3 0.8 0.3 1.0 0.005 0.946
 Change at 3 months from baseline  -6.0 2.4 -5.5 2.3 -6.7 2.6 1,318 0.265
 Change at 3 months from baseline        -5.9 0.2 -6.0 0.3 0.002 0.964
 Negative dimension
 Basal  4.7 5.2 4.5 5.5 5.0 5.0 0.055 0.817
 3 months  3.5 3.2 2.9 2.4 4.2 4.2 0.845 0.369
 Change at 3 months from baseline  -1.2 6.0 -1.5 6.2 -0.8 6.1 0.081 0.779
 Change at 3 months from baseline        -1.8 0.9 -0.5 1.1 0.792 0.385
 Disorganized dimension
 Basal  5.8 2.8 6.1 2.7 5.3 3.0 0.365 0.552
 3 months  0.0 0.2 0.1 0.3 0.0 0.0 0.682 0.419
 Change at 3 months from baseline  -5.7 2.8 -6.0 2.8 -5.3 3.0 0.281 0.602
 Change at 3 months from baseline        -6.0 0.8 -5.3 1.0 0.281 0.602
 CDSS
 Basal  2.0 3.1 1.2 2.5 3.0 3.7 1,806 0.194
 3 months  1.4 3.6 2.3 4.6 0.0 0.0 2,277 0.147
 Change at 3 months from baseline  -0.6 5.3 1.1 5.7 -3.0 3.7 3.558 0.074
 Change at 3 months from baseline        0.2 1.0 -1.8 1.2 1,526 0.232
 Mania Young scale
 Basal  10.9 6.7 10.5 7.3 11.6 6.2 0.135 0.718
 3 months  0.4 1.0 0.4 1.0 0.4 1.0 0.020 0.890
 Change at 3 months from baseline  -10.5 6.9 -10.1 7.3 -11.1 6.5 0.116 0.737
 Change at 3 months from baseline        -10.5 0.3 -10.5 0.3 0.025 0.875

BPRS: Brief Psychiatric Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; SANS: Scale of the Assessment of Negative Symptoms; SAPS: Scale of the Assessment of Positive Symptom; CGI: Clinical Global Impression; Mean, average. SD, standard deviation.
 5
Laboratory evaluations
Venous blood samples were obtained under the same conditions with people (patients and controls) fasting and were collected between 08: 00-10: 00 a.m. This extraction protocol was similar in the initial (baseline) extraction and three months later. The patients
they were without antipsychotic treatment at the time of blood collection from baseline.

RNA extraction.
Total RNA was extracted from blood using the "Tempus ™ Blood RNA Tube" 5 system with "Tempus ™ Spin RNA Isolation Kit (AppliedBiosystems, Foster City, CA, USA)", using the manufacturer's protocols. To define expression profiles, a key factor is that the RNA is as intact as possible, that is, with the least possible degradation. To select good quality RNA, the "IntegrityNumber RNA" (RIN) was obtained using a Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). Samples with an RIN of ≥ 6.9 were 10 selected. The set of selected samples have RINs ranging from 6.9 to 9.4 with an average of 8.4.

Next generation sequencing RNA (“next generation sequencing”).
Sequences (readings) of single fragments of 35 nucleotides were obtained using the GenomeAnalyzerIIx massive sequencing platform (Illumina Inc.). The sequences obtained were filtered using quality criteria (reliability of the reading of each base provided by the software of the platform used, IlluminaIIx). The quality filters passed an average of 76% of the readings obtained. The sequence readings that passed the quality filters were aligned with the human reference genome [hg19, February 20 2009 human referencesequence (GRCh37), Genome Reference Consortium] obtained from UCSC Genome Bioinformatics. The alignment of the readings was carried out using the Illumina Casava 1.8.1 software package, with software specifically configured to process RNA-Seq data. The length of the sequences read varies between 35 base pairs (bp) to 38bp, so the alignment was configured to mask the sequences until a uniform length of 35 nucleotides was obtained. This masking was done in order to avoid the alignment biases in the genome that we observed when the sequences analyzed varied in length.

