Compound preparation for treating depression

Abstract

The invention provides the composite injection containing ketamine and citalopram, and when the composite injection is used for treating depressive disorder, the composite injection takes effect more quickly and responds more accurately, the effect delay period can be further shortened, and the anti-depression curative effect can be further improved. And the medicine is more convenient to take, and the medication compliance is greatly improved.

Description

[0001] This application claims the benefit of priority of the following prior patent applications:

[0002] The applicant's prior application, filed with the State Intellectual Property Office of China on March 6, 2024, with patent application number 202410255973.3, entitled "A composite preparation for treating depression";

[0003] The entire contents of the above-mentioned prior patent applications are incorporated into this application by reference. Technical Field

[0004] The present invention relates to a compound preparation for treating depression. Background Art

[0005] Depression is a common and devastating mental disorder, requiring effective medications and treatment options. During the lag phase before conventional antidepressants show clinical efficacy, patients are at risk of suicide. Current medications and treatment options are inadequately addressing this issue. Therefore, there is a continued need for medications and treatment options that can improve antidepressant efficacy, shorten the lag phase, and reduce suicidal behavior during the early stages of antidepressant treatment. Summary of the Invention

[0006] In order to improve the above technical problems, the present invention provides a composite injection of ketamine and citalopram and its use in treating depression.

[0007] The present invention provides a compound injection, which comprises the following components:

[0008] 1) ketamine or a pharmaceutically acceptable salt thereof;

[0009] 2) Citalopram or a pharmaceutically acceptable salt thereof.

[0010] According to an embodiment of the present invention, the mass ratio of ketamine to citalopram is 1:100-100:1, preferably 1:50-50:1, more preferably 1:20-20:1, 1:10-10:1, for example 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5.

[0011] According to an embodiment of the present invention, the compound injection is used to prevent, alleviate or treat depression.

[0012] According to an embodiment of the present invention, the depression is major depressive disorder; further preferably, the major depressive disorder is a first-onset major depressive disorder, recurrent major depressive disorder, and refractory depression. According to an embodiment of the present invention, the major depressive disorder is a first-onset major depressive disorder.

[0013] According to an embodiment of the present invention, the depression is major depression, unipolar depression, refractory depression, intractable depression, anxious depression, or bipolar depression.

[0014] According to an embodiment of the present invention, the compound injection solution is administered by intravenous injection.

[0015] According to an embodiment of the present invention, the compound injection solution is an intravenous injection dosage form.

[0016] According to an embodiment of the present invention, the pharmaceutically acceptable salt of ketamine is ketamine hydrochloride. According to an embodiment of the present invention, the pharmaceutically acceptable salt of citalopram is citalopram hydrobromide or citalopram oxalate.

[0017] According to an embodiment of the present invention, in the compound injection, the dosage of ketamine or a pharmaceutically acceptable salt thereof is 0.5 mg / kg ketamine or a salt thereof, or 0.25 mg / kg S-(+)ketamine or a salt thereof.

[0018] According to an embodiment of the present invention, in the compound injection, the dosage of citalopram or a pharmaceutically acceptable salt thereof is 20-60 mg / day, preferably 20-40 mg / day; the dosage of escitalopram or a pharmaceutically acceptable salt thereof is 10-20 mg / day, preferably 10 mg / day; more preferably 10 mg / day of citalopram or a pharmaceutically acceptable salt thereof.

[0019] According to an embodiment of the present invention, the concentration of ketamine or a pharmaceutically acceptable salt thereof is 0.01 mg / mL-100 mg / mL, preferably 0.1 mg / mL-80 mg / mL, more preferably 1 mg / mL-50 mg / mL, for example 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL.

[0020] According to an embodiment of the present invention, the concentration of citalopram or a pharmaceutically acceptable salt thereof is 0.01 mg / mL-100 mg / mL, preferably 0.1 mg / mL-50 mg / mL, more preferably 1 mg / mL-30 mg / mL, for example 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL.

[0021] According to an embodiment of the present invention, the compound injection solution optionally further comprises a pH regulator.

[0022] According to an embodiment of the present invention, the pH adjuster is selected from inorganic acids or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, citric acid, fumaric acid, malic acid, maleic acid, etc.

[0023] According to an embodiment of the present invention, the pH value of the compound injection is 2.0-5.0, preferably 3.0-4.0, such as 3.5.

[0024] According to an embodiment of the present invention, the composite injection solution optionally further comprises a stabilizer, such as sorbitol.

[0025] According to an embodiment of the present invention, the concentration of the stabilizer is 5 mg / mL-100 mg / mL, preferably 10 mg / mL-50 mg / mL, for example 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 37.9 mg / mL, 40 mg / mL, 45 mg / mL.

[0026] According to an embodiment of the present invention, the compound injection solution optionally further comprises an osmotic pressure regulator, such as sodium chloride.

[0027] According to an embodiment of the present invention, the concentration of the osmotic pressure regulator is 1 mg / mL-30 mg / mL, preferably 5 mg / mL-20 mg / mL, for example 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 15 mg / mL.

[0028] According to an embodiment of the present invention, the compound injection solution optionally further comprises a solvent; preferably, the solvent is water, such as water for injection.

[0029] According to an embodiment of the present invention, the volume of the compound injection is 500mL-5000mL, preferably 1000mL-4000mL, for example 1000mL, 1500mL, 2000mL, 2500mL, 3000mL, 3500mL, 4000mL.

[0030] According to an embodiment of the present invention, the compound injection (2000 mL) comprises the following components:

[0031] 20 g of citalopram or a pharmaceutically acceptable salt thereof (calculated as citalopram);

[0032] 20g-60g of ketamine or a pharmaceutically acceptable salt thereof (calculated as ketamine);

[0033] Adjust the pH to 3.5 with acid and add water to 2000 mL.

