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CompletedNCT01920555Updated Jun 19, 2018Results posted

Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

A Phase 2 interventional study of Ketamine and Ketamine in Treatment Resistant Depression, sponsored by Massachusetts General Hospital. Completed at 6 sites in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2018-06-19.

Sponsored by Massachusetts General Hospital · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
99
Allocation
Randomized
Ages
18 Years to 70 Years
Sex
All
01

Study summary

This study is looking at the efficacy, durability, safety, and tolerability of multiple single doses of Ketamine vs. active placebo for treating patients with treatment resistant depression who are taking an antidepressant that is not working for them.

Read the detailed description

The primary objective is to investigate whether all doses (0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, and 1.0 mg/kg) of ketamine are superior to active placebo (midazolam 0.045 mg/kg) therapy in the acute treatment of patients with treatment resistant depression within 72 hours (Day 3), when added to ongoing and stable antidepressant therapy.

02

Conditions studied

  • Treatment Resistant Depression

Keywords

  • Depression
  • Treatment Resistant Depression
  • Ketamine
  • Antidepressant
  • MDD
  • Major Depression
03

In context

Depression

8,057 studies on the registry are indexed under Depression; 1,641 are open to participants now.

This study's enrollment of 99 is above the median of 84 across 6,720 interventional studies indexed under Depression.

Browse Depression studies →

Lead sponsor

Massachusetts General Hospital is the lead sponsor of 2,536 studies on the registry; 446 are open to participants now.

Of its 214 completed or terminated interventional studies of FDA-regulated products, 161 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Male or female, 18-70 years old.
  • Able to read, understand, and provide written, dated informed consent prior to screening.
  • Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening.
  • Has a history of TRD during the current MDE.
  • Meet the threshold on the total MADRS score of greater than or equal to 20 at both screening and baseline visits (Day -7/-28 and Day 0), as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit.
  • In good general health
  • For female participants, status of non-childbearing potential or use of an acceptable form of birth control
  • Body mass index between 18-35 kg/m2
  • Concurrent psychotherapy will be allowed if the type and frequency of the therapy has been stable for at least three months prior to screening and is expected to remain stable during participation in the study
  • Concurrent hypnotic therapy will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.

Exclusion criteria

Exclusion Criteria:

  • Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study
  • Female that is pregnant or breastfeeding
  • Female with a positive pregnancy test at screening or baseline
  • History during the current MDE of failure to achieve a satisfactory response to >7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode
  • Total MADRS score of \<20 at the screen or baseline visits, or as assessed by the remote, independent MGH CTNI rater and reported to the site
  • Current diagnosis of a Substance Use Disorder (Abuse or Dependence) with the exception of nicotine dependence, at screening or within 6 months prior to screening
  • Current Axis I disorder that is the principal focus of treatment and MDD the secondary focus of treatment for the past 6 months or more
  • History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes
  • History of eating disorders within five years of screening
  • Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant at any time within 6 months prior to screening
  • Subject is considered at significant risk for suicidal behavior during the course of their participation in the study
  • Has failed to respond to electroconvulsive therapy (ECT) during the current depressive episode
  • Has received vagus nerve stimulation (VNS) at any time prior to screening
  • Has dementia, delirium, amnestic, or any other cognitive disorder
  • Has a clinically significant abnormality on the screening physical examination
  • Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation

  • Current episode of:

    1. Hypertension, Stage 1 as defined by a systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements (standing and supine) at least 15 minutes apart.
    2. Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5 hours prior to randomization on two of three measurements (standing and supine) at least 15 minutes apart.
    3. Recent myocardial infarction (within one year) or a history of myocardial infarction.
    4. Syncopal event within the past year.
    5. Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2
    6. Angina pectoris.
    7. Heart rate \<50 or >105 beats per minute at screening or randomization (Baseline Visit).
    8. QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit).
  • Current history of hypertension, or on antihypertensives for the purpose of lowering blood pressure, who have either had an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last 2 months.
  • Chronic lung disease excluding asthma.
  • Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder, epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system, or a history of significant head trauma within the past 2 years

  • Presents with any of the following lab abnormalities:

    1. Thyroid stimulating hormone outside of the normal limits and clinically significant as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level is high. Subject will be excluded if T4 level is clinically significant.
    2. Patients with diabetes mellitus fulfilling any of the following criteria:

    i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at screening ii. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks iii. Not under physician care for diabetes mellitus iv. Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than 8 weeks.

    c. Any other clinically significant abnormal laboratory result (as determined after evaluation by study investigator and MGH CTNI medical monitor) at the time of the screening exam.