Statistical analysis of differential expression. 30
The Bedtools 2.15.0 tool (“bedtoolscoverage”) was used to compute the amount of readings (sequences) assigned to each gene. The DESeq 1.9.6 package (Anders S and Huber JS Genome Biology 2010 11: R106)) for R in Bioconductor was used to analyze the differential expression of the human reference genes (22,278 RefSeqs) according to the computed number 35 of sequences obtained for each gene The fit-only configuration was used as the adjustment method. Casava 1.8.1 was used to calculate RPKMs (readings per kilobase per million readings mapped in the reference genome). RPKM values allow comparison of gene expression data obtained in different experiments and of different genes when normalized. 40

Validation of expression data using QRT-PCR.

In order to validate the expression data obtained by RNA-Seq, QRT-PCR (“Real-Time Quantitative Reverse Transcription PCR”) was performed on 10 selected genes with 45 samples from 30 randomly selected patients (15 cases and 15 controls ). Pre-designed TaqMan probes (Life Technologies®) were used according to the manufacturer's instructions for the LAMP3 (Hs00180880_m1), RFX2 (Hs01100925_m1), CTAG2 (Hs00535628_m1), GPR128 (Hs00262184_m1), IFI27 (Hs0101) H1111 (Hs0106) BRS3 (Hs00179951_m1), MSLN (Hs00245879_m1), RSAD2 (Hs00369813_m1) and IFI144L 50 (Hs00119115_m1), using the GADPH gene (Hs02758991_g1) as internal control. The expression ratio obtained from each gene compared to the control of the housekeeping gene used as a control (GAPDH) was compared, in each sample, with the ratio of the same genes calculated from the RNA-Seq data. . This comparison was made
calculating Pearson's product-moment linear correlation coefficient between the data obtained in the two platforms (RNA-seq and QTR-PCR) using the Libre Office statistical package. On average, a correlation coefficient of 87.15% was obtained between the data obtained with the two technologies, with individual gene correlation ratios ranging from 75% (CTAG2) to 99.9% (MSLN). Lower correlation rates of 5 poorly expressed genes have been observed, probably due to a lower sensitivity of the QRT-PCR platform compared to that of RNA-Seq. Apart from this, the high degree of correlation observed between the QRT-PCR and RNA-Seq data supports the expression data obtained in the present invention.

权利要求:
Claims (56)
[1]

1. Method of obtaining useful data for the monitoring of an antipsychotic treatment in a subject diagnosed with psychosis comprising the detection and / or quantification of the expression of the RPPH1 gene in an isolated biological sample from said subject before and after administration of the antipsychotic treatment and / or to indicate the clinical response to an antipsychotic treatment.

[2]
2. Method according to claim 1 further comprising the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF , GPER, MIR3198, 10 ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof.

[3]
3. The method according to claim 1 further comprising the detection and / or quantification of the expression of the ALPL gene. fifteen

[4]
4. Method according to claim 3 which further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198, or any combination thereof. twenty

[5]
5. Method according to claim 4 wherein the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.

[6]
6. The method according to claim 1 further comprising the detection and / or quantification of the expression of the ADAMTS2 gene.

[7]
7. Method according to claim 6 which further comprises the detection and / or quantification of the expression of the UNC45B gene.
 30
[8]
A method according to claim 7 which further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 or any combination thereof.

[9]
9. Method according to claim 8 wherein the genes are CD177, RFX2, CNTNAP3 and ENTPD2.

[10]
10. Method according to claim 2 wherein the genes are ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2. 40

[11]
11. Method according to any one of claims 1 to 10 wherein psychosis is caused by at least one of the diseases selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol or drug withdrawal syndrome . Four. Five

[12]
12. The method according to any of claims 1 to 11 wherein the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, chlorpromazine, fluphenazine , loxapine, perphenazine, pimozide, ziprasidone and 50 zuclopenthixol.

[13]
13. Method according to any one of claims 1 to 12 wherein the expression is RNA and / or protein.

