Depression is a mental disorder characterized by significant and prolonged feelings of low mood, accompanied by symptoms such as loss of interest, sleep disturbances, and low self-esteem. Severe cases may involve suicidal ideation or self-harming behavior. Current pharmacological treatments for depression mainly include tricyclic antidepressants, monoamine oxidase inhibitors, selective SSRIs, and dual serotonin-norepinephrine reuptake inhibitors. However, these medications often have slow onset of action, requiring several weeks or even months of continuous use, with significant side effects and lack of efficacy in about one-third of depressed patients.
Ketamine is commonly used as an anesthetic in medical practice, and in 2019, it was approved by the Food and Drug Administration (FDA) in the United States and granted breakthrough therapy designation for the treatment of treatment-resistant depression and severe depression with imminent suicide risk. Compared to traditional antidepressants, ketamine works quickly, significantly improving patient symptoms within hours of administration, and can even reduce suicidal ideation, making it one of the most important “star” molecules in the field of antidepressants in recent decades. However, ketamine can cause side effects such as dissociative hallucinations and carries a risk of addiction, greatly limiting its clinical use. Therefore, developing new antidepressants with milder side effects and rapid onset of action is the focus of many scientists worldwide.
As an NMDA (N-methyl-D-aspartate) receptor antagonist in the brain, ketamine regulates brain signaling pathways, repairing synaptic damage caused by chronic stress and facilitating rapid recovery in depression patients. Analyzing ketamine’s binding sites and mechanism of action on NMDA receptors is crucial for designing novel antidepressants.
Racemic ketamine, an NMDA antagonist, antagonizes NMDA receptors, enhances excitatory synaptic transmission and synaptic plasticity, providing rapid antidepressant effects. Preclinical trial results suggest that racemic ketamine is effective in multiple depression models and can act rapidly. Racemic ketamine is expected to have lighter psychiatric symptoms and lower addiction potential than S-ketamine.
Study Drug: Racemic Ketamine Hydrochloride Injection (Phase I/II)
Registration Number: CTR20241004
Study Type: Controlled Trial (vs. Placebo)
Indication: Depression with acute suicidal ideation or behavior
Treatment Duration
Racemic Ketamine Hydrochloride Injection Specifications: 10ml:300mg; Dosage: Intravenous infusion, 30mg, 60mg, 90mg; Administration: Intravenous infusion for 40 minutes, twice a week for 4 consecutive weeks.
Inclusion Criteria
1. Male and female subjects aged between 18-64 years at the time of signing informed consent.
2. Body Mass Index (BMI) between 18-30kg/m2 at screening, with male volunteers weighing at least 50 kg and female volunteers weighing at least 45 kg.
3. Subjects must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for depression, without psychotic features, confirmed based on clinical assessment and the Mini-International Neuropsychiatric Interview (MINI).
4. Subjects must currently have suicidal ideation and intent as confirmed by answering “yes” to MINI questions B3 [“Have you ever thought about hurting yourself (even if just for a moment): and at least had some idea or awareness that a result might be death; or thought about suicide (kill oneself)?] and B10 [“Have you thought about carrying out the idea of suicide?”].
5. Subjects must have a Montgomery-Ã…sberg Depression Rating Scale (MADRS) total score ≥28 during screening, with a score of ≥3 on item 10 “Suicidal Thoughts”.
6. Subjects must agree to receive the protocol-specified standard antidepressant therapy after randomization until the end of the double-blind treatment period.
7. Willing and able to communicate well with the researcher, understand the purpose, content, and procedures of the study, and willing to adhere to the lifestyle restrictions and complete the trial.
Exclusion Criteria
1. Subjects currently diagnosed with Bipolar Disorder (or related disorders), Personality Disorder Cluster B (e.g., Borderline Personality Disorder, Antisocial Personality Disorder, Histrionic Personality Disorder, and Narcissistic Personality Disorder), or Obsessive-Compulsive Disorder.
2. Subjects currently clinically diagnosed with Autism, Dementia, or Intellectual Disabilities.
3. Subjects currently or previously diagnosed with depressive disorders with psychotic symptoms or depressive disorders with features of psychosis according to DSM-5.