  • History of hypothyroidism and has been on a stable dosage of thyroid replacement medication for less than 2 months prior to screening. (Subjects on a stable dosage of thyroid replacement medication for at least 2 months or more prior to screening are eligible for enrollment.)
  • History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening
  • Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation
  • History of positive screening urine test for drugs of abuse at screening
  • Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications
  • Patients on exclusionary concomitant psychotropic medications, the half-life of which would not allow sufficient time for patients to have been free of the medication post-taper for five half-lives within the maximum screening period (28 days).
  • Patient who have participated in studies of ketamine or AZD6765 or other NMDA receptor antagonists for depression and received active treatment.
  • Patients with narrow angle glaucoma
  • Patients with a lifetime history of PCP/Ketamine drug use
  • Liver Function Tests higher than 2.5 times upper limit of normal
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
99 participants (actual)

Study arms

  • Active comparator
    Ketamine 0.1mg

    Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

    Drug: Ketamine

  • Active comparator
    Ketamine 0.2mg

    Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

    Drug: Ketamine

  • Active comparator
    Ketamine 0.5mg

    Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

    Drug: Ketamine

  • Active comparator
    Ketamine 1.0mg

    Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

    Drug: Ketamine

  • Placebo comparator
    Midazolam (Active Placebo)

    Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion

    Drug: Placebo Midazolam

Interventions

  • DrugKetamine

    Dose of Ketamine will be 0.1 mg/kg - one single infusion

  • DrugKetamine

    Dose of Ketamine will be 0.2 mg/kg - one single infusion

  • DrugKetamine

    Dose of Ketamine will be 0.5 mg/kg - one single infusion

  • DrugKetamine

    Dose of Ketamine will be 1.0 mg/kg - one single infusion

  • DrugPlacebo Midazolam

    Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion

06

What researchers measure

Primary outcomes

  1. Hamilton Rating Scale for Depression - 6 Items

    The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3

Secondary outcomes

  1. Montgomery-Asberg Depression Rating Scale (MADRS)

    The MADRS is a 10-item clinician-rated scale measuring depression severity. Symptoms are rated on a 7-point scale, where 0 = "not present", and 1-6 represent increasing severity. Values 2, 4, and 6 have specific anchoring text (e.g., 2="Difficulties in starting activities." 4="Difficulties in starting simple routine activities which are carried out with effort, 6="Complete lassitude. Unable to do anything without help.") Values 1, 3, and 5 do not have specific text. The possible scale range is 0-60, where higher values represent higher severity. In this study, the MADRS was used to rate symptoms occurring in the past 3 days.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3.

  2. Clinical Global Impressions-Severity (CGI-S)

    The CGI-S is a clinician rated single-item scale: "How depressed is the patient at this time?", rated on a 7-point response scale: 1 = Normal, not at all depressed, 2 = Borderline depressed, 3 = Mildly depressed, 4 = Moderately depressed. 5 = Markedly depressed, 6 = severely depressed, 7 = Among the most severely depressed patients. When rating patients, clinicians were asked to consider the past 24 hours.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

  3. Clinical Global Impressions-Improvement (CGI-I) Scale

    The CGI-I is a clinician rated single-item scale: "Compared to the patient's condition at admission, how much has the patient changed?", rated on a 7-point response scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. In this case, "admission" referred to the CGI-S screening assessments performed between Day -28 an -7, one conducted during the screening visit, and a second rating conducted by a remote, independent rater.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

  4. Symptoms of Depression Questionnaire (SDQ)

    The SDQ is a 44-item self-report scale, which aims to measure depression more comprehensively by including the assessment of symptoms in the anxiety-depression spectrum, including symptoms of irritability, anger attacks, and anxiety. Items are rated on an 6-point Likert scale, where participants are asked to rate if a specific symptom (e.g. "How has your mood been over the past 24 hours?") is normal for him or her (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The total scale score is calculated by averaging across the items, resulting in a possible range from 1 to 6. Higher scores indicate greater depression severity. When rating, patients were asked to consider their symptoms during the past 24 hours.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

