Combined medicine for treating depression and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a combined medicine for treating depression and application thereof. The combined medicine provided by the invention comprises the antidepressant and the Tibetan capillary which are administrated simultaneously and / or sequentially. The combination of the antidepressant and Tibetan capillaris realizes the antidepressant effect, can effectively prevent and reduce liver injury caused by the antidepressant, enlarges the use population of the antidepressant, and has important significance in clinical treatment of depression.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a combined drug for treating depression and an application thereof. Background Art

[0002] Depression, also known as depressive disorder, is a mental disorder with high incidence, high clinical cure rate, but low treatment acceptance rate and high recurrence rate. Its main feature is significant and persistent low mood. Some patients may have self-harm, suicidal behavior, and may even be accompanied by psychotic symptoms such as delusions and hallucinations. Clinically, depressive disorders can be divided into mild, moderate and severe according to the number, type and severity of symptoms. They are targeted at different groups such as the elderly, children, and postpartum women, and are called elderly depression, childhood depression, postpartum depression, etc. Depression is not contagious, but it is closely related to stressful life events, pessimistic personality traits, a history of other mental illnesses, serious chronic diseases, alcoholism, and drug abuse.

[0003] The treatment of depression mainly includes drug therapy, psychotherapy and physical therapy. Drug therapy is the main treatment method. Antidepressants include tricyclic antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other types of antidepressants. Currently, the antidepressants recommended for clinical use include selective serotonin reuptake inhibitors (SSRIs), selective serotonin norepinephrine reuptake inhibitors (SNRIS), norepinephrine and specific serotonin reuptake inhibitors (NaSSAs), norepinephrine and dopamine reuptake inhibitors (NDRIS), etc.

[0004] Research results show that the cure rate of depression treatment with a single drug is 30%, and about 2 / 3 of patients who are ineffective must change their treatment plan. A course of antidepressant treatment lasts at least 6 weeks, and a 3-month course is required after changing the drug. About half of the patients relapse during this period, so the initial stage is crucial to the treatment effect of depression. About 60% of patients with depression are treated with selective 5-HT reuptake inhibitors. Studies have shown that the effect of combined drug treatment in the initial stage of depression is better than single drug treatment.

[0005] Most drugs used to treat depression are excreted through the liver and kidneys. Moreover, drug treatment for depression may cause liver and kidney damage such as elevated liver enzymes, liver damage, drug-induced hepatitis, kidney damage, and drug-induced nephropathy. Although the risk of severe liver damage or even liver failure is significantly lower than that of some other drugs (analgesics, antibiotics, Chinese herbal medicines, etc.), there are certain restrictions on the treatment population.

[0006] For example, Chinese patent CN115300571A discloses an antidepressant drug composition and its preparation method and application. The application provides an antidepressant drug composition including a water extract of Chinese medicine Bupleurum Soothing Liver Powder and a bifidobacterium solution. The water extract of Bupleurum Soothing Liver Powder combined with a bifidobacterium solution can significantly improve the depressive behavioral indicators of rats with chronic unpredictable mild stress depression model, protect hippocampal neurons, and synergistically regulate the intestinal microbial balance of the depression rat model to achieve a synergistic effect: compared with existing antidepressants, the water extract of Chinese medicine Bupleurum Soothing Liver Powder combined with bifidobacteria has better efficacy, no toxic side effects, no addiction, etc. in regulating depression. There is a synergistic effect between the water extract of Chinese medicine Bupleurum Soothing Liver Powder and bifidobacteria. After combined use, it can better regulate the intestinal flora balance of depression model rats, providing a new method for antidepressant treatment. However, the application has complex ingredients and is not suitable for large-scale production.

[0007] Another example is Chinese patent CN104435298B, which provides an antidepressant pharmaceutical composition, which is a preparation prepared from the following raw materials by weight: 3-10 parts of bupleurum, 3-9 parts of nard, 6-12 parts of schisandra, and 2-10 parts of liquorice. The pharmaceutical composition prepared by the present invention has an antidepressant effect and is used to treat depression, especially the treatment of liver qi stagnation type and liver depression spleen type depression. The drug effect is clear, and a new drug selection is provided for clinical use. However, the application also has the above problems.

[0008] Therefore, it is particularly important to study a pharmaceutical composition for treating depression and capable of preventing and reducing liver damage caused by antidepressant drugs. Summary of the invention

[0009] Based on the problems existing in the prior art, the present invention provides a combined drug for treating depression and its application. The present invention achieves its antidepressant effect by combining an antidepressant with Tibetan Artemisia capillaris, and can effectively prevent and reduce liver damage caused by antidepressants, expand the user population of antidepressants, and has important significance in the clinical treatment of depression.

