Ketamine as a Rapidly-Acting Antidepressant in Depressed Emergency Department Patients

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02106325
• Collaborator: (none)
• Enrollment: 21
• Locations: 2
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Investigators will conduct a trial to evaluate the use of Ketamine as an alternate treatment for people with Major Depressive Disorder. This study plans to explore the potential that Ketamine's rapid antidepressant action holds for improving outcomes in patients presenting to the Emergency Department with severe depression. Since this is a controlled trial we will use an IV of Ketamine or and equivalent volume of Diphenhydramine. Subjects will be randomly assigned to receive Ketamine or Benadryl. Investigators will then compare measures of mood pre- and post-infusion in the Emergency Department. To supplement self-reported measures of depressive symptoms(e.g. mood), investigators will obtain objective measures of the biological aspects of Major Depressive Disorder.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: Ketamine; Drug: Diphenhydramine	Phase 2

Detailed Description

To explore the use of ketamine as a potential rapidly-acting antidepressant (RAA) for Emergency Department (ED) patients with major depressive disorder (MDD).

Investigators will conduct a randomized controlled study to evaluate the rapidity and persistence of antidepressant effects of a single sub-anesthetic dose of intravenous (IV) ketamine (0.25mg/kg) or an equivalent volume of diphenhydramine (25mg) delivered IV over 1-2 minutes, by comparing measures of mood pre- and post-infusion in Emergency Department (ED) patients with MDD. Subjects will be randomly assigned (1:1) to receive a bolus of ketamine or diphenhydramine. To supplement self-reported measures of depressive symptoms (e.g., mood, suicidal ideation, etc.), investigators will obtain objective measures of heart rate and heart rate variability, measure serum levels of the pro- and anti-inflammatory cytokines (interleukin IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and tissue necrosis factor, TNF-α), which have been shown to play an important role in stress, depression and suicidal behavior. In addition, investigators will obtain serum levels of brain derived neurotrophic factor (BDNF) because reduced serum BDNF has been described during acute depressive episodes in patients with MDD, with reports of rescue effects following treatment with various antidepressants and with ketamine (Aydemir 2005, Gervasoni 2005, Karege 2002, Karege 2005, Duncan 2013, Shimizu 2003). Investigators will also measure serum magnesium levels, as these have been shown to correlate in a predictive manner with response to conventional antidepressants (Camardese 2012), and there are data to suggest that ketamine's efficacy in treatment-resistant depression could be related to a relative magnesium deficiency in such patients (Murck 2013).

This study will allow investigators to determine to what extent low-dose ketamine, an N-Methyl-D-Aspartate (NMDA) antagonist, achieves a rapid reduction in symptoms for severely depressed ED patients with or without suicidal ideation. For decades, much higher doses of IV ketamine (1-2mg/kg) have been used routinely in the ED as a dissociative anesthetic (Green 2011). In 2011, an open-label study was the first published of the use of low dose ketamine (0.2mg/kg), administered by rapid intravenous infusion, in the ED setting for acutely depressed patients which demonstrated its feasibility, safety, preliminary efficacy and acceptability to both ED patients and staff (Larkin 2011). One long-term goal of this research is to expand treatment options available to depressed ED patients that mitigate the need for inpatient admission and serve as a safety bridge to future out-patient treatment for major depression. As an adjunct to standard treatment, low-dose NMDA receptor antagonists have the potential to positively impact: ED waiting times; repeat visits to the ED; short-term risk of suicide attempts; length of stay on inpatient units and the need for hospital admissions for many acutely depressed patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blinded Controlled Trial of an N-Methyl D-Aspartate Antagonist as a Rapidly-Acting Antidepressant in Depressed Emergency Department Patients
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine IV Ketamine .25mg/kg	Drug: Ketamine; IV of Ketamine (.25mg/kg); Other Names: Other names for ketamine: ketalar
Placebo Comparator: Diphenhydramine 25mg Diphenhydramine	Drug: Diphenhydramine; Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department; Other Names: Other names for diphenhydramine: benadryl

Outcome Measures

Primary Outcome Measures

1. Evaluate the Effects of Ketamine on Depressive Symptomatology by Measuring Change in Score on the Montgomery-Asberg Depressive Rating Scale [Baseline and 16 weeks]

   40 Minutes Post Infusion, The MADRS-S instrument has nine questions, with an overall score ranging from 0 to 54 points. 0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression.