  5. Clinical Positive Affect Scale (CPAS)

    The CPAS is a 16-item self-report scale to assess the level to which participants experience persistent distress due to feeling that they have not returned to their normal or premorbid state. Items (e.g., "I look forward to things") are rated on a 5-point scale (0=not at all, 1=very much less than normal, 2=much less than normal, 3=slightly less than normal, 4=same as best or normal self). The possible scale range is 0 to 64, with higher scores indicating greater recovery from depression. Patients were asked to rate their experience of the past 24 hours.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

  6. Snaith-Hamilton Pleasure-Scale (SHAPS)

    The SHAPS is a 14-item self-report scale to measure hedonic tone. Items (e.g., "I would enjoy reading a book, magazine, or newspaper.") are rated on a 4-point scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). Either of the 'disagree' responses scores 1 point, and either of the 'agree' responses scores 0 points, for a total scale range of 0-14. Higher scores indicate greater inability to experience pleasure. Patients were asked to rate their experience of the past 24 hours.

    Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3

  7. Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion

    The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before infusion, and 40, 80 minute and 120 minutes after the start of infusion. The timeframe is "at this moment".

    Time frame: Day 0/baseline at 0, 40, 80, and 120 minutes

  8. Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)

    The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.

    Time frame: Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined

  9. Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment

    1. CBC 2. Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid) Testing was performed by study site laboratories and used institutional normal lab value ranges.

    Time frame: Day 3 and Early Termination Visit (approximately 3 weeks following intervention)

07

Results

Posted Apr 17, 2018

Participant flow

Participant flow — Overall Study
MilestoneKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)
Started1820222019
Completed1416211718
Not completed44131
Withdrew: Physician decision12120
Withdrew: Lack of efficacy20000
Withdrew: Travel difficulties11001
Withdrew: Lost to follow-up01010

Outcome measures

PrimaryHamilton Rating Scale for Depression - 6 Items

The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3
Reported as:
Mean · units on a scale
Hamilton Rating Scale for Depression - 6 Items
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 012.5555556 ± 1.822158512.7500000 ± 2.489451412.5909091 ± 1.469016212.6315789 ± 2.087277013.0526316 ± 2.2967050
Day 17.5000000 ± 4.32049389.2631579 ± 3.69447195.8636364 ± 4.48590876.9000000 ± 4.506136210.6666667 ± 3.3606722
Day 36.8000000 ± 4.61673978.4736842 ± 4.98183845.9047619 ± 4.30005547.2000000 ± 3.81961709.0555556 ± 4.5435439
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.14 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -3.18 · 95% CI -5.93 to -0.43
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.79 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.13 · 95% CI -3.75 to 1.49
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = <0.01 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -4.79 · 95% CI -7.35 to -2.24
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.04 · Mean difference (final values): -3.76 · 95% CI -6.37 to -1.15
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.72 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -2.04 · 95% CI -5.04 to 0.95
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.80 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.36 · 95% CI -3.18 to 2.46
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.14 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -3.12 · 95% CI -5.97 to -0.44
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.72 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.84 · 95% CI -4.65 to 0.96
SecondaryMontgomery-Asberg Depression Rating Scale (MADRS)

The MADRS is a 10-item clinician-rated scale measuring depression severity. Symptoms are rated on a 7-point scale, where 0 = "not present", and 1-6 represent increasing severity. Values 2, 4, and 6 have specific anchoring text (e.g., 2="Difficulties in starting activities." 4="Difficulties in starting simple routine activities which are carried out with effort, 6="Complete lassitude. Unable to do anything without help.") Values 1, 3, and 5 do not have specific text. The possible scale range is 0-60, where higher values represent higher severity. In this study, the MADRS was used to rate symptoms occurring in the past 3 days.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3.
Reported as:
Mean · units on a scale
Montgomery-Asberg Depression Rating Scale (MADRS)
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 033.8333333 ± 5.933454534.4500000 ± 8.457167631.5909091 ± 3.935904232.6500000 ± 5.887319133.6315789 ± 7.0884141
Day 319.6666667 ± 10.814452422.6315789 ± 11.729405214.7619048 ± 8.988352317.1000000 ± 11.570834524.8333333 ± 10.5286723
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.33 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -5.15 · 95% CI -12.44 to 2.14
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.53 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -2.16 · 95% CI -9.03 to 4.72
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.02 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -9.85 · 95% CI -16.56 to -3.15
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.08 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -7.72 · 95% CI -14.52 to -0.93
SecondaryClinical Global Impressions-Severity (CGI-S)