[0010] Tibetan Artemisia capillaris grows in the Qinghai-Tibet Plateau area with high altitude in my country. It is an annual dwarf herbaceous medicinal plant of the Gentianaceae family. It is the most distinctive medicinal plant in Tibetan medicine and is used to treat liver and gallbladder diseases, fever and blood diseases. It has the effects of reducing fever and diuresis. The Tibetan Artemisia capillaris of this patent includes but is not limited to Tibetan Artemisia capillaris Chinese medicine raw materials, various preparations including Tibetan Artemisia capillaris active ingredients prepared with Tibetan Artemisia capillaris as raw materials, such as Tibetan Artemisia capillaris tablets, Tibetan Artemisia capillaris capsules, Tibetan Artemisia capillaris pills, Tibetan Artemisia capillaris granules, etc.

[0011] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0012] First, the present application provides a combination drug for treating depression, characterized in that the combination drug comprises an antidepressant and a traditional Chinese medicine administered simultaneously and / or sequentially, and the traditional Chinese medicine comprises Tibetan Artemisia Capillaris.

[0013] Preferably, the type of antidepressant in the combined pharmaceutical composition for treating depression is: one or more of: melatonin receptor agonists, selective serotonin reuptake inhibitors SSRIs or serotonin and norepinephrine reuptake inhibitors SNRIs;

[0014] Preferably, the mass ratio of the antidepressant to the Tibetan Artemisia Capillaris is 0.01-0.02:6.38-19.14;

[0015] Further preferably, when the antidepressant is a melatonin receptor agonist, the mass ratio of the antidepressant to Tibetan Artemisia Capillaris is 0.01:6.38-19.14; when the antidepressant is a selective serotonin reuptake inhibitor SSRIs, the mass ratio of the antidepressant to Tibetan Artemisia Capillaris is 0.015:6.38-19.14; when the antidepressant is a serotonin and norepinephrine reuptake inhibitor SNRIs, the mass ratio of the antidepressant to Tibetan Artemisia Capillaris is 0.02:6.38-19.14.

[0016] Preferably, the melatonin receptor agonist mainly comprises: agomelatine;

[0017] Preferably, the selective serotonin reuptake inhibitor includes but is not limited to fluvoxamine, fluoxetine, paroxetine, escitalopram or sertraline hydrochloride.

[0018] Preferably, the serotonin and norepinephrine reuptake inhibitors include but are not limited to: duloxetine, milnacipran or venlafaxine hydrochloride.

[0019] Further preferably, the selective serotonin reuptake inhibitor mainly comprises: sertraline hydrochloride.

[0020] More preferably, the serotonin and norepinephrine reuptake inhibitor mainly comprises: venlafaxine hydrochloride.

[0021] In addition, the present application also provides the use of a combination drug for treating depression in the preparation of a pharmaceutical preparation for preventing and / or treating depression.

[0022] The present application also provides a pharmaceutical preparation for treating depression, characterized in that the pharmaceutical preparation comprises: a combined drug for treating depression and a pharmaceutically acceptable excipient.

[0023] Preferably, the pharmaceutically acceptable excipients include: one or more of a filler, a wetting agent, a binder, a disintegrant and a lubricant.

[0024] Preferably, the dosage form of the pharmaceutical preparation is: powder, granules, capsules, tablets, oral liquid or pills.

[0025] The present application also provides the use of the combined drug in the preparation of a drug for treating liver damage caused by antidepressants.

[0026] The present application also provides the use of the Tibetan Artemisia capillaris described in the combined drug in the preparation of a drug for treating liver damage caused by antidepressants.

[0027] Preferably, the antidepressant is selected from one of melatonin receptor agonists, selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs).

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) The present application adopts a method of combining Chinese and Western medicine, combining antidepressants with Tibetan Artemisia capillaris, which has a synergistic effect.

[0030] (2) The present application combines antidepressants with Tibetan Artemisia capillaris to effectively prevent and reduce liver damage caused by antidepressants.

[0031] (3) The combination drug provided in this application can effectively expand the user population of antidepressant drugs and has important significance in the clinical treatment of depression. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The graph shows the latency time for each group of mice to jump off the platform.

[0033] Figure 2 The graph shows the time percentage of each group of mice in the open arm.

[0034] Figure 3 Graph showing the immobility time of each group of mice during forced swimming.

[0035] Figure 4 The graph shows the immobility time of mice in each group during tail suspension.

[0036] Figure 5 Figure 2 shows the serum AST content of mice in each group.