[0034] According to an embodiment of the present invention, the compound injection (2000 mL) comprises the following components:

[0035] 20 g of citalopram or a pharmaceutically acceptable salt thereof (calculated as citalopram);

[0036] 20g-60g of ketamine or a pharmaceutically acceptable salt thereof (calculated as ketamine);

[0037] Stabilizer (e.g., sorbitol) 75.8g;

[0038] Osmotic pressure regulator (e.g., sodium chloride) 22g;

[0039] Adjust the pH to 3.5 with acid and add water to 2000 mL.

[0040] According to an embodiment of the present invention, the compound injection (2000mL) includes the following components: citalopram 20g, ketamine 20g, hydrochloric acid adjusts pH to 3.5, and the remainder is water for injection. According to an embodiment of the present invention, the compound injection (2000mL) includes the following components: citalopram 20g, ketamine 40g, hydrochloric acid adjusts pH to 3.5, and the remainder is water for injection. According to an embodiment of the present invention, the compound injection (2000mL) includes the following components: citalopram 20g, ketamine 60g, hydrochloric acid adjusts pH to 3.5, and the remainder is water for injection.

[0041] According to an embodiment of the present invention, the compound injection (2000mL) includes the following components: citalopram 10g, ketamine 10g, sorbitol 75.8g, sodium chloride 22g, acetic acid adjusts pH value to 3.5, and the remainder is water for injection. According to an embodiment of the present invention, the compound injection (2000mL) includes the following components: citalopram 10g, ketamine 20g, sorbitol 75.8g, sodium chloride 22g, acetic acid adjusts pH value to 3.5, and the remainder is water for injection. According to an embodiment of the present invention, the compound injection (2000mL) includes the following components: citalopram 10g, ketamine 30g, sorbitol 75.8g, sodium chloride 22g, acetic acid adjusts pH value to 3.5, and the remainder is water for injection.

[0042] The present invention also provides a method for preparing the above-mentioned composite injection, which comprises the following steps:

[0043] Ketamine or a pharmaceutically acceptable salt thereof, citalopram or a pharmaceutically acceptable salt thereof, and optional excipients are mixed to obtain the compound injection.

[0044] The present invention also provides a freeze-dried powder injection, which is prepared by freeze-drying the above-mentioned composite injection.

[0045] The present invention also provides use of the above-mentioned compound injection and the above-mentioned freeze-dried powder injection in the preparation of medicines for preventing, alleviating or treating depression.

[0046] According to an embodiment of the present invention, the depression is major depressive disorder; further preferably, the major depressive disorder is a first-onset major depressive disorder, recurrent major depressive disorder, and refractory depression. According to an embodiment of the present invention, the major depressive disorder is a first-onset major depressive disorder.

[0047] According to an embodiment of the present invention, the depression is major depression, unipolar depression, refractory depression, intractable depression, anxious depression, or bipolar depression.

[0048] The present invention also provides a method for preventing, alleviating or treating depression, which comprises administering a therapeutically effective amount of the above-mentioned compound injection or the above-mentioned freeze-dried powder injection to a patient.

[0049] According to an embodiment of the present invention, the depression is major depressive disorder; further preferably, the major depressive disorder is a first-onset major depressive disorder, recurrent major depressive disorder, and refractory depression. According to an embodiment of the present invention, the major depressive disorder is a first-onset major depressive disorder.

[0050] According to an embodiment of the present invention, the depression is major depression, unipolar depression, refractory depression, intractable depression, anxious depression, or bipolar depression.

[0051] Beneficial effects

[0052] The present invention provides a compound injection containing ketamine and citalopram. This compound injection, when used to treat depressive disorders, exhibits faster onset, more precise response, a shorter lag phase for onset of effect, and enhanced antidepressant efficacy. Furthermore, it is more convenient to administer, significantly improving medication compliance. Furthermore, the compound injection exhibits high stability, contains acceptable levels of intermediates and visible foreign matter, and has a simple preparation process. DETAILED DESCRIPTION

[0053] The term "pharmaceutically acceptable salt" refers to a salt made from a pharmaceutically acceptable nontoxic acid (including inorganic or organic acid). The compound of the present invention can be a monosalt, a disalt or a trisalt, depending on the number of acidic functional groups present in the free base form of the compound. As an example, the acid includes acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucose, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, tartaric acid, p-toluenesulfonic acid, etc.

[0054] Ketamine's chemical name is 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. Ketamine is a racemic mixture, and its S-enantiomer, (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, also known as S-(+)-ketamine, has higher potency or affinity for NMDA receptors, thus allowing for lower doses to be used in treatment. Ketamine and S-(+)-ketamine, as well as their pharmaceutically acceptable salts, can all be used in the present invention. Preferably, the pharmaceutically acceptable salt of ketamine or (S)-(+)-ketamine is a hydrochloride.

[0055] The chemical name of Citalopram is 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, and commonly used pharmaceutically acceptable salts include hydrobromide or oxalate. Citalopram has two enantiomers, S-type and R-type, in which a basic site on the 5HT receptor can bind to S-type citalopram and thus produce therapeutic effects. S-type citalopram is also known as escitalopram, and its chemical name is S(+)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, and commonly used pharmaceutically acceptable salts are its oxalate. Citalopram, escitalopram, and their pharmaceutically acceptable salts can all be used in the present invention. Preferably, the pharmaceutically acceptable salt of citalopram is hydrobromide or oxalate; the pharmaceutically acceptable salt of escitalopram is oxalate.

[0056] In the present invention, ketamine, S-(+)-ketamine, or pharmaceutically acceptable salts thereof, such as hydrochloride, are referred to as ketamine compounds.

[0057] In the present invention, citalopram, escitalopram, or pharmaceutically acceptable salts thereof, such as hydrobromide or oxalate, are referred to as citalopram compounds.