The CGI-S is a clinician rated single-item scale: "How depressed is the patient at this time?", rated on a 7-point response scale: 1 = Normal, not at all depressed, 2 = Borderline depressed, 3 = Mildly depressed, 4 = Moderately depressed. 5 = Markedly depressed, 6 = severely depressed, 7 = Among the most severely depressed patients. When rating patients, clinicians were asked to consider the past 24 hours.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Reported as:
Mean · units on a scale
Clinical Global Impressions-Severity (CGI-S)
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 05.0000000 ± 0.76696505.2000000 ± 0.69585244.8636364 ± 0.63960215.2000000 ± 0.76777195.000000 ± 0.7453560
Day 13.5625000 ± 1.45916644.2631579 ± 1.24016603.2727273 ± 1.27920433.5000000 ± 1.10023924.555556 ± 0.7838234
Day 33.4000000 ± 1.63881493.7368421 ± 1.48481593.1428571 ± 1.38873013.3000000 ± 1.45457544.1666667 ± 1.3394468
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.08 · Mean difference (final values): -1.03 · 95% CI -1.83 to -0.22
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.82 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.26 · 95% CI -1.02 to 0.51
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.00720 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.28 · 95% CI -2.02 to -0.54
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.04884 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.05 · 95% CI -1.81 to -0.29
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.48 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.71 · 95% CI -1.70 to 0.28
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.82 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.39 · 95% CI -1.32 to 0.55
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.16 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.00 · 95% CI -1.91 to -0.09
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.27 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.86 · 95% CI -1.78 to 0.07
SecondaryClinical Global Impressions-Improvement (CGI-I) Scale

The CGI-I is a clinician rated single-item scale: "Compared to the patient's condition at admission, how much has the patient changed?", rated on a 7-point response scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. In this case, "admission" referred to the CGI-S screening assessments performed between Day -28 an -7, one conducted during the screening visit, and a second rating conducted by a remote, independent rater.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Reported as:
Mean · units on a scale
Clinical Global Impressions-Improvement (CGI-I) Scale
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 03.8888889 ± 0.32338084.0500000 ± 0.22360684.1363636 ± 0.71016134.0000000 ± 0.45883154.1578947 ± 0.6021404
Day 13.0625000 ± 1.43614073.3684211 ± 1.06513052.6363636 ± 0.90213793.0500000 ± 1.23437603.6111111 ± 0.6076850
Day 32.9333333 ± 1.27988092.8421053 ± 1.25888652.5714286 ± 0.92582012.5500000 ± 1.09904263.1666667 ± 1.0431852
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.54 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (net): -0.54 · 95% CI -1.25 to 0.17
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.10 · 95% CI -0.78 to 0.58
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.03 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.98 · 95% CI -1.64 to -0.31
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.54 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.56 · 95% CI -1.24 to 0.11
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.19 · 95% CI -0.96 to 0.57
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.21 · 95% CI -0.93 to 0.51
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.52 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.64 · 95% CI -1.35 to 0.06
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.54 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.62 · 95% CI -1.33 to 0.10
SecondarySymptoms of Depression Questionnaire (SDQ)

