Skip to main content
  • Study protocol
  • Open access
  • Published:

The efficacy and safety of esketamine in the treatment of major depressive disorder with suicidal ideation: study protocol for a randomized controlled trial



Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation.


This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation.


This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation.

Trial registration

Chinese Clinical Trial Register, ChiCTR2000041232. Registered 22 December 2020.

Peer Review reports


Major depressive disorder (MDD), as a major contributor to the global burden of disease, is a common mental illness with high lifetime prevalence and disability rates [1, 2]. Suicide is the most serious public health crisis, being the second leading cause of death among 15–29 years worldwide [3]. Evidence suggests that MDD is a high risk factor for suicide, with approximately 2/3 of MDD patients experiencing suicidal ideation and up to 20% of MDD patients attempting suicide during their lifetime [2, 4]. Despite this, current conventional antidepressant treatment faces great dilemmas: slow onset of action, low efficiency, and the inability to control risky behavioral suicides quickly and effectively [5, 6]. Therefore, it is particularly important to explore drugs that rapidly improve depressive symptoms, especially suicidal ideation/behavior, in MDD patients.

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to have rapid and potent as well as relatively long-lasting antidepressant efficacy in animal and clinical studies [7,8,9]. Of note, the U.S. Food and Drug Administration (FDA) officially approved a nasal spray form of esketamine (the S-enantiomer of ketamine) for the treatment of refractory depression (TRD) in 2019, the same year the drug was approved for the same indication in Europe.

An increasing number of studies in recent years have focused on ketamine in the treatment of suicide. Several studies have shown rapid efficacy of multiple ketamine infusions for the alleviation of suicidal ideation [10, 11]. A Meta-analysis showed that a single dose of intravenous ketamine provides rapid alleviation of suicidal ideation, with its antisuicidal effect manifesting within 24 hours [11]. This rapid antisuicidal effect is well suited to clinical needs. Also, this review also shown that the antisuicidal effect of ketamine is remained significant after adjusting for concurrent changes in severity of depressive symptoms. Our team conducted a clinical study on this in the early stage. We used six-dose infusions of ketamine (0.5 mg/kg) over 2 weeks to treat a total of 86 depressed patients with suicidal ideation. 57% of them had immediate remission of suicidal symptoms after the first dose, and the remission rate reached 65.1% at the end of six infusions, indicating that ketamine has a rapid and strong efficacy in alleviating suicidal ideation [12]. On August 3, 2020 the FDA also approved its enantiomer esketamine nasal spray in combination with oral antidepressants for the treatment of depressive symptoms in adults with depression with suicidal ideation/behavior. However, the literature on repeated infusion of esketamine for the treatment of suicidal ideation in MDD patients is sparse and mostly open-label, and controlled trials, particularly in adolescents, remain blank, requiring larger controlled studies.

In addition, our previous study showed that nearly 40% of MDD patients failed to response to ketamine, consistent with other studies [8, 13]. Therefore, finding markers for predicting treatment response and selecting the best treatment for each individual is a key issue. Inflammatory factors as well as neurotrophic factors are popular among alternative response biomarkers. Evidence showed that antidepressant therapy is ineffective in depressed patients with increased inflammatory levels [14, 15]; and neurotrophic factors levels increased after antidepressant treatment [16, 17]. However, current results are inconsistent [18, 19]. Additional studies showed abnormalities in brain structure and function in MDD patients [20, 21], and their brain structure and function change after treatment [22, 23]. The above mentioned biomarkers would be very valuable information in ketamine’s clinical study.


In summary, treatment of suicidal ideation in MDD patients with suicidal ideation is currently very challenging and few effective rapid interventions have been found in robust trials of sufficient quality. So far, intravenous ketamine has been preliminarily found to have a rapid but transient anti-suicide effect, but there is still lack evidence on the efficacy and safety of repeated intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. Therefore, this randomized, double-blind, placebo-controlled trial was designed to evaluate the effect of esketamine for suicidal ideation in MDD patients with suicidal ideation by comparing esketamine plus conventional therapy and placebo plus conventional therapy, as an additional strategy in addition to conventional therapy. At the same time, the effects of esketamine on self-reported severity of depression, cognitive function, quality of life, safety and tolerance were investigated. In addition, we also aim to determine biological markers for predicting esketamine’s treatment response and explore the mechanisms associated with its antidepressant and antisuicidal effects.

Esketamine and placebo both combined with conventional therapy are conditions we wish to evaluate with difference in suicidal ideation as the primary outcome measure. We hypothesized that intervention with esketamine in combination with conventional therapy would reduce suicidal ideation better than placebo in combination with conventional therapy in MDD patients with suicidal ideation.