4. Subjects currently or previously clinically diagnosed with treatment-resistant depression (defined as ineffective or minimally effective treatment with two or more adequate antidepressants for ≥6 weeks).
5. Subjects who meet the DSM-5 criteria for moderate or severe substance or alcohol use disorder in the past 6 months during screening; or subjects with positive urine drug screening test results during screening.
6. Subjects with any of the following conditions: 1) Abnormal liver function (defined as ALT and/or AST ≥1.5×ULN, TBIL ≥1.5×ULN); 2) Abnormal kidney function (defined as BUN or Urea ≥1.5×ULN; Cr ≥1.2×ULN); 3) Clinically significant diseases or functional impairments in past and present medical history that the investigator determines to be of clinical significance and could affect the clinical trial, including but not limited to the central nervous system, cardiovascular system (including unstable coronary artery disease), and more.
7. Subjects with uncontrolled hypertension despite at least 2 weeks of stable antihypertensive therapy at screening (SBP >140mmHg or DBP >90mmHg); or with a history of hypertensive crisis; 1) Excluded are subjects with elevated blood pressure who may pose a serious danger (including unstable heart failure, severe cardiovascular disease, recent brain injury, increased intracranial pressure/intracranial mass lesions, intracerebral hemorrhage or acute stroke, untreated glaucoma or eye perforating injury). 2) Abnormal blood pressure values at screening can be repeated after relaxing for 5 minutes to determine if the subject meets the exclusion criteria.
8. Any surgical conditions or illnesses that may significantly affect the distribution, metabolism, and excretion of drugs or represent a potential harm to the subjects participating in the trial; such as a history of gastrointestinal surgery (gastrectomy, gastrojejunostomy, enterectomy, etc.), urinary obstruction or difficulty urinating, gastritis, peptic ulcers, gastrointestinal bleeding history, etc.
9. Use of any drugs that inhibit or induce hepatic enzymes within 1 month prior to screening (e.g., inducers—phenobarbital, rifampicin, carbamazepine, phenytoin, dexamethasone, etc.; inhibitors—fluvoxamine, S-mephenytoin, propofol, isoniazid, thiothixene, etc.).
10. Subjects who have not discontinued use of monoamine oxidase inhibitors (MAOIs) for less than 2 weeks before randomization.
11. Known allergy to any components of the investigational drug, or individuals with allergic constitution (allergy to two or more drugs or foods).
12. Lack of response to previous use of sertindole, ketamine, R-ketamine, or S-ketamine.
13. Abnormal vital signs, laboratory, and ECG parameters with clinical significance (e.g., male QTc >450ms, female QTc >470ms, corrected Fridericia formula).
14. Non-negativity for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV-Ab), HIV antibody (HIV-Ab), Syphilis spirochete antibody (TP-Ab).
15. Pregnant and lactating women; and women with potential fertility who refuse to use effective non-drug contraceptive measures throughout the study and for 3 months post-study completion (menoapusal women are considered infertile after at least 12 months of amenorrhea. Women who have confirmed tubal ligation, uterine or bilateral oophorectomy are exempt from pregnancy testing).
16. Participation in any clinical trial in the past 3 months prior to screening.
17. Blood donation (including component donation) or significant blood loss (≥200 mL) within the past 3 months; receiving blood transfusion or using blood products.
18. History of surgery in the past 3 months; not recovered from surgery, or anticipated surgery during the trial period.
19. Poor compliance or other issues that the investigator deems unsuitable for participation in the study.
Study Centers
Beijing (Activated)
Baoding, Hebei
Zhumadian, Henan
Tianjin
Wuhan, Hubei
Chengdu, Sichuan
Urumqi, Xinjiang
Hangzhou and Huzhou, Zhejiang
Siping, Jilin
Guangzhou, Guangdong
Suzhou and Wuxi, Jiangsu
Changsha, Hunan
Kunming, Yunnan
Daqing, Heilongjiang
Exact activation status subject to later consultation
[Important Note] All information provided is for reference only; please follow medical advice for specific treatments!