2. Beck Depression Inventory-II (BDI-II) [120 min post-infusion]

   BDI-II items are rated on a 4-point scale ranging from 0 to 3 based on severity of each item. The maximum total score is 63. 0-13 Indicates minimal depression 14-19 Indicates mild depression 20-28 Indicates Moderate depression 29-63 Indicates Severe depression

3. Hamilton Depression Scale (Ham-D) [4-6 hours post-infusion]

   Although the HAM-D form lists 21 items, the scoring is based on the first 17. It generally takes 15-20 minutes to complete the interview and score the results. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. Sum the scores from the first 17 items 0-7= Normal 8-13= Mild Depression 14-18= Moderate Depression 19-22= Severe Depression >23= Very Severe Depression

Secondary Outcome Measures

1. Change in Treatment Alliance Score [Baseline and 16 weeks]

   The I-TAS is a 10-item, Likert-style rating scale designed to assess a patient's composite treatment alliance as it develops across multi-disciplinary treatment components. The I-TAS was intended to measure the primary alliance factors identified by Hatcher and Barends (1996) of bond, goals and collaboration. Each question is scored on a scale of 0 (Completely False) to 6 (Completely True). Total scores on the ITAS range from 0 to 60, with higher scores representing greater alliance with the treatment team (better outcome). The reported score is an average of each participant's total score on the ITAS.

2. Beck Scale for Suicidal Ideation (BSSI) [40 minutes post-infusion]

   BDI-II items are rated on a 4-point scale ranging from 0 to 3 based on severity of each item. The maximum total score is 63. 0-13 Indicates minimal depression 14-19 Indicates mild depression 20-28 Indicates Moderate depression 29-63 Indicates Severe depression

3. Montgomery-Åsberg Depression Rating Scale Suicide Ideation Item (MADRS-SI) [40 minutes post-infusion]

   40 Minutes Post Infusion, The MADRS-S instrument has nine questions, with an overall score ranging from 0 to 54 points. 0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression.

4. Length of Inpatient Stay [2 Weeks Post-infusion]

5. Outpatient Follow-up Compliance [1 Day]

   Scoring System: 0= not compliant, 1=compliant

6. Inpatient Treatment Alliance Scale (ITAS) [7 days post-infusion]

   The I-TAS is a 10-item, Likert-style rating scale designed to assess a patient's composite treatment alliance as it develops across multi-disciplinary treatment components. The I-TAS was intended to measure the primary alliance factors identified by Hatcher and Barends (1996) of bond, goals and collaboration. Each question is scored on a scale of 0 (Completely False) to 6 (Completely True). Total scores on the ITAS range from 0 to 60, with higher scores representing greater alliance with the treatment team (better outcome). The reported score is an average of each participant's total score on the ITAS.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Medically stable as determined by the medical physician

• Meets criteria for Major Depressive Disorder (MDD) based on a structured clinical Interview (MINI International Neuropsychiatric Interview).

• Reports symptoms of severe depression at the time of presentation, defined as a score of 24 or greater on the MADRS.

• Patients for whom a psychiatric evaluation and disposition decision has been made by emergency psychiatry staff to admit to an inpatient psychiatric unit at Bellevue Hospital Center or NYU Tisch Hospital.

• Each subject must have a level of understanding sufficient to sign an informed consent stating that the treatment being offered is not FDA approved for the treatment of depression and is being provided as an off-label option.

Exclusion Criteria:

• Pregnancy

• Inability to read or understand English

• Current clinical signs of intoxication or delirium at time of study intervention

• Overdose, within previous 24 hours, of any agent which would impair ketamine metabolism

• Lifetime misuse/abuse of ketamine, phencyclidine (PCP),or related substances

• Lifetime history of psychotic spectrum illness

• First-degree relative with history of psychotic illness

• Lifetime diagnosis of borderline personality disorder, or as confirmed by assessment using items #90-104 of the SCID-II (for DSM-IV).