Methods/ design

Study design and setting

The trial is a prospective, randomized, double-blind, interventional, controlled study with 2 parallel arms as a supplement to conventional antidepressant medications: one group was esketamine (intervention) and the other was placebo (control). Our study control used midazolam, which has no established antidepressant or antisuicidal effects and is generally considered to be the best effective control for ketamine. Throughout the study, there was no interference or restriction for the patient ‘s physician in charge to adjust psychiatric medications according to the patient’ s condition, but phenobarbital could not be used throughout the acute treatment period, while the patients were not allowed to undergo concurrent electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS).

This study was approved by the Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University (Ethics number: 2020 [057]) and was currently registered with the China Clinical Trials Center under the registration number ChiCTR2000041232. The study was supervised by the Hospital Department of Education and Information (HDEI) and the Academic Management Committee of the Affiliated Brain Hospital of Guangzhou Medical University. HDEI staff audit the trial twice a year and provide feedback to the investigators.

This study will be conducted at the Affiliated Brain Hospital of Guangzhou Medical University. The institution conducting the study procedures will provide the necessary hospital structure, medications, and human resources.


Our research will be advertised on the hospital’s online public website and other media platforms. Prior to screening, all potential participants will receive a verbal and written explanation of the study process, potential benefits and risks. They will all be informed that participation is voluntary and that they can withdraw at any time for any reason. All subjects and their legal guardians must give full informed consent to this project and sign a written informed consent form before being enrolled in this study.


The study will enroll in patients with moderate to severe depression, and patients will be selected for the study based on the inclusion and exclusion criteria listed in Table 1. During the study period, if a patient has a medical emergency or a change in the patient’s condition, the investigator may decide whether the patient will withdraw from the study.

Table 1 Inclusion and exclusion criteria

Randomization and blinding

The raters and participants as well as their clinician will be kept blind to the assigned treatment at randomization. A designated psychiatrist, who is not involved in subjects registration or assessment scales, will generate the random assignment sequence through the SPSS random number generator program and the two drugs will be randomly assigned to subjects for treatment in a 1:1 ratio. If unblinding is required at the end of follow-up or during the course of the study for reasons such as serious side effects, the psychiatrist esponsible for randomly generated assignment sequences will also perform unblinding according to the randomized sequence number. The psychiatrist will prepare the study medications with a nurse who is not involved in other aspects of the study in each participating department. Since both drugs will be diluted in saline bottles, they cannot be identified by the naked eye. Blinding will occur at the level of the clinician and the assessor, the participant. The only professional with knowledge of the drugs infused is the investigator in charge of the distribution process, who is not involved in any clinical evaluation.


All patients who meet the inclusion criteria will enter into this study and will be treated with one of two randomized drug infusion in addition to oral antidepressant medication, receiving either 0.25 mg/kg of esketamine (Jiangsu Hengrui Medicine Co.,Ltd. Specifications:2 ml:50 mg National Drug Approval:H20193336) or 0.02 mg/kg of midazolam (Commercial brand: Jiangsu Nhwa Pharmaceutical Co.,Ltd., Specifications:2 ml: 10 mg,National Drug Approval:H10980025) added to 50 ml of 0.9% sodium chloride infusion, pumped once every other day for three times over 40 minutes. Infusions will be administered in the ward in the morning and a psychiatrist is involved during each infusion. Fig. 1 represents the research procedure schematically.

Fig. 1
figure 1

Research flow chart

Safety and monitoring

All participants fasted overnight (at least 8 hours) prior to each infusion until 30 minutes after the infusion. Blood pressure and heart rate will be recorded at 10-minute intervals during each infusion. After the infusion is completed, participants are instructed to rest in a hospital bed under medical supervision for at least 30 minutes until free of discomfort while blood pressure and heart rate is checked again. Patients will also be asked to report any other possible adverse events not only during the intervention but also at 30 minutes, 24 hours after the infusion and at the follow-up phases (Days 12, 19 and 33). The investigator will decide to withdraw the patient from the study if the patient encounter the following withdrawal criteria.

Withdrawal Criteria:

Patients have the right to withdraw from the study at any time for any reason.

In addition, patients were excluded from the study if they answered “yes” to the following statements.

  1. (i)

    Somatic contraindications, including the following: a. Unstable vital signs: systolic or diastolic blood pressure increased by 20% from baseline, or systolic blood pressure > 180 mmHg and diastolic blood pressure > 100 mmHg, or heart rate > 110 beats/min, or heart rate < 40 beats/min, or respiration > 30 breaths/min, or respiration < 10 breaths/min; b. Excessive sedation and unresponsiveness to verbal commands; c. Partial or complete airway obstruction; d. Blood oxygen saturation (SpO2) < 95% for more than 5 minutes.

  2. (ii)

    Intolerable adverse reactions.

  3. (iii)

    Manic episode or severe psychotic symptoms.

  4. (iv)

    Deteriorating clinical condition and risk assessment indicating unsuitability for continued participation in this trial (e.g., recurrent severe suicidal tendencies to self-injury), etc.

Patients who withdraw from treatment early are encouraged to continue to schedule regular outpatient visits to complete the study safety and efficacy assessments as if they were still on the study medication. If a patient discontinues study drug therapy, he or she immediately enters the follow-up phase.