[0058] In the present invention, the major depressive disorder can be a first-time episode, that is, the first time depression occurs and is diagnosed as a major depressive disorder; it can also be a recurrent episode, that is, a recurrence after a period of relief from the first episode; it can also be refractory, that is, a major depressive disorder that is ineffective or ineffective in response to two or more adequate antidepressant treatments.

[0059] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0060] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0061] Example 1 Preparation of Citalopram Injection

[0062] Citalopram hydrobromide 10.0g (calculated as citalopram)

[0063] Appropriate amount of hydrochloric acid (adjust pH to 2.0-5.0)

[0064] Add water for injection to 2000mL

[0065] Take the appropriate amount of water for injection in the prescribed amount, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Adjust the pH to 2.0-5.0 with hydrochloric acid, and top up with water. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and sterilized at 121°C for 15 minutes. If it passes inspection for visible foreign matter, it is ready.

[0066] Example 2 Preparation of Citalopram Injection

[0067] Citalopram hydrobromide 20.0g (calculated as citalopram)

[0068] An appropriate amount of acetic acid (adjust pH to 2.0-5.0)

[0069] Add water for injection to 2000mL

[0070] Take the appropriate amount of water for injection, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Adjust the pH to 2.0-5.0 with acetic acid, and top up with water. Filter to remove pyrogens, and test the intermediate for compliance. If the qualified liquid intermediate is sealed in a 2mL glass ampoule, sterilize at 121°C for 15 minutes, and inspect for visible foreign matter, the product is ready.

[0071] Example 3 Preparation of Citalopram Injection

[0072] Citalopram hydrobromide 40.0g (calculated as citalopram)

[0073] An appropriate amount of acetic acid (adjust pH to 2.0-5.0)

[0074] Add water for injection to 2000mL

[0075] Take the appropriate amount of water for injection, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Adjust the pH to 2.0-5.0 with acetic acid, and top up with water. Filter to remove pyrogens, and test the intermediate for compliance. If the qualified liquid intermediate is sealed in a 2mL glass ampoule, sterilize at 121°C for 15 minutes, and inspect for visible foreign matter, the product is ready.

[0076] Example 4 Preparation of Citalopram Injection

[0077] Citalopram hydrobromide 20.0g (calculated as citalopram)

[0078] Appropriate amount of hydrochloric acid (adjust pH to 2.0-5.0)

[0079] Add water for injection to 2000mL

[0080] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Adjust the pH to 2.0-5.0 with hydrochloric acid, and top up with water. Sterile filter and test the intermediate for compliance. If the qualified liquid intermediate passes inspection for visible foreign matter, seal it in a 2mL glass ampoule.

[0081] Example 5 Preparation of Citalopram Injection

[0082] Citalopram hydrobromide 20.0g (calculated as citalopram)

[0083] An appropriate amount of acetic acid (adjust pH to 2.0-5.0)

[0084] Add water for injection to 2000mL

[0085] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Adjust the pH to 2.0-5.0 with acetic acid, and top up with water. Sterile filter and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and inspected for visible foreign matter.

[0086] Example 6 Preparation of Escitalopram Oxalate Injection

[0087] Escitalopram oxalate 5.0g (calculated as citalopram)

[0088] Appropriate amount of hydrochloric acid (adjust pH to 2.0-5.0)

[0089] Add water for injection to 2000mL

[0090] Take the appropriate amount of water for injection in the prescribed amount, add the prescribed amount of escitalopram oxalate, and stir to dissolve. Adjust the pH to 2.0-5.0 with hydrochloric acid, and top up with water. Filter to remove pyrogens, and test the intermediate for compliance. If the qualified liquid intermediate is sealed in a 2mL glass ampoule, sterilize at 121°C for 15 minutes, and inspect for visible foreign matter, the product is ready.

[0091] Example 7 Preparation of Escitalopram Oxalate Injection

[0092] Escitalopram oxalate 10.0g (calculated as citalopram)

[0093] An appropriate amount of acetic acid (adjust pH to 2.0-5.0)

[0094] Add water for injection to 2000mL

[0095] Take the appropriate amount of water for injection and add the prescribed amount of escitalopram oxalate, stirring to dissolve. Adjust the pH to 2.0-5.0 with acetic acid and top up with water. Filter to remove pyrogens and test the intermediate for compliance. If the qualified liquid intermediate is sealed in a 2mL glass ampoule, sterilize at 121°C for 15 minutes, and inspect for visible foreign matter, the product is ready.

[0096] Example 8 Preparation of Escitalopram Oxalate Injection

[0097] Escitalopram oxalate 20.0g (calculated as citalopram)

[0098] An appropriate amount of acetic acid (adjust pH to 2.0-5.0)

[0099] Add water for injection to 2000mL

[0100] Take the appropriate amount of water for injection and add the prescribed amount of escitalopram oxalate, stirring to dissolve. Adjust the pH to 2.0-5.0 with acetic acid and top up with water. Filter to remove pyrogens and test the intermediate for compliance. If the qualified liquid intermediate is sealed in a 2mL glass ampoule, sterilize at 121°C for 15 minutes, and inspect for visible foreign matter, the product is ready.

[0101] Example 9 Preparation of Escitalopram Oxalate Injection

[0102] Escitalopram oxalate 10.0g (calculated as citalopram)

[0103] Appropriate amount of hydrochloric acid (adjust pH to 2.0-5.0)

[0104] Add water for injection to 2000mL

[0105] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of escitalopram oxalate, and stir to dissolve. Adjust the pH to 2.0-5.0 with hydrochloric acid, and top up with water. Sterile filter and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and inspected for visible foreign matter.

[0106] Example 10 Preparation of Escitalopram Oxalate Injection

[0107] Escitalopram oxalate 10.0g (calculated as citalopram)

[0108] An appropriate amount of acetic acid (adjust pH to 2.0-5.0)

[0109] Add water for injection to 2000mL

[0110] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of escitalopram oxalate, and stir to dissolve. Adjust the pH to 2.0-5.0 with ethyl hydrochloric acid, and add water to the full volume. Sterile filter and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and inspected for visible foreign matter.

