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    • 专利摘要:
    In vitro method and kit for the prognosis or prediction of the response to treatment with antipsychotic agents by patients who have suffered a first psychotic episode. The present invention refers to an in vitro method of predicting or predicting the response to treatment with antipsychotic drugs, by subjects who have suffered a first psychotic episode (fep), and in particular, the use of expression value, in an isolated biological sample of said subjects, of the ratio formed by two of the isoforms - active and truncated isoform - of the receptor (trkb) of the neuronal growth factor bdnf, called trkb-fl and trkb-t, respectively. The present invention further discloses kits and uses thereof for carrying out the method of the invention. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2598248A2
    申请号:ES201530918
    申请日:2015-06-26
    公开日:2017-01-26
    发明作者:Mónica MARTÍNEZ CENGOTITABENGOA；Ana María GONZÁLEZ-PINTO；Susana ALBERICH MESA；Juan Carlos LEZA CERRO；Karina MACDOWELL MATA；María José PARELLADA REDONDO；Roberto RODRÍGUEZ JIMÉNEZ；Miguel BERNARDO ARROYO；Pilar Alejandra SÁIZ MARTÍNEZ；Juan Antonio MICÓ SEGURA；Antonio LOBO SATUÉ；Carlos Matute Almau
    申请人:Euskal Herriko Unibertsitatea；Universidad Complutense de Madrid；Universitat Autonoma de Barcelona UAB；Universidad de Zaragoza；Universitat de Barcelona UB；Universidad de Oviedo；Universidad de Cadiz；Hospital Clinic de Barcelona；Administracion General de la Comunidad Autonoma de Euskadi；Centro de Investigacion Biomedica en Red CIBER；
    IPC主号:
    专利说明:

    The present invention is within the field of medicine and molecular biology, and refers to an in vitro method of prognosis or prediction of the response to a treatment with antipsychotic drugs, by subjects who have suffered a
    The first psychotic episode, and specifically the use of the expression value of the ratio formed by the active and truncated forms of the receptor (TrKB) of the neuronal growth factor BDNF, called TrKB-FL and TrkB-T, respectively. STATE OF THE TECHNIQUE
    15 A first episode of psychosis (FEP, acronym in English First-Episode Psycosis) occurs in approximately 3% of the population and involves a serious mental illness in which the patient usually suffers hallucinations and delusions that are usually accompanied by other symptoms ( manic symptoms, depressive symptoms,
    20 cognitive dysfunctions, behavioral alterations, etc.) and may even represent the onset of a serious and chronic mental illness such as schizophrenia or bipolar disorder. The SPF, in certain cases, improves completely with treatment, especially with the use of antipsychotic medications, although this is not always the case. In fact, compared to the
    25 general healthy population, patients with a first episode of psychosis have a very high mortality rate.
    The study of the early phases of an SPF has the objective of capturing the pathophysiological changes present in the patient when the symptoms appear due to
    30 for the first time, allowing this complex disease to be studied before it progresses, avoiding potential confounding factors, such as prolonged treatment with antipsychotics or the appearance of concomitant pathologies. In addition, it is of particular importance when an SPF occurs, firstly carry out the correct diagnosis of the patient and on the other hand, apply a specific treatment and
    35, since the application of inappropriate treatment can lead to


    neuroanatomic and cognitive alterations, as well as a worse functional outcome of the patient.
    The most used diagnostic criteria in an FEP are the DSM criteria (acronym
    5 of the English Diagnostic and Statistical Manual of Mental Disorders) of the American Psychiatric Association (APA) and the World Health Organization (WHO), whose latest version is the DSM-V. In this version of the diagnostic guides currently used, biological markers with prognostic value for said pathology are not included. Recently, the National Institute of Mental Health (NIMH)
    10 American, has stressed the need to seek neurobiological roots in psychiatric diseases, asking the scientific community an effort to try to understand the pathophysiological foundations of this disease (Reardon
    S. Nature. 2014; 507: 288).
    15 The prognosis of patients who have suffered an SPF can be divided into 3 categories: 25% of patients show a complete response to treatment that leads to a complete recovery after FEP, 50% of patients are recurrent suffering exacerbations and remissions, and the last 25% of patients show an unfavorable evolution with response and an incomplete recovery after suffering the
    20 FEP. Thus, lack of response or a partial response to treatment remains common, and such lack of response is associated with a longer duration of hospitalization, in addition to obtaining poor long-term results. In this sense, since an SPF can lead, in many cases, to a serious and chronic pathology such as schizophrenia, psychosis, bipolar disorder, etc., it is of great relevance.
    25 perform an early approach to the disease to fight for the best possible prognosis for the patient. The importance of rapid intervention is widely accepted but not always the same intervention is equally effective for all patients with an SPF. For this reason, it is necessary to focus on the different endophenotypes of the disease at this early stage in order to design the approach
    30 more appropriate therapeutic, since the success of the treatment of an SPF is one of the main factors that affects the long-term prognosis. This fact highlights the need to find biomarkers capable of predicting or predicting, at very early stages of the disease, specifically at the time when the first psychotic outbreak occurs, with high specificity and sensitivity, the
    35 response to treatment in said subjects, in order to design and apply the most appropriate treatment for each particular case.


    In this sense, in recent years the focus has been mainly on the detection of biomarkers related to the inflammatory component of these processes, but also with oxidative stress components and genetic markers, among others (Fond G, et al. Schizophr Bull. 2015; 41 (3): 559-73). Damage caused by inflammatory and oxidative processes during the process of an SPF tends to be counteracted or compensated by various protective or repair systems (Meyer U. Brain Behav Immun. 2011; 25 (8): 1507-18; Gomes JR, et al. J Neurosci Off J Soc Neurosci. 2012; 32 (13): 4610-22; Miller BJ, et al. Biol Psychiatry. 10 2011; 70 (7): 663-71), such as neurotrophins, specifically the neurotrophins Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF), which play an important role in neurodevelopment and adult brain plasticity, in the survival and differentiation of neurons, in neuronal functioning and in repair mechanisms. Said neurotrophins exert their actions through the activation of their tyrosine kinase-like receptors, TrKB in the case of BDNF and TrKA, in the case of NGF. Several preclinical and clinical studies carried out in the last 10 years have found changes in plasma neurotrophin levels, as well as a decrease in their expression in certain brain areas in patients with schizophrenia (Wong J, et al. Schizophr Bull. 20 2013; 39 (1): 130-40; Mondelli V, et al. J Clin Psychiatry. 2011; 72 (12): 1677-84; Weickert CS, et al. Mol Psychiatry. 2005; 10 (7): 637-50). These studies have shown that BDNF levels are generally decreased in patients with a first episode of psychosis (Toll A, Mané A. World J Psychiatry. 2015; 5 (1): 154-9). On the other hand, it has also been described that the imbalance between the active (TrKB-FL) and truncated (TrKB-T) isoforms of the BDNF receptor is associated with both neuronal death (Vidaurre OG, et al. Cell Death Dis. 2012; 3: e256) as with schizophrenia (Wong J, et al. Schizophr Bull. 2013; 39 (1): 130-40). Thus, although a large number of biomarkers have been proposed for the diagnosis and / or prognosis of PEF, none of them are currently applied in the clinical routine.
    30 daily.
    Therefore, biomarkers useful for forecasting do not exist in the state of the art
    or predict the response of patients who have suffered an SPF to a treatment with
    antipsychotic drugs Consequently, there is a clear and urgent need in the state of the art to search for biomarkers, with high specificity and


