WO2019063026A1 - 一种常见精神疾病辅助筛选试剂盒及方法 - Google Patents

一种常见精神疾病辅助筛选试剂盒及方法 Download PDF

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WO2019063026A1
WO2019063026A1 PCT/CN2018/117236 CN2018117236W WO2019063026A1 WO 2019063026 A1 WO2019063026 A1 WO 2019063026A1 CN 2018117236 W CN2018117236 W CN 2018117236W WO 2019063026 A1 WO2019063026 A1 WO 2019063026A1
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solution
subject
minutes
niacin
score
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PCT/CN2018/117236
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English (en)
French (fr)
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万春玲
孙丽雅
杨旭涵
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上海添音生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/16—Devices for psychotechnics; Testing reaction times ; Devices for evaluating the psychological state
    • A61B5/165—Evaluating the state of mind, e.g. depression, anxiety
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/0035—Vaccination diagnosis other than by injuring the skin, e.g. allergy test patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/16—Devices for psychotechnics; Testing reaction times ; Devices for evaluating the psychological state
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0006—Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity

Definitions

  • the invention relates to the technical field of medical detection, in particular to a common mental disease auxiliary screening kit and method.
  • Schizophrenia is a long-lasting, debilitating and extremely complex psychotic disorder. Clinically, it often manifests as a syndrome with different symptoms, involving many obstacles such as perception, thinking, emotion and behavior, and disharmony of mental activity. The patient is generally conscious and the intelligence is basically normal, but some patients will suffer cognitive function damage during the disease process.
  • Mood disorders also known as affective disorders (AD)
  • AD affective disorders
  • Mood disorders are a type of disease caused by various causes of significant and persistent emotional and mood changes.
  • the main manifestations are emotional ups and downs, accompanied by corresponding cognitive and behavioral changes and psychotic symptoms such as hallucinations.
  • phase characteristics of emotions they can be divided into three categories: single-phase mania, unipolar depression, and bipolar disorder.
  • Mood disorder and schizophrenia are two different types of mental illness, but because of the close relationship between the two, the symptoms are similar, and the clinical misdiagnosis rate is high, resulting in poor drug treatment response and poor prognosis. Therefore, special attention should be paid to two types of clinical diagnosis. Identification and differentiation of diseases. There is currently no objective clinical diagnostic marker for accurate diagnosis of common mental illnesses (such as schizophrenia and affective disorder), which also makes it difficult to target the treatment of the disease.
  • Another object of the present invention is to provide a common psychotic disease auxiliary screening kit and method.
  • a reagent combination for preparing a kit for detecting whether a subject has a mental illness; and/or (b) for Distinguish whether the subject has schizophrenia (SZ) and affective disorder (MD), and the subject is a person;
  • reagent combination comprises:
  • a first solution the first solution being a niacin compound solution of 0.08-0.12 M;
  • the detection includes an auxiliary detection, a screening test, a confirmatory test, and a pre-test.
  • the method for distinguishing whether the subject has schizophrenia (SZ) and affective disorder (MD) means that when the subject is a suspected SZ and MD patient, it is used to assist in distinguishing or prompting the test. Whether they have SZ or MD.
  • the subject is a male.
  • the subject is a male and the kit is for detecting whether the subject has a mental illness.
  • the mental illness includes SZ and MD.
  • the kit further includes a timer for setting the timing.
  • the timer can set a timing selected from the group consisting of 5 minutes, 10 minutes, 15 minutes, 20 minutes, or a combination thereof.
  • the niacin compound is selected from the group consisting of niacin, methyl nicotinate (AMN), ethyl nicotinate, or a combination thereof.
  • the reagent combination comprises:
  • a fourth solution which is a 0.0001 M methyl nicotinate solution.
  • the mental disorder is selected from the group consisting of schizophrenia, affective disorder, or a combination thereof.
  • the kit further includes a label or instructions.
  • the label or the specification records a criterion for judging the following:
  • the label or the specification records a criterion for judging the following:
  • the total is divided into a total of 16 scoring values (4 concentrations x 4 time points), wherein 4 concentrations are 0.0001 M, 0.001 M, 0.01 M, and 0.1 M, 4 times.
  • the points are 5 minutes, 10 minutes, 15 minutes and 20 minutes.
  • the scoring value is performed according to the following criteria: the subject's skin is in contact with the first, second, third, and fourth solutions, respectively, 0.5- After 2 minutes (such as 1 minute), stop contact, then stop the contact at 5th, 10th, 15th, and 20th minutes to score the redness of the skin: no redness reaction is 0 points, part of the redness reaction is 1 point, contact The total redness reaction in the area was 2 points, and the redness reaction exceeded the contact area by 3 points.
  • the kit further includes n patches, n being a positive integer of ⁇ 4.
  • the patches are the same size.
  • each of the patches has been infiltrated with the first solution, the second solution, the third solution, and/or the optional fourth solution, respectively.
  • first solution, the second solution, the third solution, and/or the optional fourth solution are each located in separate containers.
  • kits for screening for a psychiatric disorder comprising:
  • the second solution is a niacin compound solution of 0.008-0.012M
  • the third solution is a niacin compound solution of 0.0008-0.0012M
  • the kit further comprises: (c) a timer.
  • the niacin compound is selected from the group consisting of niacin, methyl nicotinate, ethyl nicotinate, or a combination thereof.
  • the kit further includes n patches, n being a positive integer of ⁇ 4.
  • the patch is a circular filter paper, preferably a circular filter paper having a diameter of 1.0 to 1.5 cm, more preferably a diameter of 1.2 to 1.30 cm.