[0111] Example 11 Preparation of Citalopram for Injection

[0112]

[0113]

[0114] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Then, sequentially add the prescribed amount of sorbitol, sodium chloride, and acetic acid, stir, and top up with water. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is placed in a 5 mL vial, sealed with a stopper, and freeze-dried to a water content of less than 0.1%.

[0115] Example 12 Preparation of Escitalopram Oxalate for Injection

[0116]

[0117] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram hydrobromide, and stir to dissolve. Add the prescribed amount of sorbitol and sodium chloride, stir, adjust the pH to 3.5 with hydrochloric acid, and top up with water. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is placed in a 5 mL vial, sealed with a stopper, and freeze-dried to a water content of less than 0.1%.

[0118] Example 13 Preparation of Citalopram Ketamine Injection

[0119]

[0120] Take the appropriate amount of water for injection in the prescribed amount, add the prescribed amount of citalopram hydrobromide and ketamine hydrochloride, stir to dissolve, adjust the pH to 3.5 with hydrochloric acid, and add water to the full volume. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and sterilized at 121°C for 15 minutes. If it passes the inspection for visible foreign matter, it is ready.

[0121] Example 14 Preparation of Escitalopram Ketamine for Injection

[0122]

[0123] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram oxalate and ketamine hydrochloride, and stir to dissolve. Then, add the prescribed amount of sorbitol and sodium chloride, stir, adjust the pH to 3.5 with acetic acid, and add water to the full volume. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is placed in a 5 mL vial, sealed with a stopper, and freeze-dried to a water content of less than 0.1%.

[0124] Example 15 Preparation of Citalopram Ketamine Injection

[0125]

[0126] Take the appropriate amount of water for injection in the prescribed amount, add the prescribed amount of citalopram hydrobromide and ketamine hydrochloride, stir to dissolve, adjust the pH to 3.5 with hydrochloric acid, and add water to the full volume. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and sterilized at 121°C for 15 minutes. If it passes the inspection for visible foreign matter, it is ready.

[0127] Example 16 Preparation of Escitalopram Ketamine for Injection

[0128]

[0129] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram oxalate and ketamine hydrochloride, and stir to dissolve. Then, add the prescribed amount of sorbitol and sodium chloride, stir, adjust the pH to 3.5 with acetic acid, and add water to the full volume. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is placed in a 5 mL vial, sealed with a stopper, and freeze-dried to a water content of less than 0.1%.

[0130] Example 17 Preparation of Citalopram Ketamine Injection

[0131]

[0132] Take the appropriate amount of water for injection in the prescribed amount, add the prescribed amount of citalopram hydrobromide and ketamine hydrochloride, stir to dissolve, adjust the pH to 3.5 with hydrochloric acid, and add water to the full volume. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is sealed in a 2mL glass ampoule and sterilized at 121°C for 15 minutes. If it passes the inspection for visible foreign matter, it is ready.

[0133] Example 18 Preparation of Escitalopram Ketamine for Injection

[0134]

[0135] Take an appropriate amount of the prescribed amount of water for injection, add the prescribed amount of citalopram oxalate and ketamine hydrochloride, and stir to dissolve. Then, add the prescribed amount of sorbitol and sodium chloride, stir, adjust the pH to 3.5 with acetic acid, and add water to the full volume. Filter to remove pyrogens, and test the intermediate for compliance. The qualified liquid intermediate is placed in a 5 mL vial, sealed with a stopper, and freeze-dried to a water content of less than 0.1%.

[0136] Example 19 Evaluation of the rat depression model induced by olfactory bulbectomy

[0137] Olfactory bulbectomy is the most commonly used surgical method for modeling depression in animals, consistent with the neurochemical alterations seen in patients with depression. The olfactory bulbectomy model is known for its stability, lack of drug interactions, and minimal experimental error, making it a classic model for evaluating the efficacy of antidepressant drugs in animals.

[0138] 1) Animal modeling

[0139] Two hundred quarantined WKY rats weighing 180-220 g were randomly divided into a normal control group and a model group. In addition to the control group, the model group rats were anesthetized with isoflurane and fixed in a stereotaxic apparatus. The skin of the rat heads was disinfected with iodine and cut open to expose the three sutures (coronal, sagittal, and lambdoid) and the two bregma (anterior and posterior). After removing the periosteum, two holes approximately 2 mm in diameter were drilled with an electric bone drill 2 mm on either side of the midline 8 mm in front of the anterior bregma. The olfactory bulb was destroyed with a special blunt needle and then aspirated. The wounds were packed with hemostatic packing, sealed with bone wax, and treated with anti-infection agents before the skin was sutured.

[0140] 2) Animal grouping

[0141] After 14 days of postoperative recovery in single-cage feeding, the surviving rats were randomly divided into 10 groups according to the sucrose preference index, namely, normal control group, model control group, ketamine injection group 1 and ketamine injection group 2, citalopram oral administration group (i.e., escitalopram oxalate oral administration group), citalopram injection group (escitalopram oxalate injection group), ketamine injection + citalopram oral administration group 1 and ketamine injection + citalopram oral administration group 2, ketamine + citalopram combined injection group 1 and ketamine + citalopram combined injection group 2, with 20 rats in each group. Rats in the normal and model control groups were gavaged with distilled water, while rats in the remaining groups received the corresponding drug solutions either gavage or intravenously. Citalopram was administered orally by grinding citalopram tablets into a powder and then suspending them in 0.1% sodium carboxymethylcellulose solution at a dose of 10 mL / kg. Ketamine was administered by injection, dissolving ketamine in 0.9% sodium chloride saline for injection. All doses were calculated based on the intended human clinical dosage and weight, administered once daily for 28 consecutive days. Behavioral testing was performed 14 and 28 days after administration. Groups and dosages are shown in Table 1.