Efficacy evaluations/endpoints

The primary outcome is the change in suicidal ideation from Day 0 to Day 6 as assessed by clinician-rated Columbia suicide severity rating scale (C-SSRS) [24] Ideation and Intensity during the double-blind phase. The clinician-rated C-SSRS quantifies suicidal ideation and behavior through a semistructured interview. The first 5 items of the scale refer to suicidal ideation and have binary yes/no responses (yes = 1, no = 0): wish to be dead, nonspecific active suicidal thoughts, suicidal thoughts with methods, suicidal intent, and suicidal intent with plan. The next 5 items address the intensity of suicidal ideation: frequency, duration, controllability and deterrents of ideation, and reasons for ideation, and each item scales 0 (suicidal ideation denied) to 5 (suicidal ideation with a plan, i.e. severe suicidal ideation) to 5 (planned suicidal ideation, i.e., severe suicidal ideation), with a total score range of 0 to 25. C-SSRS assessment will be performed at baseline (day 0, past week recall), then 24 hours after each infusion (Days 2, 4, and 6, modified from past 24-hour recall), and then again 1, 2, and 4 weeks after the final infusion (Days 12, 19, and 33, based on past week recall).

Key secondary outcomes include changes in depressive symptoms assessed by the clinician-rated Montgomery-Osberg Depression Rating Scale (MADRS) [25] from day 0 to day 6 and given at the same time points and same recall periods as the C-SSRS.

The MADRS will be used to measure depressive symptoms because it is more sensitive in adult to ketamine-related acute changes (e.g., hours or less) than the HAMD. The Children’s Depression Rating Scale-Revised (CDRS-R), a widely used pediatric tool in pediatric depression trials, is not used because the scale is based on the HAMD and assesses similar content to the HAMD. A large portion of the CDRS-R items relate to school performance and friend socialization, which are difficult measures to adapt to hospitalized adolescents.

Other secondary efficacy outcomes include clinical response and remission at each time point up to the end of 4-week follow-up (Day 33). Anti-suicidal response is defined as ≥50% improvement in C-SSRS Ideation score compared to baseline and remission was defined as C-SSRS Ideation score = 0). Antidepressant response is defined as improvement ≥50% reduction in MADRS total score compared to baseline and remission was defined as a MADRS total score ≤ 12.

The change in self-reported suicidal ideation from Day 0 to Day 6 is another secondary efficacy outcome. We will utilize the first five items of the SSI (SSI-5) [26], which measure the hope to live, hope to die, reasons for living or dying, desire to actively attempt suicide, and passive suicidal thoughts. This scale will be self-assessed by the patient throughout the course of the study. Anxiety symptoms will be assessed by the 10 and 11 items of 17-item of the Hamilton Depression Inventory (HAMD-17) [27].

The evaluator conducted an interrater reliability exercise for all above scale (except for patient self-assessment scales) and found an intraclass correlation coefficient > 0.9.

Safety assessments

General adverse events will be recorded using the Systematic Assessment for Treatment Emergent Events (SATEE) [28]. Other safety assessments include: (1) five items of the Brief Psychiatric Rating Scale (BPRS-5, hallucinations, grandiosity, suspiciousness, unusual thought content, conceptual disorganization); (2) the first item (elevated mood) of the Young Mania Rating Scale (YMRS) [29]; (3) Clinician Administered Dissociative Symptoms Scale (CADSS) [30], will be measured at baseline, then at 30 minutes and 24 hours after each infusion (Days 1, 2, 3 4, 5, 6, 12) and again at Days 12, 19 and 33. All these safety measures will be assessed covering the period since the previous assessment. Suicidal behavior will be assessed via the C-SSRS Behavior.

Cognitive function was assessed using the MATRICS consensus cognitive battery (MCCB) [31], administrated at baseline, Days 6 and 12. Four dimensions were selected from the MCCB, including processing speed, working memory, visual learning and verbal learning. Processing speed was measured by Brief Assessment of Cognition in Schizophrenia (BACS), Trail Making A test, and the Category Fluency test. Working memory was evaluated using the subtests Spatial Span of the Wechsler Memory Scale-III. Visual learning and verbal learning were assessed by the Hopkins Verbal Learning Test-Revised, and the Brief Visuospatial Memory Test-Revised, respectively. There are two test versions, version A and B, in visual learning and verbal learning, which had different topics but equal difficulty. In order to reduce potential learning effect in subjects, we used version A at baseline and Day 12, and version B at Day 6. The score of each dimension in MCCB was standardized to a T score with a mean of 50 and a standard deviation of 10, with higher score indicating better cognition.