  • the patch impregnated with the first, second, third or fourth solution is in contact with the skin of the subject, preferably the skin of the forearm inside the subject.
  • the contact time is from 0.5 to 2 minutes, preferably 1 minute.
  • the kit further comprises a carrier, the carrier comprising a test zone, wherein the test zone comprises at least 4 patches immersed in the first, second, third, and fourth solutions, respectively (Preferably a circular filter paper having a diameter of 1.25 to 1.3 cm).
  • the carrier further includes a scale.
  • the carrier is a viscous carrier.
  • the carrier is provided with a seal, the seal being removable, and the test zone of the carrier being contacted with the skin after removal.
  • the seal is a removable cover film, more preferably a removable plastic film.
  • the kit (a) is for detecting whether the subject has a mental illness; and/or (b) for distinguishing whether the subject has schizophrenia and affective disorder.
  • a method of detecting a mental illness comprising the steps of:
  • a method of detecting a mental illness comprising the steps of:
  • a method of distinguishing whether a subject has schizophrenia and affective disorder comprising the steps of:
  • the patient is prompted (or an auxiliary diagnosis) to have schizophrenia or schizophrenia.
  • the probability is higher than the normal population
  • the subject When the subject is suspected of SZ and MD patients, if the score of ⁇ 2.5 at 15 minutes and the total score of ⁇ 20 at 0.1M AMN concentration, then (or auxiliary diagnosis) the subject has an affective disorder or affective disorder. The probability is higher than the normal population.
  • Fig. 1 is a graph showing the distribution of mean value distribution values of niacin skin test scores in schizophrenia, affective disorder and healthy control population obtained in Example 1 of the present invention.
  • Figure 2 shows the scatter plot of the score distribution of the three groups of schizophrenia, affective disorder and healthy controls at two fractional nodes: two score nodes are “0.1M AMN concentration under 15min score ⁇ 2.5” and “all scores combined” ⁇ 20"; where A is male; B is female.
  • Figure 3 shows a schematic diagram of the use of a prefabricated methyl nicotinate patch, in which a 1-scale, 2-test zone, 3-lead gradient gradient concentration of methyl nicotinate solution, 4-breakpoint tear line.
  • the present inventors have discovered for the first time that with the reagent combination or kit of the present invention, it is possible to assist in detecting or diagnosing whether or not suffering from mental illness (including mentality) for a specific population, especially a male subject. Schizophrenia and affective disorder), the specificity of the test is nearly 100%, and the accuracy is very high.
  • the reagent combination of the present invention can further provide information for distinguishing schizophrenia and affective disorder with high accuracy. On the basis of this, the inventors completed the present invention.
  • schizophrenia and “SZ” are used interchangeably and refer to one of a psychiatric disorder. Common symptoms include delusions, hallucinations, confusion, auditory hallucinations, reduced levels of social participation and emotional expression, and lack of motivation. Clinical diagnosis is usually judged by the clinician based on the diagnostic criteria of DSM-5 or ICD-10 combined with clinical experience.
  • the terms "affective disorder” and “MD” are used interchangeably to refer to a class of psychiatric disorders characterized by significant and persistent emotional and mood changes that are caused by a variety of causes. Clinically, the main manifestations are emotional ups and downs, accompanied by corresponding cognitive and behavioral changes and psychotic symptoms such as hallucinations. According to the phase characteristics of emotions, they can be divided into three categories: single-phase mania, unipolar depression, and bipolar disorder.
  • nicotinic acid compound includes the following compounds: niacin, methyl nicotinate, ethyl nicotinate, or a combination thereof.
  • the niacin redness reaction is a reaction of epidermal vasodilation and skin flushing regulated by Hydroxy-carboxylic acid receptor 2 (HCA2).
  • HCA2 Hydroxy-carboxylic acid receptor 2
  • the invention adopts a semi-quantitative Aqueous methyl nicotinate (AMN) patch and scores to study the nicotinic redness reaction in the Han population in two common mental diseases (schizophrenia and affective disorder) and normal
  • ATN Aqueous methyl nicotinate
  • the different manifestations in the population are aimed at finding an effective way to isolate the niacin-insensitive subgroup of patients with common mental illnesses from the normal population and to differentiate patients with schizophrenia and affective disorders to reduce the rate of misdiagnosis.
  • the auxiliary detection method of the present invention comprises: contacting the skin of the subject with the first, second, third and fourth solutions respectively described in the first aspect of the invention for 0.5 to 2 minutes (eg 1 minute) After stopping contact, then the 5th, 10th, 15th and 20th minutes after the contact was stopped, the redness and swelling of the skin were scored: no redness reaction was 0, part of the redness reaction was 1 point, and the contact area was completely red and swollen. 2 points, the redness reaction exceeded the contact area by 3 points; assisted detection according to the scoring situation and the judgment criteria of the present invention.
  • the method of assisting in detecting a mental illness comprises the steps of:
  • the use of the reagent combination of the present invention can provide information for distinguishing between schizophrenia and affective disorder, and has high specificity and high accuracy.
  • the invention adopts a patch of methyl nicotinic acid solution attached in vitro, and diagnoses common mental diseases such as schizophrenia through skin redness reaction, and has the advantages of convenient operation and non-invasiveness.
  • Example 1 The niacin redness reaction varied in schizophrenia, affective disorder, and normal control groups.
  • a circular filter paper having a diameter of 1.29 cm was used as a patch and infiltrated in four concentrations of AMN solution.
  • the skin is red and swollen, using the 4-point scoring method: 0- no redness reaction, 1-part redness reaction, 2-complete redness in the patch range, 3-redness The reaction is outside the range of the patch. Two trained researchers scored independently.