[0037] Figure 6 The figure shows the serum ALT content of mice in each group. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is clearly and completely described below with specific implementation methods. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0039] The purchase manufacturers and specifications of the reagents used in the following examples are as follows:

[0040] drug factory Specification Agomelatine Jiangsu Hausen Pharmaceutical Group Co., Ltd. 25mg Sertraline Hydrochloride Zhejiang Huahai Pharmaceutical Co., Ltd. 50mg Venlafaxine Hydrochloride Xi'an Yuanda Detian Pharmaceutical Co., Ltd. 75mg Silymarin Capsules MEDAPHARMAGMBH&CO.KG 140mg Tibetan Artemisia Capsule Xi'an Yuanda Detian Pharmaceutical Co., Ltd. 0.35g

[0041] 1. The effect of Tibetan Artemisia capillaris on the efficacy of various antidepressant drugs

[0042] Example 1 A combined drug for treating depression

[0043] Including the following ingredients:

[0044] Agomelatine 10mg / Kg, content of Tibetan Artemisia Capsule 6.38g / Kg.

[0045] Example 2 A combination drug for treating depression

[0046] Including the following ingredients:

[0047] Agomelatine 10mg / Kg, content of Zangyinchen capsule 19.14g / Kg.

[0048] Comparative Example 1 A combined drug for treating depression

[0049] Including the following ingredients:

[0050] Agomelatine 10mg / Kg, Silymarin 800mg / Kg.

[0051] Comparative Example 2 A combined drug for treating depression

[0052] Including the following ingredients:

[0053] Agomelatine 10mg / Kg.

[0054] Example 3 A combined drug for treating depression

[0055] Including the following ingredients:

[0056] Sertraline hydrochloride 15mg / Kg, content of Cang Yinchen capsule 6.38g / Kg.

[0057] Example 4 A combined drug for treating depression

[0058] Including the following ingredients:

[0059] Sertraline hydrochloride 15mg / Kg, content of Cang Yinchen capsule 19.14g / Kg.

[0060] Comparative Example 3 A combined drug for treating depression

[0061] Including the following ingredients:

[0062] Sertraline hydrochloride 15mg / Kg, silymarin 800mg / Kg.

[0063] Comparative Example 4 A combined drug for treating depression

[0064] Including the following ingredients:

[0065] Sertraline hydrochloride 15mg / Kg.

[0066] Example 5 A combination drug for treating depression

[0067] Including the following ingredients:

[0068] Venlafaxine hydrochloride 20mg / Kg, content of Zang Yinchen capsule 6.38g / Kg.

[0069] Example 6 A combination drug for treating depression

[0070] Including the following ingredients:

[0071] Venlafaxine hydrochloride 20mg / Kg, content of Zang Yinchen capsule 19.14g / Kg.

[0072] Comparative Example 5 A combined drug for treating depression

[0073] Including the following ingredients:

[0074] Venlafaxine hydrochloride 20mg / Kg, silymarin 800mg / Kg.

[0075] Comparative Example 6 A combined drug for treating depression

[0076] Including the following ingredients:

[0077] Venlafaxine hydrochloride 20mg / Kg.

[0078] Effect Experiment

[0079] (1) Experimental animals: 6-7 week old SPF grade C57BL / 6 mice (purchased from the Animal Experiment Center of Xi'an Jiaotong University) with an average body weight of 18-20 g. These mice were housed in a controlled environment with room temperature maintained at 22±2°C, humidity at 55%±5%, and a 12 h light / dark cycle. They had free access to food and water. All experimental procedures involving mice were in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

[0080] (2) Animal grouping:

[0081] The animals were placed for 7 days to adapt to the environment, and body weight and sugar preference rate were tested, and mice with abnormal values ​​were eliminated. They were randomly divided into groups, with 10 mice in each group. The groups were blank group, model group, embodiment group and comparative group.

[0082] (3) Animal modeling and intervention methods:

[0083] The model group, the example group and the comparative example group were subjected to a 5-week chronic unpredictable mild stimulation (CUMS) method to establish a depression and anxiety mouse model. The chronic unpredictable mild stimulation included the following 8 different stimuli:

[0084] 4.1 Mandatory swimming

[0085] A 22-cm-deep glass jar was filled with water at 23 ± 2 °C, and mice were placed in the glass jar for 10 min, which was carefully covered with a heavy lid to prevent them from escaping. Then the mice were returned to a clean, dry cage with fresh bedding to avoid chills and colds.

[0086] 4.2 Binding Force

[0087] Place the mouse in a 50 mL plastic tube adjusted on the outside with plastic tape so that the animal cannot move, with a hole at the distal end of the tube to facilitate normal breathing.

[0088] 4.3 Water scarcity

[0089] The water bottle was removed from the cage within 24 h and returned after the time point was reached.

[0090] 4.4 Isolation

[0091] Mice were placed individually in a new cage for 24 h, and then returned to their cages with their cagemates.

[0092] 4.5 Food shortage

[0093] Remove food from the cage for 24 h and then return the food.

[0094] 4.6 Wet litter

[0095] Mice were placed individually in a new cage with 200 ml of water per 100 g of bedding for 24 h and returned to the cage with their littermates.