During the follow-up phase, the probable dependence of the study drug will be assessed with the severity dependence scale (SDS) [32]. One item: “Did you wish you could stop?” is excluded from the present study because the study drug will be stopped during the follow-up phase. Thus only four items will be assessed. Each item is scored from 0 to 3. A cutoff point of 2/3 will be chosen to identify probable ketamine dependence. In addition, the visual analog scale (VAS [33], range 0–10) will be used to measure the aspects of craving for the study drug. The SDS and VAS will be assessed at Days 12, 19 and 33, covering the period since the previous assessment.

Blood sample collection

Peripheral blood samples will be collected at baseline, Days 6 and 12 and processed into plasma, which will be used for testing BDNF, inflammatory factors, kynurenine metabolites, proteomics, metabolomics and other biological indicators. Whole blood will also be collected in Tempus tubes for direct isolation of RNA.

Brain magnetic resonance imaging

Magnetic Resonance Imaging (MRI) scans will be performed at baseline, Days 6 and 12. All participants will be scanned Structural and functional MRI data on a 3.0 Tesla MRI system (Achieva X-series, Philips Medical Systems, Best, Netherlands). Foam pads and headphones will be used to minimize head motion and scanner noise. High-resolution T1-weighted images will be collected with a sagittal T1-weighted 3D turbo field echo (T1W 3D TFE) sequence (field of view 256 × 256 mm2; repetition time 8.2 ms; echo time 3.8 ms; view matrix 256 × 256; slice thickness 1 mm).

During the follow-up phase, the aforementioned efficacy and safety evaluations will be required to be completed even if the participants receive only one or two infusions.

All measures and time points are shown in Fig. 2.

Fig. 2
figure 2

Measurements and time points. Abbreviations: SCID-5: Structured Clinical Interview for DSM-V; C-SSRS: Columbia suicide severity rating scale; MADRS: Montgomery–Asberg Depression Rating Scale; HAMD-17: 17-item Hamilton Rating Scale for Depression: SSI-5: The first five items of Baker Suicide Scale: HAMA: Hamilton Anxiety Scale [34]; CADSS: Clinician Administered Dissociative Symptoms Scale; YMRS: Young Mania Rating Scale; BPRS: Brief Psychiatric Rating Scale positive symptoms [35]; SDS: Severity Dependence Scale; VAS: Visual Analog Scale; MCCB: Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery; GAF: Global Assessment Function [36]; PHQ-9: Patien Health Questionnare-9 [37]; BPIC-SS: Bladder Pain/Interstitial Cystitis- Symptom Score [38]; SATEE: Systematic Assessment for Treatment Emergent Events; NSSI: Non-suicide Self-inflicted Injury

Data management

All participant demographic and scale related results will be recorded in the case report form (CRF) and then stored in epidata (double data entry). To protect patient privacy, personal information such as names, contact numbers, and addresses that are not relevant to the data analysis will be removed from the data entry process. Numbering will be used to differentiate between patients. Also, the original CRFs are stored in a secure, convenient location throughout the study. Raw CRFs and epidata data are only accessible to the project leader and principal investigator.

Our study does not have the oversight of a data monitoring committee, but the subject group has a dedicated person to oversee.

Statistical analysis

Sample size calculation

Our study will be divided into two treatment cohorts, one for adolescents and the other for adults, and the two cohorts will be conducted independently, having separate randomization numbers. Power analysis determines sample size using a meta-analytic estimate of effect size = 0.85 for the change in clinician-rated suicidal ideation score for a single dose of ketamine vs control. This effect size requires a sample size of 22 participants per treatment group to achieve 80% power at two-sided significance level of 0.05. Assuming a 10% dropout rate after the first infusion, at least a sample size of 25 participants was needed for each treatment group. That is, at least 50 participants in adolescent cohort and 50 participants in adult cohort.

Data analyses

Efficacy Data will be analyzed based on analysis sets that includes all randomized patients who complete both a baseline and Day 2 assessment with the C-SSRS. Safety analyses will be performed based on a safety analysis set that included all randomized participants who receive at least one infusion of study drug. Two treatment cohorts (adolescents and adults) will be independently statistically analyzed. Analysis will be performed using IBM SPSS Statistics version 27. The significance level for all statistical analyses is set at 0. 05.

Baseline analyses

Baseline characteristics will be compared in groups using two-sample t-tests, chi-square tests, or Mann-Whitney U tests.

Efficacy analyses

Linear mixed models will be used for efficacy analyses to assess changes from baseline to day 6 in C-SSRS Ideation and Intensity score, MADRS score and SSI-5 score, with time (Days 0, 2, 3 and 6), drug (esketamine and midazolam) and time-by-drug interactions as fixed factors, and total antidepressant class (selective serotonin reuptake inhibitor [SSRI] or non-SSRI), plus augmentation therapy, and respective baseline scores for the instruments as covariates. The Bonferroni-corrected simple effects post hoc tests will be used to examine differences in medications synchronized with significant interactions. Effect sizes (Cohen’s d) will be calculated using the mean difference between the two treatment groups at each time point. At the 6-day endpoint, a linear mixed models will be calculated based on intention-to-treat (ITT). Post hoc summaries of the proportion of participants who achieved clinical responses and remission will be provided, and differences between groups at each time point will be compared using two sample proportion tests.