  • Each subject has 16 scoring values (4 concentrations x 4 time points), a sum of 4 concentrations, a sum of 4 time points, and a total sum of all 16 scoring values.
  • BMI, education level, and nicotine dependence (FTND) were used as covariates to compare between different disease groups and genders.
  • the niacin redness reaction varied in schizophrenia, affective disorder, and normal control groups.
  • the scoring value of the schizophrenia group was generally lower than that of the normal control group, meaning that patients with schizophrenia were insensitive to methyl nicate, slow in response, and low in response (Fig. 1).
  • the affective disorder group showed similarity to the schizophrenia group at the lowest concentration of methyl nicotinic acid (0.0001M) or the shortest time (5min), but with the increase of methyl nicotinic acid concentration and prolonged time, the redness reaction and the normal control group Nearly, even at 0.1 M methyl nicotinate for 20 min, the redness reaction exceeded that of normal people. This indicates that the skin redness and swelling reaction caused by methyl niacin is delayed in patients with affective disorders, but it is not attenuated.
  • the experimental results showed that in the high concentration of methyl nicotinate, the normal control group rapidly developed skin redness and swelling, while the schizophrenia group and the affective disorder group had a slow skin reaction. Therefore, the niacin skin redness reaction is used to assist screening of patients with common mental illness.
  • This indicator was used as a clinical adjuvant screening marker for people with common mental illnesses, including schizophrenia and affective disorder, with a sensitivity of 26.22% and a specificity of 96.83% (Table 1). As can be seen from Table 1, in males, the specificity of this index as a clinical adjuvant screening marker can reach 100%, the sensitivity is 26.98%; in women, the specificity and sensitivity are 96.23% and 25.25%, respectively.
  • the total score refers to the sum of 16 scores (4 concentrations ⁇ 4 time points). Gender is one of the influencing factors affecting the skin redness reaction of niacin. According to different genders, different thresholds are used in males and females as screening criteria.
  • the standard score is ⁇ 19 or 0.1M 15min ⁇ 3"
  • those who meet the criteria are judged to be niacin-insensitive (ie, have a high incidence of common mental illness or mental illness).
  • the specificity of screening for common mental illness reached 90.00% with a sensitivity of 62.20% (Table 2).
  • the standard score is ⁇ 13 or 0.1M 15min ⁇ 2.5", and those who meet the criteria are judged to be niacin-insensitive (ie, have a high incidence of common mental illness or mental illness).
  • the specificity of screening for common mental illness reached 79.25% with a sensitivity of 49.49% (Table 2).
  • 0.1M AMN 15min scored the largest ⁇ 2 (0.045) between the schizophrenia group and the affective disorder group, and the sum of all scores was the largest ⁇ 2 (0.115) between the schizophrenia group and the normal control group, representing both Indicators can better distinguish between different disease groups.
  • the invention adopts "0.1M AMN 15min ⁇ 2.5 and the total score of ⁇ 20" as the standard, and the qualified person thinks that niacin is not sensitive (that is, the possibility of suffering from common schizophrenia or schizophrenia is high)
  • Table 3 uses "0.1M AMN 15min score ⁇ 2.5 and all scores ⁇ 20" as nodes
  • Example 4 niacin skin test screening common mental illness niacin insensitive population kit
  • the product is a pre-formed methyl nicotinate patch.
  • the prefabricated methyl nicotinate patch is shown in Figure 3.
  • the viscous carrier is divided into two parts: the scale (1) and the test area (2).
  • the test area has four circular filter papers (3) with a diameter of 1.29 cm, which are sequentially immersed in 0.1 M, 0.01 M, 0.001 M, and 0.0001 M. Methyl nicotinate solution.
  • the adhesive carrier is covered with a plastic film, the plastic film is peeled off, and the entire adhesive carrier is evenly attached to the inner side of the upper arm, and a low concentration (0.0001 M) of the methyl nicotinate patch is placed close to the wrist.
  • test area After attaching for 1 minute, the test area is torn off by the dotted line (4), and the photos are uploaded to the remote end such as a mobile phone at 5 min, 10 min, 15 min, and 20 min respectively. Ask the subject to take a picture as perpendicular to the arm as possible and take the part of the ruler together. The redness of the subject's arm was scored (Table 4).
  • AMN is a solution of methyl nicotinate.