[14]
14. In vitro method for the monitoring of an antipsychotic treatment and / or the indication of the clinical response to said treatment in a subject diagnosed with psychosis which includes:
to. detecting and / or quantifying the levels of an RPPH1 gene expression product in an isolated biological sample from said subject before the administration of the treatment;
b. detect and / or quantify the level of the gene expression product described in step 10 (a) in an isolated biological sample from the same subject after treatment administration;
C. compare the levels obtained in steps (a) and (b);
d. Associate a significant decrease in the expression of the RPPH1 gene with adequate follow-up of antipsychotic treatment and / or with a favorable response to it.

[15]
15. Method according to claim 14, further comprising the detection and / or quantification in step (a) and stage (b) of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13 , CEACAM8, MMP8, OLFM4, OLR1, LTF, 20 GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof; and in step (d) a significant decrease in the expression of ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and / or ENTPD2 is associated; and / or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and / or LTF, or any combination thereof, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.

[16]
16. Method according to claim 14 further comprising the detection and / or quantification in step (a) and in step (b) of the expression of the ALPL gene; and in step (d) the association of a significant decrease in ALPL expression with treatment follow-up 30 and / or a favorable response to antipsychotic treatment.

[17]
17. Method according to claim 16 which further comprises the detection and / or quantification in step (a) and in step (b) of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, 35 OLR1, LTF, GPER and MIR3198 or any combination thereof; and in step (d) a significant decrease in the expression of GPER, MIR3198, is associated; or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 or LTF, or any combination thereof, with treatment follow-up and / or a favorable response to antipsychotic treatment. 40

[18]
18. Method according to claim 17 wherein the detection and / or quantification in step (a) and in step (b) is of the genes CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198; and in step (d) a significant decrease in the expression of GPER and MIR3198 is associated; or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.

[19]
19. Method according to claim 14 further comprising the detection and / or quantification in step (a) and in step (b) of ADAMTS2 gene expression; and in step (d) the association of a significant decrease in ADAMTS2 expression with treatment follow-up and / or a favorable response to antipsychotic treatment.

[20]
20. The method according to claim 19 further comprising the detection and / or quantification in step (a) and in step (b) of the level of expression of the UNC45B gene; and in step (d) the association of a significant decrease in the expression of UNC45B with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.
 5
[21]
21. Method according to claim 20 further comprising the detection and / or quantification in step (a) and in step (b) of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 or any combination thereof; and in step (d) the association of a significant decrease in the expression of the CD177, RFX2, CNTNAP3 and ENTPD2 genes, or any of its 10 combinations, with the treatment follow-up and / or a favorable response to antipsychotic treatment.

[22]
22. Method according to claim 21 wherein the detection and / or quantification in step (a) and in step (b) is of the CD177, RFX2, CNTNAP3 and ENTPD2 genes; and in step (d) a significant decrease in the expression of CD177, RFX2, CNTNAP3 and ENTPD2 is associated with treatment follow-up and / or a favorable response to antipsychotic treatment.

[23]
23. Method according to claim 14 wherein the detection and / or quantification in step (a) and in step (b) is of the genes RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; and in step (d) a significant decrease in the expression of RPPH1, ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2 is associated; and a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and 25 LTF, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.

[24]
24. Method according to any of claims 14 to 23 wherein psychosis is caused by at least one of the diseases selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol withdrawal syndrome or drugs

[25]
25. A method according to any of claims 14 to 24 wherein the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, chlorpromazine, fluphenazine haloperidol, loxapine, perphenazine, pimozide and zuclopenthixol.

[26]
26. Method according to any of claims 14 to 25 wherein the expression is messenger RNA and / or protein. 40

[27]
27. Method according to any of claims 14 to 26 wherein the detection and / or quantification is performed by sequencing, PCR, microarray or SAGE.

[28]
28. Use of the expression of the RPPH1 gene as a biomarker for monitoring an antipsychotic treatment and / or indicating the clinical response to said antipsychotic treatment in a subject diagnosed with psychosis.

[29]
29. Use according to claim 28 which further comprises the use of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, 50 CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof.

[30]
30. Use according to claim 29 wherein the gene is ALPL.

[31]
31. Use according to claim 30 which further comprises the use of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198 or any of their combinations. 5

[32]
32. Use according to claim 31 wherein the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.