[0096] No bedding: Place mice individually in a new cage without bedding for 24 h and return the animals to their cages with their littermates.

[0097] 4.7 Tilt Cage

[0098] Tilt the cage at 45° for 24 h and return the cage to its normal state.

[0099] Tail clamp: clamp the tail 2 cm from the end with plastic forceps for 3 minutes each time, 3 times a day, and return the animals to the cage with their companions.

[0100] 4.8 Crowded Space

[0101] Place a plastic partition in the cage to reduce the activity area by half, and after 24 hours, remove the partition.

[0102] In order to avoid the animals' adaptation to specific stimuli, which would affect the accuracy of the experimental results, these stimuli were randomly applied 1-2 times a day, and 6 days a week. In addition, in order to ensure the unpredictability of the experiment, each stimulus was used no more than three times during the entire experiment. This method aims to create a complex and varied stress environment to induce behavioral and physiological responses in mice similar to human depression and anxiety.

[0103] During the entire experimental period, the blank group and the model group were routinely fed, while the example group and the comparative example group were routinely fed and administered by gavage starting from the 36th day, with the dosage according to the dosage of the corresponding composition drug in the examples and comparative examples, wherein except for comparative examples 2, 4, and 6, the other groups were administered at the same time.

[0104] (5) Behavioral evaluation:

[0105] Behavioral evaluations of all mice began in the seventh week, including the jumping platform test, elevated plus maze test, forced swimming test, and tail suspension test.

[0106] 5.1 Jumping platform experiment

[0107] The mice were placed on the platform for motor training, and the grid was energized (0.2 mA); when the mouse jumped off the platform, it received an electric shock, which produced a pain memory; the training time was three minutes; if the mice did not jump off the platform within 3 minutes, they were driven away. After the training, all mice returned to their original cages. 24 hours after training was the memory reproduction stage: the mice were placed on the platform and tested for 3 minutes. This test was not powered on, and the latency time for each group of mice to jump off the platform was counted.

[0108] Table 1-1 Latency time of mice in each group jumping off the platform

[0109] Grouping Mean ± SD blank 12.81±6.76 Model Group <![CDATA[40.84±9.20 a*** ]]> Example 1 <![CDATA[19.21±6.66 b***,c**,d* ]]> Example 2 <![CDATA[16.55±7.52 b***,c**,d** ]]> Comparative Example 1 <![CDATA[29.54±9.41 b** ]]> Comparative Example 2 <![CDATA[28.26±10.43 b** ]]>

[0110] a vs blank group, b vs model group, c vs comparative example 1, d vs comparative example 2,

[0111] *P<0.05, **P<0.01, ***P<0.001

[0112] Table 1-2 Latency time of mice in each group jumping off the platform

[0113] Grouping Mean ± SD blank 12.81±6.76 Model Group <![CDATA[40.84±9.20 a*** ]]> Example 3 <![CDATA[18.97±4.44 b***,c*,d* ]]> Example 4 <![CDATA[15.81±7.88 b***,c**,d** ]]> Comparative Example 3 <![CDATA[27.68±10.25 b** ]]> Comparative Example 4 <![CDATA[27.81±8.73 b** ]]>

[0114] a vs blank group, b vs model group, c vs comparative example 3, d vs comparative example 4,

[0115] *P<0.05, **P<0.01, ***P<0.001

[0116] Table 1-3 Latency time of mice in each group jumping off the platform

[0117] Grouping Mean ± SD blank 12.81±6.76 Model Group <![CDATA[40.84±9.20 a*** ]]> Example 5 <![CDATA[22.14±8.22 b***,c*,d* ]]> Example 6 <![CDATA[18.66±10.16 b***,c**,d** ]]> Comparative Example 5 <![CDATA[29.87±9.14 b** ]]> Comparative Example 6 <![CDATA[30.33±6.46 b** ]]>

[0118] a vs blank group, b vs model group, c vs comparative example 5, d vs comparative example 6,

[0119] *P<0.05, **P<0.01, ***P<0.001

[0120] The results are shown in Table 1 and Figure 1 As shown, compared with the blank group, the latency time of the mice in the model group to jump off the platform in the jumping platform experiment was longer, which suggested that the mice had hesitant and anxious behaviors. The latency times of the embodiment group and the comparative group were significantly reduced compared with those of the model group, indicating that agomelatine, sertraline hydrochloride and venlafaxine hydrochloride had obvious therapeutic effects on depression, and after adding Tibetan Artemisia Capillaris and silymarin respectively, the latency time was further shortened. Compared with Tibetan Artemisia Capillaris and silymarin, the combination of Tibetan Artemisia Capillaris and antidepressants had a stronger antidepressant effect.