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Abstract

一种基于烟酸皮肤测试的精神疾病辅助诊断试剂盒及方法，采用该试剂组合或试剂盒，可以针对特定人群，尤其是男性受测者，辅助性检测或诊断是否患有精神疾病（包括精神分裂症和情感障碍），检测的特异性好，准确性高。同时，该试剂组合还可进一步为区分精神分裂症和情感障碍提供有效性信息，准确性高。

Description

一种常见精神疾病辅助筛选试剂盒及方法 技术领域
本发明涉及医学检测技术领域，具体涉及一种常见精神疾病辅助筛选试剂盒及方法。
背景技术
精神分裂症是一种长期的、使人衰弱的且极其复杂的精神病性精神障碍。临床上往往表现为症状各异的综合征，涉及感知觉、思维、情感和行为等多方面的障碍以及精神活动的不协调。患者一般意识清楚，智能基本正常，但部分患者在疾病过程中会出现认知功能的损害。
心境障碍(mood disorders,MD)亦称情感障碍(affective disorders,AD)，是由各种原因引起的以显著而持久的情感和心境改变为主要特征的一类疾病。临床上主要表现为情感高涨或低落，伴有相应的认知和行为改变和有幻觉尧妄想等精神病性症状。按照情感的相位特征，可以分为三类：单相狂躁、单相抑郁和双相情感障碍。
心境障碍和精神分裂症是两类不同的精神疾病，但由于两者关系密切，症状相似，临床上误诊率高，导致药物治疗反应差、预后不理想，因此在临床诊断时需要特别注意两类疾病的鉴别和区分。目前尚无客观的临床诊断标记对常见精神疾病(如精神分裂症和情感障碍)进行精确的诊断，这也为该疾病的针对性治疗增加了难度。
因此，本领域迫切需要开发一种对常见精神疾病快速检测筛查，以及区分精神分裂症和情感障碍的方法。
发明内容
本发明的目的在于提供一种对常见精神疾病快速检测筛查，以及区分精神分裂症和情感障碍的方法。
本发明的另一目的在于提供一种常见精神疾病辅助筛选试剂盒及方法。
本发明的第一方面，提供了一种试剂组合的用途，用于制备一试剂盒，所述试剂盒(a)用于检测受测者是否患有精神疾病；和/或(b)用于区分受测者是否患有精神分裂症(SZ)和情感障碍(MD)，所述的受测者为人；
其中所述试剂组合包括：
(1)第一溶液，所述第一溶液为0.08-0.12M的烟酸化合物溶液；
(2)第二溶液，所述第二溶液为0.008-0.012M的烟酸化合物溶液；
(3)第三溶液，所述第三溶液为0.0008-0.0012M的烟酸化合物溶液；和
(4)任选的第四溶液，所述第四溶液为0.00008-0.00012M的烟酸化合物溶液。
在另一优选例中，所述的检测包括辅助性检测、筛查性检测、确认性检测、预先性检测。
在另一优选例中，所述用于区分受测者是否患有精神分裂症(SZ)和情感障碍(MD)指当受测者为疑似SZ和MD患者，用于辅助区分或提示受测者是患有SZ还是患有MD。
在另一优选例中，所述的受测者为男性。
在另一优选例中，所述的受测者为男性，并且所述的试剂盒用于检测受测者是否患有精神疾病。
在另一优选例中，所述的精神疾病包括SZ和MD。
在另一优选例中，在所述试剂盒中，包括以下判断标准的说明：
(a)当所述男性受测者在0.1M烟酸甲酯溶液浓度下5min分数为0时，则提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；和/或
(b)当所述女性受测者在0.1M烟酸甲酯溶液浓度下5min分数为0时，则提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
在另一优选例中，所述的试剂盒还包括一用于设定计时时间的计时器。
在另一优选例中，所述计时器可设定选自下组的计时：5分钟、10分钟、15分钟、20分钟、或其组合。
在另一优选例中，所述的烟酸化合物选自下组：烟酸、烟酸甲酯(AMN)、烟酸乙酯、或其组合。
在另一优选例中，所述试剂组合包括：
(1)第一溶液，所述第一溶液为0.1M的烟酸甲酯溶液；
(2)第二溶液，所述第二溶液为0.01M的烟酸甲酯溶液；
(3)第三溶液，所述第三溶液为0.001M的烟酸甲酯溶液；和
(4)第四溶液，所述第四溶液为0.0001M的烟酸甲酯溶液。
在另一优选例中，所述精神疾病选自下组：精神分裂症、情感障碍、或其组合。
在另一优选例中，所述的试剂盒还包括一标签或说明书。
在另一优选例中，所述标签或说明书记载有判断标准，所述判断标准注明以下内容：
(1)0.1M烟酸甲酯溶液浓度下5min分数为0时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
(2)当受测者为男性，且总分<19或0.1M烟酸甲酯溶液浓度下15min打分<3时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；和/或
(3)当受测者为女性，且总分<13或0.1M烟酸甲酯溶液浓度下15min打分<2.5时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
在另一优选例中，所述标签或说明书记载有判断标准，所述判断标准注明以下内容：
(4)当受测者为疑似SZ和MD患者，若0.1M烟酸甲酯溶液浓度下15min打分<2.5且全部打分总和<20，则提示(或辅助性诊断)该受测者患有精神分裂症；和/或
(5)当受测者为疑似SZ和MD患者，若0.1M烟酸甲酯溶液浓度下15min打分≥2.5和/或全部打分总和≥20，则提示(或辅助性诊断)该受测者患有情感障碍。