[33]
33. Use according to claim 29 wherein the gene is ADAMTS2. 10

[34]
34. Use according to claim 33 which further comprises the use of the expression of the UNC45B gene.

[35]
35. Use according to claim 34 which further comprises the use of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof.

[36]
36. Use according to claim 35 wherein the genes are CD177, RFX2, CNTNAP3 and ENTPD2.
 twenty
[37]
37. Use according to claim 29 wherein the genes are ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.

[38]
38. Use according to any of claims 28 to 37 wherein psychosis is caused by at least one of the diseases selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol withdrawal syndrome or drugs

[39]
39. Use according to any of claims 28 to 38 wherein the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, chlorpromazine, fluphenazine, fluphenazine haloperidol, loxapine, perphenazine, pimozide and zuclopenthixol.

[40]
40. Use according to any of claims 28 to 39 wherein the expression is of RNA and / or protein.

[41]
41. Kit comprising primers, probes or antibodies specific for the detection and / or quantification of RPPH1 gene expression.
 40
[42]
42. Kit according to claim 41 further comprising primers, probes or antibodies specific for the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof. Four. Five

[43]
43. Kit according to claim 42 wherein the gene is ALPL.

[44]
44. Kit according to claim 43 further comprising primers, probes or antibodies specific for the detection and / or quantification of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198 or any combination thereof.

[45]
45. Kit according to claim 44 wherein the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.

[46]
46. Kit according to claim 41 consisting of primers, probes or antibodies specific for the detection and / or quantification of at least one of the genes that are selected from the list comprising: RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.

[47]
47. Kit according to claim 42 wherein the gene is ADAMTS2.
 10
[48]
48. Kit according to claim 47 further comprising primers, probes or antibodies specific for the detection and / or quantification of the expression of the UNC45B gene.

[49]
49. Kit according to claim 48 further comprising primers, probes or antibodies specific for the detection and / or quantification of the expression of at least one of the 15 genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 , or any of its combinations.

[50]
50. Kit according to claim 49 wherein the genes are CD177, RFX2, CNTNAP3 and ENTPD2.
 twenty
[51]
51. Kit according to claim 41 consisting of specific primers, probes or antibodies for the detection and / or quantification of the expression of the genes that are selected from the list comprising: RPPH1, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.

[52]
52. Kit according to claim 42 comprising primers, probes or specific antibodies for the detection and / or quantification of gene expression are RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.

[53]
53. Kit according to claim 41 consisting of specific primers, probes or antibodies for the detection and / or quantification of gene expression are RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER , MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.

[54]
54. Use of the kit according to any of claims 41 to 53 for the monitoring of an antipsychotic treatment and / or the indication of the clinical response to said antipsychotic treatment in a subject diagnosed with psychosis.

[55]
55. Use according to claim 54 wherein psychosis is caused by at least one of the diseases that are selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol or drug withdrawal syndrome.

[56]
56. Use according to any of claims 54 to 55 wherein the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, chlorpromazine, fluphenazine, fluphenazine haloperidol, loxapine, perphenazine, pimozide and zuclopenthixol.

类似技术:

---

公开号 | 公开日 | 专利标题

---

ES2562684B1|2017-02-06|ANTIPSYCHOTIC TREATMENT MONITORING METHOD

---

ES2774519T3|2020-07-21|A method of diagnosing a disease by detecting cirRNA in body fluids

---

Gulsuner et al.2013|Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network

---

Hu et al.2015|The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies

---

US20190002982A1|2019-01-03|Systems For Biomarker Detection

---

García-Gutiérrez et al.2020|Biomarkers in psychiatry: concept, definition, types and relevance to the clinical reality

---

Lardenoije et al.2019|Alzheimer’s disease-associated | methylomic changes in the brain and blood

---

US11047009B2|2021-06-29|Blood biomarkers for suicidality

---

Gau et al.2012|Identification of two inherited copy number variants in a male with autism supports two‐hit and compound heterozygosity models of autism

---

Chien et al.2011|Association study of the CNS patterning genes and autism in Han Chinese in Taiwan

---

US20180275149A1|2018-09-27|Method for predicting a subject&#39;s response to valproic acid therapy

