This study is a randomized, double-blind parallel controlled and clinical experiment. The control group will have an active medical control in the form of a single I.V. injection of midazolam maleate.
The samples will consist of 32 outpatients with TRD recruited from the Department of Clinical Psychology, Beijing Chaoyang Hospital, Capital Medical University. Participants will be randomly divided into a study group and a control group, with 20 in each group.
Patients who meet the diagnostic criteria for depression in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) without psychotic symptoms diagnosed by a psychiatrist;
Meet the criteria for TRD. The treatment was ineffective after a sufficient and complete course of treatment with at least two antidepressants (over six weeks);
The total score is great than or equal to 17 on the 17-item Hamilton Rating Scale for Depression (HAMD);
25-64 years old, both genders;
No antidepressants, antipsychotics, mood stabilizers, electrical shock treatments in the last two weeks;
Have the ability to understand the content of the scale and cooperate with the assessment;
Sign research informed consent and be able to follow up.
Patients with a previous history of substance use disorders or acute poisoning; patients with psychotic disorder, bipolar disorder, obsessive-compulsive disorder;
The primary diagnosis is not depression;
History of inefficacy or intolerance to Venlafaxine;
Women who are pregnant or breastfeeding;
Patients who are at high risk of suicide: suicide attempts, recent suicide attempts; no family caregivers;
Patients who are contraindicated in using ketamine, or midazolam maleate, or venlafaxine hydrochloride;
Patients who have used ECT or NMDA receptor antagonists within the past six months;
There are currently patients with respiratory disease, hypertension, or other physical severe diseases, such as patients with severe cardiovascular disease and hyperthyroidism, patients with intracranial hypertension or cerebral haemorrhage and glaucoma.
Participant withdrawal and termination criteria
The patient has a concomitant physical illness or serious adverse effect and others, who are unable or unwilling to continue to complete the study protocol;
The patient of lost follow-up;
The patient switch to mania, hypomania during the study;
The patient suicide or attempted suicide occurred during the study;
The patient no longer wishes to be part of the trial.
The anesthesiologist and nurse will give the injection treatment in the operating room. During the injection process, the blood pressure, oxyhemoglobin saturation and other significant physiological indicators will be monitored in real-time. The psychiatrist will evaluate and record the side effects throughout the injection treatment. Any discomfort of the patient during the whole treatment process will be reported to the psychiatrist and anesthesiologist, who will act to alleviate this and record the side effects. Four hours after the injection treatment, the patient can be discharged from the hospital, only if they do not have discomfort and have been safely evaluated without side effects.
Randomization and allocation concealment
Block randomization will be used, the length of the block is four, which means there are 4 study subjects in each block. SAS software will be used to generate a random allocation list. Based on the random allocation list, the research subjects in the block group will be randomly allocated to the experimental group and the control group at a ratio of 1: 1. The random allocation is sealed with an opaque random concealed letter printed by a pinhole and given to a designated person (not involved in clinical observation assigned by the project center for keeping).
The double-blind method will be used in this study，neither the experimenter nor the participants know which treatment is received. We chose midazolam maleate instead of the placebo used in previous experiments-0.5% saline, because ketamine can cause some unique drug interactions within patients. Participants are randomly assigned to a single intravenous infusion of I.V.-ketamine 0.5mg/kg or midazolam maleate 0.045mg/kg. Questionnaires will be scored by professional raters who do not know which kind of drugs participants have been administered.
Primary outcome measures
The time required to reach the clinical effective standard and clinical cure standard will be measured. The effective standard is the remission rates of the total Montgomery–Asberg Depression Rating Scale (MADRS) score ≥50% compared with the baseline, and the clinical cure standard is defined as the total MADRS score ≤10.
16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16 ). Patients will be assessed at baseline, after I.V.-ketamine at 1, 2, 4, 24, 48, 72 hours, 7, 14, 21 and 28 days.
Side Effects and Safety
Record vital signs (blood pressure, heart rate, and oxygen saturation) every 5 minutes in the duration I.V.-ketamine.
Adverse psychopathological effects will be measured by/with the Brief Psychiatric Rating Scale-4 (BPRS-4), Young Manic Rating Scale (YMRS), the Clinician Administered Dissociative States Scale (CADSS), Frequency and Intensity of Side Effects Rating/Global Rating of Side Effects Burden (FISER/GRSEB), and Patient Rated Inventory of Side Effects (PRISE). Patients will be assessed at baseline, after I.V.-ketamine at 1, 2, 4, 24, 48, 72 hours, 7, 14, 21 and 28 days. The schedule of assessments and procedures is summarized in Table 1.
Table 1. Study procedures and schedule of assessments
Participants will meet the criteria and sign informed consent. Participants will undergo a psychotropic medications washout period of two weeks (fluoxetine hydrochloride for four weeks).
The injection treatment is performed on the first day of the intervention. Preparation before treatment: The patient fasts for 12 hours and drinks water for 4 hours. Control Groups: establish an intravenous infusion channel in the operating room, and inject physiological saline at a rate of 20-30 drops/min. Connect a physiological monitor to monitor BP, SpO2, ECG. Ketamine Group: 0.5mg / kg ketamine hydrochloride injection, diluted with a physiological saline injection to 50ml intravenous for 40 minutes. Control group: midazolam maleate injection, a dose of 0.045mg / kg, diluted with a saline injection to 50ml intravenous injection for 40 minutes. Both groups: Blood pressure, heart rate, and oxygen saturation will be recorded every 5 minutes during drug injection. Observe the patient's consciousness and mental state for 4 hours during and after administration.
Both groups are treated with venlafaxine hydrochloride 150 mg/day (the initial dose was 75 mg / d and increased to 150 mg/d one week later) from the first day of the intervention for four weeks.
In the study, if the subject has severe insomnia (cannot fall asleep half an hour after going to bed), zolpidem tartrate can be temporarily administered 5-10 mg, ≤ 3 times a week. Do not use systemic psychotherapy, electroconvulsive therapy, antidepressants, and antipsychotics other than research medications.
Sample size calculation: using the superiority hypothesis test, setting unilateral ɑ = 0.05, β = 0.2.With reference to the previous study setting , the treatment time of the control group that reached the clinical cure standard was set to 28.0 ± 0.0 days, and the mean treatment standard deviation of the experimental group was 15.8 ± 13.0 days. Based on previous literature and the time required for clinical cure [4-6], the optimal effect cut-off value △ = -5 days was calculated using PASS14.0 software. 13 samples were required for each group. Considering the 15% missed follow-up rate and random block capacity, the number of expanded samples is 16 in each group, and 32 samples are required for the two combinations.
statistical analytical plan
Primary outcome analysis
Kaplan-Meier survival analysis will be used as the time required to reach the effective standard and clinical cure standard. Cox proportional-hazards regression models are to be used to compare the estimated time to respond and to remission between the two groups, controlling the baseline effects.
Secondary outcome analysis
Baseline demographics, clinical feature analysis, effectiveness, and clinical cure rate between the two groups will be measured using two independent samples' t-test or Mann-Whitney U test or χ2 test or Fisher's exact test. The significance level will be set at 0.05( in a two-tailed test).
Data management and monitoring strategies
Researchers fill in the data on the case report form in time after each visit, and this is to be consistent with the original record. The data will be collected on Epidata to build the database. Special management and double verification are adopted to ensure the accuracy of data entry. According to the Intention to Treat (ITT), an intent analysis data set (subjects who took at least one drug after enrollment) will be established to analyze the research data statistically.
For subjects who did not observe the full effect evaluation, a mixed model will be used for data processing.