在另一优选例中，所述总分为16个打分值(4个浓度×4个时间点)的全部总和，其中4个浓度为0.0001M、0.001M、0.01M和0.1M，4个时间点为5分钟、10分钟、15分钟和20分钟。
在另一优选例中，所述打分值(或“分数”或“打分”)按以下标准进行：受测者皮肤在分别与所述第一、第二、第三和第四溶液接触0.5-2分钟(如1分钟)后停止接触，然后停止接触后第5分钟、10分钟、15分钟和20分钟时对皮肤的红肿情况打分：没有红肿反应为0分，部分红肿反应为1分，接触面积内完全红肿反应为2分，红肿反应超出接触面积为3分。
在另一优选例中，所述的试剂盒中还包括n个贴片，n为≥4的正整数。
在另一优选例中，所述各贴片的大小是相同的。
在另一优选例中，所述的各贴片已经分别浸润有所述第一溶液、第二溶液、第三溶液、和/或任选的第四溶液。
在另一优选例中，所述第一溶液、第二溶液、第三溶液、和/或任选的第四溶液分别位于不同的容器中。
本发明的第二方面，提供了一种用于筛查精神疾病的试剂盒，所述试剂盒含有：
(a)第一容器，以及位于所述第一容器内的第一溶液，所述第一溶液为0.08-0.12M的烟酸化合物溶液；
第二容器，以及位于所述第二容器内的第二溶液，所述第二溶液为0.008-0.012M的烟酸化合物溶液；
第三容器，以及位于所述第三容器内的第三溶液，所述第三溶液为0.0008-0.0012M的烟酸化合物溶液；
任选的第四容器，以及位于所述第四容器内的第四溶液，所述第四溶液为0.00008-0.00012M的烟酸化合物溶液；和
(b)标签或说明书。
在另一优选例中，所述试剂盒还包括：(c)计时器。
在另一优选例中，所述的烟酸化合物选自下组：烟酸、烟酸甲酯、烟酸乙酯、或其组合。
在另一优选例中，所述的试剂盒中还包括n个贴片，n为≥4的正整数。
在另一优选例中，所述贴片为圆形滤纸，较佳地，直径为1.0-1.5cm，更佳地，直径为1.25-1.30cm的圆形滤纸。
在另一优选例中，所述浸有第一、第二、第三或第四溶液的贴片分别与受测者皮肤接触，优选受测者前臂内侧皮肤。
在另一优选例中，所述接触时间为0.5-2分钟，较佳地为1分钟。
在另一优选例中，所述试剂盒还包括载体，所述载体包括测试区，其中所述测试区含有至少4个分别浸有第一、第二、第三、和第四溶液的贴片(优选为直径1.25-1.3cm的圆形滤纸)。
在另一优选例中，所述载体还包括标尺。
在另一优选例中，所述载体为粘性载体。
在另一优选例中，所述载体外设有密封，所述密封是可移除的，且移除后 可使所述载体的测试区与皮肤接触。优选地，所述密封是可移除的覆盖膜，更优选地是可移除的塑料贴膜。
在另一优选例中，所述试剂盒(a)用于检测受测者是否患有精神疾病；和/或(b)用于区分受测者是否患有精神分裂症和情感障碍。
本发明的第三方面，提供了一种检测精神疾病的方法，所述方法包括步骤：
(i)提供一烟酸化合物溶液(如烟酸甲酯溶液)，其中所述烟酸甲酯溶液的浓度为0.08-0.12M；和
(ii)将受测者的皮肤与所述烟酸化合物溶液(如烟酸甲酯溶液)接触0.5-2分钟后停止接触，然后停止接触后第5分钟后检测皮肤的红肿情况，如果无红肿则提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
本发明的第四方面，提供了一种检测精神疾病的方法，所述方法包括步骤：
a)提供一如本发明第二方面所述的试剂盒；和
b)将受测者皮肤在分别与所述第一、第二、第三和第四溶液接触0.5-2分钟后停止接触，然后停止接触后第5分钟、10分钟、15分钟和20分钟时对皮肤的红肿情况打分：没有红肿反应为0分，部分红肿反应为1分，接触面积内完全红肿反应为2分，红肿反应超出接触面积为3分；其中
当受测者为男性，且总分<19或0.1M烟酸甲酯溶液浓度下15min打分<3时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
当受测者为女性，且总分<13或0.1M烟酸甲酯溶液浓度下15min打分<2.5时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
本发明的第五方面，提供了一种区分受测者是否患有精神分裂症和情感障碍的方法，所述方法包括步骤：
a)提供一如本发明第二方面所述的试剂盒；和
b)将受测者皮肤在分别与所述第一、第二、第三和第四溶液接触0.5-2分钟后停止接触，然后停止接触后第5分钟、10分钟、15分钟和20分钟时对皮 肤的红肿情况打分：没有红肿反应为0分，部分红肿反应为1分，接触面积内完全红肿反应为2分，红肿反应超出接触面积为3分；其中
当受测者为疑似SZ和MD患者，若0.1M AMN浓度下15min打分<2.5且全部打分总和<20，则提示(或辅助性诊断)该受测者患有精神分裂症或精神分裂症发病的机率高于正常人群；
当受测者为疑似SZ和MD患者，若0.1M AMN浓度下15min打分≥2.5和/或全部打分总和≥20，则提示(或辅助性诊断)该受测者患有情感障碍或情感障碍发病的机率高于正常人群。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明实施例1得到的精神分裂症、情感障碍及健康对照人群烟酸皮肤测试打分值均值分布折线图。
图2显示了两个分数节点下精神分裂症、情感障碍及健康对照三组人群打分值分布散点图：两个分数节点分别为“0.1M AMN浓度下15min打分<2.5”及“全部打分总和<20”；其中A为男性；B为女性。
图3显示了预制烟酸甲酯贴片使用示意图，其中1-标尺，2-测试区，3-浸有梯度浓度烟酸甲酯溶液原片，4-断点式易撕线。
具体实施方式
