阅读说明：本技术 血清淀粉样蛋白p在制备抑郁症诊断治疗相关产品的用途 (Application of serum amyloid P in preparation of products related to depression diagnosis and treatment ) 是由 杨健 王刚 周晶晶 孙作厘 周佳 张国富 于 2019-09-05 设计创作，主要内容包括：本发明提供了血清淀粉样蛋白P或检测血清淀粉样蛋白P的试剂在制备用于诊断抑郁症的试剂或试剂盒中的用途,以及在制备用于预测和/或判断抗抑郁药的治疗效果的试剂或试剂盒中的用途。血清淀粉样蛋白P可以作为诊断抑郁症的生物标记物,对抑郁症诊断有较高的灵敏度和特异性,同时,还能在用药前较好的区分抗抑郁药的疗效,指导临床用药。只需测定所述外周血中血清淀粉样蛋白P水平一个指标,即可进行诊断和预测,方便推广使用。(The invention provides an application of serum amyloid P or a reagent for detecting serum amyloid P in preparing a reagent or a kit for diagnosing depression and an application in preparing a reagent or a kit for predicting and/or judging the treatment effect of an antidepressant. The serum amyloid P can be used as a biomarker for diagnosing depression, has higher sensitivity and specificity for depression diagnosis, and can better distinguish the curative effect of the antidepressant before medication to guide clinical medication. Diagnosis and prediction can be carried out only by measuring one index of the serum amyloid P level in the peripheral blood, and the method is convenient to popularize and use.)

1. Use of serum amyloid P or a reagent for detecting serum amyloid P for the preparation of a reagent or kit for the diagnosis of depression.

2. Use of serum amyloid P or a reagent for detecting serum amyloid P for the manufacture of a reagent or kit for predicting and/or judging the therapeutic effect of an antidepressant drug.

3. The use according to claim 1 or 2, wherein the kit is selected from a biochemical diagnostic kit, an immunodiagnostic kit or a molecular diagnostic kit; preferably, the kit is selected from one or more of Western blot kit, enzyme-linked immunosorbent assay (ELISA) kit, Radioimmunoassay (RIA) kit, radioimmunodiffusion kit, two-dimensional biphasic immunodiffusion kit, rocket immunoelectrophoresis kit, immunohistochemical staining kit, immunoprecipitation assay kit, complement fixation assay kit, Fluorescence Activated Cell Sorting (FACS) kit, aptamer chip kit, microarray kit and protein chip kit.

4. The use according to any one of claims 1-3, wherein the kit comprises a depression rating scale; preferably, the depression rating scale is selected from one or more of the hamilton depression scale (HAMD), the montgomery depression scale (MADRS), the Zung depression self-rating scale (SDS), the Beck depression self-rating scale (BDI), the depression symptom rapid rating scale (QIDS), the hypomania self-rating scale (HCL-32), the Mood Disorder Questionnaire (MDQ), the young mania scale (YMRS), and the depression screening scale (PHQ 9); more preferably, the depression rating scale is the hamilton depression scale (HAMD).

5. The use according to claim 1, wherein the diagnosis of depression comprises the steps of:

step 1: determining the concentration of serum amyloid P in the peripheral blood of the subject;

step 2: comparing the concentration of serum amyloid P measured in step 1 with a standard concentration; and

and step 3: the subject is judged to be at risk for depression, e.g., if the plasma SAP concentration is above 77.9ng/ml, the probability of depression is about 61.5%.

6. The use of claim 2, wherein predicting and/or judging the therapeutic effect of an antidepressant comprises the steps of:

step 1: determining the concentration of serum amyloid P in the peripheral blood of the subject prior to treatment, and comparing the concentration of serum amyloid P in the peripheral blood of the subject to a second standard concentration; and/or the presence of a gas in the gas,

step 2: measuring the serum amyloid P concentration in the peripheral blood of the subject at different time points of the treatment, and comparing the serum amyloid P concentrations in the peripheral blood of the subject measured at the different time points;

preferably, in step 1, the second standard concentration is the concentration of serum amyloid P in peripheral blood in the population with ineffective drug therapy, and further preferably, the second standard concentration is 85000-92000 pg/mL;

further preferably, in step 2, the drug therapy is indicated to be ineffective if the concentration of serum amyloid P in the peripheral blood of the subject tends to increase with the progress of the therapy, and the drug therapy is indicated to be effective if the concentration of serum amyloid P in the peripheral blood of the subject tends to decrease with the progress of the therapy.