• Subjects with clinically significant abnormal findings as determined by medical history, physical examination, vital signs (blood pressure, heart rate, and respiration rate), O2 saturation measure, 12-lead ECG, clinical laboratory tests (CBC, chemistry panel, thyroid function tests), urine drug screen, and urine pregnancy test (for females of childbearing potential only).

• Clinically unstable medical, surgical or neurological conditions at ED presentation

• History of stroke or intracranial hypertension

• History of glaucoma

• Subjects with one or more seizures without a clear and resolved etiology

• Current NMDA antagonist medications (eg. Amantadine, Rimantadine, Lamotrigine, Memantine, Dextromethorphan)

• Known hypersensitivity to ketamine or amantadine

• Anti-psychotic medications (Typicals or Atypicals), with the exception of low-dose quetiapine (total daily dose of 100mg or less).

• Actively trying to commit suicide, even in a hospital setting

• Current homicide risk

• Unable or unwilling to give informed consent according to HIC guidelines

• Unable or unwilling to provide 2 contact phone numbers or be followed up per study protocol.

• Previous enrollment in this study.

• Concurrent enrollment in a research protocol investigating experimental pharmacologic treatments for depression at this or any other institution.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bellevue Hospital Center	New York	New York	United States	10016
2	NYU Langone Medical Center/Tisch Hospital	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: Stephen Ross, MD, NYU Langone Health
• Study Chair: K. Casey Paleos, MD, New York Unversity School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02106325
• Other Study ID Numbers: 13-00794
• First Posted: Apr 8, 2014
• Last Update Posted: Sep 14, 2018
• Last Verified: Aug 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by NYU Langone Health: Ketamine; Ketlar; Depression; Antidepressants; Treatment; Acute
• Additional relevant MeSH terms: Emergencies; Depression; Diphenhydramine; Promethazine; Ketamine

Study Results

Participant Flow

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Period Title: Phase 1
STARTED	5	3
COMPLETED	3	1
NOT COMPLETED	2	2
Period Title: Phase 1
STARTED	4	4
COMPLETED	2	1
NOT COMPLETED	2	3
Period Title: Phase 1
STARTED	2	3
COMPLETED	0	2
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Ketamine	Diphenhydramine	Total
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department	Total of all reporting groups
Overall Participants	11	10	21
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	40	31	38
Sex: Female, Male (Count of Participants)
Female	4 36.4%	4 40%	8 38.1%
Male	7 63.6%	6 60%	13 61.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 9.1%	0 0%	1 4.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 9.1%	0 0%	1 4.8%
White	8 72.7%	10 100%	18 85.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 9.1%	0 0%	1 4.8%

Outcome Measures

1. Primary Outcome

Title	Evaluate the Effects of Ketamine on Depressive Symptomatology by Measuring Change in Score on the Montgomery-Asberg Depressive Rating Scale
Description	40 Minutes Post Infusion, The MADRS-S instrument has nine questions, with an overall score ranging from 0 to 54 points. 0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [units on a scale]	28.82 (2.95)	25.20 (3.10)

2. Primary Outcome

Title	Beck Depression Inventory-II (BDI-II)
Description	BDI-II items are rated on a 4-point scale ranging from 0 to 3 based on severity of each item. The maximum total score is 63. 0-13 Indicates minimal depression 14-19 Indicates mild depression 20-28 Indicates Moderate depression 29-63 Indicates Severe depression
Time Frame	120 min post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [Scored units on a scale]	20.00 (3.94)	24.72 (4.06)

3. Primary Outcome

Title	Hamilton Depression Scale (Ham-D)
Description	Although the HAM-D form lists 21 items, the scoring is based on the first 17. It generally takes 15-20 minutes to complete the interview and score the results. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. Sum the scores from the first 17 items 0-7= Normal 8-13= Mild Depression 14-18= Moderate Depression 19-22= Severe Depression >23= Very Severe Depression
Time Frame	4-6 hours post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [Scored units on a scale]	21.48 (2.08)	17.00 (2.26)