    sensitivity, that makes them extrapolated to clinical practice, and that are useful for predicting the response to antipsychotic treatment in patients after suffering an SPF. DESCRIPTION OF THE INVENTION
    The present invention relates to an in vitro method for the prognosis or prediction of the response to treatment with at least one antipsychotic agent, by patients who have suffered an SPF, where the prognosis is made according to the expression value resulting from the ratio TrKB-FL / TrKB-T, in an isolated biological sample of 10 such patients at the time of disease debut. In a preferred embodiment of the in vitro method of the invention, this is characterized in that when the expression value resulting from the ratio is ≥ 0.70, said value is indicative that the patient will have a good prognosis of response to treatment with at least an antipsychotic drug, that is, it will be a patient responding to the antipsychotic treatment. On the other hand, when the resulting value of the ratio is <0.70, this value is indicative that the patient will have a poor prognosis of response to treatment with at least one antipsychotic drug, that is, it will be a patient not corresponding to the antipsychotic treatment . Therefore, a low expression of the truncated form (TrKB-T) of the TrkB receptor, with respect to the active form (TrKB-FL) thereof, 20 is related to a good treatment response. Consequently, evaluate the expression of BDNF receptor forms, and obtain their expression ratio, in a sample of biological fluid, preferably in a sample of blood, plasma or serum, more preferably in a sample of peripheral blood mononuclear cells ( PBMC), provides us with a tool to predict whether a patient who
    25 just suffered your SPF will respond well or not to antipsychotic treatment. The determination of the value of said ratio at the time of the debut of the disease is of great importance because it allows us to establish an appropriate treatment that can improve the long-term evolution of these patients.
    Therefore, in the present invention the use of the relative proportion of the two isoforms of the TrKB receptor, TrKB-FL (active isoform) with respect to TrKB-T (truncated isoform), measured at the time of the debut of the invention is described. disease, as a biomarker for the prognosis or prediction of the response to treatment with at least one antipsychotic agent by patients who have suffered an SPF, since
    35 said value of expression of the ratio is significantly related to patients responding to antipsychotic treatment, obtaining in these patients very


    Good functional results in recovery six months after suffering the first psychotic episode. Moreover, as shown in the examples that accompany the present invention, the expression levels of the ratio described herein, during the first six months of follow-up after the disease debut, arrives
    5 to be statistically and significantly higher than the level of expression of said ratio in control subjects who do not suffer from the disease.
    Thus, the technical problem solved by the present invention refers to an in vitro method for the prognosis or prediction of the response to treatment with at least one antipsychotic agent, by patients who have suffered an SPF, from a sample Biological obtained from these patients at the time of the debut of the disease, which is simple (based on the analysis of two specific proteins and / or the genes that encode them), little invasive for the patient and also presents a sensitivity ( 79.1%) and very high specificity (61.1%), thus allowing its
    15 use in daily clinical practice.
    In this sense, the prediction of the response to treatment by patients who have suffered an SPF is useful in several main ways: (1). Prediction of non-responders to treatment with at least one antipsychotic agent (poor prognosis): in this way the patient could be directed to alternative treatments without the need to apply, as a first treatment, antipsychotic therapy. (2). Prediction of patients responding to treatment with at least one antipsychotic agent (good prognosis): this tool is very useful to start treatment very early since in the particular case of patients who
    25 have suffered an SPF it has been shown that treatment in early stages of the disease can be very effective in preventing its progression towards chronic pathologies such as schizophrenia or psychosis, in addition to allowing the patient to lead a normal life, defined as a overall good functioning of the patient in his daily life.
    Thus, the first aspect of the present invention relates to an in vitro method, from here we will call it, the first method of the invention, for the prognosis or prediction of the response to treatment with at least one antipsychotic agent by patients who have suffered a first psychotic episode, where the prognosis
    35 is carried out according to the expression value of the TrkB-FL / TrkB-T ratio, in an isolated sample of said patients at the time of disease debut, where a


    expression value of the ratio ≥ 0.70 is indicative of a patient responding to the treatment and an expression value of the ratio <0.70 is indicative of a patient not responding to the treatment. Alternatively, the present invention also relates, therefore, to the use in vitro of the expression value of the TrKB-FL / TrKB-T 5 ratio as a prognostic or predictive biomarker of the response to treatment with at least one antipsychotic agent, on the part of patients who have suffered a first psychotic episode, where when the expression value resulting from said ratio is ≥ 0.70, said value is indicative that the patient will have a good prognosis of response to treatment with at least one antipsychotic drug, it is say is going to be a
    10 patient responding to antipsychotic treatment. On the other hand, when the resulting value of the ratio is <0.70, this value is indicative that the patient will have a poor prognosis of response to treatment with at least one antipsychotic drug, that is, it will be a patient not responding to the treatment antipsychotic
    15 The terms "First Psychotic Outbreak" or "First Psychotic Episode" or "FEP" or "PEP" used interchangeably throughout this document, often in the state of the art are mistakenly used as a synonym for schizophrenia. To delimit these terms, it should be noted that schizophrenia is characterized by “the
    20 presence of delusions, hallucinations, disorganized language, catatonic and / or disorganized behavior and negative symptoms such as affective flattening, praise or ablution and at least two of these symptoms may have been present for 6 months (unless the patient is have previously tried) and are associated with a social and labor dysfunction (Ballesteros, J. Psychotic outbreaks.
    25 Psychiatry Fundación Santa Fe de Bogotá. 2013. pp. 1330-1332). The nuance that highlights the difference with the psychotic outbreak is seen in the fact that schizophrenia is a form of long-lasting psychosis, while the psychotic outbreak would be an abrupt manifestation of what could be considered the positive symptomatology of the schizophrenia for a short period of time.
    30 The term "TrKB" (also known, among other synonyms as the tropomyosin kinase B receptor, or tyrosine kinase B receptor or BDNF and NT3 growth factor receptor or neurotrophic tyrosine kinase type 2 receptor) refers to a protein that in humans it is encoded by the NTRK2 gene located on chromosome 9
    35 (87.28–87.64 Mb). TrKB acts as a high affinity catalytic receptor for BDNF and NT-3 and -4 neurotrophic factors. Its denomination is usually abbreviated with the following