[0121] 5.2 Elevated plus maze test

[0122] The mice were placed in the central area of ​​the maze, facing the open arms, and allowed to move freely for 6 min. The proportion of time (%) spent by mice in each group in the open arms was counted.

[0123] Table 2-1 The proportion of time each group of mice spent in the open arm

[0124] Grouping Mean ± SD blank 43.61±7.65 Model Group <![CDATA[26.94±10.94 a** ]]> Example 1 <![CDATA[41.68±15.56 b** ]]> Example 2 <![CDATA[45.23±8.82 b** ]]> Comparative Example 1 <![CDATA[43.47±10.34 b** ]]> Comparative Example 2 <![CDATA[41.84±13.36 b** ]]>

[0125] a vs blank group, b vs model group,

[0126] *P<0.05, **P<0.01, ***P<0.001

[0127] Table 2-2 Latency time of mice in each group jumping off the platform

[0128] Grouping Mean ± SD blank 43.61±7.65 Model Group <![CDATA[26.94±10.94 a** ]]> Example 3 <![CDATA[39.03±14.35 b* ]]> Example 4 <![CDATA[38.49±12.36 b* ]]> Comparative Example 3 35.24±11.27 Comparative Example 4 37.22±11.78

[0129] a vs blank group, b vs model group,

[0130] *P<0.05, **P<0.01, ***P<0.001

[0131] Table 2-3 Latency time of mice in each group jumping off the platform

[0132] Grouping Mean ± SD blank 43.61±7.65 Model Group <![CDATA[26.94±10.94 a** ]]> Example 5 <![CDATA[40.29±14.30 b* ]]> Example 6 <![CDATA[44.67±14.90 b* ]]> Comparative Example 5 <![CDATA[40.17±10.15 b** ]]> Comparative Example 6 <![CDATA[39.16±11.85 b* ]]>

[0133] a vs blank group, b vs model group,

[0134] *P<0.05, **P<0.01, ***P<0.001

[0135] The results are shown in Table 2 and Figure 2 As shown, compared with the blank group, the model group mice spent less time in the open arm in the elevated plus maze experiment, which suggested that the mice had hesitant and anxious behaviors. After the intervention of antidepressant drugs, the behavioral indicators of the embodiment group and the comparative group were significantly improved. Adding Tibetan Artemisia Capillaris and silymarin to the antidepressant drugs did not affect the antidepressant effects, but had a synergistic effect. The antidepressant effects of the embodiment groups were better than those of the comparative group.

[0136] 5.3 Forced swimming test

[0137] A 30 cm glass tank containing water at 23-25 ​​°C was used. On the first day, all mice were forced to swim for 15 min for training. On the second day, the mice were placed in the same environment for 10 min. Locomotor activity was monitored using a video tracking system, and the immobility time during the test was calculated for each animal (immobility was defined as no movement except for the floating movements required to keep the head above the water).

[0138] Table 3-1 Immobility time of mice in each group during forced swimming

[0139] Grouping Mean ± SD blank 39.64±11.88 Model Group <![CDATA[121.04±13.95 a*** ]]> Example 1 <![CDATA[60.36±13.30 b***,c***,d* ]]> Example 2 <![CDATA[55.12±15.15 b***,c***,d** ]]> Comparative Example 1 <![CDATA[82.71±11.34 b*** ]]> Comparative Example 2 <![CDATA[74.37±12.56 b*** ]]>

[0140] a vs blank group, b vs model group, c vs comparative example 1, d vs comparative example 2,

[0141] *P<0.05, **P<0.01, ***P<0.001

[0142] Table 3-2 Immobility time of mice in each group during forced swimming

[0143] Grouping Mean ± SD blank 39.64±11.88 Model Group <![CDATA[121.04±13.95 a*** ]]> Example 3 <![CDATA[69.69±13.00 b***,c**,d** ]]> Example 4 <![CDATA[68.62±14.17 b***,c**,d** ]]> Comparative Example 3 <![CDATA[90.18±15.71 b*** ]]> Comparative Example 4 <![CDATA[89.35±15.93 b*** ]]>

[0144] a vs blank group, b vs model group, c vs comparative example 3, d vs comparative example 4,

[0145] *P<0.05, **P<0.01, ***P<0.001

[0146] Table 3-3 Immobility time of mice in each group during forced swimming

[0147] Grouping Mean ± SD blank 39.64±11.88 Model Group <![CDATA[121.04±13.95 a*** ]]> Example 5 <![CDATA[63.84±11.20 b***,d* ]]> Example 6 <![CDATA[57.52±18.27 b***,c**,d** ]]> Comparative Example 5 <![CDATA[75.59±12.21 b*** ]]> Comparative Example 6 <![CDATA[79.33±12.97 b*** ]]>

[0148] a vs blank group, b vs model group, c vs comparative example 5, d vs comparative example 6,

[0149] *P<0.05, **P<0.01, ***P<0.001

[0150] The results are shown in Table 3 and Figure 3 As shown, compared with the blank group, the immobility time of the model group mice in the forced swimming test was significantly increased, which reflects a higher level of despair behavior, which is a typical manifestation of depression. After the intervention of antidepressant drugs, the behavioral index was significantly improved. Compared with the example group and the comparative group, Tibetan Artemisia capillaris had no effect on the therapeutic effect of antidepressant drugs, and had a certain improvement effect, and its effect was better than silymarin.