To investigate the relationship between antidepressant effect and antisuicidal effect, we will use correlation analyses to explore the correlation between reduction in MADRS score and reduction in C-SSRS Ideation or Intensity scorein each group; Mediation analysis will be used to examine whether the effect of the intervention on overall depressive symptoms mediates the effect of the intervention on suicidal ideation. Mediated analyses will be conducted using the process v3.5 in SPSS. The model will use the study drug as the independent variable, the reduction in C-SSRS Ideation or Intensity score as the dependent variable, and the decrease in MADRS scores as mediator.

Safety analysis

The frequency distribution of treatment-emergent adverse events and suicidal behaviors will be depicted, while CADSS, BPRS-5 and YMRS item 1 scores will be compared between groups at each time point using univariate tests. Differences in SDS and VAS scores between groups will be analyzed by two independent samples t-tests. The proportion of participants meeting study drug dependence criteria at each time point will be compared between groups using a two-sample proportion test. A mixed-effects repeated measures model was conducted to examined differences in four dimensions of MCCB between groups from baseline to endpoint (Day 12).


This manuscript describes the study protocol of a randomized double-blind controlled trial of three infusions of intravenous esketamine in MDD patients with suicidal ideation, with the primary objective of exploring whether esketamine treatment reduces suicidal ideation as well as depressive symptom in this population.

Suicidal ideation in MDD patients is a serious and urgent condition that requires immediate treatment. However, acute pharmacological management of suicidal risk in MDD remains relatively unstudied in clinical practice. Antidepressants have been shown in numerous studies to reduce overall suicide risk, but they are slow to take effect, while some studies have found an increased risk of suicide within the first month after SSRI treatment. In the United States, the issue is followed by the FDA black box warning on the use of SSRIs in children, adolescents and young adults [39]. In addition, MDD patients with suicidal ideation is indicative of ECT [40]. One study has shown that ECT has better antisuicidal effects in patients with monophasic disorder and bipolar depression compared with psychopharmacological treatment [41]. However, there are significant drawbacks to the use of ECT, and public acceptance is relatively low (10–32%) [42]. Repeated anesthesia carries the potential for serious cognitive risk and can be very distressing for those with memory impairment after ECT [43]. Ketamine appears to show a more favorable cognitive side effect profile than ECT, and there is evidence that ketamine has similar and faster antidepressant efficacy than ECT, despite the different sources of patient recruitment [44]. The conclusions drawn from our study are expected to provide an evidence base for treatment options for patients with concomitant suicidal depression.

In terms of study population, our study will recruit not only adults, but also adolescents. Previous ketamine-related trials have mostly focused on adults but lack evidences from adolescents. Only one open-label trials and one randomized controlled trial have reported antidepressant efficacy of ketamine in adolescents [45, 46]. In addition, two adolescent case reports assessing measures of suicidal ideation both found ketamine has rapid antisuicidal effects [47, 48]. These findings lack further randomized double-blind controlled studies. In addition, one study has reported a high level of acceptance of parental attitudes toward ketamine use in adolescent mood disorders with suicide ideation [49]. This implies the feasibility of replicating our study in adolescents with suicidal ideation.

In terms of intervention modality, we chose three-dose of intravenous esketamine. Although data from chronic pain management suggest that oral ketamine can often be used safely for longer periods of time [50], there are limited reports of antidepressant studies of oral esketamine, with only a few small studies reporting the antidepressant properties of oral ketamine [51,52,53,54]. Bioavailability considerations are a major concern. The bioavailability of oral ketamine is variable and low compared to intravenous ketamine, and the absorption rate of oral ketamine appears to vary considerably between and within patients [55, 56]. Some oral (es) ketamine studies have shown antidepressant effects within a few hours of administration, but most studies have shown such effects only after several weeks of treatment [54]. In addition, a systematic review and meta-analysis showed that intravenous ketamine showed more significant overall response and remission rates, as well as lower withdrawal rates due to adverse events, compared to intranasal esketamine [57]. Previous studies did show a prolonged duration of response after repeated dosing compared to single dose ketamine infusion [7,8,9]. MDD patients with suicidal ideation need rapid relief of suicidal ideation, and from the above, repeated intravenous dosing seems to be the preferred dosing method.

A dose of 0.5 mg/kg ketamine is the most commonly used dose in depression trials, and esketamine is considered to be 2 times more effective than racemic ketamine as an anesthetic [58,59,60]. Therefore, we selected 0.25 mg/kg esketamine for the intervention. Studies have shown that there may be a dose-response relationship between the effects of ketamine on depressive symptoms with TRD. Previous studies found that the use of 0.5 mg/kg ketamine was more effective than lower doses of ketamine in adult MDD patients, and increasing the dose from 0.5 to 0.75 mg/kg may effective in some patients [61, 62]. Higher doses of ketamine may result in more pronounced acute side effects [60]. In addition, ketamine is an addictive drug, and it is unclear whether its use as a treatment for depression may lead to increased rates of abuse. Bladder toxicity is another potentially worrisome side effect that can result from chronic ketamine exposure [63]. In the future direction, not only further controlled trials with more flexible doses are needed, but also an in-depth exploration of the mechanism of action of ketamine.