The SDQ is a 44-item self-report scale, which aims to measure depression more comprehensively by including the assessment of symptoms in the anxiety-depression spectrum, including symptoms of irritability, anger attacks, and anxiety. Items are rated on an 6-point Likert scale, where participants are asked to rate if a specific symptom (e.g. "How has your mood been over the past 24 hours?") is normal for him or her (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The total scale score is calculated by averaging across the items, resulting in a possible range from 1 to 6. Higher scores indicate greater depression severity. When rating, patients were asked to consider their symptoms during the past 24 hours.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Reported as:
Mean · units on a scale
Symptoms of Depression Questionnaire (SDQ)
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 03.5164141 ± 0.50818563.4636364 ± 0.54167353.5392562 ± 0.58383973.4113636 ± 0.43366523.4264507 ± 0.4719770
Day 12.5752843 ± 0.70918412.9096195 ± 0.71239102.3109504 ± 0.63156772.6113636 ± 0.5005672.9200573 ± 0.6464210
Day 32.5106061 ± 0.71581202.7828283 ± 0.73987342.5573593 ± 0.90177792.5909091 ± 0.57363412.8751353 ± 0.6668931
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.74 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.35 · 95% CI -0.79 to 0.08
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 0.04 · 95% CI -0.37 to 0.45
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.02 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.61 · 95% CI -1.01 to -0.21
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.80 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.31 · 95% CI -0.72 to 0.10
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.88 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.33 · 95% CI -0.83 to 0.18
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.05 · 95% CI -0.53 to 0.44
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.88 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.32 · 95% CI -0.79 to 0.15
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.88 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.29 · 95% CI -0.76 to 0.19
SecondaryClinical Positive Affect Scale (CPAS)

The CPAS is a 16-item self-report scale to assess the level to which participants experience persistent distress due to feeling that they have not returned to their normal or premorbid state. Items (e.g., "I look forward to things") are rated on a 5-point scale (0=not at all, 1=very much less than normal, 2=much less than normal, 3=slightly less than normal, 4=same as best or normal self). The possible scale range is 0 to 64, with higher scores indicating greater recovery from depression. Patients were asked to rate their experience of the past 24 hours.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Reported as:
Mean · units on a scale
Clinical Positive Affect Scale (CPAS)
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 019.3333333 ± 12.189677420.5000000 ± 15.435775320.6363636 ± 11.700815821.2500000 ± 14.678573721.2631579 ± 12.1052886
Day 135.2500000 ± 20.993649827.0526316 ± 18.851683340.8696964 ± 19.528478533.0000000 ± 16.264265024.4444444 ± 15.2053482
Day 338.8666667 ± 22.866666728.3888889 ± 20.245955039.7619048 ± 22.531987837.4500000 ± 18.709623233.3750000 ± 15.8445574
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.49 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 11.18 · 95% CI -0.94 to 23.29
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 1.37 · 95% CI -10.19 to 12.93
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.03 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 16.54 · 95% CI 5.31 to 27.77
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.82 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 8.68 · 95% CI -2.81 to 20.16
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 5.11 · 95% CI -8.83 to 19.05
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -6.64 · 95% CI -19.87 to 6.59
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 7.64 · 95% CI -5.26 to 20.53
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 4.80 · 95% CI -8.31 to 17.91
SecondarySnaith-Hamilton Pleasure-Scale (SHAPS)

The SHAPS is a 14-item self-report scale to measure hedonic tone. Items (e.g., "I would enjoy reading a book, magazine, or newspaper.") are rated on a 4-point scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). Either of the 'disagree' responses scores 1 point, and either of the 'agree' responses scores 0 points, for a total scale range of 0-14. Higher scores indicate greater inability to experience pleasure. Patients were asked to rate their experience of the past 24 hours.

Time frame:
A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Reported as:
Mean · units on a scale
Snaith-Hamilton Pleasure-Scale (SHAPS)
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Day 07.2222222 ± 3.90407867.5500000 ± 3.91320306.5909091 ± 3.23167497.3500000 ± 4.19617626.4736842 ± 3.7471237
Day 13.9375000 ± 4.28125765.7368421 ± 4.25365342.22727273 ± 3.57480364.3000000 ± 4.56646825.0000000 ± 4.6272848
Day 33.5333333 ± 3.37779876.3888889 ± 4.52624883.0000000 ± 3.78153413.6500000 ± 4.83708264.2500000 ± 3.8384024
Statistical analysis
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.21 · 95% CI -3.99 to 1.56
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.17 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 0.76 · 95% CI -1.90 to 3.43
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.30 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -2.74 · 95% CI -5.32 to -0.16
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.71 · 95% CI -3.35 to 1.93
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.29 · 95% CI -3.25 to 2.66
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 0.39 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): 2.76 · 95% CI -0.06 to 5.59
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -1.17 · 95% CI -3.91 to 1.58
  • Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg · Mixed Models Analysis · p = 1.00 (Holm's method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.) · Mean difference (final values): -0.43 · 95% CI -3.22 to 2.35
SecondaryClinician-Administered Dissociative States Scale (CADSS) Scores During Infusion

