Application of coprophilous fungus transplantation in depressive disorder treatment

Abstract

The invention relates to application of fecal microbe transplantation (FMT) in depressive disorder treatment, in particular to application of a fecal microbe transplantation (FMT) composition based on a human intestinal tract fecal microbe composition in depressive disorder treatment. The invention also relates to application of the pharmaceutical composition or the medicine box in preparation of a medicine for treating depressive disorder, and the pharmaceutical composition or the medicine box contains a therapeutically effective amount of the human intestinal tract coprophilous fungus composition.

Description

Technical Field

[0001] The present invention relates to the field of treatment of mental illness, and particularly to the application of fecal microbiota transplantation (FMT) in the treatment of depressive disorders, and in particular to the application of fecal microbiota transplantation (FMT) based on a human intestinal fecal microbiota composition in the treatment of depressive disorders. Background Art

[0002] Depressive disorder (DD) is a common and serious mental illness that affects more than 264 million people worldwide, significantly impairs patients' function and quality of life, and has a high prevalence, high misdiagnosis rate, and high disability rate. Current clinical treatment mainly relies on medication, but the therapeutic effect of first-line antidepressants is unsatisfactory, with a treatment remission rate of less than 1 / 3 and an effective rate of only 50%. Among them, 35% of patients will develop refractory depressive disorder, resulting in poor patient compliance, high relapse rate, increased risk of suicide and disability, and further causing social and economic burdens. Therefore, the development of new diagnostic and treatment technologies is an important direction in the field of depressive disorders.

[0003] In recent years, more and more studies have focused on the biochemical signal transmission between the intestine and the central nervous system, namely the "microbiome-gut-brain axis" (MGBA). Intestinal microorganisms are the largest and most direct external environment of the human body. Their number far exceeds that of human cells, and the number of genes is 150 times that of human genes. Intestinal microorganisms establish a two-way information exchange network with the brain through the "gut-brain" axis to regulate the functions of the autonomic nervous system, immune system, enteroendocrine signals, neurotransmitters, etc. Many studies have shown that there is a correlation between the imbalance of intestinal microorganisms and depressive disorders. Dysfunction of the "gut-brain" axis can cause depressive disorders, autism, schizophrenia, bipolar disorder and other diseases. The composition of the intestinal flora of patients with depressive disorders is often abnormal, with an increased proportion of harmful flora or a decrease in beneficial flora. This flora imbalance may be associated with depressive symptoms because the gut-brain axis is a two-way information pathway involving multiple communication mechanisms such as metabolites, the immune system and the vagus nerve. Accordingly, regulating the "gut-brain" axis can also alleviate the symptoms of depressive disorders.

[0004] Methods for changing the intestinal flora include supplementing with prebiotics, probiotics, postbiotics, or performing fecal microbiota transplants (FMT). In preclinical studies, scientists obtained fecal samples from patients with depressive disorders and transplanted them into germ-free mice, and the results showed that the mice exhibited depressive-like behaviors. Zheng et al. found that mice that received intestinal microbiota transplants from patients with depressive disorders showed more depressive-like behaviors than mice that received microbiota transplants from healthy people. The study linked these behaviors to changes in carbohydrate and amino acid metabolism in mice [Zheng et al., 2016]. Hanuschak et al. transplanted fecal samples from patients with depressive disorders into germ-free mice, and the mice exhibited depressive-like behaviors, and found that some specific bacteria were associated with this behavior. However, the researchers also found that combining samples from different patients weakened these effects [Hanuschak et al., 2020]. Similarly, in 2020, Medina-Rodriguez et al. transplanted the intestinal flora of mice with learned helplessness behavior into another group of mice and found that the recipient mice also exhibited depressive-like behavior [Medina-Rodriguez et al., 2020].

[0005] These phenomena have attracted researchers' attention to the potential of FMT. There is a close connection between intestinal microbes and depressive disorders. By adjusting intestinal microbes and transplanting fecal microbes from healthy people into patients with depressive disorders, it may help alleviate depressive symptoms. The core concept of FMT is to reconstruct the patient's intestinal flora and restore the ecological balance of intestinal microbes by transplanting healthy intestinal flora from donors into patients.

[0006] FMT has been shown to have significant therapeutic effects on recurrent Clostridium difficile infections. However, FMT research for depressive disorders is still very limited, with only individual case reports. In this context, the present invention provides an FMT technology based on a human intestinal fecal bacteria composition, which systematically evaluates its effect in the auxiliary treatment of patients with moderate to severe depressive disorders through randomized, double-blind, placebo-controlled experiments. This program aims to transplant the intestinal flora of healthy people to patients with depressive disorders, provide objective evidence for the therapeutic effect of FMT combined with antidepressants, and thus provide a new method for the clinical treatment of depressive disorders. Summary of the invention

[0007] The present invention provides use of a composition or a medicine kit in preparing a medicine for treating depressive disorders, wherein the composition or the medicine kit comprises a therapeutically effective amount of a human intestinal fecal bacteria composition.

[0008] Depression is a common mental health disorder that affects millions of people worldwide, and its treatment mainly relies on medication and psychotherapy. However, traditional antidepressants are not always effective for all patients and are often accompanied by side effects. In recent years, scientific research has revealed the complex interaction between intestinal microorganisms and brain function, the so-called "gut-brain axis", which provides new perspectives and methods for the treatment of depressive disorders.

[0009] The composition or medicine kit containing the bacterial flora preparation provided by the present invention can be used to treat depressive disorders.

[0010] The bacterial flora contained in the composition or kit of the present invention is screened from healthy donors and is strictly processed and tested to ensure its safety and effectiveness. The innovation of this method is that it not only indirectly regulates the patient's mood and cognitive function by improving the intestinal microbiome, but also enhances the therapeutic effect by combining it with antidepressants. The bacterial flora contained in the preparation includes muciniphila-Eckermanniella, Bacteroides dornoni, etc., which have been shown to have potential benefits in regulating mood.

[0011] In one embodiment, the flora contained in the oral flora preparation of the present invention includes but is not limited to: Eckermannia muciniphila; Bacteroides dornoni; Bacteroides ovatus; Bacteroides xylanisolvens; Bifidobacterium adolescentis; Bifidobacterium bifidum; Bifidobacterium breve; Bifidobacterium longum; Bifidobacterium animalis; Eubacterium hallii; Faecalibacterium prausnitzii; Lactobacillus acidophilus; Lactobacillus crispatus; Lactobacillus reuteri; Lactobacillus rhamnosus; Lactobacillus salivarius; Lactobacillus bulgaricus; Lactobacillus fermentum; Lactobacillus plantarum; Lactococcus lactis; Parabacteroides gordonii; Streptococcus salivarius or Streptococcus thermophilus.

[0012] Furthermore, the composition or medicine kit of the present invention further comprises a therapeutically effective amount of other drugs.

[0013] In one embodiment, the therapeutically effective amount of other drugs is an antidepressant, such as escitalopram. In one embodiment, the therapeutically effective amount of the oral flora preparation of the present invention has active ingredients derived from healthy human intestinal flora.