    modes: NTRK2; GP145-TrkB; TRKB; trk-B. Said receiver has two TrKB-FL and TrKB-T isoforms. The TrKB-FL isoform is the complete active form of the TrKB receptor. This complete form transduces the BDNF signal through Ras-ERK, PI3K, and PLCγ. The TrKB-T isoform is the truncated form of the TrKB receptor that lacks kinase activity and opposes the function of the TrKB-FL form. This truncated form has the same extracellular and transmembrane domains as the complete form but differs in the terminal sequence. The TrkB accession number in the UniProtKB / Swiss-Prot database is Q16620, where the protein sequences for the active isoform and for the truncated isoform appear. The access number for the sequence
    10 genomic of NTRK2 in the NCBI database is NG_012201.2.
    To detect and / or quantify the protein biomarkers described in the invention, it is sufficient to detect one or more fragments of said proteins since said fragments are a constituent of the amino acid sequence and the structure of
    15 proteins That is, the method of the present invention contemplates the possibility of associating the detection of a fragment that unequivocally belongs to said protein to the presence of the protein in question. For the detection, and / or quantification of said fragment of the protein or of the complete protein, any technique known to the person skilled in the art can be used.
    Any of the proteins of the present invention are the product of the expression of a nucleotide sequence. This nucleotide sequence can be, for example but not limited to, any RNA such as, but not limited to, messenger RNA (mRNA), or any of its fragments. The nucleotide sequence can
    25 also be complementary DNA (cDNA) or any of its fragments. The cDNA is a complementary DNA to an mRNA or is also the nucleotide sequence that comprises the exons of the genomic nucleotide sequence but not the introns, that is, the cDNA is the coding sequence. The transcription of the genomic nucleotide sequence of the gene that codes for the protein and its cDNA code for
    30 the same mRNA and, therefore, for the same protein. In the present invention it is also possible to detect any RNA or any DNA, or any of its fragments, instead of the detection of the protein, or simultaneously.
    Thus, in another preferred embodiment of the in vitro method described in the present invention it is characterized in that the TrKB-FL and TrKB-T proteins or any fragment thereof, is detected and / or quantified by electrophoresis, immunoassay,


    chromatography and / or microarray technology, also evaluating its presence or absence.
    Electrophoresis is an analytical separation technique based on movement or
    5 migration of dissolved macro-molecules in a medium (electrophoresis buffer), by means of a matrix or a solid support as a result of the action of an electric field. The behavior of the molecule depends on its electrophoretic mobility and this mobility depends on the charge, size and shape. There are numerous variations of this technique based on the equipment used, supports and conditions to carry
    10 out protein separation. Electrophoresis is selected from the list comprising, but not limited to, capillary electrophoresis, paper electrophoresis, agarose gel electrophoresis, polyacrylamide gel electrophoresis, isoelectric focusing or two-dimensional electrophoresis.
    15 An immunoassay is a biochemical test that measures the concentration of a substance in a biological liquid using the reaction of an antibody or antibodies with any of its antigens. The assay takes advantage of the specificity of an antibody with its antigen. The amount of antibody or antigen can be detected by methods known in the state of the art. One of the most common methods is
    20 which is based on the labeling of the antigen or antibodies. Labeling can be carried out, but not limited to, an enzyme, radioisotopes (radioimmunoassay), magnetic tags (magnetic immunoassay) or fluorescence, and also other techniques including agglutination, nephelometry, turbidimetry or Western Blot. Heterogeneous immunoassays can be competitive or non-competitive. He
    25 immunoassay can be competitive: the response will be inversely proportional to the concentration of antigen in the sample, or it may be non-competitive (also known as "sandwich assay"): the results are directly proportional to the concentration of the antigen. An immunoassay technique that can be used in the present invention is the ELISA (Enzyme-Linked ImmunoSorbent Assay) assay.
    30 By means of chromatographic techniques, the molecules can be separated, but not limited, by their charge, size, molecular mass, by their polarity or by their redox potential. The chromatography technique is selected, but not limited to, liquid chromatography (partition chromatography, chromatography of
    Adsorption, exclusion chromatography or ion exchange chromatography), gas chromatography or supercritical fluid chromatography.


    The microarray technology of the present invention is based, for example, on the fixation on a solid support of a molecule that recognizes the protein of the present invention. The antibody-based microarray is the most common protein microarray. In this case, the antibodies are fixed on the solid support (the term chip can also be used to refer to microarray). These antibodies are used to capture molecules that allow the detection of proteins from, but not limited to, biological samples, cell lysates, blood, plasma, serum, PBMCs or urine. The term "solid support" as
    10 used in the present invention refers to a wide variety of materials, for example, but not limited to, ion exchange or adsorption resin, glass, plastic, latex, nylon, gel, cellulose esters, paramagnetic spheres or the combination of some from them.
    The term "antibody", as used in the present description, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, that is, molecules containing an antigen binding site that specifically binds (immunoreacts) With a protein There are five isotypes or major classes of immunoglobulins: IgM, IgD, IgG, IgA and IgE. For the purpose
    Any antibody capable of detecting the expression of TrKB-FL and / or TrKB-T proteins can be used. Antibodies known in the state of the art capable of detecting TrKB-FL and / or TrKB-T proteins are selected from any of the following: Anti-TrkB antibodies of references ab18987 and ab33665, reference Anti-TrkB antibody [EPR1294] ab134155, from Abcam Inc
    25 (Cambridge, MA); TrkB antibody # 4606 from Cell Signaling (Cell Signaling Technology, Inc., Beverly, MA, USA); TrkB (C-13) sc-119 antibody, TrkB (F-1) sc-377218 antibody and TrkB (794) sc-12 antibody from Santa Cruz Biotechnology Inc. (Santa Cruz, California, USA); anti-TrkB antibody (Ab-705) from Sigma (Spain).
    In a preferred embodiment of the first method of the invention, it is also possible, in addition to the detection of a fragment of the proteins used as biomarkers, the detection and quantification of a functionally equivalent variant thereof.
    In the sense used in this description, the term "variant" refers to proteins substantially homologous to TrKB-FL and TrKB-T proteins. In general, a