The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before infusion, and 40, 80 minute and 120 minutes after the start of infusion. The timeframe is "at this moment".

Time frame:
Day 0/baseline at 0, 40, 80, and 120 minutes
Reported as:
Mean · units on a scale
Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion
units on a scaleKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Minute 00.1111111 ± 0.47140450.1000000 ± 0.44721360 ± 00.1000000 ± 0.30779350.4210526 ± 1.01739326
Minute 403.0000000 ± 5.07589464.0500000 ± 4.260899314.2727273 ± 9.607664424.6842105 ± 17.71080222.6842105 ± 3.5127171
Minute 800.4444444 ± 0.78382340.1000000 ± 0.44721360.7727273 ± 2.11416581.8000000 ± 2.96647941.1578947 ± 1.8337320
Minute 1200.0555556 ± 0.23570230 ± 00.1363636 ± 0.63960210.6500000 ± 1.59851910.5789474 ± 0.9015905
SecondaryNumber of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)

The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.

Time frame:
Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined
Reported as:
Count of participants · Participants
Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
ParticipantsKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Screening: # with suicidal ideation/behavior1715171417
Follow-Up: # with suicidal ideation/behavior15910613
SecondaryNumber of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment

1. CBC 2. Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid) Testing was performed by study site laboratories and used institutional normal lab value ranges.

Time frame:
Day 3 and Early Termination Visit (approximately 3 weeks following intervention)
Reported as:
Count of participants · Participants
Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment
ParticipantsKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam 0.045mg
Chemistry ALT(SGPT)01000
Chemistry AST(SGOT)01000
Chemistry Total Bilirubin01000
Chemistry Remaining Tests00000
CBC00000

Adverse events

Collected over Number of patients with adverse events post infusion (treatment) up to 30 days.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Ketamine 0.1mg0/18 (0%)0/18 (0%)17/18 (94.4%)
Ketamine 0.2mg0/20 (0%)1/20 (5%)18/20 (90%)
Ketamine 0.5mg0/22 (0%)0/22 (0%)14/22 (63.6%)
Ketamine 1.0mg0/20 (0%)0/20 (0%)17/20 (85%)
Midazolam (Active Placebo)0/19 (0%)0/19 (0%)10/19 (52.6%)
Most frequent serious events
Most frequent serious events
EventKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)
Suicide AttemptPsychiatric disorders0/181/200/220/200/19
Most frequent other events
Showing 10 of 45
Most frequent other events
EventKetamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)
HeadacheNervous system disorders3/182/201/223/200/19
NauseaGastrointestinal disorders2/180/203/223/200/19
DyspepsiaGastrointestinal disorders0/182/200/220/200/19
Blood Pressure IncreaseCardiac disorders0/180/200/222/200/19
VomitingGastrointestinal disorders1/181/201/221/200/19
DepressionPsychiatric disorders1/181/201/220/200/19
Back PainMusculoskeletal and connective tissue disorders1/180/200/220/201/19
DiarrheaGastrointestinal disorders1/180/201/220/200/19
InsomniaPsychiatric disorders1/180/200/221/200/19
Pain In ExtremityMusculoskeletal and connective tissue disorders1/180/201/220/200/19