[0142] Table 1 Animal grouping and dosage design

[0143]

[0144] 3) Detection indicators

[0145] Sugar Water Preference Test: The experiment consisted of a training phase and a testing phase. During the training phase, animals were acclimated to sucrose drinking water. For the first 24 hours, they were given two bottles of 1% sucrose water. For the second 24 hours, they were given one bottle of 1% sucrose water and one bottle of pure water. They were not fasted or watered for 8 hours before the test. During the testing phase, animals were also given one bottle of 1% sucrose water and one bottle of pure water for 24 hours. To minimize the influence of positional preference, the two bottles were swapped during the test. At the end of the test, the sugar water preference index was calculated: sugar water preference index = sugar water consumption / (sugar water consumption + pure water consumption) × 100%.

[0146] Rat marble burying test: Prepare a clear plastic cage approximately 40cm x 25cm x 20cm. Cover the cage floor with approximately 5cm of sawdust or other suitable bedding material. Randomly place 12-20 marbles approximately 1.5cm in diameter in the cage. Ensure that the marbles are equidistant from each other and from the edge of the cage. Place the rat in the cage and allow it to acclimate to its new environment for 10-15 minutes. Observe the rat's burying behavior for 30 minutes. Behavioral data can be recorded in real time or with a camera. At the end of the test, record the number of marbles buried by the rat. A marble is considered buried if at least two-thirds of it is covered in sawdust. Statistical analysis of the experimental data is performed to assess the rat's anxiety level. Mice that bury a large number of marbles may have higher anxiety levels.

[0147] Forced swimming test: The JL Behv forced swimming video analysis system was used to detect the immobility and activity time of rats within 5 minutes.

[0148] 4) Data processing and statistical analysis

[0149] The significant figures of the experimental data were rounded off and statistical analysis was performed in accordance with the "Statistical Processing of Experimental Data" (SOP-Rd-003). The statistical software used was SPSS. The measurement data were expressed as mean ± standard deviation. Normality and homogeneity of variance were tested using the Leven's test. If there was no statistical significance (P>0.05), one-way analysis of variance (ANOVA) was used for statistical analysis. If the ANOVA was statistically significant (P≤0.05), the LSD test (parametric method) was used for comparative analysis. If the variances were unequal (P≤0.05), the Kruskal-Wallis test was used. If the Kruskal-Wallis test was statistically significant (P≤0.05), the Dunnett's test (nonparametric method) was used for comparative analysis. Statistical results were tested with an α=0.05 threshold, where P≤0.05 indicated statistical significance and P≤0.01 indicated that the difference being tested was highly significant.

[0150] 5) Experimental results

[0151] 5.1) Effects on the sugar preference index in the olfactory bulbectomized rat depression model

[0152] As shown in Table 2, compared with the normal control group, the sucrose preference index of rats in the model control group was significantly decreased (P ≤ 0.01). Compared with the model control group, the sucrose preference index of rats in ketamine injection groups 1 and 2, ketamine injection + citalopram oral administration groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 was significantly increased (P ≤ 0.05 or P ≤ 0.01). Among them, ketamine injection groups 1 and 2 achieved effective effects on day 28 (P ≤ 0.05); ketamine injection + citalopram oral administration groups 1 and 2 also showed effective therapeutic effects on day 28 (P ≤ 0.05); and ketamine + citalopram combined injection groups 1 and 2 showed significant therapeutic effects on day 14 (P ≤ 0.01), reaching the level of the normal control group and maintaining this level until day 28. This shows that the combination of ketamine and citalopram has significant efficacy, and the onset time of the combined injection of the two has a faster onset time and better therapeutic effect than the injection + oral administration regimen.

[0153] Table 2 Effects of different groups on the sugar water preference test in olfactory bulbectomized rats ( n=20)

[0154]

[0155] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0156] 5.2) Effects on the immobility time of forced swimming in rats

[0157] As shown in Table 3, compared with the normal control group, the forced swimming immobility time of rats in the model control group was significantly increased (P ≤ 0.01). Compared with the model control group, the forced swimming immobility time of rats in ketamine injection groups 1 and 2, ketamine injection + citalopram oral administration groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 were significantly reduced (P ≤ 0.05 or P ≤ 0.01). Among them, ketamine injection groups 1 and 2 achieved effective effects by day 28 (P ≤ 0.05); ketamine injection + citalopram oral administration groups 1 and 2 showed effective therapeutic effects on day 28 (P ≤ 0.05); and ketamine + citalopram combined injection groups 1 and 2 showed significant therapeutic effects on day 14 (P ≤ 0.01) and maintained this level until day 28. This shows that the combination of ketamine and citalopram has significant efficacy, and the onset time of the combined injection of the two has a faster onset time and better therapeutic effect than the injection + oral administration regimen.

[0158] Table 3 Effects of different groups on the immobility time of forced swimming in rats ( n=20)

[0159]

[0160] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, **P≤0.01.

[0161] 5.3) Effects of marble burying in olfactory bulbectomized rats

[0162] As shown in Table 4, compared with the normal control group, the number of marbles buried in the model control group was significantly increased (P ≤ 0.01). Compared with the model control group, the number of marbles buried in the olfactory bulbectomized rats in groups 1 and 2 receiving ketamine injection plus oral citalopram and in groups 1 and 2 receiving combined ketamine plus citalopram injection was significantly reduced (P ≤ 0.05 or P ≤ 0.01). Ketamine injection plus oral citalopram in groups 1 and 2 demonstrated an effective therapeutic effect on day 28 (P ≤ 0.05); ketamine plus citalopram in groups 1 and 2 demonstrated a significant therapeutic effect on day 14 (P ≤ 0.01), reaching the level of the normal control group and maintaining this level until day 28. This suggests that the combined ketamine plus citalopram treatment has significant pharmacodynamics, and the combined injection of the two has a faster onset of action and a superior therapeutic effect than the injection plus oral administration regimen.