[0151] 5.4 Tail suspension test:

[0152] The tip of the mouse's tail (2 cm from the tip of the tail) was taped to a suspension rod (30 cm above the ground). When the mouse touched the suspension, it would instinctively struggle violently to escape the predicament at first, but if it could not escape, it would fall into a desperate state and remain motionless, showing depressive-like behavior. The longer the immobility, the more depressed it was. The motor activity was monitored by a video tracking system for 6 minutes, and the immobility time of each animal during the test was calculated (immobility was defined as no voluntary or escapist movement).

[0153] Table 4-1 Immobility time of mice in each group during tail suspension

[0154] Grouping Mean ± SD blank 105.33±12.8 Model Group <![CDATA[191.71±14.85 a*** ]]> Example 1 <![CDATA[126.92±10.72 b***,c* ]]> Example 2 <![CDATA[112.78±10.11 b***,c***,d*** ]]> Comparative Example 1 <![CDATA[140.75±16.06 b*** ]]> Comparative Example 2 <![CDATA[138.26±12.76 b*** ]]>

[0155] a vs blank group, b vs model group, c vs comparative example 1, d vs comparative example 2,

[0156] *P<0.05, **P<0.01, ***P<0.001

[0157] Table 4-2 Immobility time of mice in each group during tail suspension (s)

[0158] Grouping Mean ± SD blank 105.33±12.8 Model Group <![CDATA[191.71±14.85 a*** ]]> Example 3 <![CDATA[130.31±14.28 b***,c**,d* ]]> Example 4 <![CDATA[117.62±11.83 b***,c***,d*** ]]> Comparative Example 3 <![CDATA[146.79±12.68 b*** ]]> Comparative Example 4 <![CDATA[142.67±10.51 b*** ]]>

[0159] a vs blank group, b vs model group, c vs comparative example 3, d vs comparative example 4,

[0160] *P<0.05, **P<0.01, ***P<0.001

[0161] Table 4-3 Immobility time of mice in each group during tail suspension

[0162] Grouping Mean ± SD blank 105.33±12.8 Model Group <![CDATA[191.71±14.85 a*** ]]> Example 5 <![CDATA[121.83±15.43 b***,d* ]]> Example 6 <![CDATA[117.12±13.4 b***,c*,d** ]]> Comparative Example 5 <![CDATA[130.12±13.44 b*** ]]> Comparative Example 6 <![CDATA[136.75±14.23 b*** ]]>

[0163] a vs blank group, b vs model group, c vs comparative example 5, d vs comparative example 6,

[0164] *P<0.05, **P<0.01, ***P<0.001

[0165] The results are shown in Table 4 and Figure 4 As shown, compared with the blank group, the immobility time of mice in the model group in the tail suspension test was significantly increased, which reflects a higher level of despair behavior, which is a typical manifestation of depression. After the intervention of antidepressant drugs, the behavioral index tended to normalize. Comparing the test group and the control group, Tibetan Artemisia Capillaris had no effect on the therapeutic effect of antidepressant drugs, and even had a certain improvement and enhancement effect, and its effect was better than that of silymarin.

[0166] Based on the above experimental data, Tibetan Artemisia capillaris has no effect on the effects of antidepressant drugs, and has a certain synergistic effect. Its overall effect is better than silymarin.

[0167] 2. The therapeutic effect of Tibetan Artemisia capillaris on liver damage caused by various antidepressant drugs

[0168] Example 7 A combined drug for treating depression

[0169] Including the following ingredients:

[0170] Agomelatine 400mg / Kg, content of Tibetan Artemisia Capsule 6.38g / Kg.

[0171] Example 8 A combined drug for treating depression

[0172] Including the following ingredients:

[0173] Agomelatine 400mg / Kg, content of Zang Yinchen capsule 19.14g / Kg.

[0174] Comparative Example 7 A combined drug for treating depression

[0175] Including the following ingredients:

[0176] Agomelatine 400mg / Kg, Silymarin 800mg / Kg.

[0177] Comparative Example 8 A combined drug for treating depression

[0178] Including the following ingredients:

[0179] Agomelatine 400mg / Kg.

[0180] Example 9 A combined drug for treating depression

[0181] Including the following ingredients:

[0182] Sertraline hydrochloride 300mg / Kg, content of Cang Yinchen capsule 6.38g / Kg.