    variant includes additions, deletions or substitutions of amino acids, always with the proviso that said variants are functionally equivalent to the original protein. The term "variant" also includes proteins resulting from posttranslational modifications such as, but not limited to, glycosylation,
    5 phosphorylation or methylation.
    The term "functionally equivalent", as used herein, means that the protein or the fragment of the protein in question essentially maintains the immunological properties described herein. These properties
    Immunological agents can be determined by conventional methods such as those described in the examples that accompany this description.
    The term "fragment", as used in the present description refers to a portion of the TrKB-FL and TrKB-T proteins or one of its variants.
    For the purposes of the present invention, the term "prognosis" or "prediction" is understood as the expected evolution of a disease and refers to the assessment of the probability according to which a subject suffers from a disease as well as the assessment of its onset, state of development, evolution, or its regression, and / or the prognosis of
    20 course of the disease in the future. As those skilled in the art will understand, such assessment, although preferred, may not be correct for 100% of the subjects to be diagnosed. The term, however, requires that a statistically significant part of the subjects can be identified as having the disease or having a predisposition to it. If a part is
    Statistically significant can be determined without further ado by the person skilled in the art using several well-known statistical evaluation tools, for example, determination of confidence intervals, determination of p-values, Student's t-test, Mann-Whitney test, or functions Fisher discriminants, Mann Whitney non-parametric measures, Spearman correlation, logistic regression,
    30 linear regression, area under the ROC curve (AUC), etc. Preferred confidence intervals are at least 50%>, at least 60%>, at least 70%>, at least 80%>, at least 90%, at least 95%, at least 97 %, at least 98% or at least 99%. P values are preferably 0.1, 0.05, 0.01, 0.005 or 0.0001. etc.


    'Prediction of the response' means, in the context of the present invention, the determination of the probability that the patient responds favorably or unfavorably to a given therapy or treatment. Especially, the term 'prediction', as used here, refers to an individual evaluation of any 5 parameters that may be useful in determining the evolution of a patient. As those skilled in the art will understand, the prediction of the clinical response to treatment, although it is preferred, does not need to be correct for 100% of the subjects to be diagnosed or evaluated. The term, however, requires that a statistically significant part of the subjects can be identified as having an increased probability of having a positive response. The person skilled in the art can easily determine if a subject is statistically significant using several well-known statistical evaluation tools, for example, determination of confidence intervals, determination of p values, Student's t-test, Mann Whitney test, or Fisher discriminant functions, Mann Whitney non-parametric measures 15, Spearman correlation, logistic regression, linear regression, area under the ROC curve (AUC), etc. Preferred confidence intervals are at least 50%>, at least 60%>, at least 70%>, at least 80%>, at least 90%, at least 95%, at least 97 %, at least 98% or at least 99%. P values are preferably 0.1, 0.05, 0.01, 0.005 or 20 0.0001. Preferably, the present invention makes it possible to predict the response to the treatment differentially by at least 60%, more preferably at least 70%, much more preferably at least 80%, or even more preferably at least 90 % of the subjects of a certain group or population analyzed. The prediction of the clinical response can be done using
    25 any assessment criteria used in psychiatry and known to the person skilled in the art.
    For the purposes of the present invention the term "good prognosis" or "responding patients" refers to those patients who after suffering an SPF and starting a
    30 treatment with at least one antipsychotic drug, recover from the disease, having a satisfactory functional life. On the other hand, the term "poor prognosis" or "non-responders" refers to those patients who after suffering an SPF starting an antipsychotic treatment will not make them recover from the disease and their functioning in daily life goes to look deteriorated


    For the purposes of the present invention, the term "specificity" refers to the ability of a diagnostic and / or prognostic method or test to correctly classify a healthy individual (eg negative diagnosis of carcinoma, when the patient is not affected by carcinoma) , that is, the probability that for a healthy subject
    5 get a negative result; a specificity of 100% means that there are no false positives. The specificity shown by the method described in the present invention is 79.1%. Thus, a specificity of 79.1% means that the value of the TrkBFL / TrkB-T ratio obtained correctly predicts 79.1% of subjects with poor functionality.
    For the purposes of the present invention, the term "sensitivity" refers to the ability of a diagnostic and / or prognostic method or test to correctly classify a sick individual (eg positive diagnosis of carcinoma, when the patient is affected by carcinoma) , that is, the probability that for a sick subject
    15 get a positive result; 100% sensitivity means that there are no false negatives. The sensitivity shown by the method described in the present invention is 61.1%. Thus, a sensitivity of 61.1% means that the method correctly predicts 61.1% of subjects with good functionality.
    For the purposes of the present invention, the term "positive predictive value" or "PPV" refers to the probability that a patient is ill if the prognosis or prediction method is positive (eg being affected by carcinoma when the diagnosis / prognosis of the test is positive), that is, the proportion of patients with a positive result in the diagnostic method and / or prognosis that finally
    25 turned out to be sick. In the particular case of the method of the invention, the PPV is 85.3%, which means that 85.3% of the subjects who, by the method of the invention, are predicted as responders, will be responders and will have good functionality.
    For the purposes of the present invention, the term "negative predictive value" or "NPV" refers to the probability that a patient is healthy if the prognostic or prediction method is negative (eg not being affected by carcinoma when the diagnosis / prognosis of the test is negative), that is, the proportion of patients with a negative result in the diagnostic method and / or prognosis that finally
    35 turned out to be healthy. In the particular case of the method of the invention, the NPV is 57.9% which means that 57.9% of the subjects that by the method of


    The invention is predicted as non-responders and that would present poor functionality if they were treated with antipsychotic drugs, they will eventually be non-responders who will have malfunction.
    For the purposes of the present invention the term "antipsychotic agent" or "antipsychotic compound" or "antipsychotic drug" refers to those substances capable of treating the patient's psychotic symptoms such as delusions and / or hallucinations. The term antipsychotic refers to a wide family of drugs traditionally classified into two groups, depending on their safety profile and their effectiveness.
    10 on the depressive symptoms of schizophrenia. Thus the main groups of antipsychotics are typical antipsychotics (AT) and atypical antipsychotics (AA). TAs are the oldest antipsychotic drugs, with a fundamentally antidopaminergic action and characterized by their efficacy in the control of positive psychotic symptoms (delusions, hallucinations), but which are not very effective on
    15 negative symptoms (depression, social isolation). Its use is frequently associated with extrapyramidal symptoms (SEP) and hyperprolactinemia. For the purposes of the present invention, the AT drugs that can be used in the treatment of an SPF are selected from any of the following: chlorpromazine, fluphenazine, levomepromazine, perphenazine, trifluoperazine, haloperidol, zuclopenthixol, pimozide,
    20 suppressed, tiapride, or combinations thereof. Atypical antipsychotic drugs are characterized by simultaneously blocking dopaminergic and serotonergic receptors and being effective in both positive and negative symptoms. Overall, AA are associated with fewer extrapyramidal symptoms (side effect) than AT; however, they are not without problems since
    25 the use of AA has been associated with a higher incidence of metabolic adverse reactions (hyperglycemia, weight gain, ...) that sometimes limit its use. For the purposes of the present invention, the AA drugs that can be used in the treatment of an SPF are selected from any of the following: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone,
    Asenapine, sertindole, amisulpride, or combinations thereof. On the other hand, it is also possible to combine any of the AT drugs or combinations thereof with any of the AA drugs or combinations thereof in the same antipsychotic treatment.
    For the purposes of the present invention, the term "isolated biological sample" includes, but is not limited to, cells, tissues and / or biological fluids of an organism, obtained