[0014] In a preferred embodiment, the intestinal flora excludes pathogenic microorganisms during the donor screening and sample testing stages;

[0015] Preferably, the donor screening process includes physical examination, virus screening, medical history review and intestinal flora testing to ensure that the donor has no infectious diseases, metabolic syndrome, gastrointestinal diseases and neurological or neurodevelopmental problems;

[0016] Preferably, the pathogenic microorganisms include but are not limited to parasites, pathogenic bacteria and viruses;

[0017] Preferably, the parasites include but are not limited to Cryptosporidium, Giardia, hookworms, tapeworms, Toxoplasma, or Amoeba;

[0018] Preferably, the pathogenic bacteria include but are not limited to Clostridioides difficile, Salmonella spp., methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli O157:H7, Shigella, Klebsiella pneumoniae, Streptococcus pneumoniae, Mycobacterium tuberculosis or Pseudomonas aeruginosa, etc.;

[0019] Preferably, the virus includes but is not limited to HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus (HTLV), norovirus, human papillomavirus (HPV), herpes virus (HSV-1, HSV-2, VZV) or respiratory syncytial virus (RSV) and the like.

[0020] In one embodiment, the donor is between 18 and 30 years old and has a body mass index (BMI) between 18.5 and 23.9 kg / m 2 within the range.

[0021] In one embodiment, the donor's blood test results, including blood routine, liver and kidney function, electrolytes, and C-reactive protein, remain normal.

[0022] In one embodiment, the donor's stool routine examination is normal, without the presence of Clostridium difficile, Salmonella, Shigella, pathogenic Vibrio, ova, parasites, Yersinia enterocolitica, etc., and the Helicobacter pylori test in the stool should also be negative.

[0023] In one embodiment, the donor needs to conduct self-assessment using tools such as the Self-Rating Depression Scale, the Self-Rating Anxiety Scale, and the Pittsburgh Sleep Quality Index, and be interviewed by a psychologist or counselor to ensure that the donor is in a good mental state.

[0024] In one embodiment, the donor has not experienced intestinal discomfort in the past two weeks and has not used antibiotics or immunosuppressants in the past three months. The donor should have a regular work and rest schedule and healthy eating habits, no bad sexual behavior, no smoking, drinking, drug abuse and other hobbies, and no drug addiction. In addition, the donor has no family history of genetic diseases, such as intestinal lesions, malignant tumors, infectious diseases, etc. It is also necessary to ensure that the donor is not menstruating or pregnant.

[0025] In one embodiment, the donor's flora is stable. The composition and diversity of the flora are ensured to remain stable through fecal microbial genome testing. Five days before providing feces, the donor needs to adjust his diet to avoid high-sugar, high-fat and irritating foods, and test the tolerance of food restriction through food restriction experiments to avoid the recipient's food allergy or intolerance affecting the treatment effect.

[0026] In one embodiment, the human intestinal fecal bacteria composition of the present invention includes but is not limited to tablets, capsules, powders, granules, solutions, and lozenges.

[0027] In one embodiment, the human intestinal fecal bacteria composition of the present invention is an oral flora capsule.

[0028] In one embodiment, the preparation of the oral flora capsule of the present invention comprises the following steps:

[0029] Fecal samples collected from healthy donors are screened to remove bulky impurities and non-bacterial components;

[0030] A three-stage separation technology is used to finely extract intestinal microorganisms. This technology involves preliminary, step-by-step, high-speed centrifugation and filtration steps to effectively separate and concentrate the target flora, while removing fine suspended matter and soluble impurities to ensure the purity and activity of the resulting flora;

[0031] To the concentrated clean intestinal microorganisms after centrifugal filtration, a preparation auxiliary liquid is added, which includes betaine, glucose, sodium chloride (NaCl), ascorbic acid, D-sorbitol, skimmed milk, and HEPES (4-hydroxyethylpiperazineethanesulfonic acid).

[0032] After mixing, freeze-drying is performed to obtain a freeze-dried preparation of intestinal flora.

[0033] Purified bacterial flora are encapsulated in capsules under sterile conditions through vacuum-sealed packaging to ensure that they are free of debris and odor during storage and transportation, extending the shelf life of the product and maintaining its therapeutic efficacy.

[0034] In one embodiment, the present invention provides a detailed treatment plan that optimizes the treatment effect of depressive disorders through a staged treatment process.

[0035] In one embodiment, the initial treatment phase uses a human intestinal fecal bacteria composition and antidepressants to rapidly improve the patient's depression and anxiety symptoms. This phase aims to achieve rapid relief of depression and anxiety symptoms through the regulatory effects of intestinal microorganisms and the synergistic effects of antidepressants.

[0036] In one embodiment, the patient's symptoms are regularly evaluated during the evaluation and adjustment phase, and the drug dosage is adjusted according to the actual efficacy and tolerability to ensure the effectiveness and individual adaptability of the treatment. After the initial treatment phase, that is, at the end of the second week, the patient's depression and anxiety symptoms are evaluated in detail using scales such as HAMD-17, QIDS-SR16, and GAD-7. The dose of escitalopram is adjusted according to the evaluation results, with an adjustment range of 10-20 mg / day, and the specific dose will be determined based on the patient's symptom improvement and drug tolerance. The purpose of this stage is to optimize the treatment plan through personalized adjustments, maximize efficacy, and reduce adverse reactions.

[0037] In one embodiment, the maintenance treatment phase continues treatment and monitoring to stabilize the efficacy, prevent symptom recurrence, and improve the patient's quality of life. From the end of the evaluation and adjustment phase, that is, from the third week, the patient will continue to maintain the adjusted escitalopram dose and conduct regular symptom assessments every 2 weeks. This phase of treatment will last for 6 weeks, and long-term drug management and symptom monitoring will ensure that the patient is in a stable state throughout the treatment period. The maintenance treatment phase aims to consolidate the effects of the initial treatment, prevent the recurrence of depression and anxiety symptoms, and continue to pay attention to the patient's overall health status to ensure long-term efficacy and safety.

[0038] In one embodiment, the composition or kit of the present invention adopts the following administration regimen:

[0039] The daily dosage of the human intestinal fecal bacteria composition is 0.84 grams, and two capsules are taken on an empty stomach with breakfast for 2 consecutive weeks.

[0040] In one embodiment, the composition or kit of the present invention adopts the following administration regimen:

[0041] The starting dose of escitalopram is 5 mg / day, which is increased to 10 mg / day on the 5th day of treatment and maintained until the end of the 2nd week; for the following 6 weeks, the escitalopram dose is maintained at 10-20 mg / day.

[0042] In one embodiment, the composition or kit of the present invention can be used in combination with one or more of the following schemes:

[0043] For patients with severe insomnia, benzodiazepines (eszolam ≤ 2 mg / night, alprazolam ≤ 0.8 mg / night, lorazepam ≤ 1 mg / night, oxazepam ≤ 30 mg / night) or non-benzodiazepines (zolpidem ≤ 10 mg / night, zopiclone ≤ 7.5 mg / night) can be used for treatment, but they cannot be used continuously for more than 2 weeks. The above drugs should be avoided 8 hours before the assessment.

[0044] For anxiety or agitation, temporary oral administration of lorazepam (≤3 mg / d) or oxazepam (≤45 mg / d) is recommended. It can only be used temporarily when necessary. Continuous use and preventive medication are not recommended. Avoid using the above drugs 8 hours before the assessment.

[0045] For general physical diseases, symptomatic treatment can be given; it is recommended that the type and dosage of therapeutic drugs remain unchanged during the study.