4. Secondary Outcome

Title	Change in Treatment Alliance Score
Description	The I-TAS is a 10-item, Likert-style rating scale designed to assess a patient's composite treatment alliance as it develops across multi-disciplinary treatment components. The I-TAS was intended to measure the primary alliance factors identified by Hatcher and Barends (1996) of bond, goals and collaboration. Each question is scored on a scale of 0 (Completely False) to 6 (Completely True). Total scores on the ITAS range from 0 to 60, with higher scores representing greater alliance with the treatment team (better outcome). The reported score is an average of each participant's total score on the ITAS.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [Scored units on a scale]	43.52 (3.69)	53.15 (4.17)

5. Secondary Outcome

Title	Beck Scale for Suicidal Ideation (BSSI)
Description	BDI-II items are rated on a 4-point scale ranging from 0 to 3 based on severity of each item. The maximum total score is 63. 0-13 Indicates minimal depression 14-19 Indicates mild depression 20-28 Indicates Moderate depression 29-63 Indicates Severe depression
Time Frame	40 minutes post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [units on a scale]	1.58 (1.40)	1.08 (1.42)

6. Secondary Outcome

Title	Montgomery-Åsberg Depression Rating Scale Suicide Ideation Item (MADRS-SI)
Description	40 Minutes Post Infusion, The MADRS-S instrument has nine questions, with an overall score ranging from 0 to 54 points. 0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression.
Time Frame	40 minutes post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [units on a scale]	0.83 (0.46)	0.75 (0.40)

7. Secondary Outcome

Title	Length of Inpatient Stay
Time Frame	2 Weeks Post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [Days]	6.33 (1.32)	7.80 (1.25)

8. Secondary Outcome

Title	Outpatient Follow-up Compliance
Description	Scoring System: 0= not compliant, 1=compliant
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [units on follow up compliance scale]	0.73 (.14)	.70 (.14)

9. Secondary Outcome

Title	Inpatient Treatment Alliance Scale (ITAS)
Description	The I-TAS is a 10-item, Likert-style rating scale designed to assess a patient's composite treatment alliance as it develops across multi-disciplinary treatment components. The I-TAS was intended to measure the primary alliance factors identified by Hatcher and Barends (1996) of bond, goals and collaboration. Each question is scored on a scale of 0 (Completely False) to 6 (Completely True). Total scores on the ITAS range from 0 to 60, with higher scores representing greater alliance with the treatment team (better outcome). The reported score is an average of each participant's total score on the ITAS.
Time Frame	7 days post-infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)	25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
Measure Participants	11	10
Mean (Standard Error) [Scored units on ITAS Scale]	43.52 (3.69)	53.15 (4.17)

Adverse Events

Arm/Group Title	Ketamine		Diphenhydramine
Arm/Group Description	IV Ketamine .25mg/kg Ketamine: IV of Ketamine (.25mg/kg)		25mg Diphenhydramine Diphenhydramine: Intravenous Diphenhydramine (25mg) at the time of presentation to Emergency Department
All Cause Mortality
	Ketamine		Diphenhydramine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/10 (0%)
Serious Adverse Events
	Ketamine		Diphenhydramine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)		0/10 (0%)
Psychiatric disorders
Psychosis and Suicidality	1/11 (9.1%)	1	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	Ketamine		Diphenhydramine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)		8/10 (80%)
General disorders
Tiredness	1/11 (9.1%)	1	3/10 (30%)	3
Perceptual Disturbance	2/11 (18.2%)	2	2/10 (20%)	2
Headache	1/11 (9.1%)	1	0/10 (0%)	0
Dizziness	2/11 (18.2%)	2	1/10 (10%)	1
Toe Numbness	0/11 (0%)	0	1/10 (10%)	1
GI Distress	2/11 (18.2%)	2	0/10 (0%)	0
Vascular disorders
Elevated Systolic BP	0/11 (0%)	0	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.