---

Li et al.2016|Characterization of variations in IL23A and IL23R genes: possible roles in multiple sclerosis and other neuroinflammatory demyelinating diseases

---

Chaumette et al.2019|Longitudinal analyses of blood transcriptome during conversion to psychosis

---

Adewuyi et al.2021|Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

---

Piccoli et al.2016|Novel PSEN1 mutations | associated with familial Alzheimer's disease identified by targeted exome sequencing

---

ES2716995T3|2019-06-18|Biomarkers associated with irritable bowel syndrome and Crohn&#39;s disease

---

Daily et al.2012|Spatial and temporal silencing of the human maternal UBE3A gene

---

Ferwerda et al.2016|Variation of 46 innate immune genes evaluated for their contribution in pneumococcal meningitis susceptibility and outcome

---

Anderson‐Schmidt et al.2013|Selected rapporteur summaries from the XX world congress of psychiatric genetics, Hamburg, Germany, october 14–18, 2012

---

MXPA06014127A|2007-01-31|Biomarkers for the prediction of responsiveness to clozapine treatment.

---

US9714450B2|2017-07-25|Methods for diagnosing and treating schizophrenia

---

Huang et al.2016|Higher blood MLL1 mRNA and BDNF promoter IV on histone H3K4me3 levels in patients with schizophrenia

---

ES2389199B1|2013-09-17|METHOD OF DIAGNOSIS OF ALZHEIMER&#39;S DISEASE THAT USES SFRP1 AS A BIOMARCATOR.

---

Liedtke et al.2017|Correlated expression analysis of genes implicated in schizophrenia: identification of putative disease-related pathways

---

JP2003235557A|2003-08-26|Method for analyzing nucleic acid specifying gene changing expression level with schizophrenia

同族专利:

---

公开号 | 公开日

---

ES2562684B1|2017-02-06|

---

WO2016020573A1|2016-02-11|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB0712524D0|2007-06-28|2007-08-08|Mitsubishi Pharma Corp|Novel schizophrenia associated genes|JP2020503381A|2016-12-20|2020-01-30|エルテーエス ローマン テラピー−ジステーメ アーゲー|Transdermal therapeutic system containing asenapine|

---

WO2018178071A1|2017-03-29|2018-10-04|Consejo Superior De Investigaciones Cientificas|Method for predicting the therapeutic response to antipsychotic drugs|

---

BR112019027037A2|2017-06-26|2020-06-30|Lts Lohmann Therapie-Systeme Ag|transdermal therapeutic system containing asenapine and acrylic silicone hybrid polymer|

---

JP2021505595A|2017-12-05|2021-02-18|サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ．|Crystal form and its manufacturing method|

---

WO2019113079A1|2017-12-05|2019-06-13|Sunovion Pharmaceuticals Inc.|Nonracemic mixtures and uses thereof|

---

EP3959340A1|2019-04-24|2022-03-02|Institut National de la Santé et de la Recherche Médicale |Method for predicting the response of antipsychotic drugs|

---

AU2020286441A1|2019-06-04|2022-01-06|Sunovion Pharmaceuticals Inc.|Modified release formulations and uses thereof|

法律状态:
2014-10-15| PC2A| Transfer of patent|Owner name: FUNDACION INSTITUTO DE INVESTIGACION MARQUES DE VA Effective date: 20141009 |

---

2017-02-06| FG2A| Definitive protection|Ref document number: 2562684 Country of ref document: ES Kind code of ref document: B1 Effective date: 20170206 |

---

2017-07-20| PC2A| Transfer of patent|Owner name: UNIVERSIDAD DE CANTABRIA Effective date: 20170714 |

优先权:

---

申请号 | 申请日 | 专利标题

---

ES201431188A|ES2562684B1|2014-08-04|2014-08-04|ANTIPSYCHOTIC TREATMENT MONITORING METHOD|ES201431188A| ES2562684B1|2014-08-04|2014-08-04|ANTIPSYCHOTIC TREATMENT MONITORING METHOD|

---

PCT/ES2015/070608| WO2016020573A1|2014-08-04|2015-08-04|Method for monitoring antipsychotic treatment|