7. A kit for diagnosing depression or for predicting and/or judging the therapeutic effect of an antidepressant, said kit comprising serum amyloid P and a depression assessment scale; preferably, the depression rating scale is selected from one or more of the hamilton depression scale (HAMD), the montgomery depression scale (MADRS), the Zung depression self-rating scale (SDS), the Beck depression self-rating scale (BDI), the depression symptom rapid rating scale (QIDS), the hypomania self-rating scale (HCL-32), the Mood Disorder Questionnaire (MDQ), the young mania scale (YMRS), and the depression screening scale (PHQ 9); more preferably, the depression rating scale is the hamilton depression scale (HAMD).

8. A kit for diagnosing depression or for predicting and/or judging the therapeutic effect of an antidepressant, said kit comprising a reagent for detecting serum amyloid P and a depression assessment scale; preferably, the depression rating scale is selected from one or more of the hamilton depression scale (HAMD), the montgomery depression scale (MADRS), the Zung depression self-rating scale (SDS), the Beck depression self-rating scale (BDI), the depression symptom rapid rating scale (QIDS), the hypomania self-rating scale (HCL-32), the Mood Disorder Questionnaire (MDQ), the young mania scale (YMRS), and the depression screening scale (PHQ9), more preferably, the depression rating scale is the hamilton depression scale (HAMD).

9. The use according to claim 1 or 2 or the kit according to claim 8, wherein the reagent for detecting serum amyloid P is selected from one or more than two of serum amyloid P ligand or an antibody to serum amyloid P ligand, an antibody to serum amyloid P, a chromogenic reagent, a luminescent marker, a dye and a fluorescent marker.

10. The use according to any one of claims 1 to 6 or the kit according to any one of claims 7 to 9, wherein the kit further comprises reagents for detecting 24-hydroxycholesterol, 27-hydroxycholesterol and/or vascular cell adhesion molecules.

Technical Field

The invention belongs to the technical field of biology, and relates to application of a peripheral blood marker Serum Amyloid P (SAP) in depression diagnosis and antidepressant drug efficacy prediction, and application in preparation of a corresponding reagent.

Background

Depression is an affective disorder characterized primarily by persistent mood depression and loss of pleasure, accompanied by appetite and sleep disturbance. The global prevalence rate of depression is about 4.3%, and the number of patients exceeds 3 hundred million, which has become the leading cause of disability worldwide. According to the statistics of the world health organization, depression is the fourth leading cause of disease burden, and by 2020, depression becomes the second leading cause of disease burden next to cardiovascular disease.

The pathogenesis and pathological changes of depression are numerous, and mainly include neurogenesis disorder, monoamine neurotransmitter deficiency, oxidative stress disorder, immunoregulation disorder and the like, but the pathogenesis and pathological changes are not widely adopted. In addition, the diagnosis of depression mainly depends on symptom and inquiry for definite diagnosis and differential diagnosis, and the misdiagnosis and missed diagnosis rate of depression are high due to the lack of objective laboratory diagnosis methods, and the effective rate of the antidepressant is not ideal, so that the state of illness is delayed. The biomarker is an indicator which can objectively measure and evaluate normal biological processes, pathological processes or interference response to drugs, and screening the biomarker related to depression helps to reveal the potential pathophysiological mechanism and develop an objective diagnosis and identification method. Therefore, the significance of screening pathophysiological markers of depression, developing laboratory diagnosis markers and searching drug response markers is great. The research on the pathogenesis of the depression and the biomarkers capable of reflecting the severity of the depression, and the timely intervention and treatment aiming at the causes of the depression are key factors for treating diseases and relieving the social burden.

Disclosure of Invention

Drawings

In order to more clearly illustrate the technical solution of the present invention, the drawings which are needed to be used are briefly described below, and it is obvious that the drawings in the following description are only some embodiments described in the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.

FIG. 1-1: healthy controls and depressed patients had pre-treatment plasma SAP concentrations.

FIGS. 1-2: plasma ROC curves before treatment for healthy controls and depressed patients.

FIG. 2-1: patients with depression are scored on the hamilton depression scale (HAMD) after 12 weeks of antidepressant treatment.

FIG. 2-2: patients with depression had a quick rating scale for depression symptoms (QIDS) score after 12 weeks of antidepressant treatment.

FIGS. 2 to 3: patients with depression are scored for young mania scale (YMRS) after 12 weeks of antidepressant treatment.

FIGS. 2 to 4: depression patients were scored on the depression screening scale (PHQ9) after 12 weeks of antidepressant treatment.

FIG. 3: plasma SAP concentration varied across groups of people.

FIG. 4: difference in plasma SAP concentration after 12 weeks treatment in patients with different therapeutic effects.

FIG. 5-1: correlation of difference in plasma SAP concentration at 12 weeks with fraction of HAMD reductions.

FIG. 5-2: ROC curve for 12 week efficacy prediction.