[0046] The present invention verifies the effect of the composition or kit through randomized, double-blind, controlled clinical trials. Studies have shown that on multiple depression and anxiety rating scales such as HAMD-17, QIDS-SR16, and GAD-7, the experimental group using oral flora capsules showed significant improvement compared with the placebo group. This result demonstrates the potential of intestinal microbial regulation strategies in the treatment of depressive disorders and their clinical application value, which not only reflects the potential of flora capsules in the traditional treatment of depression symptoms, but also reveals its comprehensive effect in regulating emotions and improving physiological functions.

[0047] The composition or medicine kit of the present invention shows good effects on improving depressive disorders, anxiety symptoms and generalized anxiety symptoms in a short period of time, and can quickly improve depressive symptoms.

[0048] On the other hand, the composition or kit of the present invention is suitable for alleviating various mood and cognitive dysfunctions associated with intestinal microbial imbalance, including but not limited to anxiety or cognitive impairment.

[0049] In one embodiment, the pharmaceutical composition or kit is suitable for alleviating a variety of mood and cognitive dysfunctions, including but not limited to anxiety disorders or cognitive disorders.

[0050] In one embodiment, the pharmaceutical composition or kit can rapidly alleviate a variety of mood and cognitive dysfunctions, including but not limited to anxiety or cognitive disorders;

[0051] In one embodiment, the pharmaceutical composition or kit can rapidly alleviate a variety of mood and cognitive dysfunctions, including but not limited to anxiety disorders or cognitive disorders, within 2 weeks after treatment.

[0052] In one embodiment, the multiple mood and cognitive dysfunctions are associated with gut microbial dysbiosis.

[0053] The present invention is not only suitable for the treatment of depressive disorders, but also for alleviating a variety of mood and cognitive dysfunctions associated with intestinal microbial imbalance, including anxiety or cognitive impairment. This expands its application range in the fields of mental health and neuroscience. Due to the complex two-way communication mechanism between intestinal microorganisms and the central nervous system, the "gut-brain axis", oral flora capsules are also expected to be used to treat cognitive dysfunction caused by neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Studies have shown that patients with the above-mentioned diseases are often accompanied by intestinal microbial imbalance, and regulating intestinal microorganisms may help with symptoms. The therapeutic effect of oral flora capsules is not limited to alleviating psychological symptoms. Its direct benefits to intestinal health may also improve other clinical symptoms related to intestinal dysfunction, such as irritable bowel syndrome (IBS) and chronic inflammatory bowel disease (IBD), which are often highly comorbid with mood disorders.

[0054] In one embodiment, the therapeutically effective amount of other drugs of the present invention further comprises:

[0055] benzodiazepines or nonbenzodiazepines;

[0056] Preferably, the benzodiazepine is selected from:

[0057] estazolam, alprazolam, lorazepam, or oxazepam;

[0058] Preferably, the non-benzodiazepine drug is selected from:

[0059] Zolpidem or zopiclone;

[0060] Preferably, the therapeutically effective amount of other drugs and the therapeutically effective amount further include:

[0061] Lorazepam or oxazepam.

[0062] In one embodiment, the composition or kit of the present invention comprises 0.5-1.0 g of a human intestinal fecal bacteria composition;

[0063] Preferably, the therapeutically effective amount of the human intestinal fecal bacteria composition is as follows:

[0064] The daily dose is 0.84 g, taken on an empty stomach with breakfast, for 2 weeks;

[0065] Preferably, the composition or kit further comprises 0-50 mg of a therapeutically effective amount of other drugs;

[0066] Preferably, the therapeutically effective amount of the other drug is escitalopram, and the therapeutically effective amount is as follows:

[0067] The initial dose is 5 mg / day, which is increased to 10 mg / day on the fifth day of treatment and maintained until the end of the second week. For the next 6 weeks, the escitalopram dose is maintained at 10-20 mg / day.

[0068] Preferably, the therapeutically effective amount of other drugs further comprises benzodiazepines, and the therapeutically effective amount is as follows:

[0069] Estazolam ≤2 mg / night, alprazolam ≤0.8 mg / night, lorazepam ≤1 mg / night, oxazepam ≤30 mg / night;

[0070] Preferably, the therapeutically effective amount of other drugs further comprises non-benzodiazepine drugs, and the therapeutically effective amount is as follows:

[0071] Zolpidem ≤10 mg / night, zopiclone ≤7.5 mg / night;

[0072] Preferably, the therapeutically effective amount of other drugs further comprises lorazepam or oxazepam, and the therapeutically effective amount is as follows:

[0073] Lorazepam ≤ 3 mg / day or oxazepam ≤ 45 mg / day.

[0074] In one embodiment, the therapeutically effective amount of the human intestinal fecal bacteria composition of the present invention and the therapeutically effective amount of other drugs can be administered simultaneously, separately or sequentially.

[0075] Another aspect of the present invention provides a product set, wherein the set comprises a therapeutically effective amount of oral flora capsules and a therapeutically effective amount of other drugs.

[0076] Preferably, the therapeutically effective amount of other drugs is a therapeutically effective amount of antidepressant drugs;

[0077] Preferably, the therapeutically effective amount of the antidepressant drug is a therapeutically effective amount of escitalopram;

[0078] The product set of the present invention further comprises instructions for use, which include the therapeutically effective amount, the administration method or the application.

[0079] The present invention has the following significant advantages:

[0080] 1. Verification by randomized, double-blind, controlled trials: The FMT human intestinal fecal bacteria composition in the present invention has undergone rigorous randomized, double-blind, controlled trial research, showing that in the difference in scores of HAMD-17 (Hamilton Depression Rating Scale), QIDS-SR16 (Quick Inventory of Depressive Symptomatology Self-Report), GAD-7 (Generalized Anxiety Disorder 7-item scale), HAMD-6 (Hamilton Depression Rating Scale 6-item), and HAMD-17 anxiety / somatic symptoms, the experimental group had significant differences compared with the placebo, proving its effectiveness in improving depressive symptoms.

[0081] 2. Applicability to multiple symptoms and patient types: The present invention is not only applicable to the treatment of depressive disorders, but also to the alleviation of a variety of mood and cognitive dysfunctions associated with intestinal microbial imbalance, including anxiety or cognitive impairment, etc. This expands its application scope in the fields of mental health and neuroscience.

[0082] 3. Application scheme of combined antidepressant drugs: The composition or medicine kit of the present invention also contains antidepressants, such as escitalopram, to enhance the therapeutic effect. The combined medication scheme utilizes the unique role of the human intestinal fecal bacteria composition in regulating intestinal flora and improving neurotransmitter levels, combined with the mechanism of antidepressants to increase the concentration of 5-hydroxytryptamine in the synaptic cleft, to form a synergistic effect and quickly relieve depression and anxiety symptoms. This innovative method not only improves the efficacy of a single treatment method, but also proves its safety and tolerability through clinical trials. Compared with the prior art, the combined medication scheme of the present application shows more significant efficacy and faster onset time in improving depressive symptoms, proving its unique advantages in the treatment of depressive disorders.

[0083] 4. Detailed treatment plan: The present invention proposes a systematic and personalized detailed treatment plan, including an initial treatment stage, an evaluation and adjustment stage, and a maintenance treatment stage. In the initial treatment stage, the human intestinal fecal bacteria composition and antidepressant drugs are used in combination to quickly take effect and significantly improve the patient's depression and anxiety symptoms. In the evaluation and adjustment stage, the patient's symptoms are regularly evaluated, and the drug dosage is adjusted according to the actual efficacy and tolerability to ensure the effectiveness and individual adaptability of the treatment. In the final maintenance treatment stage, continuous treatment and monitoring are used to stabilize the efficacy, prevent symptom recurrence, and improve the patient's quality of life. Through this phased treatment plan, the present application not only optimizes the treatment process, but also realizes personalized treatment, significantly improving the overall efficacy and quality of life of the patient. This systematic method has not been reported in the prior art, reflecting the significant progress and creativity of the present application in the treatment of depressive disorders.