Baseline characteristics

Age, Continuous
Age, Continuous(years)Ketamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)Total
Mean43.1 ± 11.945.5 ± 14.648.6 ± 12.947.4 ± 10.145.6 ± 13.846.04 ± 12.64
Sex: Female, Male
Sex: Female, Male(Participants)Ketamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)Total
Female1091181149
Male8111112850
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Ketamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)Total
Hispanic or Latino102003
Not Hispanic or Latino172020201996
Unknown or Not Reported000000
BMI
BMI(kg/m^2)Ketamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)Total
Mean25.2 ± 3.124.9 ± 3.725.3 ± 5.726.1 ± 3.826.3 ± 4.124.96 ± 4.08
Abnormal and Clinically Significant Labs
Abnormal and Clinically Significant Labs(Participants)Ketamine 0.1mgKetamine 0.2mgKetamine 0.5mgKetamine 1.0mgMidazolam (Active Placebo)Total
CBC000000
Chemistry000000
Hormonal Measures (testosterone, SHBG, Free T)020002
Hormonal Measures (DHEA)000101
Hormonal Measures (remaining tests)000000
Pregnancy Test000000
Urine Toxicology Screen000000
08

Study locations

6 sites
  • Stanford University
    Palo Alto, California 94304, United States
  • Yale University
    New Haven, Connecticut 06520, United States
  • Massachusetts General Hospital
    Boston, Massachusetts 02114, United States
  • Mount Sinai School of Medicine
    New York, New York 10029, United States
  • University of Texas Southwestern
    Dallas, Texas 75390, United States
  • Baylor College of Medicine
    Houston, Texas 77030, United States
09

References and documents

Publications

  • HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available. PubMed 14399272 ↗
  • Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967 Dec;6(4):278-96. doi: 10.1111/j.2044-8260.1967.tb00530.x. No abstract available. PubMed 6080235 ↗
  • Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382. PubMed 444788 ↗
  • Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976.
  • Nierenberg AA, Bentley KH, Farabaugh AH, Fava M, Deckersbach T. The absence of depressive symptoms is not the presence of wellness: validation of the Clinical Positive Affect Scale. Aust N Z J Psychiatry. 2012 Dec;46(12):1165-72. doi: 10.1177/0004867412459810. Epub 2012 Sep 18. PubMed 22990434 ↗
  • Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-43. doi: 10.1176/ajp.2007.164.7.1035. PubMed 17606655 ↗
  • Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99. PubMed 7551619 ↗
  • Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998 Jan;11(1):125-36. doi: 10.1023/A:1024465317902. PubMed 9479681 ↗
  • Feeney A, Hoeppner BB, Freeman MP, Flynn M, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, DeBattista C, Ionescu DF, Cusin C, Papakostas GI, Jha MK, Fava M. Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. J Clin Psychiatry. 2022 Nov 14;84(1):22m14491. doi: 10.4088/JCP.22m14491. PubMed 36383742 ↗
  • Feeney A, Hock RS, Freeman MP, Flynn M, Hoeppner B, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, Debattista C, Ionescu DF, Fava M, Papakostas GI. The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study. Eur Neuropsychopharmacol. 2021 Aug;49:122-132. doi: 10.1016/j.euroneuro.2021.04.024. Epub 2021 Jun 3. PubMed 34090255 ↗
  • Freeman MP, Hock RS, Papakostas GI, Judge H, Cusin C, Mathew SJ, Sanacora G, Iosifescu DV, DeBattista C, Trivedi MH, Fava M. Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder. J Clin Psychopharmacol. 2020 May/Jun;40(3):287-292. doi: 10.1097/JCP.0000000000001209. PubMed 32332464 ↗
  • Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020 Jul;25(7):1592-1603. doi: 10.1038/s41380-018-0256-5. Epub 2018 Oct 3. Erratum In: Mol Psychiatry. 2020 Jul;25(7):1604. doi: 10.1038/s41380-018-0311-2. PubMed 30283029 ↗
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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 19, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT01920555
Lead sponsor
Massachusetts General Hospital
Collaborators
National Institute of Mental Health (NIMH), Baylor College of Medicine, Icahn School of Medicine at Mount Sinai, Stanford University, University of Texas, Yale University
Responsible party
Maurizio Fava, MD (Overall Principal Investigator, Massachusetts General Hospital) — Principal investigator
First posted
Aug 12, 2013
Start date
Dec 2014
Primary completion
Jan 2017
Completion
Feb 2017
Results posted
Apr 17, 2018
Last update
Jun 19, 2018

Study contacts

Maurizio Fava, MD
principal investigator · Massachusetts General Hospital

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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