[0163] Table 4 Effects of different groups on the marble burying test in rats with olfactory bulbectomy ( n=20)

[0164]

[0165]

[0166] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, **P≤0.01

[0167] Example 20: Evaluation of drug efficacy in non-human primate models

[0168] Non-human primates share a high degree of genetic homology with humans, and animal models developed using these species can generally mirror the results of human clinical trials. To assess the potential therapeutic effects of different drug combinations in humans, this application further evaluated the efficacy of drugs using a non-human primate depression model. Using marmosets as model animals, chronic social isolation was used to induce a depressive-like state in common marmosets, and the drug's efficacy was then assessed by observing depression-related behavioral indicators.

[0169] 1) Experimental animals and models

[0170] The experimental animals were marmosets, half male and half female, that had not previously participated in any disease modeling. These animals lived with their families in an outdoor masonry enclosure (2.0X2.0X1.0m) under natural light, humidity, and temperature conditions. 3 ). The front of each enclosure is a one-way glass wall, while the back wall contains a wire mesh door through which food and water can be obtained. Each enclosure has a nesting box, as well as wooden boards and branches to enrich the environment and allow free movement. During the 4-week baseline phase (BL), the behavior of the marmosets was observed and fecal cortisol was measured every other day. Social isolation was used to induce depression. The specific modeling process was as follows: the animals were removed from their family and isolated in a smaller breeding box (1.0X2.0X1.0m 3 ). These isolated animals had auditory and olfactory contact with conspecifics living in the enclosure, but no visual contact. Social isolation (IC) lasted for 8 weeks, with behavioral indicators including self-grooming time, sleepiness, eating habits, sucrose intake frequency, scratching time, and piloerection time being monitored during the first and final weeks. Animals with significant differences in any of these indicators compared to normal animals were considered successful models.

[0171] 2) Animal grouping

[0172] A total of 120 animals with successful modeling were randomly divided into three groups for treatment: normal control group, model control group, ketamine injection group 1 and ketamine injection group 2, citalopram oral administration group (i.e., escitalopram oxalate oral administration group), citalopram injection group (escitalopram oxalate injection group), ketamine injection + citalopram oral group 1 and ketamine injection + citalopram oral group 2, ketamine + citalopram combined injection group 1 and ketamine + citalopram combined injection group 2, with 12 animals in each group. Rats in the normal and model control groups were gavaged with distilled water, while rats in the remaining groups received the corresponding drug solutions gavage or intravenously. Oral administration of citalopram consisted of a powdered citalopram tablet suspended in 0.1% sodium carboxymethylcellulose solution at a dose of 10 mL / kg. Ketamine injections consisted of ketamine dissolved in 0.9% sodium chloride saline for injection. All doses were calculated based on the intended human clinical dose and animal body weight. Administration was once daily for seven consecutive days, with behavioral assessments performed on the day of the last dose and on the seventh day. Anhedonia was measured by the frequency of ingestion of a 4.16% sucrose solution. To minimize the influence of circadian rhythm fluctuations, all tests were performed within 30 minutes between 6:30 and 7:30 AM. Animal grouping and dosing schedule are shown in Table 5.

[0173] Table 5 Animal grouping and dosage design

[0174]

[0175] 3) Detection indicators

[0176] The detection indicators mainly include behavioral indicators closely related to the depressive state of animals, such as self-grooming time, sleepiness, eating conditions, sucrose intake frequency, scratching time, and hair erection time. Throughout the study, water was provided ad libitum, and the animals were fed the same diet twice a day, which included seasonal fruits such as bananas, papayas, watermelons, and mangoes, as well as potatoes and a protein mixture containing milk, oats, eggs, and bread. Twice a week, a multivitamin supplement was diluted into the food. The animals were weighed every 15 days to monitor their health.

[0177] 4) Data processing and statistical analysis

[0178] Data were normalized using logarithmic transformation, and bootstrap resampling statistical techniques were applied to multivariate analyses of behavioral data. Behavioral changes across study phases were analyzed using generalized linear models (GLM) and Fisher's post hoc test (least significant difference [LSD]). Additionally, parametric Student's t-tests were used to analyze behavioral data between specific phases. Differences were considered statistically significant at p < 0.05.

[0179] 5) Experimental results

[0180] 5.1) Impact on the self-grooming time of animals

[0181] As shown in Table 6, self-grooming time was significantly reduced in the model control group compared with the normal control group (P ≤ 0.01), consistent with a decrease in self-appreciation after depression. Compared with the model control group, self-grooming time was significantly increased in ketamine injection groups 1 and 2, ketamine injection + citalopram oral groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 (P ≤ 0.05 or P ≤ 0.01). Ketamine injection groups 1 and 2 achieved effective treatment effects on day 7 (P ≤ 0.05). Ketamine injection + citalopram oral groups 1 and 2 showed effective treatment effects on day 1 (P ≤ 0.05), but no significant improvement was observed by day 7 (P ≤ 0.05). Ketamine + citalopram combined injection groups 1 and 2 showed significant treatment effects on day 1 (P ≤ 0.01), reaching the level of the normal control group and maintaining this level until day 7. This shows that the combination of ketamine and citalopram has significant efficacy, and the onset time of the combined injection of the two has a faster onset time and better therapeutic effect than the injection + oral administration regimen.

[0182] Table 6 Effects of different groups on self-grooming time in marmosets (X ± SEM, n = 12)

[0183]

[0184] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0185] 5.2) Effects on Animal Sleep Time

[0186] Table 7 shows changes in sleep time in model animals under the influence of different drugs. Compared with the normal control group, the model control group had significantly decreased sleep time (P ≤ 0.01), an indicator of decreased sleep quality after depression. Compared with the model control group, sleep time was significantly increased in ketamine injection groups 1 and 2, ketamine injection + citalopram oral administration groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 (P ≤ 0.05 or P ≤ 0.01). Ketamine injection groups 1 and 2 achieved effective effects on day 7 (P ≤ 0.05); ketamine injection + citalopram oral administration groups 1 and 2 also demonstrated effective therapeutic effects on day 7 (P ≤ 0.05); and ketamine + citalopram combined injection groups 1 and 2 demonstrated significant therapeutic effects on day 1 (P ≤ 0.01), reaching the level of the normal control group and maintaining this level until day 7. This shows that the combination of ketamine and citalopram has significant efficacy, and the onset time of the combined injection of the two has a faster onset time and better therapeutic effect than the injection + oral administration regimen.

[0187] Table 7 Effects of different groups on sleep time of marmosets (X±SEM, n=12)

[0188]

[0189] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0190] 5.3) Impact on animal eating time

[0191] Table 8 shows the feeding time of animals in different groups. Compared with the normal control group, the model control group had a significantly decreased feeding time (P ≤ 0.01), consistent with decreased appetite after depression. Compared with the model control group, the feeding time of ketamine injection groups 1 and 2, ketamine injection + citalopram oral administration groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 was significantly increased (P ≤ 0.05 or P ≤ 0.01). Ketamine injection groups 1 and 2 achieved an effective effect on day 7 (P ≤ 0.05). Ketamine injection + citalopram oral administration groups 1 and 2 showed an effective therapeutic effect on day 1 (P ≤ 0.05), but did not significantly increase by day 7 (P ≤ 0.05). Ketamine + citalopram combined injection groups 1 and 2 showed a significant therapeutic effect on day 1 (P ≤ 0.01), reaching the level of the normal control group and maintaining this level until day 7. This shows that the combination of ketamine and citalopram has significant efficacy, and the onset time of the combined injection of the two has a faster onset time and better therapeutic effect than the injection + oral administration regimen.

[0192] Table 8 Effects of different groups on the feeding time of marmosets (X ± SEM, n = 12)

[0193]

[0194] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0195] 5.4) Effects on the frequency of sucrose intake in animals

[0196] The effects of different drug treatments on sucrose intake frequency are shown in Table 9. Compared with the normal control group, the model control group showed a significant decrease in sucrose intake frequency (P ≤ 0.01), consistent with a decrease in reward-seeking desire after depression. Compared with the model control group, the ketamine injection group 1 and 2, the ketamine injection + citalopram oral group 1 and 2, and the ketamine + citalopram combined injection group 1 and 2 showed a significant increase in sucrose intake frequency (P ≤ 0.05 or P ≤ 0.01). Ketamine injection groups 1 and 2 showed effective therapeutic effects on day 1 (P ≤ 0.05), but there was no significant improvement on day 7 (P ≤ 0.05). Ketamine injection + citalopram oral administration groups 1 and 2 showed effective therapeutic effects on day 1 (P ≤ 0.05), which significantly improved on day 7 (P ≤ 0.01). Ketamine + citalopram combined injection groups 1 and 2 showed significant therapeutic effects on day 1 (P ≤ 0.01), reaching the level of the normal control group, and maintained this level until day 7. This indicates that the combination of ketamine and citalopram has significant pharmacodynamics, and the onset of action of the combined injection of the two has a faster onset time than the injection + oral administration regimen.

[0197] Table 9 Effects of different groups on the frequency of sucrose intake in marmosets (X ± SEM, n = 12)

[0198]

[0199] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0200] 5.5) Effect on the Animal's Scratching Time

[0201] Table 10 shows the changes in scratching time in animals following drug treatment. Compared with the normal control group, the model control group had a significant increase in scratching time (P ≤ 0.01), consistent with increased anxiety following depression. Compared with the model control group, scratching time was significantly reduced in ketamine injection groups 1 and 2, ketamine injection + citalopram oral administration groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 (P ≤ 0.05 or P ≤ 0.01). Ketamine injection groups 1 and 2 showed an effective therapeutic effect on day 7 (P ≤ 0.05); ketamine injection + citalopram oral administration groups 1 and 2 showed an effective therapeutic effect on day 1 (P ≤ 0.05), but this effect did not improve by day 7 (P ≤ 0.05); and ketamine + citalopram combined injection groups 1 and 2 showed a significant therapeutic effect on day 1 (P ≤ 0.01), reaching the level of the normal control group and maintaining this level until day 7. This shows that the combination of ketamine and citalopram has significant efficacy, and the onset time of the combined injection of the two has a faster onset time than the injection + oral administration regimen, and has a better therapeutic effect.

[0202] Table 10 Effects of different groups on the scratching time of marmosets (X ± SEM, n = 12)

[0203]

[0204] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0205] 5.6) Effects on the duration of animal piloerection

[0206] The effects of different drug treatments on the duration of piloerection are shown in Table 11. Compared with the normal control group, the model control group had a significant increase in piloerection time (P ≤ 0.01), consistent with post-depression emotional irritability. Compared with the model control group, piloerection time was significantly reduced in ketamine injection groups 1 and 2, ketamine injection + citalopram oral groups 1 and 2, and ketamine + citalopram combined injection groups 1 and 2 (P ≤ 0.05 or P ≤ 0.01). Among them, ketamine injection groups 1 and 2 showed effective therapeutic effects on the first day (P≤0.05), but there was no significant improvement on the seventh day (P≤0.05); ketamine injection + citalopram oral administration groups 1 and 2 showed effective therapeutic effects on the first day (P≤0.05), but there was no further improvement on the seventh day (P≤0.05); ketamine + citalopram combined injection groups 1 and 2 showed significant therapeutic effects on the first day (P≤0.01), reaching the level of the normal control group, and maintained this level until the seventh day. This shows that the combination of ketamine and citalopram has significant pharmacodynamics, and the onset time of the combined injection of the two has a faster onset time than the injection + oral administration regimen, and has a better therapeutic effect.