[0084] In summary, the present invention not only provides a new treatment option for depression through an innovative treatment scheme, but also may provide treatment possibilities for other mood and cognitive dysfunctions related to intestinal microbial imbalance, such as anxiety or cognitive impairment. The development and application of this method heralds a major advancement in the field of mental health treatment and provides new directions and hopes for future treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Figures 1 to 5 The difference in scores of each symptom scale between the experimental group (FMT group) and the control group (placebo group) before and after treatment is shown, where:

[0086] Figure 1 The differences in HAMD-17 scores are shown.

[0087] Figure 2 The differences in HAMD-6 scores are shown.

[0088] Figure 3 Shown are the differences in HAMD-17 anxiety / somatic symptom scores.

[0089] Figure 4 QIDS-SR16 score differences are shown.

[0090] Figure 5 GAD-7 score differences are shown.

[0091] Related definitions

[0092] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0093] As used herein, the term "depressive disorder (DD)" refers to a common and serious mental illness that affects more than 264 million people worldwide. This disease significantly impairs the patient's function and quality of life, and has a high prevalence, high misdiagnosis rate, and high disability rate. Depressive disorder is associated with individual psychological, physiological, and social dysfunction, and is often accompanied by symptoms such as low mood, loss of interest, and decreased energy.

[0094] As used herein, the term "fecal microbiota transplant (FMT)" refers to a treatment method in which the intestinal flora of healthy people is transplanted into patients with depressive disorders to adjust the intestinal microorganisms and help relieve depressive symptoms. In recent years, FMT has shown potential as an adjuvant treatment to improve depressive symptoms, especially when traditional antidepressant treatments are ineffective. However, the safety and long-term effects of FMT still need to be verified through more clinical trials.

[0095] As used herein, the term "microbial preparation" refers to a preparation containing intestinal flora selected from healthy donors, which has been strictly processed and tested to improve the intestinal microbial composition of patients and to enhance the therapeutic effect in combination with antidepressant drugs. This method uses oral form to conveniently deliver beneficial intestinal flora, aiming to improve the patient's mental health level by adjusting the intestinal environment.

[0096] As used herein, the term "gut-brain axis" refers to a complex network of interactions between intestinal microbes and the brain, involving the autonomic nervous system, immune system, endocrine signaling, and neurotransmitters. Dysfunction of this axis is associated with a variety of psychiatric disorders, including depressive disorders. Studies have shown that this axis can be intervened by adjusting the intestinal flora, which may improve the symptoms of neuropsychiatric diseases such as depressive disorders.

[0097] As used herein, the term "gut microbiota" refers to the complex microbial community living in the human intestine, including bacteria, fungi, viruses, and protozoa, which has a profound impact on human health and disease. The gut microbiota affects nutrient absorption, immune function, and even behavioral performance through interactions with the host.

[0098] As used herein, the term "antidepressant combination therapy" refers to the combined use of antidepressants with other treatment options, such as microbiome preparations, to provide new treatment options for patients who do not respond well to traditional antidepressant treatments. This combination therapy strategy aims to enhance the therapeutic effect through multiple mechanisms of action.

[0099] As used herein, the term "donor" refers to a healthy individual provided for fecal microbiota transplantation or preparation of microbiota preparations. The selection of donors is very critical, and it is necessary to ensure that they have no infectious diseases, no chronic diseases, and their intestinal flora is in a healthy state. The donor's intestinal flora is transferred to the patient through a specific treatment process, aiming to improve the patient's symptoms through the transfer of this microbiome.

[0100] As used herein, the term "donor screening" refers to a series of physical examinations, virus screening, medical history review, and intestinal flora testing to ensure that the donor is healthy and free of infectious diseases, metabolic syndrome, gastrointestinal diseases, and neurological or neurodevelopmental problems. This process includes a detailed medical evaluation and laboratory testing of potential donors to rule out various possible health risks and ensure the quality and safety of the donor's flora.

[0101] As used herein, the term "randomization" refers to the random assignment of study participants to different treatment groups in clinical trials to ensure objectivity and reduce bias in trial results. This method can effectively balance potential variables between groups, thereby improving the reliability and validity of the study.

[0102] As used herein, the term "double-blind" refers to a clinical trial in which neither the researchers nor the participants know which participants received the experimental drug or the placebo. This design is used to prevent the experimental results from being influenced by subjective expectations. The double-blind method is an important research design that aims to eliminate bias in the research process and ensure the objectivity and scientificity of the data.

[0103] As used herein, the term "Hamilton Depression Rating Scale (HAMD-17)" refers to a scale widely used in clinical and research to assess the severity of symptoms in patients with depressive disorders. The scale contains 17 items covering multiple aspects such as mood, insomnia, anxiety, etc. HAMD-17 is scored by psychologists based on the patient's experience of depressive symptoms in the past week and is widely regarded as the "gold standard" for assessing the severity of depression.

[0104] As used herein, the term "QIDS-SR16 (Quick Inventory of Depressive Symptomatology Self-Report)" refers to a self-assessment scale for quickly assessing the presence and severity of depressive symptoms, which contains 16 questions covering aspects such as sleep, mood, and appetite. It allows patients to self-assess their depressive symptoms in the past week to quickly understand changes in symptoms and treatment responses.

[0105] As used herein, the term "GAD-7 (Generalized Anxiety Disorder 7-item scale)" refers to a concise self-rating scale specifically used to assess and monitor the severity of generalized anxiety disorder, which contains 7 items. It is a tool designed to quickly screen the severity of anxiety and monitor the effectiveness of treatment.

[0106] As used herein, the term "Hamilton Depression Rating Scale 6-item (HAMD-6)" refers to a shortened version of the HAMD-17 scale, which contains 6 core items for assessing the main symptoms of depressive disorders. This shortened version focuses on assessing the most common and most diagnostically valuable depressive symptoms, facilitating rapid assessment.

[0107] As used herein, the term "HAMD-17 anxiety / somatic symptoms" refers to the part of the HAMD-17 scale specifically used to assess anxiety and somatic related symptoms. These items include assessments of anxiety, somatic discomfort, and other non-emotional symptoms of patients, helping clinicians to fully understand the patient's state. DETAILED DESCRIPTION

[0108] To verify the application of the composition or kit of the present invention in the treatment / relief of depressive symptoms, a randomized, double-blind, controlled trial design was adopted, and 60 patients with depressive disorders who met the criteria were included. The study was divided into a randomized intervention period and a follow-up treatment period for a total of 8 weeks. Randomized intervention period: The study was randomly divided into an experimental group and a control group (according to 1:1, 30 cases in each group), and escitalopram plus FMT (flora preparation) and escitalopram plus placebo were used for treatment, respectively, and the intervention period was 2 weeks. Both groups of patients continued to maintain escitalopram monotherapy for 6 weeks and were followed up to the end of the 8th week.