本发明人经过广泛而深入的研究，首次意外地发现，采用本发明的试剂组合或试剂盒，可以针对特定人群，尤其是男性受测者，辅助性检测或诊断是否患有精神疾病(包括精神分裂症和情感障碍)，检测的特异性近乎100％，准确性非常高。同时，本发明的试剂组合还可进一步为区分精神分裂症和情感障碍提供有效性信息，准确性高。在此基础上，本发明人完成了本发明。
术语
如本文所用，术语“精神分裂症”和“SZ”可互换使用，指精神疾病的一种。 常见症状包括妄想、幻觉、思维混乱、幻听、社会参与和情绪表达的程度减少，以及缺乏动机等。临床诊断通常由临床医生依据DSM-5或ICD-10的诊断标准结合临床经验来判断。
如本文所用，术语“情感障碍”和“MD”可互换使用，指是由各种原因引起的以显著而持久的情感和心境改变为主要特征的一类精神疾病。临床上主要表现为情感高涨或低落，伴有相应的认知和行为改变和有幻觉尧妄想等精神病性症状。按照情感的相位特征，可以分为三类：单相狂躁、单相抑郁和双相情感障碍。
如本文所用，术语“烟酸化合物”包括以下化合物：烟酸、烟酸甲酯、烟酸乙酯、或其组合。
烟酸红肿
烟酸红肿反应是一种由羟基羧酸受体(Hydroxy-carboxylic acid receptor 2,HCA2)调节的表皮血管舒张及皮肤潮红的反应。在白种人群中的研究发现，相对于情感障碍及健康人群，这种反应在精神分裂症人群中有明显减弱的趋势。
本发明采用半定量的水溶性烟酸甲酯(Aqueous methyl nicotinate,AMN)贴片并打分的方法，研究汉族人群中烟酸红肿反应在两种常见精神疾病(精神分裂症和情感障碍)及正常人群中的不同表现，旨在寻找能够将常见精神疾病患者烟酸不敏感亚组从正常人群中筛选出来，并对精神分裂症和情感障碍患者做区分从而降低误诊率的有效方法。
检测方法
如本文所用，本发明的辅助性检测方法包括：将受测者皮肤在分别与本发明第一方面所述的第一、第二、第三和第四溶液接触0.5-2分钟(如1分钟)后停止接触，然后停止接触后第5分钟、10分钟、15分钟和20分钟时对皮肤的红肿情况打分：没有红肿反应为0分，部分红肿反应为1分，接触面积内完全红肿反应为2分，红肿反应超出接触面积为3分；根据打分情况和本发明的判断标准来辅助性检测。
在另一优选例中，辅助性检测精神疾病的方法包括步骤：
(i)提供一烟酸甲酯溶液，其中所述烟酸甲酯溶液的浓度为0.08-0.12M；和(ii)将受测者的皮肤与所述烟酸化合物溶液(如烟酸甲酯溶液)接触0.5-2分钟 后停止接触，然后停止接触后第5分钟后检测皮肤的红肿情况，如果无红肿则提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
判断标准
(1)0.1M烟酸甲酯溶液浓度下5min分数为0时，提示所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
(2)当受测者为男性，且总分<19或0.1M烟酸甲酯溶液浓度下15min打分<3时，提示所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
(3)当受测者为女性，且总分<13或0.1M烟酸甲酯溶液浓度下15min打分<2.5时，提示所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
(4)当受测者为疑似SZ和MD患者，若0.1M AMN浓度下15min打分<2.5且全部打分总和<20，则提示该受测者患有精神分裂症或精神分裂症发病的机率高于正常人群；
(5)当受测者为疑似SZ和MD患者，若0.1M AMN浓度下15min打分≥2.5和/或全部打分总和≥20，则提示该受测者患有情感障碍或情感障碍发病的机率高于正常人群。
本发明的主要优点包括：
1.利用本发明的试剂组合可以为区分精神分裂症和情感障碍提供有效性信息，并且特异性强，准确性高。
2.对于特定群体，特别是男性受测者，可准确诊断是否患有精神疾病(包括精神分裂症和情感障碍)，特异性近乎100％，准确性非常高。
3.本发明采用体外贴附烟酸甲酯溶液贴片，通过皮肤红肿反应来进行精神分裂症等常见精神疾病的诊断，具有方便操作、无创伤性等优点。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
如无特别说明，则本发明实施例中所用的材料和试剂均为市售产品。
实施例1烟酸红肿反应在精神分裂症、情感障碍和正常对照组中表现各异
1.样本收集
收集了通过ICD-10诊断的精神分裂症患者163例，情感障碍患者63例和正常对照63例。所有入组个体均无糖尿病、恶性肿瘤、发热、炎症等躯体疾病，所有女性个体均未处于妊娠期。本研究已通过芜湖市第四人民医院伦理委员会审查，实验方案符合道德原则，且通过书面方式正式告知所有入组人员。
2.试剂制备与皮肤测试打分
1)新鲜配制四个浓度(0.1、0.01、0.001和0.0001M)的盐酸甲酯溶液(AMN,C7H7NO2,99％,Sigma-Aldrich,St.Louis,MO,US)。
2)将直径1.29cm的圆形滤纸片作为贴片，浸润在四个浓度AMN溶液中。
3)将透明标尺贴在受测者前臂内侧，以便定位贴片。
4)将4个浸有不同浓度AMN的贴片依次贴附在受测者前臂内侧皮肤上，持续一分钟后取下贴片。
5)分别在5分钟、10分钟、15分钟和20分钟后，垂直于前臂内侧贴片位置拍照。
6)根据照片中受测者贴片部位皮肤红肿情况进行打分，采用4分制打分法：0-没有红肿反应，1-部分红肿反应，2-在贴片范围内完全红肿反应，3-红肿反应超出贴片范围。两位经过训练后的研究者分别独立打分。
3.数据分析