The results of this randomized controlled trial are expected to have a potentially important impact on the treatment of MDD patients with suicidal ideation. Our data may support the use of repeated esketamine infusions, which could meet the urgent need for rapid relief of suicidal ideation as well as depressive symptoms in this population. We will begin formal recruitment in January 1, 2021 and recruitment will continue through December 31, 2023.

Availability of data and materials

Not applicable.



Major depressive disorder


randomized, double-blind, placebo-controlled trial




Food and Drug Administration


refractory depression


electroconvulsive therapy


the case report form


the Hospital Department of Education and Information


repetitive transcranial magnetic stimulation


Blood oxygen saturation


Brief Assessment of Cognition in Schizophrenia


Magnetic Resonance Imaging


selective serotonin reuptake inhibitor




Structured Clinical Interview for DSM-V


Columbia suicide severity rating scale


Montgomery–Asberg Depression Rating Scale


17-item Hamilton Rating Scale for Depression


The first five items of Baker Suicide Scale


Hamilton Anxiety Scale


Clinician Administered Dissociative Symptoms Scale


Young Mania Rating Scale


Brief Psychiatric Rating Scale positive symptoms


Severity Dependence Scale


Visual Analog Scale


Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery


Global Assessment Function


Patien Health Questionnare-9


Bladder Pain/Interstitial Cystitis- Symptom Score


Systematic Assessment for Treatment Emergent Events


Non-suicide Self-inflicted Injury


  1. Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. Plos Med. 2013;10(11):e1001547.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiat. 2018;75(4):336–46.

    Article  Google Scholar 

  3. Arensman E, Scott V, De Leo D, Pirkis J. Suicide and suicide prevention from a global perspective. Crisis. 2020;41(1):S3–7.

    Article  PubMed  Google Scholar 

  4. Holma KM, Melartin TK, Haukka J, Holma IA, Sokero TP, Isometsa ET. Incidence and predictors of suicide attempts in DSM-IV major depressive disorder: a five-year prospective study. Am J Psychiatry. 2010;167(7):801–8.

    Article  PubMed  Google Scholar 

  5. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40.

    Article  PubMed  Google Scholar 

  6. Lopez-Castroman J, Jaussent I, Gorwood P, Courtet P. Suicidal depressed patients respond less well to antidepressants in the short term. Depress Anxiety. 2016;33(6):483–94.

    Article  CAS  PubMed  Google Scholar 

  7. Zheng W, Zhou YL, Liu WJ, Wang CY, Zhan YN, Li HQ, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression. J Psychiatr Res. 2018;106:61–8.

    Article  PubMed  Google Scholar 

  8. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan HRM, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250–6.

    Article  CAS  PubMed  Google Scholar 

  9. Aan HRM, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139–45.

    Article  Google Scholar 

  10. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175(4):327–35.

    Article  PubMed  Google Scholar 

  11. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data Meta-analysis. Am J Psychiatry. 2018;175(2):150–8.

    Article  PubMed  Google Scholar 

  12. Zhan Y, Zhang B, Zhou Y, Zheng W, Liu W, Wang C, et al. A preliminary study of anti-suicidal efficacy of repeated ketamine infusions in depression with suicidal ideation. J Affect Disord. 2019;251:205–12.

    Article  CAS  PubMed  Google Scholar 

  13. Murrough JW, Iosifescu DV, Chang LC, Al JR, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134–42.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chamberlain SR, Cavanagh J, de Boer P, Mondelli V, Jones D, Drevets WC, et al. Treatment-resistant depression and peripheral C-reactive protein. Br J Psychiatry. 2019;214(1):11–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacol. 2000;22(4):370–9.

    Article  CAS  Google Scholar 

  16. Rocha RB, Dondossola ER, Grande AJ, Colonetti T, Ceretta LB, Passos IC, et al. Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: a meta-analysis study. J Psychiatr Res. 2016;83:47–53.

    Article  PubMed  Google Scholar 

  17. Zhou C, Zhong J, Zou B, Fang L, Chen J, Deng X, et al. Meta-analyses of comparative efficacy of antidepressant medications on peripheral BDNF concentration in patients with depression. Plos One. 2017;12(2):e172270.

    Article  Google Scholar 

  18. Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacol. 2011;36(12):2452–9.

    Article  CAS  Google Scholar 

  19. Fornaro M, Martino M, Battaglia F, Colicchio S, Perugi G. Increase in IL-6 levels among major depressive disorder patients after a 6-week treatment with duloxetine 60 mg/day: a preliminary observation. Neuropsychiatr Dis Treat. 2011;7:51–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang L, Hermens DF, Hickie IB, Lagopoulos J. A systematic review of resting-state functional-MRI studies in major depression. J Affect Disord. 2012;142(1–3):6–12.