[0109] Subject inclusion criteria

[0110] Inclusion criteria (all 6 items must be met):

[0111] a. Meet the diagnostic criteria for depression in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), either first episode or relapse, without psychotic symptoms;

[0112] b. Age range: 18-65 years old, regardless of gender;

[0113] c. BMI is within the normal range (18-24 kg / m2);

[0114] d. Not taking antidepressant medication for at least 14 days before enrollment (patients treated with fluoxetine before enrollment should stop taking it for at least 28 days);

[0115] e. The score of 17-item Hamilton Depression Rating Scale (HAMD-17) at screening and baseline was ≥17 points;

[0116] f. The subjects are able to understand and comply with the study requirements and sign the informed consent form.

[0117] Exclusion criteria (one of the criteria is sufficient to exclude):

[0118] a. Subjects who are currently or have been diagnosed with disorders other than depressive disorder according to the MINI diagnostic criteria;

[0119] b. Current or past substance abuse;

[0120] c. The patient currently has a serious suicide risk, with a HAMD-17 suicide risk item score of ≥ 3 points;

[0121] d. This depressive episode is accompanied by psychotic symptoms;

[0122] e. Subjects with unstable physical illnesses who require medication or surgery;

[0123] f. Suffering from inflammation-related diseases;

[0124] g. Suffering from gastrointestinal infections, tumors and other organic diseases of the digestive tract with structural abnormalities, including but not limited to irritable bowel syndrome, Crohn's disease, ulcerative colitis, celiac disease, etc.;

[0125] h. History of gastrointestinal surgery;

[0126] i. Continuous use of antibiotics, probiotics or prebiotics products for medical purposes for more than 2 weeks within 3 months before entering the study;

[0127] j. Those who have been allergic to escitalopram or have had no effect on it;

[0128] k. Those who are allergic to the capsule ingredients and contents;

[0129] l. Patients who are currently using antipsychotics, antidepressants and mood stabilizers with a washout period of less than 5 half-lives before baseline;

[0130] m. Patients who are pregnant or breastfeeding;

[0131] n. Patients who are unable (such as difficulty swallowing) or unwilling to swallow capsules;

[0132] o. Patients who have received MECT treatment in the past six months.

[0133] Exit / Termination Criteria:

[0134] a. Those who have serious adverse events or request to stop taking the drug due to adverse events;

[0135] b. Those who withdraw informed consent;

[0136] c. Lost to follow-up;

[0137] d. Those who the researcher believes should be withdrawn for safety reasons;

[0138] e. Poor compliance (compliance with study drug or control drug <80% or >120%; compliance with behavioral training <80% or >120%);

[0139] f. Other situations that the researchers consider inappropriate to continue the research.

[0140] Experimental Grouping

[0141] Grouping criteria:

[0142] This study adopted a randomized, double-blind, controlled trial design. According to the randomization and blinding rules, the subjects who met the inclusion criteria were randomly divided into an experimental group and a control group (1:1, 30 cases in each group), and escitalopram plus FMT (intestinal flora extract flora preparation) and escitalopram plus placebo were used for treatment, respectively.

[0143] Experimental group (FMT group): From the baseline, the subjects were given 0.84 g / day of the flora preparation, two capsules orally taken on an empty stomach with breakfast, for 2 consecutive weeks.

[0144] Control group (placebo group): From baseline, 0.84 g / day of placebo was administered, two capsules were taken orally on an empty stomach with breakfast, for 2 consecutive weeks.

[0145] Both groups started with escitalopram at 5 mg / d, which was increased to 10 mg / d on the 5th day of treatment and maintained at this dose until the end of the 2nd week. Escitalopram 10-20 mg / d was then given for the next 6 weeks (until the 8th week after treatment).

[0146] The manufacturer of the intervention drug intestinal flora extract preparation is Shenzhen Junchangyi Biotechnology Co., Ltd. The product name is intestinal flora extract capsules, and each capsule contains a total solid amount of intestinal flora extract of 0.42g. The preparation process refers to the patent ZL202010408501.9 of Shenzhen Rongsi Biotechnology Co., Ltd., a subsidiary of Shenzhen Junchangyi Biotechnology Co., Ltd.

[0147] The dosage is oral administration, on an empty stomach with breakfast, with warm water. Take 2 capsules once a day for 14 consecutive times (2 weeks).

[0148] The active ingredients of the intervention drug microbiota preparation are healthy human intestinal flora, and pathogenic microorganisms are excluded during the donor screening and sample testing stages. Representative species include, but are not limited to: Eckermannia muciniphila; Bacteroides dornini; Bacteroides ovatus; Bacteroides xylanisolvens; Bifidobacterium adolescentis; Bifidobacterium bifidum; Bifidobacterium breve; Bifidobacterium longum; Bifidobacterium animalis; Eubacterium hallii; Faecalibacterium prausnitzii; Lactobacillus acidophilus; Lactobacillus crispatus; Lactobacillus reuteri; Lactobacillus rhamnosus; Lactobacillus salivarius; Lactobacillus bulgaricus; Lactobacillus fermentum; Lactobacillus plantarum; Lactococcus lactis; Parabacteroides gordonii; Streptococcus salivarius; Streptococcus thermophilus.

[0149] The extraction of the bacterial liquid of the intervention drug flora capsule adopts a three-layer separation technology, which can accurately separate the pure bacterial liquid without impurities, ensure that the capsule has no odor and the appearance will not cause discomfort to patients, thereby improving patient acceptability.

[0150] The microbiota donors of intervention drug microbiota preparations have all undergone rigorous screening, including physical examination, virus screening, medical history review, intestinal microbiota testing and more than 80 other related tests, so as to exclude infectious diseases, metabolic syndrome, gastrointestinal diseases, neurological or neurodevelopmental problems and various potential pathogens. And the donor's physical condition will be retested regularly (6 months) to confirm the stability and safety of the donor's intestinal microbiota. In addition, a "donor-recipient" database has been established to match more suitable donor microbiota according to the imbalance of the recipient's microbiota, thereby improving the adaptability of the recipient. At present, the adverse events related to FMT reported in clinical studies are mostly abdominal discomfort, such as abdominal pain and constipation, and this adverse reaction disappears after stopping FMT.

[0151] The placebo capsules are starch capsules, and their administration method, specifications and appearance are consistent with those of the intervention drug flora capsules.

[0152] Follow-up treatment continued with escitalopram monotherapy until the end of the 8th week. The treatment dose was adjusted by the research physician according to the patient's condition and maintained at 10 mg / d-20 mg / d.

[0153] Prohibited drugs and treatments:

[0154] 1) During the clinical trial, any other antipsychotic drugs, antidepressants, antiepileptic drugs, mood stabilizers, and traditional Chinese medicines that have effects on the central nervous system are not allowed to be combined;

[0155] 2) During the trial period, it is prohibited to use antibiotics or anti-inflammatory drugs, probiotics, prebiotic products or foods (such as yogurt, sauerkraut, fermented bean curd, rice wine and other fermented products); if used, it should be recorded and the subjects should be removed from the group;

[0156] 3) During the trial period, electroconvulsive therapy, TMS therapy, acupuncture, light therapy, biofeedback therapy, vagus nerve stimulation and other treatments are prohibited;

[0157] 4) During the trial period, patients are prohibited from receiving systematic psychological treatment (psychoanalysis, cognitive insight, desensitization therapy, hypnosis therapy, Morita therapy), but general supportive psychological treatment is allowed.