[0183] Example 10 A combination drug for treating depression

[0184] Including the following ingredients:

[0185] Sertraline hydrochloride 300mg / Kg, content of Cang Yinchen capsule 19.14g / Kg.

[0186] Comparative Example 9 A combined drug for treating depression

[0187] Including the following ingredients:

[0188] Sertraline hydrochloride 300mg / Kg, silymarin 800mg / Kg.

[0189] Comparative Example 10 A combined drug for treating depression

[0190] Including the following ingredients:

[0191] Sertraline hydrochloride 300mg / Kg.

[0192] Example 11 A combined drug for treating depression

[0193] Including the following ingredients:

[0194] Venlafaxine hydrochloride 200mg / Kg, content of Zang Yinchen capsule 6.38g / Kg.

[0195] Example 12 A combined drug for treating depression

[0196] Including the following ingredients:

[0197] Venlafaxine hydrochloride 200mg / Kg, content of Zang Yinchen capsule 19.14g / Kg.

[0198] Comparative Example 11 A combined drug for treating depression

[0199] Including the following ingredients:

[0200] Venlafaxine hydrochloride 200mg / Kg, silymarin 800mg / Kg.

[0201] Comparative Example 12 A combined drug for treating depression

[0202] Including the following ingredients:

[0203] Venlafaxine hydrochloride 200mg / Kg.

[0204] Effect Experiment

[0205] (1) Experimental animals: 6-7 week old SPF grade C57BL / 6 mice (purchased from the Animal Experiment Center of Xi'an Jiaotong University) with an average body weight of 18-20 g. These mice were housed in a controlled environment with room temperature maintained at 22±2°C, humidity at 55%±5%, and a 12 h light / dark cycle. They had free access to food and water. All experimental procedures involving mice were in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

[0206] (2) Animal grouping:

[0207] The animals were placed for 7 days to adapt to the environment, and body weight and sugar preference rate were tested, and mice with abnormal values ​​were eliminated. They were randomly divided into groups, with 10 mice in each group. The groups were blank group, example group, and comparative example group.

[0208] (3) Animal modeling and intervention methods:

[0209] The blank group was given 0.9% sodium chloride injection, 1mL / 100g, twice a day throughout the whole process; the comparative examples 8, 10, and 12 were given corresponding doses of drug solutions, once a day, for 14 consecutive days; the embodiment and the other control groups took the corresponding contents of Tibetan Artemisia Capillaris solution and silymarin solution while taking the corresponding antidepressants.

[0210] (4) Index detection:

[0211] The subjects were fasted for 12 hours the night before the end of the experiment. After anesthesia, the eyeballs were removed and blood was collected. The blood was allowed to stand at room temperature for 30 minutes and then centrifuged at 4°C and 3500r / min for 15 minutes. The upper serum was collected and tested using the Ruixin Bio ELISA kit (Cat. No.: RX201960M) to determine the activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

[0212] Table 5-1 Serum AST concentration of mice in each group (U / L)

[0213] Grouping Mean ± SD Blank Group 83.68±8.82 Example 7 <![CDATA[156.16±10.76 a***,b***,c*** ]]> Example 8 <![CDATA[110.37±12.38 a***,b***,c*** ]]> Comparative Example 7 <![CDATA[132.95±12.53 a*** ]]> Comparative Example 8 <![CDATA[186.24±12.6 a*** ]]>

[0214] a vs blank group, b vs comparative example 7, c vs comparative example 8

[0215] *P<0.05, **P<0.01, ***P<0.001

[0216] Table 5-2 Serum AST concentrations of mice in each group (U / L)

[0217] Grouping Mean ± SD Blank Group 83.68±8.82 Example 9 <![CDATA[125.21±14.93 a***,b***,c*** ]]> Example 10 <![CDATA[124.32±10.83 a***,b***,c*** ]]> Comparative Example 9 <![CDATA[148.85±12.43 a*** ]]> Comparative Example 10 <![CDATA[172.26±11.03 a*** ]]>

[0218] a vs blank group, b vs comparative example 9, c vs comparative example 10

[0219] *P<0.05, **P<0.01, ***P<0.001

[0220] Table 5-3 Serum AST concentration of mice in each group (U / L)

[0221] Grouping Mean ± SD Blank Group 83.68±8.82 Embodiment 11 <![CDATA[131.29±8.60 a***,b*,c*** ]]> Example 12 <![CDATA[108.74±11.46 a***,b***,c*** ]]> Comparative Example 11 <![CDATA[142.57±9.28 a*** ]]> Comparative Example 12 <![CDATA[169.35±13.22 a*** ]]>

[0222] a vs blank group, b vs comparative example 11, c vs comparative example 12