[0207] Table 11 Effects of different groups on the duration of piloerection in marmosets (X ± SEM, n = 12)

[0208]

[0209]

[0210] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0211] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound injection, comprising the following components: 1) ketamine or a pharmaceutically acceptable salt thereof; 2) Citalopram or a pharmaceutically acceptable salt thereof.

2. The compound injection according to claim 1, characterized in that The mass ratio of ketamine to citalopram is 1:100-100:1, preferably 1:50-50:1, more preferably 1:20-20:1, 1:10-10:

1.

3. The compound injection according to claim 1 or 2, characterized in that: In the composite injection, the dosage of ketamine or a pharmaceutically acceptable salt thereof is 0.5 mg / kg ketamine or a salt thereof, or 0.25 mg / kg S-(+)ketamine or a salt thereof; Preferably, in the compound injection, the dosage of citalopram or a pharmaceutically acceptable salt thereof is 20-60 mg / day, preferably 20-40 mg / day; the dosage of escitalopram or a pharmaceutically acceptable salt thereof is 10-20 mg / day, preferably 10 mg / day; more preferably 10 mg / day of citalopram or a pharmaceutically acceptable salt thereof.

4. The compound injection according to any one of claims 1 to 3, characterized in that: The concentration of ketamine or a pharmaceutically acceptable salt thereof is 0.01 mg / mL-100 mg / mL, preferably 0.1 mg / mL-80 mg / mL; Preferably, the concentration of citalopram or a pharmaceutically acceptable salt thereof is 0.01 mg / mL-100 mg / mL, preferably 0.1 mg / mL-50 mg / mL.

5. The compound injection according to any one of claims 1 to 4, characterized in that: The composite injection solution optionally further comprises a pH regulator; Preferably, the pH regulator is selected from inorganic acids or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, citric acid, fumaric acid, malic acid, maleic acid, etc. Preferably, the pH value of the compound injection is 2.0-5.0, preferably 3.0-4.0, such as 3.

5.

6. The compound injection according to any one of claims 1 to 5, characterized in that: The composite injection solution optionally further comprises a stabilizer, such as sorbitol; preferably, the concentration of the stabilizer is 5 mg / mL-100 mg / mL, preferably 10 mg / mL-50 mg / mL; Preferably, the compound injection optionally further comprises an osmotic pressure regulator, such as sodium chloride; preferably, the concentration of the osmotic pressure regulator is 1 mg / mL-30 mg / mL, preferably 5 mg / mL-20 mg / mL; Preferably, the composite injection solution optionally further comprises a solvent; preferably, the solvent is water, such as water for injection; Preferably, the volume of the compound injection is 500 mL-5000 mL, preferably 1000 mL-4000 mL.

7. The compound injection according to any one of claims 1 to 6, characterized in that: The compound injection (2000 mL) comprises the following components: 20 g of citalopram or a pharmaceutically acceptable salt thereof (calculated as citalopram); 20g-60g of ketamine or a pharmaceutically acceptable salt thereof (calculated as ketamine); Adjust the pH to 3.5 with acid and add water to 2000 mL; Preferably, the compound injection (2000 mL) comprises the following components: 20 g of citalopram or a pharmaceutically acceptable salt thereof (calculated as citalopram); 20g-60g of ketamine or a pharmaceutically acceptable salt thereof (calculated as ketamine); Stabilizer (e.g., sorbitol) 75.8g; Osmotic pressure regulator (such as sodium chloride) 22g; Adjust the pH to 3.5 with acid and add water to 2000 mL; Preferably, the compound injection (2000 mL) comprises the following components: 20 g of citalopram, 20 g of ketamine, hydrochloric acid adjusting the pH to 3.5, and the balance being water for injection; or, the compound injection (2000 mL) comprises the following components: 20 g of citalopram, 40 g of ketamine, hydrochloric acid adjusting the pH to 3.5, and the balance being water for injection; or, the compound injection (2000 mL) comprises the following components: 20 g of citalopram, 60 g of ketamine, hydrochloric acid adjusting the pH to 3.5, and the balance being water for injection; Preferably, the compound injection (2000 mL) comprises the following components: citalopram 10 g, ketamine 10 g, sorbitol 75.8 g, sodium chloride 22 g, acetic acid to adjust the pH to 3.5, and the balance is water for injection; or, the compound injection (2000 mL) comprises the following components: citalopram 10 g, ketamine 20 g, sorbitol 75.8 g, sodium chloride 22 g, acetic acid to adjust the pH to 3.5, and the balance is water for injection; or, the compound injection (2000 mL) comprises the following components: citalopram 10 g, ketamine 30 g, sorbitol 75.8 g, sodium chloride 22 g, acetic acid to adjust the pH to 3.5, and the balance is water for injection.

8. A method for preparing the compound injection according to any one of claims 1 to 7, comprising the following steps: Ketamine or a pharmaceutically acceptable salt thereof, citalopram or a pharmaceutically acceptable salt thereof, and optional excipients are mixed to obtain the compound injection.

9. A freeze-dried powder injection, which is prepared by freeze-drying the composite injection according to any one of claims 1 to 7.

10. Use of the compound injection according to any one of claims 1 to 7 or the freeze-dried powder injection according to claim 9 in the preparation of a drug for preventing, alleviating or treating depression; Preferably, the depression is major depressive disorder; further preferably, the major depressive disorder is first-onset major depressive disorder, recurrent major depressive disorder, and refractory depression; Preferably, the major depressive disorder is a first-episode major depressive disorder; Preferably, the depression is major depression, unipolar depression, refractory depression, intractable depression, anxious depression, or bipolar depression.

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