[0158] Restrictions on concurrent use of drugs:

[0159] In the following cases, if confirmed to be necessary, the following drugs can be used in combination:

[0160] 1) For patients with severe insomnia, benzodiazepines (eszolam ≤ 2 mg / night, alprazolam ≤ 0.8 mg / night, lorazepam ≤ 1 mg / night, oxazepam ≤ 30 mg / night) or non-benzodiazepines (zolpidem ≤ 10 mg / night, zopiclone ≤ 7.5 mg / night) are allowed to treat insomnia, but they cannot be used continuously for more than 2 weeks. The above drugs should be avoided 8 hours before the assessment.

[0161] 2) If anxiety or agitation occurs, lorazepam (≤3 mg / d) or oxazepam (≤45 mg / d) may be temporarily taken orally. It can only be used temporarily when necessary. Continuous use and preventive medication are not recommended. Avoid using the above drugs 8 hours before the assessment.

[0162] 3) If patients have general physical diseases, symptomatic treatment may be given; it is recommended that the type and dosage of therapeutic drugs remain unchanged during the study.

[0163] Follow-up plan

[0164] This study used the Mini-International Neuropsychiatric Interview (MINI 7.0.2) as a diagnostic tool.

[0165] The case report form is used to collect the data. The content includes but is not limited to:

[0166] 1) General demographic information: date of birth, gender, height, weight, education level, marital status, work status, and place of residence;

[0167] 2) Past medical history: history of physical illness and mental illness, including family history of mental illness.

[0168] Clinical symptom data were collected using the following methods:

[0169] 1) 17-item Hamilton Rating Scale for Depression (HAMD-17): There are 17 items in total, and the total score can reflect the severity of depressive symptoms. The researchers will evaluate the patients at baseline, 2 weeks, 4 weeks, and 8 weeks.

[0170] 2) 7-item Generalized Anxiety Disorder-7 (GAD-7): The scale has 7 items that reflect the severity of anxiety symptoms. Patients self-assess at baseline, 2 weeks, 4 weeks, and 8 weeks.

[0171] 3) 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16): There are 16 items in total, which are scored from 0 to 3. It can quickly understand the degree of depression. The patients will self-assess at the baseline, 2 weeks, 4 weeks and 8 weeks.

[0172] 4) Young Mania Rating Scale (YMRS): There are 11 items in total, which are used to evaluate manic symptoms and severity. The researchers will evaluate the patients at baseline, 2 weeks, 4 weeks, and 8 weeks.

[0173] 5) Eating Behavior Questionnaire (EBQ): reflects the subjects’ recent living and eating conditions. The patients completed the paper version of the self-assessment at the baseline, 2 weeks and 8 weeks of the corresponding sample collection point.

[0174] 6) FIBSER (Frequency, Intensity, and Burden of Side Effects Rating): There are three items, which are scored from 0 to 6 to evaluate the frequency, intensity, and burden of side effects. The researchers will evaluate the patients at baseline, 2 weeks, 4 weeks, and 8 weeks.

[0175] Patients were given medication diary cards and asked to keep a record every day. The diary cards were collected at the next visit to record the subjects' medication use and the amount of returned medication since the last visit. Whether the patients took medication according to the doctor's instructions every day was assessed to determine the subjects' compliance (compliance = actual medication amount / should be taken x 100%).

[0176] During each visit, the patient is asked in detail whether he or she experiences any physical discomfort during medication treatment, the location and severity of the discomfort, and whether it is tolerable. The doctor determines the specific nature and whether it is related to the medication, and fills out the adverse event record form.

[0177] Efficacy and safety evaluation

[0178] Main efficacy evaluation:

[0179] The difference in remission rate (HAMD-17 ≤ 7 points) between the two groups after the follow-up period (8 weeks).

[0180] Secondary efficacy evaluation:

[0181] 1) After the follow-up period (8 weeks), the difference in effective rate (HAMD-17 score reduction rate ≥ 50%) between the two groups.

[0182] 2) The difference in effective rate (HAMD-17 score reduction rate ≥ 50%) between the two groups at the end of the 2-week double-blind treatment period;

[0183] 3) the change in the total score of the GAD-7 scale at each follow-up point relative to the total score at baseline;

[0184] 4) the change in the total score of the QIDS-SR scale at each follow-up point relative to the total score at baseline;

[0185] 5) Differences in the reduction values ​​of the HAMD-17 scale in the four different symptom dimensions of depression (1 / 2 / 3 / 7 / 8 items), anxiety (9 / 10 / 11 / 15 / 17 items), insomnia (4 / 5 / 6 items), and somatic (12 / 13 / 14 / 16 items) at each follow-up point;

[0186] Safety evaluation:

[0187] 1) Safety evaluation includes adverse event monitoring during treatment, clinical laboratory tests (blood routine, biochemical, urine routine), pregnancy test (for women of childbearing potential), electrocardiogram, vital signs, physical examination and body weight; to evaluate the safety of escitalopram added to FMT for the treatment of depressive disorders;

[0188] 2) Changes in symptoms and severity scores of the FIBSER scale at each follow-up point;

[0189] 3) Abnormal values ​​of vital signs, laboratory and electrocardiogram examinations during the study, and reports of adverse events and adverse reactions during the study.

[0190] Data and statistical analysis

[0191] The researcher completes the research medical record, which is self-checked by the researcher and quality controlled by the quality control personnel. After completion, the data entry clerk enters the data in the research medical record in a timely and accurate manner.

[0192] The data manager writes a logic verification plan based on the research plan and research medical records, and the final version is used after review and approval by the principal investigator. The data is verified according to the logic verification plan, and system questions are raised in real time. In addition to system questions, the data manager manually verifies the text data and raises manual questions when there are problems.

[0193] After all subjects complete the trial, all medical records are entered into the system. The principal investigator, statistical analyst, and data manager will review the data and confirm that the established database is correct. The data manager will then lock the data. After the data is locked, the data manager will export the data to the designated database and hand it over to the statistician for statistical analysis. The locked data cannot be edited. Problems found after the data is locked can be corrected in the statistical analysis program after confirmation. If there is definite evidence that it is necessary to unlock the data after it is locked, the consent of the principal investigator must be obtained.

[0194] Statistical analysis population:

[0195] 1) Full analysis set FAS: According to the intention-to-treat analysis principle, efficacy analysis was conducted on all cases that took the drug once and underwent at least one efficacy evaluation. For case data where the entire treatment process could not be observed, the last observation data were carried forward to the final outcome of the trial (LOCF).

[0196] 2) PPS-compliant: Meet the inclusion criteria, do not meet the exclusion criteria, complete the observation period treatment plan for at least 2 weeks, and do not use other evaluated drugs or treatment measures that may affect the efficacy during the trial. The efficacy evaluation of this study was conducted on the FAS and PPS data sets.

[0197] 3) Safety analysis set SS: All enrolled cases who have used the trial drug at least once and have safety records after taking the drug belong to the safety analysis set, which is used for safety analysis.

[0198] Statistical analysis methods:

[0199] General principles: The statistical analysis software used was SAS 9.4 based on Windows system. All numerical derivative variables were retained to two decimal places, unless otherwise specified; all statistical tests were two-sided tests, and the differences tested were considered statistically significant when the P value was less than or equal to 0.05 (unless otherwise specified).