将两个研究者的打分值取平均作为最终打分值。每个受测者有16个打分值(4个浓度×4个时间点)、4个浓度的总和、4个时间点的总和及全部16个打分值的全部总和。BMI、受教育程度、尼古丁依赖程度(FTND)作为协变量，在不同疾病组和不同性别之间进行比较。
从图1可以看出，烟酸红肿反应在精神分裂症、情感障碍和正常对照组中表现各异。精神分裂症组打分值普遍低于正常对照组，意味着精神分裂症病人对烟酸甲酯不敏感、反应速度慢、反应程度低(图1)。而情感障碍组在最低浓度烟酸甲酯(0.0001M)或者最短时间(5min)时表现和精神分裂症组相似，但随着烟酸甲酯浓度升高、时间延长，红肿反应与正常对照组接近，甚至在0.1M烟酸甲酯20min时红肿反应超过了正常人。这说明烟酸甲酯引起的皮肤红肿反应在情感障碍患者中发生了 延迟，但并没有减弱。
实施例2常见精神疾病的筛查
实验结果表明，在高烟酸甲酯浓度时，正常对照组迅速出现皮肤红肿，而精神分裂症组和情感障碍组皮肤反应迟缓。因此，用烟酸皮肤红肿反应辅助筛选常见精神疾病患者。
1.以“0.1M AMN浓度下5min打分为0”为标准(又称指标或节点)，符合条件者则判定为烟酸不敏感(即患有常见精神疾病或精神疾病发病可能性高)
用此指标作为常见精神疾病(包括精神分裂症和情感障碍)人群的临床辅助筛查标记，灵敏度为26.22％，特异性96.83％(表1)。从表1可以看出，在男性中，该指标作为临床辅助筛查标记的特异性可达到100％，敏感性26.98％；在女性中特异性和敏感性分别为96.23％和25.25％。
表1以“0.1M AMN浓度下5min打分＝0”为节点
辅助筛查常见精神疾病的特异性与敏感性
  男 女 总和
敏感性 26.98％ 25.25％ 26.22％
特异性 100.00％ 96.23％ 96.83％
2.用0.1M AMN浓度下15min打分值及全部打分总和(总分)两个条件来筛查常见精神疾病。全部打分总和(总分)指16个打分值(4个浓度×4个时间点)的全部总和。性别是影响烟酸皮肤红肿反应的影响因素之一，本发明根据性别不同，在男性和女性中分别采用不同的阈值作为筛查标准。
在男性人群中，以“总分<19或0.1M 15min<3”为标准，符合条件者则判定为烟酸不敏感(即患有常见精神疾病或精神疾病发病可能性高)，以此标准筛查常见精神疾病的特异性达到90.00％，敏感性62.20％(表2)。
在女性人群中，以“总分<13或0.1M 15min<2.5”为标准，符合条件者则判定为烟酸不敏感(即患有常见精神疾病或精神疾病发病可能性高)，以此标准筛查常见精神疾病的特异性达到79.25％，敏感性49.49％(表2)。
表2以“0.1M AMN浓度下15min打分值及全部
打分总和”两个条件筛选常见为精神疾病
性别 判定为不敏感的筛选条件 敏感性 特异性
男 总分<19或0.1M 15min<3 62.20％ 90.00％
女 总分<13或0.1M 15min<2.5 49.49％ 79.25％
实施例3精神分裂症和情感障碍的筛查
在单因素分析中，偏η 2通常用来评估独立变量对疾病分组的影响。0.1M AMN 15min打分在精神分裂症组和情感障碍组组间偏η 2最大(0.045)，所有打分的总和在精神分裂症组和正常对照组间偏η 2最大(0.115)，代表着这两个指标可以更好的区分不同疾病组。本发明以“0.1M AMN 15min<2.5且全部打分总和<20”为标准，符合条件者认为烟酸不敏感(即患有常见精神分裂症或精神分裂症发病可能性高)
结果表明，在该标准下，73％的烟酸不敏感者被准确诊断为精神分裂症。用这一指标可以较好的筛选精神分裂症患者，并区分精神分裂症和情感障碍患者(表3)。以“0.1M AMN浓度下15min打分<2.5及全部打分总和<20”为节点，可区分精神分裂症烟酸不敏感患者和情感障碍烟酸不敏感患者。
表3以“0.1M AMN 15min打分<2.5且全部打分总和<20”为节点
辅助筛选精神分裂症患者，并区分精神分裂症和情感障碍
  SZ和HC SZ和MD SZ和HC+MD
敏感性 31.45％ 31.45％ 31.45％
特异性 83.33％ 87.30％ 85.37％
考虑到性别对烟酸皮肤反应的影响，将受测者按照性别进行再分组后，打分情况如图2所示。从图2中可以看出，在男性中，这一指标表现出很好的特异性。而在女性中，敏感性则达到了42.03％。
实施例4烟酸皮肤测试筛查常见精神疾病烟酸不敏感人群试剂盒
产品为预制烟酸甲酯贴片。
预制烟酸甲酯贴片如图3。有粘性的载体分为标尺(1)和测试区(2)两部分，测试区有4片直径1.29cm的圆形滤纸片(3)，依次浸有0.1M、0.01M、0.001M、0.0001M烟酸甲酯溶液。粘性载体外有塑料贴膜覆盖，揭下塑料贴膜，将整个粘性载体平整的贴附在上臂内侧，低浓度(0.0001M)烟酸甲酯贴片靠近手腕。贴附1分钟后，延虚线(4)撕下测试区，分别在5min、10min、15min、20min时拍照上传到远程端如手机。要求受测者拍照时尽量垂直于手臂，并把标尺部分一同 拍摄进去。对受测者手臂红肿部分进行打分(表4)。
表4分数表
Figure PCTCN2018117236-appb-000001
注：AMN为烟酸甲酯溶液。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 一种试剂组合的用途，其特征在于，用于制备一试剂盒，所述试剂盒(a)用于检测受测者是否患有精神疾病；和/或(b)用于区分受测者是否患有精神分裂症(SZ)和情感障碍(MD)，所述的受测者为人；
    其中所述试剂组合包括：
    (1)第一溶液，所述第一溶液为0.08-0.12M的烟酸化合物溶液；
    (2)第二溶液，所述第二溶液为0.008-0.012M的烟酸化合物溶液；