[0223] *P<0.05, **P<0.01, ***P<0.001

[0224] Table 6-1 Serum ALT concentration of mice in each group (U / L)

[0225] Grouping Mean ± SD Blank Group 39.79±8.2 Example 7 <![CDATA[88.97±11.33 a***,b**,c*** ]]> Example 8 <![CDATA[75.61±14.21 a***,b***,c*** ]]> Comparative Example 7 <![CDATA[105.36±12.2 a*** ]]> Comparative Example 8 <![CDATA[134.39±11.88 a*** ]]>

[0226] a vs blank group, b vs comparative example 7, c vs comparative example 8

[0227] *P<0.05, **P<0.01, ***P<0.001

[0228] Table 6-2 Serum ALT concentrations of mice in each group (U / L)

[0229] Grouping Mean ± SD Blank Group 39.79±8.2 Example 9 <![CDATA[82.29±11.7 a***,b***,c*** ]]> Example 10 <![CDATA[71.47±13.46 a***,b***,c*** ]]> Comparative Example 9 <![CDATA[102.37±8.70 a*** ]]> Comparative Example 10 <![CDATA[124.72±12.60 a*** ]]>

[0230] a vs blank group, b vs comparative example 9, c vs comparative example 10

[0231] *P<0.05, **P<0.01, ***P<0.001

[0232] Table 6-3 Serum ALT concentrations of mice in each group (U / L)

[0233] Grouping Mean ± SD Blank Group 39.79±8.2 Embodiment 11 <![CDATA[110.87±10.68 a***,c*** ]]> Example 12 <![CDATA[77.65±10.35 a***,b**,c*** ]]> Comparative Example 11 <![CDATA[111.26±12.22 a*** ]]> Comparative Example 12 <![CDATA[143.31±13.28 a*** ]]>

[0234] a vs blank group, b vs comparative example 11, c vs comparative example 12

[0235] *P<0.05, **P<0.01, ***P<0.001

[0236] As shown in Table 5-6 and Figure 5-6 As shown, compared with the blank group, Comparative Examples 8, 10, and 12 all caused an increase in the corresponding enzyme indicators of the mouse liver, indicating that these antidepressants all caused certain liver damage, that is, drug-induced liver damage to the mice. The mice of Examples 7-12 and Comparative Examples 7, 9, and 11 were respectively added with Tibetan Artemisia Capillaris and silymarin on the basis of the corresponding antidepressants. The results showed that the activities of aspartate aminotransferase and alanine aminotransferase were reduced. In terms of alleviating liver damage caused by antidepressants, the improvement effect of Tibetan Artemisia Capillaris was significantly better than that of silymarin.

[0237] To sum up the experimental results, the simultaneous use of Tibetan Artemisia Capillaris and antidepressants will not only not affect the antidepressant effect of antidepressants, but also have a synergistic effect, while alleviating the drug-induced liver damage caused by antidepressants.

[0238] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A combined drug for treating depression, characterized in that: The combined drug comprises an antidepressant and a traditional Chinese medicine which are administered simultaneously or sequentially, and the traditional Chinese medicine comprises Tibetan Artemisia Capillaris.

2. The combined drug for treating depression according to claim 1, characterized in that: The antidepressant includes: one or more of melatonin receptor agonists, selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs).

3. The combined drug for treating depression according to claim 2, characterized in that: The mass ratio of antidepressants to Tibetan Artemisia Capillaris is 0.01-0.02:6.38-19.

14.

4. The combined drug for treating depression according to claim 2, characterized in that: The melatonin receptor agonist is agomelatine; the selective serotonin reuptake inhibitors SSRIs include: one or more of fluvoxamine, fluoxetine, paroxetine, escitalopram and sertraline hydrochloride; the serotonin and norepinephrine reuptake inhibitors SNRIs include: one or more of duloxetine, milnacipran and venlafaxine hydrochloride.

5. The combined drug for treating depression according to claim 4, characterized in that: The selective serotonin reuptake inhibitor SSRIs is sertraline hydrochloride.

6. The combined drug for treating depression according to claim 4, characterized in that: The 5-hydroxytryptamine and norepinephrine reuptake inhibitor SNRIs is venlafaxine hydrochloride.

7. Use of the combined drug according to any one of claims 1 to 6 in the preparation of a drug for treating liver damage caused by antidepressants.

8. Use of the Tibetan Artemisia Capillaris in the combined drug according to any one of claims 1 to 6 in the preparation of drugs for treating liver damage caused by antidepressants and improving the antidepressant effect.

9. The use according to claim 7 or 8, characterized in that: The antidepressant is selected from one or more of melatonin receptor agonists, selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs).

10. The use according to claim 6 or 7, characterized in that: The mass ratio of the antidepressant to the Tibetan Artemisia Capillaris in the combined drug is 0.01-0.02:6.38-19.14.

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