    by any method known to an expert in the field. Preferably, the isolated biological sample is a biological fluid. More preferably, the biological fluid is blood or plasma or blood serum. More preferably, the biological fluid is blood and preferably peripheral blood mononuclear cells.
    5 (PBMCs). "Peripheral blood mononuclear cells" or "PBMC" includelymphocytes, monocytes and macrophages. The methods for assimilating these PBMCs from aBlood sample are well known in the art.
    The term "individual" or "subject", as used in the description, refers to
    10 animals, preferably mammals, and more preferably, humans. These terms are not intended to be limiting in any aspect, and these may be of any age, sex and physical condition.
    Another aspect of the present invention relates to a kit or device, hereinafter
    15 kit or device of the invention, comprising the elements necessary to detect and / or quantify the expression levels of the TrKB-FL and TrKB-T isoforms, or a variant thereof or a fragment thereof, in an isolated biological sample of a subject. In a preferred embodiment the elements necessary for the detection and / or quantification of the TrKB-FL and TrKB-T isoforms, or
    20 of a variant thereof or a fragment thereof are preferably selected from: oligonucleotides, probes and / or antibodies.
    In a more preferred embodiment of the kit of the invention, this comprises antibodies capable of detecting the expression of the TrKB-FL and TrKB-T isoforms or of a
    25 fragment thereof or any of its variants.
    Said kit may contain all those reagents necessary to analyze the amount of TrKB-FL and TrKB-T protein by means of any of the methods described hereinbefore, for example, but not limited to, antibodies specific to said proteins, antibodies secondary or positive and / or negative controls. The kit can also include, without any limitation, buffers, protein extraction solutions, agents to prevent contamination, inhibitors of protein degradation, etc. In the case of detection by RTqPCR, it may contain, but not limited to, primers, probes and all those reagents necessary to determine the expression of TrKB-FL and TrKB-T proteins. The kit can also include, without any limitation, the use of tampons,


    polymerases, cofactors to obtain an optimal activity of these, agents to prevent contamination, etc. On the other hand, the kit can include all the supports and containers necessary for its start-up and optimization. Preferably, the kit also includes the instructions for carrying out the methods of Ia
    5 invention.
    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 experts in the field, other objects, advantages and characteristics of the
    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. BRIEF DESCRIPTION OF THE FIGURES
    15 FIG. 1. Analysis of the expression of TrKB-FL (A) and TrkB-T (B) isoforms in PBMCs isolated from patients at the time of disease debut and 6 months later, and in healthy control subjects . (C) Graph showing the value of the TrKB-FL / TrKB-T ratio in healthy control subjects and in subjects that
    20 have suffered an SPF, at the time of the debut of their disease and after 6 months of follow-up. The densitometric data of the respective bands of interest have been normalized using the expression obtained for β-actin. Data represent the mean ± standard deviation. T test for paired samples. * p <0.05 vs. Control; #p <0.05, ## p <0.01 vs FEP debut. EXAMPLES
    The invention will now be illustrated by exposing the results obtained by the inventors. These reveal the specificity, sensitivity
    30 and efficacy of the biomarker for predicting response to an antipsychotic treatment in patients who have suffered an SPF, described in the present invention. Patients
    35 The study included blood samples from 94 patients obtained during their first year after debuting with a first psychotic episode and as healthy controls


    They have included 80 blood samples from healthy control subjects matched by sex, race and age.
    The inclusion criteria in the study for subjects who had suffered an SPF
    5 were:a) Positive psychotic symptoms of less than 12 months duration,b) Age 9 to 35 years at the time of debuting with the disease,c) Speak Spanish correctly,d) Sign the informed consent of the study.
    And the exclusion criteria: a) Mental retardation according to DSM-IV criteria, b) History of head injury with loss of consciousness, c) Systemic disease with mental repercussion.
    15 To evaluate the psychotic symptomatology we use the PANSS (Positive and Negative Syndrome Scale) (Kay SR, et al. Schizophr Bull. 1987; 13 (2): 261-76 )
    20 On the other hand, the inclusion criteria in the study for the control subjects were: a) Current or previous absence of psychiatric pathology according to DSM-IV criteria, b) Speak Spanish correctly, c) Sign the informed consent of the study.
    25 And the exclusion criteria were the same as those mentioned above for patients and also: d) History of psychotic symptoms in first-degree relatives.
    Neither patients nor healthy subjects had febrile or allergic conditions, infections or
    30 another important medical condition, and they had not received immunosuppressive medication or vaccines in the previous 6 months or anti-inflammatory medication in the two days prior to the extraction of blood samples. Table 1 shows the clinical characteristics of patients and healthy control subjects.
    35 The study was approved by the Clinical Research Ethics Committee of the participating centers. All subjects included in the study signed a report of