    Article  CAS  PubMed  Google Scholar 

  21. Serra-Blasco M, Radua J, Soriano-Mas C, Gomez-Benlloch A, Porta-Casteras D, Carulla-Roig M, et al. Structural brain correlates in major depression, anxiety disorders and post-traumatic stress disorder: a voxel-based morphometry meta-analysis. Neurosci Biobehav Rev. 2021;129:269–81.

    Article  PubMed  Google Scholar 

  22. Zhou YL, Wu FC, Liu WJ, Zheng W, Wang CY, Zhan YN, et al. Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis. Transl Psychiatry. 2020;10(1):264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chu SH, Parhi KK, Westlund SM, Lenglet C, Mueller BA, Klimes-Dougan B, et al. Effect of SSRIs on resting-state functional brain networks in adolescents with major depressive disorder. J Clin Med. 2021;10(19):4322.

  24. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–77.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.

    Article  CAS  PubMed  Google Scholar 

  26. Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: the scale for suicide ideation. J Consult Clin Psychol. 1979;47(2):343–52.

    Article  CAS  PubMed  Google Scholar 

  27. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Levine J, Schooler NR. SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacol Bull. 1986;22(2):343–81.

    CAS  PubMed  Google Scholar 

  29. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35.

    Article  CAS  PubMed  Google Scholar 

  30. Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, et al. Measurement of dissociative states with the clinician-administered dissociative states scale (CADSS). J Trauma Stress. 1998;11(1):125–36.

    Article  CAS  PubMed  Google Scholar 

  31. Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165(2):203–13.

    Article  PubMed  Google Scholar 

  32. Gossop M, Darke S, Griffiths P, Hando J, Powis B, Hall W, et al. The severity of dependence scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction. 1995;90(5):607–14.

    Article  CAS  PubMed  Google Scholar 

  33. Faiz KW. VAS--visual analog scale. Tidsskr Nor Laegeforen. 2014;134(3):323.

    Article  PubMed  Google Scholar 

  34. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–5.

    Article  CAS  PubMed  Google Scholar 

  35. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.

    Article  Google Scholar 

  36. Jones SH, Thornicroft G, Coffey M, Dunn G. A brief mental health outcome scale-reliability and validity of the global assessment of functioning (GAF). Br J Psychiatry. 1995;166(5):654–9.

  37. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Humphrey L, Arbuckle R, Moldwin R, Nordling J, van de Merwe JP, Meunier J, et al. The bladder pain/interstitial cystitis symptom score: development, validation, and identification of a cut score. Eur Urol. 2012;61(2):271–9.

    Article  PubMed  Google Scholar 

  39. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292(3):338–43.

    Article  CAS  PubMed  Google Scholar 

  40. Patel M, Patel S, Hardy DW, Benzies BJ, Tare V. Should electroconvulsive therapy be an early consideration for suicidal patients? J ECT. 2006;22(2):113–5.

    Article  PubMed  Google Scholar 

  41. Liang CS, Chung CH, Ho PS, Tsai CK, Chien WC. Superior anti-suicidal effects of electroconvulsive therapy in unipolar disorder and bipolar depression. Bipolar Disord. 2018;20(6):539–46.

    Article  CAS  PubMed  Google Scholar 

  42. Chakrabarti S, Grover S, Rajagopal R. Perceptions and awareness of electroconvulsive therapy among patients and their families: a review of the research from developing countries. J ECT. 2010;26(4):317–22.

    Article  PubMed  Google Scholar 

  43. Ingram A, Saling MM, Schweitzer I. Cognitive side effects of brief pulse electroconvulsive therapy: a review. J Ect. 2008;24(1):3–9.

    Article  PubMed  Google Scholar 

  44. Basso L, Bonke L, Aust S, Gartner M, Heuser-Collier I, Otte C, et al. Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients. J Psychiatr Res. 2020;123:1–8.

    Article  PubMed  Google Scholar 

  45. Cullen KR, Amatya P, Roback MG, Albott CS, Westlund SM, Ren Y, et al. Intravenous ketamine for adolescents with treatment-resistant depression: an open-label study. J Child Adolesc Psychopharmacol. 2018;28(7):437–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dwyer JB, Landeros-Weisenberger A, Johnson JA, Londono TA, Flores JM, Nasir M, et al. Efficacy of intravenous ketamine in adolescent treatment-resistant depression: a randomized midazolam-controlled trial. Am J Psychiatry. 2021;178(4):352–62.

    Article  PubMed  Google Scholar 

  47. Weber G, Yao J, Binns S, Namkoong S. Case report of subanesthetic intravenous ketamine infusion for the treatment of neuropathic pain and depression with suicidal features in a pediatric patient. Case Rep Anesthesiol. 2018;2018:9375910.