[0200] The description of quantitative indicators calculated the number of cases (missing), mean, standard deviation, median, minimum and maximum values; the description of qualitative indicators calculated the number of cases (percentage), and the percentage was calculated based on the non-missing number in each analysis set; the change relative to baseline was defined as the post-treatment minus the baseline. Missing data were filled using LOCF as the main method, and the missing data at the end of treatment were carried forward using the last observation data before. The LOCF method was also used to fill missing data after baseline for both primary and secondary efficacy indicators.

[0201] Example 1

[0202] Example 1.1 Subject demographic information and pre-treatment symptom assessment

[0203] In this example, 60 patients with depressive disorders who met the inclusion criteria were included and randomly divided into a FMT combined with escitalopram treatment group (referred to as: FMT group) and a placebo T combined with escitalopram treatment group (referred to as: placebo group), and a symptom assessment was performed before treatment. The demographic and clinical data of the subjects are as follows (Table 1):

[0204] Table 1: Demographic and pre-treatment clinical data of the subjects

[0205]

[0206] Example 1.2 Comparison of efficacy of subjects after treatment

[0207] This example aims to analyze the depressive symptom assessment data of two groups of subjects during an 8-week treatment. Using the HAMD-17 scale as an assessment tool, the study focuses on two efficacy indicators: remission rate (HAMD-17 ≤ 7 points) and effective rate (HAMD-17 reduction rate ≥ 50%).

[0208] During the 8-week treatment, 2 subjects in the FMT group were lost to follow-up after 2 weeks of treatment, and another subject was lost to follow-up after 4 weeks of treatment; 1 subject in the placebo group was lost to follow-up after 4 weeks of treatment. Therefore, a total of 56 subjects' evaluation data were used for follow-up studies. No serious adverse reactions or gastrointestinal reactions were found in the two groups of subjects during the follow-up period. The dose of escitalopram in the two groups of subjects during the follow-up period is shown in Table 2:

[0209] Table 2: Escitalopram dosage in the FMT group and the placebo group

[0210]

[0211]

[0212] Note: Data are expressed in the form of number of people (percentage).

[0213] Both groups of subjects received 8 weeks of antidepressant treatment, and symptom assessment was performed before treatment and 2, 4, and 8 weeks after treatment. Calculation of HAMD-17 score for depression The difference in remission rate (HAMD-17 ≤ 7 points) between the two groups after the follow-up period (8 weeks) (primary efficacy indicator); and the difference in effective rate (HAMD-17 score reduction rate ≥ 50%) between the two groups at the end of the double-blind treatment period at the 2nd and 8th weekends (secondary efficacy indicator).

[0214] As shown in Table 3, the comparison between the two groups showed that at the end of the 8th week of treatment, the clinical remission rate of the FMT group was 43.3%, while that of the placebo group was 26.7%, and the FMT group had a good trend in efficacy; at the end of the 2nd week of treatment, the effective rate of the FMT group was significantly higher than that of the placebo group (30.0% vs. 6.7%), and the difference was statistically significant (P=0.0195), and the improvement was significantly better than that of the control group. This shows that in the early stage of treatment, the combination of the FMT group and escitalopram can accelerate the onset of the drug, so that the symptoms of the subjects can be improved and relieved faster.

[0215] Table 3: Remission rate and efficacy of subjects

[0216]

[0217] Note: *The difference between the two groups is expressed as percentage.

[0218] These results reveal the potential therapeutic effect of FMT on depressive symptoms in the short term, especially in the early stages of treatment. In addition, the rapid response to FMT treatment may indicate the important role of the gut-brain axis in the treatment of depressive disorders, especially in regulating the balance of intestinal microorganisms.

[0219] Example 1.3 Comparison of symptom scale scores after treatment.

[0220] This example uses HAMD-17, HAMD-6, QIDS-SR16, and GAD-7 scales to assess changes in depression and related symptoms before and after treatment. Table 4 lists the scores of each symptom scale before and after treatment, as shown below:

[0221] Table 4: Symptom scale scores before and after treatment

[0222]

[0223] Note: HAMD-17 Anxiety / Somatic Factors: Includes 6 items in the HAMD-17 scale, namely, items 10, 11, 12, 13, 15, and 17. Data are expressed in the form of mean (standard deviation).

[0224] HAMD-17 total score: Compared with the control group, the FMT group continued to show a trend of lower HAMD-17 total scores at baseline, 4 weeks after treatment, and 8 weeks after treatment. At 2 weeks after treatment, the score of the FMT group was significantly lower than that of the placebo group (mean score 13.8 vs. 17.8), and the difference was statistically significant (P = 0.0010), indicating that FMT has a faster relief effect on depressive symptoms in the early stage of treatment.

[0225] HAMD-6 score: Numerically, the score reduction in the FMT group at each time point was slightly better than that in the placebo group, especially 2 weeks after treatment, when the FMT group dropped from 10.7 to 6.6 points, a decrease of 4.1 points, while the placebo group dropped from 10.4 to 8.2 points, a decrease of 2.2 points.

[0226] HAMD-17 anxiety / somatic factor scores: At the end of the 2nd and 8th week after treatment, the scores of the FMT group were significantly lower than those of the placebo group (average score of 4.8 vs. 6.6 at 2 weeks; average score of 3.3 vs. 4.8 at 8 weeks), and the differences were statistically significant (P2 week = 0.0007, P8 week = 0.0387), indicating that FMT may be more effective in alleviating depressive symptoms related to anxiety and somatic symptoms.

[0227] QIDS-SR16 scores: The FMT group had slightly better score reductions than the placebo group at each time point.

[0228] GAD-7 score: At the end of 2 weeks after treatment, the score in the FMT group was significantly lower than that in the placebo group (mean score 7.3 vs. 10.0), and the difference was statistically significant (P = 0.0371), indicating that FMT may be more effective in alleviating generalized anxiety symptoms in the early stages of treatment.

[0229] In summary, FMT showed good effects in improving depressive disorders, anxiety symptoms, and generalized anxiety symptoms in the short term. These results show the potential therapeutic advantages of FMT, especially in the treatment of anxiety-related symptoms.

[0230] Example 1.4 Comparison of the difference in symptom scale scores of subjects before and after treatment

[0231] In order to further analyze whether there is a statistical difference in the changes in the symptom scale scores of the two groups of subjects before and after treatment, this example calculated the difference between the scale scores before treatment and 2 weeks, 4 weeks and 8 weeks after treatment (after treatment - before treatment), and analyzed the differences between the two groups (Table 5, Figures 1 to 5 ). Figures 1 to 5 The difference in the scores of each symptom scale between the two groups before and after treatment (after treatment - before treatment) is shown. Figure 1 It is the difference of HAMD-17 score; Figure 2 It is the difference of HAMD-6 score; Figure 3 It is the difference of HAMD-17 anxiety / somatic symptom score; Figure 4 is the difference in QIDS-SR16 scores; Figure 5=The difference in GAD-7 scores. P<0.05 was found between the FMT group and the placebo group. Table 5 lists the specific data of the difference in scores of each symptom scale before and after treatment. Compared with the placebo group, the change values ​​of HAMD-17 in the FMT group at the end of the 2nd week and the end of the 8th week were significantly increased compared with those before treatment, and the difference was statistically significant (P2 week = 0.0107, P8 week = 0.0303); the change values ​​of HAMD-6 in the FMT group at the end of the 2nd week and the end of the 8th week were significantly increased compared with those before treatment, and the difference was statistically significant (P2 week = 0.0094, P8 week = 0.0083); the change values ​​of HAMD-17 anxiety / physical factors in the FMT group at the end of the 2nd week and the end of the 8th week were significantly increased compared with those before treatment, and the difference was statistically significant (P2 week = 0.0127, P8 week = 0.0356).