    consent to participate in it. In the case of subjects under 18, the consent of their parents or legal representatives was obtained and the patients themselves agreed to participate. 5 samples
    The venous blood samples obtained from the subjects participating in the study were extracted while the subjects were fasting, at the time of the disease debut and at 6 months after suffering the SPF. These blood samples were
    10 centrifuges (641g x 10 min at a temperature of 4 ° C) and the plasma obtained was stored at -80 ° C for further study. The rest of the sample was used to isolate peripheral blood mononuclear cells, known as PBMCs, which once obtained were stored at -80 ° C for further study. 15 Measurement of TrKB-FL and TrKB-T receptor expression in PBMCs
    The expression of the markers described in the present invention, TrKB-FL and TrKB-T was quantified using the Western-Blot (WB) technique, from the cytosolic extracts obtained from the PBMCs by a modified method based on the method. of Scheiber et al. Briefly, PBMCs were homogenized in 150 μL buffer (10 mmol / L N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid [H 7.9]; 1 mmol / L EDTA, 1 phenylmethylsulfonyl fluoride, 0.1 mg / mL aprotinin, 1 mg / mL leupeptin, 1 mg / mL Na-ptosyl-L-lysine-chloromethyl ketone, 5 mmol / L NaF, 1 mmol / L NaVO4, 0.5 mol / L sucrose, and 10 mmol / L Na2MoO4) at pH 7.4. After 15 min, Nonidet 25 P-40 (Roche, Mannheim, Germany) was added until reaching a concentration of 1%. The tubes were vortexed for 30 seconds and the nuclei were collected by centrifugation at 8000g x 5 min. The supernatant was considered to constitute the cytosolic fraction. The pellets were resuspended in 50 μL of the buffer, supplemented with 20% glycerol, 15 mmol / L MgCL2 and 0.4 mol / L NaCl and stirred slightly for 30 min at 4 ° C. Nuclear protein extracts were obtained by centrifugation at 13,000 g x 5 min, and aliquots of the supernatant were stored at –80 ° C. All stages of fractionation were carried out at 4 ° C. As a control method to analyze the purity of cytosolic and nuclear extracts, Western Blot was performed using glyceraldehide-3-phosphate 35 dehydrogenase (GAPDH), Specific Protein 1 (SP1) or β-actin (in cytosol: 99 ± 1;


    19 ± 5; and 98 ± 1% of total optical density signal [OD], respectively; and in cores: 0; 81 ± 7; and 99 ± 1% of total optical density signal, respectively.
    After determining and adjusting the protein concentration to 2 µg / µl, using the method
    5 from Bradford, the cytosolic extracts were mixed with equal buffer volumeLaemmli (Bio-Rad, USA) (10% SDS, distilled H2O, 50% glycerol, 1 M Tris HCl, pH6.8, dithiothreitol and bromophenol blue), with β-mercaptoethanol (50µl / ml Laemmli). Bethey loaded 12.5 µg of said mixture into an electrophoresis gel. Protein samplesseparated and transferred to a nitrocellulose membrane (Amersham, Iberian,
    10 Spain). After neutralization, the membranes were incubated with specific antibodies to detect the presence of the markers of the invention:  TrKB rabbit polyclonal antibodies at a dilution of 1: 1000 in TBS-Tween (sc-12; Santa Cruz Biotechnology, USA) , for TrKB-FL,  Rabbit TrKB polyclonal antibodies at a dilution of 1: 1000 in TBS15 Tween (sc-119; Santa Cruz Biotechnology, USA) for TrKB-T,  Mouse β-actin monoclonal antibodies at a dilution of 1: 15000 (Clone AC 15; Sigma, Spain), which was used as load control.
    Subsequently, after the washing of the primary antibodies, the membranes are
    20 incubated with their respective secondary antibodies conjugated with peroxidase (1: 2000 dilution in TBS-Tween). The immunoreactivity of the bands was detected and visualized by the Oddyssey Fc system (Licor, Germany) and quantified by densitometry (NIH ImageJ® software). All densitometric results were expressed as percentage of expression of each of the analyzed markers.
    25 regarding the control group. Evaluation of the general functioning of patients (GAF)
    In order to evaluate the general functioning of patients who had suffered a
    30 FEP uses the GAF scale (Global Assessment Functioning), which provides a score between 0 and 100 and takes into account different aspects of the patient's daily life, such as social relationships, employment status, etc. This scale was published based on a review of the Endicott Global Assessment Scale (GAS) scale (Endicott J, et al. Arch Gen Psychiatry.
    35 1976; 33 (6): 766-71). The GAF scale was published in 1987 and became the basis of V-axis diagnoses in the DSM-III-R (American Psychiatric Association.


    Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R), text revision. 3rd edition. Washington, DC: American Psychiatric Association; 1987), DSM-IV (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-
    IV. Washington, DC: American Psychiatric Association; 1994) and DSM-IV-TR (American
    5 Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), text revision. 4th edition. Washington, DC: American Psychiatric Association;2000). A high score on the scale denotes better functionality. For the purpose ofpresent invention, it is considered a good functionality when the score in theGAF scale is ≥60 points, while the patient will have a functioning
    10 deteriorated when the score on that scale is <60 points. Statistic analysis
    To assess the possible association between inflammatory status at baseline,
    15 that is to say, after suffering the FEP patients, and the expression value of the TrKBFL / TrKB-T ratio, both in the disease debut and 6 months after said debut (follow-up), multiple linear regression models were constructed. This same type of analysis was used for the evaluation of the influence of the inflammatory state and the expression value of the TrKB-FL / TrKB-T ratio in the disease debut on the
    20 global functioning of the patient (GAF) and the clinical situation of the patient (PANSS) at the end of the follow-up period, 6 months after the debut of the disease. In order to adjust this model, a “step by step backward” model was used, including all possible confounding variables (sex, age, marital status, studies, socioeconomic status, race, tobacco, alcohol, cannabis, BMI, antipsychotics) .
    25 Only those variables that were significant or those that produced a significant change in the coefficient of the independent variable were included in the regression model (BMI, tobacco and antipsychotics). Finally, the interaction terms were evaluated.
    30 Once the final model was obtained, both the adjustment of the residues and their normality were analyzed. The β coefficient, the 95% confidence interval and the p value were obtained for the t tests (evaluating the statistical significance of the regression coefficient).
    In those cases where the interaction term was significant, the effect size and 95% confidence interval were calculated for each group. In addition, the


    Effect size of the main group of the dependent variable was estimated for different values of the independent variable (percentiles 3, 25, 50, 75 and 97).
    Finally, to evaluate the predictive value of the developed model, we estimate its
    5 sensitivity, specificity, and positive and negative predictive values. Statistical analyzes were developed with the Stata version 12.1 statistical package (StataCorp LP, Texas, USA) and the level of significance was set at p <0.05. RESULTS
    10 Table 1. Baseline characteristics of the sample of subjects included in the study.
    Patients (n = 94) N (%) Controls (n = 80) N (%)Total sample (n = 174) N (%)Statistical
    Sex Woman29 (30.9%)27 (33.8%)56 (32.2%)X2 = 0.17, df = 1, p = 0.683
    Man 65 (69.1%)53 (66.3%)118 (67.8%)
    Age (years) 23.78 ± 5.8125.69 ± 7.0724.66 ± 6.47t = -1.96, df = 172 p = 0.052
    Socioeconomic level Low28 (29.8%)19 (23.8%)47 (27.0%)X2 = 1.66, df = 2, p = 0.436
    Means, medium 38 (40.4%)40 (50%)78 (44.8%)
    Tall 28 (29.8%)21 (26.3%)49 (28.2%)
    Body Mass Index (BMI) 25.02 ± 3.9723.08 ± 3.0724.12 ± 3.70t = 3.38, df = 155, p = 0.001
    Cannabis use 23 (24.5%)13 (17.3%)36 (20.6%)X2 = 1.27, df = 1, p = 0.260
    Age of onset (years) 24.45 ± 5.80
    Duration of untreated psychosis (days) 91.26 ± 97.05
    Diagnosis Affective psychosis *18 (19.1%)
    Non-affective psychosis * * 76 (80.9%)
    PANSS positive 10.21 ± 4.99
    PANSS 14.11 ± 5.73