    (3)第三溶液，所述第三溶液为0.0008-0.0012M的烟酸化合物溶液；和
    (4)任选的第四溶液，所述第四溶液为0.00008-0.00012M的烟酸化合物溶液。
  2. 如权利要求1所述的试剂组合的用途，其特征在于，所述的受测者为男性。
  3. 如权利要求1所述的试剂组合的用途，其特征在于，所述的精神疾病包括精神分裂症和情感障碍。
  4. 如权利要求1所述的试剂组合的用途，其特征在于，所述的试剂盒还包括一用于设定计时时间的计时器。
  5. 如权利要求1所述的试剂组合的用途，其特征在于，所述的烟酸化合物选自下组：烟酸、烟酸甲酯、烟酸乙酯、或其组合。
  6. 如权利要求1所述的试剂组合的用途，其特征在于，所述试剂组合包括：
    (1)第一溶液，所述第一溶液为0.1M的烟酸甲酯溶液；
    (2)第二溶液，所述第二溶液为0.01M的烟酸甲酯溶液；
    (3)第三溶液，所述第三溶液为0.001M的烟酸甲酯溶液；和
    (4)第四溶液，所述第四溶液为0.0001M的烟酸甲酯溶液。
  7. 如权利要求1所述的试剂组合的用途，其特征在于，所述的试剂盒还包括以下判断标准的说明：
    (1)0.1M烟酸甲酯溶液浓度下5min分数为0时，提示所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
    (2)当受测者为男性，且总分<19或0.1M烟酸甲酯溶液浓度下15min打分<3时，提示所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；和/或
    (3)当受测者为女性，且总分<13或0.1M烟酸甲酯溶液浓度下15min打分<2.5时，提示所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
  8. 如权利要求1所述的试剂组合的用途，其特征在于，所述的试剂盒还包括以下判断标准的说明：
    (4)当受测者为疑似SZ和MD患者，若0.1M烟酸甲酯溶液浓度下15min打分<2.5且全部打分总和<20，则提示该受测者患有精神分裂症；和/或
    (5)当受测者为疑似SZ和MD患者，若0.1M烟酸甲酯溶液浓度下15min打分≥2.5和/或全部打分总和≥20，则提示该受测者患有情感障碍。
  9. 一种用于筛查精神疾病的试剂盒，其特征在于，所述试剂盒含有：
    (a)第一容器，以及位于所述第一容器内的第一溶液，所述第一溶液为0.08-0.12M的烟酸化合物溶液；
    第二容器，以及位于所述第二容器内的第二溶液，所述第二溶液为0.008-0.012M的烟酸化合物溶液；
    第三容器，以及位于所述第三容器内的第三溶液，所述第三溶液为0.0008-0.0012M的烟酸化合物溶液；
    任选的第四容器，以及位于所述第四容器内的第四溶液，所述第四溶液为0.00008-0.00012M的烟酸化合物溶液；和
    (b)标签或说明书。
  10. 如权利要求9所述的试剂盒，其特征在于，所述试剂盒还包括载体，所述载体包括测试区，其中所述测试区含有至少4个分别浸有所述第一、第二、第三、和第四溶液的贴片。
  11. 一种检测精神疾病的方法，其特征在于，所述方法包括步骤：
    (i)提供一烟酸化合物溶液(如烟酸甲酯溶液)，其中所述烟酸甲酯溶液的浓度为0.08-0.12M；和
    (ii)将受测者的皮肤与所述烟酸化合物溶液(如烟酸甲酯溶液)接触0.5-2分钟后停止接触，然后停止接触后第5分钟后检测皮肤的红肿情况，如果无红肿则提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
  12. 一种检测精神疾病的方法，其特征在于，所述方法包括步骤：
    a)提供一如权利要求9所述的试剂盒；和
    b)将受测者皮肤在分别与所述第一、第二、第三和第四溶液接触0.5-2分 钟后停止接触，然后停止接触后第5分钟、10分钟、15分钟和20分钟时对皮肤的红肿情况打分：没有红肿反应为0分，部分红肿反应为1分，接触面积内完全红肿反应为2分，红肿反应超出接触面积为3分；其中
    当受测者为男性，且总分<19或0.1M烟酸甲酯溶液浓度下15min打分<3时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群；
    当受测者为女性，且总分<13或0.1M烟酸甲酯溶液浓度下15min打分<2.5时，提示(或辅助性诊断)所述受测者患有精神疾病或精神疾病发病的机率高于正常人群。
  13. 一种区分受测者是否患有精神分裂症和情感障碍的方法，其特征在于，所述方法包括步骤：
    a)提供一如权利要求9所述的试剂盒；和
    b)将受测者皮肤在分别与所述第一、第二、第三和第四溶液接触0.5-2分钟后停止接触，然后停止接触后第5分钟、10分钟、15分钟和20分钟时对皮肤的红肿情况打分：没有红肿反应为0分，部分红肿反应为1分，接触面积内完全红肿反应为2分，红肿反应超出接触面积为3分；其中
    当受测者为疑似SZ和MD患者，若0.1M AMN浓度下15min打分<2.5且全部打分总和<20，则提示(或辅助性诊断)该受测者患有精神分裂症或精神分裂症发病的机率高于正常人群；
    当受测者为疑似SZ和MD患者，若0.1M AMN浓度下15min打分≥2.5和/或全部打分总和≥20，则提示(或辅助性诊断)该受测者患有情感障碍或情感障碍发病的机率高于正常人群。
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