Detailed Description

In order to make the technical solutions of the present invention better understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In one embodiment of the present invention, SAP is used as a biomarker in an agent or kit for diagnosing depression or for predicting and/or judging the therapeutic effect of an antidepressant. The reagent or the kit is used for detecting the concentration of SAP in peripheral blood of a subject to be detected, so as to diagnose depression or predict and/or judge the treatment effect of the antidepressant. Specifically, peripheral blood of a subject may be drawn, plasma separated and SAP concentration measured, and the time of drawing may be before treatment to diagnose the diseased state of the subject, and for subjects identified as depression patients, the SAP concentration may also be used as an index for efficacy prediction to select a drug suitable for the patient, and the time of drawing may also be performed during or after the treatment to monitor the effect of the treatment.

Herein, the term "depression" also known as depressive disorder, is a mood disorder characterized primarily clinically by a marked and persistent mood drop.

The term "antidepressant" (antidepressant) refers to a group of psychotropic drugs that are used primarily to treat mental disorders that are predominantly symptomatic of mood depression. Antidepressants known in the art include monoamine oxidase inhibitors (MAOI), tricyclic antidepressants (TCA), selective 5-HT reuptake inhibitors (SSRI), and the like, and specific examples of applications include, but are not limited to, isoprotuzine, phenelzine, imipramine, amitriptyline, doxepin, clomipramine, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and the like.

Herein, the term "Serum amyloid P" (SAP), also known as pentraxin-2 (pentraxin-2), is a glycoprotein belonging to the pentosan protein family, which is synthesized and secreted by hepatocytes under normal conditions. SAP was originally recognized as an amyloid-depositing protein, which is believed to play an important role in the development of systemic amyloidosis. Later, it was discovered that SAP is involved in various activities in vivo, such as innate immunity, inflammatory responses, amyloidosis, etc. For example, SAP can inhibit the adhesion of neutrophils to the extracellular matrix, inhibit the differentiation of monocytes into fibroblasts, promote phagocytosis and differentiation of macrophages, and the like.

The term "diagnosis" refers to a method of detecting and/or identifying a pathological state in a subject, identifying and/or determining the course of whether a subject has a given disease or disorder, estimating or determining the future clinical progression of a subject, either before or after the onset of symptoms.

The term "predicting" refers to estimating or determining the likelihood that a patient will respond favorably or unfavorably to a drug (therapeutic agent) or group of drugs or treatment regimen.

The term "determining" refers to estimating or determining the likelihood that a patient has responded, or is responding favorably or unfavorably, to a drug (therapeutic agent) or group of drugs or treatment regimen.

In a specific embodiment of the present invention, the reagent for diagnosing depression, the reagent for predicting and/or judging the therapeutic effect of an antidepressant, and the like are prepared into a kit, and the kit may be a biochemical diagnosis kit, an immunodiagnostic kit, a molecular diagnosis kit, and the like, and is preferably prepared into the immunodiagnostic kit.

The diagnostic kit is prepared by adopting the principles or methods of immunology, microbiology, molecular biology and the like, and is used for diagnosing, detecting and epidemiological investigation of human diseases in vitro and the like.

The diagnostic kit may be of a type well known in the art, including, but not limited to, Western blot kit, enzyme linked immunosorbent assay (ELISA) kit, Radioimmunoassay (RIA) kit, radioimmunodiffusion kit, ouchterlony immunodiffusion kit, rocket immunoelectrophoresis kit, immunohistochemical staining kit, immunoprecipitation assay kit, complement fixation assay kit, Fluorescence Activated Cell Sorting (FACS) kit, aptamer chip kit, microarray kit, protein chip kit, and the like.

In the kit, the reagent for detecting serum amyloid P is included, and the reagent refers to a molecule capable of specifically determining serum amyloid P concentration, and includes, but is not limited to, a nucleic acid molecule, a protein, a compound and the like capable of specifically binding to SAP.

In one embodiment of the present invention, a protein capable of specifically binding to SAP may be selected as the reagent for detecting serum amyloid P, and in another embodiment of the present invention, an antibody, which may be an antibody specifically binding to a marker protein, including but not limited to a polyclonal antibody, a monoclonal antibody, a recombinant antibody, and an antigen-binding fragment thereof, is preferably selected as the reagent for detecting serum amyloid P, as long as it retains an antigen-binding function.

In the present invention, the reagent for detecting serum amyloid P may be linked to a detectable label molecule.

The present invention will be described in more detail with reference to specific examples, which, however, are for illustrative purposes only and do not limit the present invention.

The reagents and equipment sources used in the following examples are shown in Table 1 below, and reagents or equipment or procedures not described herein are routinely determined by one of ordinary skill in the art:

TABLE 1 reagents and apparatus used in the examples