[0232] Table 5: Differences in scores of symptom scales before and after treatment

[0233]

[0234]

[0235] The FMT group was significantly better than the placebo group within 2 weeks, indicating that FMT can quickly improve depressive symptoms. In particular, in the HAMD-17 and HAMD-6 scores, the score reduction in the FMT group was significantly greater than that in the placebo group, showing its rapid onset. In terms of the HAMD-17 score, the FMT group showed significant improvement at 2 weeks, and after stopping taking the FMT flora capsule until 8 weeks, although the degree of improvement in the FMT group was still better than the placebo group, the significance of the difference was weakened. In terms of the HAMD-6 score, the improvement in the FMT group at the end of the 8th week was also significant, indicating that the effect of FMT has a more lasting effect on key symptoms. In terms of anxiety / somatic factors, the FMT group improved significantly after 2 weeks of treatment, and this improvement was maintained until 8 weeks, indicating that FMT may have a longer-term positive effect on anxiety and somatic symptoms.

[0236] The short-term effects of FMT were sustained after discontinuation, especially in HAMD-6 scores and anxiety / somatic factors. However, the long-term improvements in HAMD-17 were less significant, suggesting that the durability of the FMT effect may require additional interventions or longer FMT treatments to enhance the effect.

[0237] These findings suggest that FMT can rapidly improve depressive symptoms, but long-term efficacy may rely on longer FMT treatments or an appropriate combination with conventional drug treatments.

[0238] The specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention are all within the scope of the present invention.

Claims

1. Use of a pharmaceutical composition or a medicine kit in the preparation of a medicine for treating depressive disorders, wherein: The pharmaceutical composition or medicine kit comprises a therapeutically effective amount of a human intestinal fecal bacteria composition.

2. The use according to claim 1, wherein: The pharmaceutical composition or kit further comprises a therapeutically effective amount of other drugs; Preferably, the other drug is escitalopram.

3. The use according to claim 1 or 2, wherein: The human intestinal fecal bacteria composition comprises one or more selected from muciniphila-Eckermannia, Bacteroides dornii, Bacteroides ovatus, Bacteroides xylanisolvens, Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium animalis, Eubacterium hallii, Faecalibacterium prausnitzii, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus bulgaricus, Lactobacillus fermentum, Lactobacillus plantarum, Lactococcus lactis, Parabacteroides gordonii, Streptococcus salivarius or Streptococcus thermophilus.

4. The use according to any one of claims 1 to 3, wherein: The effective ingredients of the human intestinal fecal bacteria composition come from healthy human intestinal flora; Preferably, the human intestinal fecal bacteria composition excludes pathogenic microorganisms during the donor screening and sample testing stages; Preferably, the donor screening process includes one or more of physical examination, virus screening, medical history review, and intestinal flora testing; Preferably, the pathogenic microorganism is selected from one or more of parasites, pathogenic bacteria, and viruses; Preferably, the parasite is selected from one or more of Cryptosporidium, Giardia, hookworm, tapeworm, Toxoplasma, and Amoeba; Preferably, the pathogenic bacteria are selected from one or more of Clostridioides difficile, Salmonella spp., methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli O157:H7, Shigella, Klebsiella pneumoniae, Streptococcus pneumoniae, Mycobacterium tuberculosis, and Pseudomonas aeruginosa; Preferably, the virus is selected from one or more of HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus (HTLV), norovirus, human papillomavirus (HPV), herpes virus (HSV-1, HSV-2, VZV), and respiratory syncytial virus (RSV).

5. The use according to any one of claims 1 to 4, wherein: The preparation form of the human intestinal fecal bacteria composition is an oral preparation, including but not limited to tablets, capsules, powders, granules, solutions, and lozenges; Preferably, the preparation form of the human intestinal fecal bacteria composition is a capsule; Preferably, the preparation of the human intestinal fecal bacteria composition comprises the following steps: Sample collection: Stool samples collected from healthy donors, Crude: after the donor screening as described in claim 4, large impurities and non-bacteria parts are removed; Purification: fine extraction of intestinal microorganisms using a three-layer separation technique, preferably, the fine extraction includes continuous centrifugation and filtration steps; Packaging: The purified bacteria are encapsulated in capsules under sterile conditions by vacuum sealing.

6. The use according to any one of claims 1 to 5, wherein: The other drugs also include: benzodiazepines or nonbenzodiazepines; Preferably, the benzodiazepine is selected from one or more of estazolam, alprazolam, lorazepam, and oxazepam; Preferably, the non-benzodiazepine drug is selected from one or more of zolpidem and zopiclone; Preferably, the therapeutically effective amount of other drugs is selected from lorazepam and / or oxazepam.

7. The use according to any one of claims 1 to 6, wherein: The single dose of the pharmaceutical composition or the medicine kit contains 0.5-1.0 g of the human intestinal fecal bacteria composition, preferably, the single dose of the pharmaceutical composition or the medicine kit contains 0.52 g or 0.84 g of the human intestinal fecal bacteria composition; Preferably, the single dose of the pharmaceutical composition or kit further comprises 0-50 mg of a therapeutically effective amount of other drugs; preferably, the therapeutically effective amount of other drugs is escitalopram, preferably, the single dose of the pharmaceutical composition or kit comprises 5-20 mg of escitalopram, the single dose of the pharmaceutical composition or kit comprises 5 mg, 10 mg or 20 mg of escitalopram; Preferably, the single-dose pharmaceutical composition or kit further comprises estazolam ≤ 2 mg, alprazolam ≤ 0.8 mg, lorazepam ≤ 1 mg and / or oxazepam ≤ 30 mg; Preferably, the single-dose pharmaceutical composition or kit further comprises zolpidem ≤ 10 mg and / or zopiclone ≤ 7.5 mg; Preferably, the single-dose pharmaceutical composition or kit further comprises lorazepam ≤ 3 mg and / or oxazepam ≤ 45 mg.

8. The use according to any one of claims 1 to 7, wherein: The therapeutically effective amount of the human intestinal fecal bacteria composition and the therapeutically effective amount of other drugs can be administered simultaneously, separately or sequentially.

9. The use according to any one of claims 1 to 8, wherein: The pharmaceutical composition or kit is suitable for alleviating a variety of mood and cognitive dysfunctions, including but not limited to anxiety or cognitive disorders; Preferably, the pharmaceutical composition or kit can rapidly alleviate a variety of mood and cognitive dysfunctions, including but not limited to anxiety or cognitive impairment; Preferably, the pharmaceutical composition or kit can rapidly alleviate a variety of mood and cognitive dysfunctions, including but not limited to anxiety or cognitive impairment, within 2 weeks after treatment; Preferably, the multiple mood and cognitive dysfunctions are associated with intestinal microbial dysbiosis.

10. A drug combination, wherein: The drug combination comprises a therapeutically effective amount of a human intestinal fecal bacteria composition as described in any one of claims 1 to 9 and a therapeutically effective amount of other drugs; Preferably, the drug combination is a pharmaceutical composition or a drug kit; Preferably, the therapeutically effective amount of other drug is a therapeutically effective amount of escitalopram.

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