    Patients ControlsSample
    (n = 94) (n = 80)total (n = 174)Statistical
    N (%)N (%)N (%)
    negative
    PANSS 50.44 ± 16.89
    MADRS 6.31 ± 6.37
    GAF 68.90 ± 13.14
    PANSS: Scale of positive and negative symptoms. * Affective psychosis: bipolar disorder, psychotic depression or schizoaffective disorder. ** Non-affective psychosis: schizophrenia, schizophreniform disorder and psychotic disorder not previously specified. Bold data indicates that the data has reached significance.
    5 statistics (p value <0.05).
    The patients object of the present study, once diagnosed, were given antipsychotic treatment. The drugs used in this treatment were selected from any of the following: risperidone, clozapine,
    10 paliperidone, aripiprazole, ziprasidone, olanzapine or quetiapine.
    After analyzing the expression levels of the TrKB-FL and TrKB-T receptors in the PBMCs of the patients and of the control subjects, and as seen in Figure 1, the expression of said receptors in the PBMCs cells is modified to over 15 time in patients who had suffered an SPF, so that the expression levels of the TrKB-FL isoform increase significantly during the follow-up period of the patients (6 months) after the debut of the disease (Fig. 1A ), while the expression levels of the TrKB-T isoform decrease significantly in this same period (Fig. 1B) and in comparison with the levels
    20 showing the group of healthy control subjects of said isoform (Fig. 1B). Similarly, the expression value of the TrKB-FL / TrKB-T ratio increases significantly throughout the follow-up compared to the expression of said ratio in healthy control subjects and with respect to the expression thereof in patients at the time. of the debut of the disease (Fig. 1C).
    25 The regression model for the association between the TrKB-FL / TrKB-T index at baseline (disease debut) and patient functionality at 6 months after debut (GAF) was adjusted taking into account the variables: Body mass index (BMI), tobacco use and antipsychotic consumption. Said model puts
    30 shows the existence of a positive and significant interaction between the expression value of the TrKB-FL / TrKB-T ratio and the antipsychotic treatment (β = 41.46, p = 0.004, 95% CI: 14,327, 68,590), which indicates that the effect of the ratio expression value


    TrKB-FL / TrKB-T at the time of the debut of the disease on the functionality of such patients at 6 months of its debut is different depending on whether or not the patient takes antipsychotic medications.
    5 Table 2 shows the sizes of the effect of taking antipsychotics for different levels of the expression value of the TrKB-FL / TrKB-T ratio on functionality (GAF) at 6 months after the disease's debut. For those patients with low levels of expression of the TrKB-FL / TrKB-T ratio at the time of disease debut (TrKBFL / TrKB-T = 0.18), it is noted that the patients taking antipsychotics had worse
    10 functionality than patients who did not take them (effect size: -30.26; 95% CI: -52.903, -30.259). On the contrary, the effect of taking antipsychotics is the opposite when patients show high levels of expression of the TrKB-FL / TrKB-T ratio (TrKB-FL / TrKB-T = 1.96) at the time of disease debut. In this case, the patients taking antipsychotics were the ones with the best functionality.
    15 present after 6 months of debut (effect size: 43.54; 95% CI: 12.189, 74.887) (Table 2).
    Table 2. Sizes of the effect of taking antipsychotics on the functionality 6 months after the debut of the disease (and its 95% CI) for the selected values of the
    20 ratio TrKB-FL / TrKB-T *
    TrKB-FL / TrKB-T Ratio Consumption of antipsychotics1
    Percentile 3 (= 0.18) -30.26 (-52.903, -30.259)
    25th percentile (= 0.67) -9.94 (-22.573, 2.685)
    Medium (= 0.90) -0.41 (-11.369, 10.552)
    75th percentile (= 1.11) 8.30 (-4.142, 20.737)
    97 percentile (= 1.96) 43.54 (12,189, 74,887)
    * Adjusted for confounding factors 1 The effect size is interpreted as the difference between GAF means between patients taking antipsychotics.
    Therefore, taking into account the results shown in the present invention, the expression levels of the TrKB-FL / TrKB-T ratio at the time of disease debut are related to the functionality of the patient in a different way depending on if the patient consumes or not antipsychotics. In addition, both the expression levels of the TrKB-FL / TrKB-T ratio, and the consumption of antipsychotics, do not
    30 show an effect on the functionality of these patients (GAF) in a way


    independent, since none shows statistical significance by including the term of the interaction in the regression equation.
    Considering the sample of patients who consume antipsychotic medication (n = 75) and
    5 using the regression model described, the potential of the expression value of the TrKB-FL / TrKB-T ratio as a biomarker for the prognosis of response to treatment with antipsychotic agents in patients who have suffered an SPF was analyzed. For this, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were studied, considering the value of ≥ 0.70 as cut-off point.
    10 for the TrKB-FL / TrKB-T index level and a value ≥ 60 as the cut-off point for the GAF scale. 0.70 was considered as the cut-off point for the index since it is the point at which sensitivity and specificity values are maximized. The cut-off point for the GAF scale was considered after reviewing the literature in this regard. Thus the proposed model shows a sensitivity of 79.1%, a specificity of 61.1%, a
    15 VPP of 85.3% and a NPV of 57.9%. The method offers a false positive ratio of 38.9% and a false negative ratio of 20.9%. According to these results, the sensitivity data, according to the regression model used, refers to the fact that 79.1% of patients with good functionality after 6 months taking antipsychotics after having suffered the SPF, had a high value of
    20 expression of the TrKB-FL / TrKB-T ratio at the time of disease debut. That is, these patients had an expression value of the TrKB-FL / TrKB-T ratio ≥0.70, at the time of disease debut. The specificity data refers to the fact that 61.1% of the patients who presented a low value of the expression of the TrKB-FL / TrKB-T ratio (<0.70) at the time of disease debut
    25 the disease began and after 6 months of taking antipsychotic medication, they presented poor functionality (<60). This analysis consolidates the use of the expression value of the TrKB-FL / TrKB-T ratio as a marker for the prediction of the response to an antipsychotic treatment in patients who have suffered an SPF, allowing those responding patients to be easily discriminated against non-responders.
    30 responders, to antipsychotic therapy.
    Sensitivity: according to the model, 79.1% of patients with good functionality after 6 months taking antipsychotics after having suffered FEP, had a high level of the TrKB-FL / TrKB-T ratio (≥0.70) at the time of start
    35 the disease.


    Specificity: The proportion of patients with low levels of the TrKB-FL / TrKB-T ratio (<0.70) when the disease started had poor functionality (<60) after 6 months after taking antipsychotic medication.
    5 PPV: a patient with a value of the TrKB-FL / TrKB-T ratio ≥ 0.70 at the time of debuting the disease and starting with an antipsychotic treatment has a 85.3% chance of having good functionality (GAF≥60) 6 months later
    10 NPV: a patient who has a low level of TrKB-FL / TrKB-T ratio (<0.70) at the time of PEP, has a probability of presenting general poor functionality (<60) after 6 months of taking antipsychotic medication .
    All these results show that 90% of patients who
    15 presented good functionality at 6 months (GAF≥60) corresponded with values of the expression of the TrKB-FL / TrKB-T ratio ≥0.70, specifically values between 0.70-1.50, at the time of disease debut. On the contrary, 90% of the patients who presented a general deteriorated functioning (GAF <60) after 6 months after debuting with the disease, had
    20 levels of the expression of the TrKB-FL / TrKB-T ratio <0.70, specifically values of the ratio between 0.25-0.70, at the time of disease debut.
    Thus, the expression value of the TrKB-FL / TrKB-T ratio serves as a prognostic marker of response to antipsychotic treatment in subjects who have suffered an SPF,
    25 showing high sensitivity (79.1%) and specificity (61.1%). Therefore, expression levels of the TrKB-FL / TrKB-T ratio ≥0.70 in subjects who suffer an SPF at the time of their debut in the disease, show a better response to antipsychotic treatment than those patients who at the time of their debut in the disease have a level of expression of the TrKB-FL / TrKB-T ratio <0.70.

    权利要求:
    Claims (15)
    [1]
    1. In vitro method for the prognosis or prediction of the response to treatment with at least one antipsychotic agent by patients who have suffered a first
    5 psychotic episode (FEP), where the prognosis is made according to the value ofexpression of the TrkB-FL / TrkB-T ratio, in an isolated sample of said patients,where an expression value of the ratio ≥ 0.70 is indicative of a patientrespondent to the treatment and an expression value of the ratio <0.70 is indicative ofa non-responding patient to the treatment.
    [2]
    2. In vitro method according to claim 1, wherein the isolated patient sample is selected from any of the following: blood, plasma or serum.
    [3]
    3. In vitro method according to any one of claims 1 to 2 wherein the sample
    Isolated is a blood sample, preferably a peripheral blood mononuclear cell sample.
    [4]
    4. In vitro method according to any of claims 1 to 3 wherein the expression value of the ratio is obtained by detecting and quantifying the levels
    Expression of TrKB-FL and TrKB-T by any of the following techniques: electrophoresis, immunoassay, chromatography and / or microarray technology.
    [5]
    5. In vitro method according to claim 4 wherein the techniques are selected from:
    electrophoresis and / or immunoassay. 25
    [6]
    6. In vitro method according to any of claims 1 to 5 wherein the antipsychotic agent is selected from any of the following: typical antipsychotics, preferably chlorpromazine, fluphenazine, levomepromazine, perfenazine, trifluoperazine, haloperidol, zuclopenthixol, pimozide, suppressed, thiapride ,
    30 or combinations thereof and / or atypical antipsychotics, preferably clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, sertindole, amisulpride, or combinations thereof.
    [7]
    7. In vitro use of the expression value of the TrkB-FL / TrkB-T ratio as a marker
    35 prognosis or predictive of the response to treatment with at least one antipsychotic agent by patients who have suffered an SPF, in an isolated biological sample of said patients, where an expression value of the TrkB ratio

    FL / TrkB-T ≥ 0.70 is indicative of a patient responding to treatment and an expression value of the TrkB-FL / TrkB-T ratio <0.70 is indicative of a patient not responding to treatment.
    5. In vitro use according to claim 7 wherein the isolated patient sample is selected from any of the following: blood, plasma or serum.
    [9]
    9. In vitro use according to claim 8 wherein the isolated sample is a sample of
    blood, preferably a sample of peripheral blood mononuclear cells.
    [10]
    10. In vitro use according to any of claims 7 to 9 wherein the expression value of the ratio is obtained by detecting and quantifying the expression levels of TrKB-FL and TrKB-T by any of the following techniques:
    15 electrophoresis, immunoassay, chromatography and / or microarray technology.
    [11]
    11. In vitro use according to claim 10 wherein the techniques are selected from: electrophoresis and / or immunoassay.
    12. In vitro use according to any of claims 7 to 12 wherein the antipsychotic agent is selected from any of the following: typical antipsychotics, preferably chlorpromazine, fluphenazine, levomepromazine, perfenazine, trifluoperazine, haloperidol, zuclopenthixol, pimozide, suppressed, thiapride,
    or combinations thereof and / or atypical antipsychotics, preferably,
    Clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, sertindole, amisulpride, or combinations thereof.
    [13]
    13. Kit comprising oligonucleotides, probes and / or antibodies for detection and / or
    quantification of the expression of TrkB-FL and TrkB-T. 30
    [14]
    14. Kit according to claim 13 comprising antibodies.
    [15]
    fifteen. Use of the kit according to any of claims 13 to 14 for forecasting or
    Predict the response to treatment with at least one antipsychotic agent in an isolated biological sample of an individual who has suffered an SPF.
    [16]
    16. Use of the kit according to claim 15 wherein the isolated sample is selected from any of the following: blood, plasma or serum.

    [17]
    17. Use of the kit according to any of claims 13 to 16 wherein the isolated sample is blood, preferably peripheral blood mononuclear cells.
    18. Use of the kit according to any of claims 13 to 17 wherein the antipsychotic agent is selected from any of the following: typical antipsychotics, preferably chlorpromazine, fluphenazine, levomepromazine, perphenazine, trifluoperazine, haloperidol, zuclopenthixol, pimozide, suppressed, thiapride,
    or combinations thereof and / or atypical antipsychotics, preferably,
    10 clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, sertindole, amisulpride, or combinations thereof.

     FIGURE DRAWINGS1
    TO
    B

    FIGURE 1 (cont.)
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