    PubMed  PubMed Central  Google Scholar 

  48. Dwyer JB, Beyer C, Wilkinson ST, Ostroff RB, Qayyum Z, Bloch MH. Ketamine as a treatment for adolescent depression: a case report. J Am Acad Child Adolesc Psychiatry. 2017;56(4):352–4.

    Article  PubMed  Google Scholar 

  49. Mathai DS, McCathern AG, Guzick AG, Schneider SC, Weinzimmer SA, Cepeda SL, et al. Parental attitudes toward use of ketamine in adolescent mood disorders and suicidality. J Child Adolesc Psychopharmacol. 2021;31(8):553–61.

    Article  PubMed  Google Scholar 

  50. Schoevers RA, Chaves TV, Balukova SM, Aan HRM, Kortekaas R. Oral ketamine for the treatment of pain and treatment-resistant depressiondagger. Br J Psychiatry. 2016;208(2):108–13.

    Article  PubMed  Google Scholar 

  51. Smith-Apeldoorn SY, Veraart J, Ruhe HG, Aan HRM, Kamphuis J, de Boer MK, et al. Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study. BJPsych Open. 2021;8(1):e4.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Jafarinia M, Afarideh M, Tafakhori A, Arbabi M, Ghajar A, Noorbala AA, et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord. 2016;204:1–8.

    Article  CAS  PubMed  Google Scholar 

  53. Arabzadeh S, Hakkikazazi E, Shahmansouri N, Tafakhori A, Ghajar A, Jafarinia M, et al. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial. J Affect Disord. 2018;235:236–41.

    Article  CAS  PubMed  Google Scholar 

  54. Rosenblat JD, Carvalho AF, Li M, Lee Y, Subramanieapillai M, McIntyre RS. Oral ketamine for depression: a systematic review. J Clin Psychiatry. 2019;80(3):13514.

  55. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71(5):539–42.

    Article  CAS  PubMed  Google Scholar 

  56. Fanta S, Kinnunen M, Backman JT, Kalso E. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur J Clin Pharmacol. 2015;71(4):441–7.

    Article  CAS  PubMed  Google Scholar 

  57. Bahji A, Vazquez GH, Zarate CJ. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542–55.

    Article  CAS  PubMed  Google Scholar 

  58. Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J Clin Psychiatry. 2017;78(7):e852–7.

    Article  PubMed  Google Scholar 

  59. Lee EE, Della SM, Liu A, Himelhoch S. Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. Gen Hosp Psychiatry. 2015;37(2):178–84.

    Article  PubMed  Google Scholar 

  60. Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020;25(7):1592–603.

    Article  CAS  PubMed  Google Scholar 

  61. Xu Y, Hackett M, Carter G, Loo C, Galvez V, Glozier N, et al. Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and Meta-analysis. Int J Neuropsychopharmacol. 2016;19(4):pyv124.

  62. Cusin C, Ionescu DF, Pavone KJ, Akeju O, Cassano P, Taylor N, et al. Ketamine augmentation for outpatients with treatment-resistant depression: preliminary evidence for two-step intravenous dose escalation. Aust N Z J Psychiatry. 2017;51(1):55–64.

    Article  PubMed  Google Scholar 

  63. Ng J, Lui L, Rosenblat JD, Teopiz KM, Lipsitz O, Cha DS, et al. Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment. Psychopharmacology. 2021;238(4):917–26.

    Article  CAS  PubMed  Google Scholar 

Download references


The authors would like to acknowledge the participants in this study and research assistants for their hard work and significant contribution.


The project is funded by Guangzhou Municipal Psychiatric Disease Clinical Transformation Laboratory (No: 201805010009), Guangdong Basic and Applied Basic Research Foundation (grant number 2019A1515011366), Science and Technology Plan Project of Guangdong Province (grant number 2019B030316001). The funder has peer-reviewed the study protocol. All funders had no role in the design of the study or in the collection, analysis and interpretation of the data and the writing of the manuscript.

Author information

Authors and Affiliations



HYL participated in the discussion of the design procotol and contributed to write the manuscript; YLZ and YPN designed this study and also provided financial support. CYW, XFL,WCL contributed to the improvement of the case report form, and a critical review of the manuscript version was conducted. FZ, YXY and ZBH critically reviewed the versions of the manuscript. ZYC was responsible for the design of recruitment ads for the study and critically reviewed the versions of the manuscript. All authors approved the final manuscript.

Corresponding authors

Correspondence to Yuping Ning or Yanling Zhou.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University (Ethics number: 2020 [057]). All subjects and their legal guardians must give full informed consent to this project and sign a written informed consent form before being enrolled in this study.

Consent for publication

Not applicable.

Competing interests

All authors declare no actual or potential conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, H., Lan, X., Wang, C. et al. The efficacy and safety of esketamine in the treatment of major depressive disorder with suicidal ideation: study protocol for a randomized controlled trial. BMC Psychiatry 22, 744 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: