KetPTSD: Ketamine as a Rapid Treatment for Post-traumatic Stress Disorder (PTSD)

• Sponsor: Dennis Charney (Other)
• Overall Status: Completed
• CT.gov ID: NCT00749203
• Collaborator: United States Department of Defense (U.S. Fed)
• Enrollment: 41
• Location: 1
• Arms: 2
• Duration (Months): 56
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The objective of the proposed study is to test if a single IV dose of ketamine (0.5 mg/kg) decreases symptoms of PTSD.

Condition or Disease	Intervention/Treatment	Phase
Stress Disorders, Post-Traumatic; PTSD; Depression; Anxiety Disorder	Drug: Midazolam; Drug: Ketamine	Phase 2

Detailed Description

PTSD is a debilitating anxiety disorder characterized by intrusive re-experiences of the traumatic events, avoidance of situations and stimuli that could serve as reminders of these events, and feeling jumpy or easily startled. Patients with PTSD are often also depressed, and many have significant memory impairments. Existing drug treatments are unsuccessful in a majority of patients, especially in those with combat-related PTSD.

Our aim is to test the effectiveness of a potential new drug for PTSD, ketamine. For many years, intravenous ketamine has been extensively used for anesthesia. More recently, using doses lower than those used in anesthesia, a single ketamine infusion was shown to rapidly reduce depressed mood as well as anxiety in patients with severe depression. Some clinical evidence of potential efficacy in depressed patients with co-morbid PTSD also exists.

Adverse effects in these studies have been limited to feeling intoxicated and having increased blood pressure during the infusion.

In the present study, we expect a single ketamine infusion to reduce core PTSD symptoms. In addition, in those patients with PTSD who are depressed, we expect ketamine to reduce depressed mood.

Finally, ketamine is known to impair memory function temporarily. We will also test if the extent of ketamine-induced memory impairment during the infusion can predict how well people do after the infusion. Forty patients with PTSD (with and without combat-related trauma histories) will be tested, using a design that will compare the effectiveness of intravenous ketamine to that of midazolam, another anesthetic drug without any known long-term effects on anxiety, depressed mood, and memory function. If ketamine is found to have the expected effects, future studies may explore additional benefits of repeated infusions and / or alternatives to intravenous drug administration. Our study may contribute to improved function of patients with PTSD by providing a new means to rapidly treat their debilitating symptoms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Ketamine as a Rapid Treatment for Post-traumatic Stress Disorder
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	Drug: Ketamine; Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes; Other Names: Racemic ketamine hydrochloride
Active Comparator: Midazolam single dose 0.045 mg/kg IV infused over 40 minutes	Drug: Midazolam; single dose 0.045 mg/kg IV infused over 40 minutes

Outcome Measures

Primary Outcome Measures

1. Impact of Event Scale - Revised (IES-R) [7 days after first infusion]

   A 22-item self-report questionnaire measuring PTSD symptoms. Items are rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"). The IES-R yields a total score ranging from 0 (not at all) to 88 (extremely)

Secondary Outcome Measures

1. Clinician-Administered PTSD Scale (CAPS) [7 days after first infusion]

   Clinician-administered structured interview measuring PTSD symptoms. frequency score - scale 0 = none of the time to 4 = most or all of the time intensity score - scale 0 = none to 4 = extreme To meet criteria for a symptom, a patient must meet criteria in both frequency and intensity score for each item. Frequency and intensity and then combined to form a single severity score. 30 questions scale, with total score ranging from 0 to 240.

2. Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) [24 hours after first infusion]

   Self-report questionnaire measuring depressive symptoms. Each item is rated 0 (no depression) to 3 (severe depression). The total score ranges from 0-27.

3. Montgomery-Asberg Depression Rating Scale (MADRS) [24 hours after first infusion]

   Clinician-administered questionnaire measuring depressive symptoms. The MADRS-S has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression). Mean difference between baseline and 2 weeks.

4. Hopkins Verbal Learning Test (HVLT) [20 to 40 minutes after infusion]

   Repeatable test of memory acquisition and delayed recall of words. It is a three-trial list learning and free recall task comprising 12 words, 4 words from each of three semantic categories. Total Recall score range is 0 to 36.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men or women, 21-55 years of age;

• Participants must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign a written informed consent document;

• Participants must fulfill DSM-IV criteria for current civilian or combat-related PTSD, based on clinical assessment by a study psychiatrist and on the CAPS (score must be at least 50 at screening and prior to each infusion - this is done to ensure at least moderate severity and to safeguard against high placebo response rates); additionally, clinicians will use clinical judgment to assess if patients are symptomatic enough to receive each infusion

• Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year);

• Women of childbearing potential must have a negative pregnancy test at screening and pre-infusion;

• Participants must be able to identify a family member, physician, or friend (i.e. someone who knows them well) who will participate in a Treatment Contract (and e.g. contact the study physician on their behalf in case manic symptoms or suicidal thoughts develop).

Exclusion Criteria:

• Women who plan to become pregnant, are pregnant or are breast-feeding (because the medical risk of using ketamine during pregnancy and breast-feeding is unknown);

• Serious, unstable medical illnesses such as hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease (including gastro-esophageal reflux disease, obstructive sleep apnea, history of difficulty with airway management during previous anesthetics, ischemic heart disease and uncontrolled hypertension, and history of severe head injury);

• Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;

• Patients with uncorrected hypothyroidism or hyperthyroidism;

• Hormonal treatment (e.g., estrogen) started in the 3 months prior to the first infusion day;

• Use of evidence-based individual psychotherapy (such as prolonged exposure) and other non-pharmacological treatments during the study;

• Histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome;

• History of one or more seizures without a clear and resolved etiology;

• History of (hypo)mania;

• Past or current presence of psychotic symptoms, or diagnosis of a lifetime psychotic disorder including schizophrenia or schizoaffective disorder;

• Drug or alcohol abuse or dependence within the preceding 3 months (given that this might otherwise contribute to their symptoms, however, a rather narrow time period was chosen such as to allow participation by individuals with a history of substance abuse or dependence problems that could be secondary to their PTSD, and to more closely approximate patients seen in real-world settings);

• Previous recreational use of ketamine or PCP;

• Current diagnosis of bulimia nervosa or anorexia nervosa;

• Diagnosis of schizotypal or antisocial personality disorder (since these are known to reduce the possibility of study completion; other Axis II diagnoses will be allowed);

• Patients judged clinically to be at serious and imminent suicidal or homicidal risk.

• A blood pressure of one reading over 160/90 or two separate readings over 140/90 at screen or baseline visits.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

Sponsors and Collaborators

• Dennis Charney
• United States Department of Defense

Investigators

• Principal Investigator: Dennis Charney, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Publications

• Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.
• Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.

• Responsible Party: Dennis Charney, Dean, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT00749203
• Other Study ID Numbers: GCO 07-1199; PT074949; IF1554104; A-15236
• First Posted: Sep 9, 2008
• Last Update Posted: Feb 14, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Dennis Charney, Dean, Icahn School of Medicine at Mount Sinai: Stress Disorders, Post-Traumatic; PTSD; anxiety disorder; ketamine; depression; depressed mood
• Additional relevant MeSH terms: Disease; Depression; Stress Disorders, Traumatic; Anxiety Disorders; Stress Disorders, Post-Traumatic; Midazolam; Ketamine

Study Results

Participant Flow

Recruitment Details	Patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements beginning Jan 2009, and were enrolled at the Icahn School of Medicine at Mount Sinai, New York, between May 2009 and December 2012.

Arm/Group Title	Ketamine Then Midazolam	Midazolam Then Ketamine
Arm/Group Description	Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes on day 1, then 2 weeks later, Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes	Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes on day 1, then 2 weeks later, Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes
Period Title: First Infusion Day 1
STARTED	22	19
COMPLETED	22	19
NOT COMPLETED	0	0
Period Title: First Infusion Day 1
STARTED	22	19
COMPLETED	22	15
NOT COMPLETED	0	4
Period Title: First Infusion Day 1
STARTED	16	15
COMPLETED	16	13
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Ketamine Then Midazolam	Midazolam the Ketamine	Total
Arm/Group Description	Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes on Day 1, then 2 weeks later, Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes	Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes on Day 1, then 2 weeks later Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	Total of all reporting groups
Overall Participants	22	19	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.4 (10.8)	35.7 (10.0)	36.05 (10.3)
Sex: Female, Male (Count of Participants)
Female	13 59.1%	6 31.6%	19 46.3%
Male	9 40.9%	13 68.4%	22 53.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 50%	12 63.2%	23 56.1%
White	5 22.7%	2 10.5%	7 17.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	6 27.3%	5 26.3%	11 26.8%
Education (participants) [Number]
less than high school	1 4.5%	0 0%	1 2.4%
high school graduate	3 13.6%	3 15.8%	6 14.6%
some college	12 54.5%	14 73.7%	26 63.4%
more than 4 years of college	5 22.7%	2 10.5%	7 17.1%
unknown	1 4.5%	0 0%	1 2.4%
Percentage Unemployed (percentage of participants) [Number]
Number [percentage of participants]	50 227.3%	73.7 387.9%	123.7 301.7%
Primary Trauma (participants) [Number]
Sexual assault or molestation	9 40.9%	0 0%	9 22%
Physical assault or abuse	4 18.2%	7 36.8%	11 26.8%
Accident or fire	1 4.5%	3 15.8%	4 9.8%
Combat exposure	2 9.1%	0 0%	2 4.9%
Witnessed violent assault or death	4 18.2%	5 26.3%	9 22%
Witnessed 9/11 terrorist attacks	2 9.1%	0 0%	2 4.9%
Unknown	0 0%	4 21.1%	4 9.8%
Duration of PTSD (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.2 (12.3)	11.9 (14.0)	13.1 (13.1)
History of treatment with psychotropic medication (percentage of participants) [Number]
Number [percentage of participants]	50 227.3%	42.1 221.6%	92.1 224.6%
Clinician-Administered PTSD Scale (CAPS) score (past month) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	82.5 (14.1)	77.1 (11.8)	80.0 (13.0)
Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	12.4 (5.2)	11.3 (5.6)	11.9 (5.4)

Outcome Measures

1. Primary Outcome

Title	Impact of Event Scale - Revised (IES-R)
Description	A 22-item self-report questionnaire measuring PTSD symptoms. Items are rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"). The IES-R yields a total score ranging from 0 (not at all) to 88 (extremely)
Time Frame	7 days after first infusion

Outcome Measure Data

Analysis Population Description

Not all participants returned for the 1 week follow up visit. There were 19 participants from the Ketamine group and 15 participants from the Midazolam group who returned for their followup visit and completed the IES-R at the 1 week follow up visit.

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	single dose 0.045 mg/kg IV infused over 40 minutes Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes
Measure Participants	19	15
Mean (Standard Deviation) [units on a scale]	25.76 (19.4)	36.32 (13.73)

2. Secondary Outcome

Title	Clinician-Administered PTSD Scale (CAPS)
Description	Clinician-administered structured interview measuring PTSD symptoms. frequency score - scale 0 = none of the time to 4 = most or all of the time intensity score - scale 0 = none to 4 = extreme To meet criteria for a symptom, a patient must meet criteria in both frequency and intensity score for each item. Frequency and intensity and then combined to form a single severity score. 30 questions scale, with total score ranging from 0 to 240.
Time Frame	7 days after first infusion

Outcome Measure Data

Analysis Population Description

Not all participants returned for the 1 week follow up visit. There were 19 participants from the Ketamine group and 15 participants from the Midazolam group who returned for their followup visit and completed the IES-R at the 1 week follow up visit.

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	single dose 0.045 mg/kg IV infused over 40 minutes Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes
Measure Participants	19	15
Mean (Standard Deviation) [units on a scale]	54 (23.63)	65.69 (16.36)

3. Secondary Outcome

Title	Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR)
Description	Self-report questionnaire measuring depressive symptoms. Each item is rated 0 (no depression) to 3 (severe depression). The total score ranges from 0-27.
Time Frame	24 hours after first infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	single dose 0.045 mg/kg IV infused over 40 minutes Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes
Measure Participants	22	19
Mean (Standard Deviation) [units on a scale]	12.4 (5.2)	11.3 (5.6)

4. Secondary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS)
Description	Clinician-administered questionnaire measuring depressive symptoms. The MADRS-S has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression). Mean difference between baseline and 2 weeks.
Time Frame	24 hours after first infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	single dose 0.045 mg/kg IV infused over 40 minutes Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes
Measure Participants	22	19
Mean (Standard Deviation) [units on a scale]	12.6 (7.9)	10.1 (9.7)

5. Secondary Outcome

Title	Hopkins Verbal Learning Test (HVLT)
Description	Repeatable test of memory acquisition and delayed recall of words. It is a three-trial list learning and free recall task comprising 12 words, 4 words from each of three semantic categories. Total Recall score range is 0 to 36.
Time Frame	20 to 40 minutes after infusion

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes	single dose 0.045 mg/kg IV infused over 40 minutes Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes
Measure Participants	0	0

Adverse Events

Time Frame	24 hours post infusion
Arm/Group Title	Ketamine		Midazolam
Arm/Group Description	Ketamine: Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes,		Midazolam: single dose 0.045 mg/kg IV infused over 40 minutes
All Cause Mortality
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/31 (0%)
Serious Adverse Events
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/38 (86.8%)		31/31 (100%)
Cardiac disorders
Palpitation	3/38 (7.9%)		0/31 (0%)
Dizziness on standing	6/38 (15.8%)		5/31 (16.1%)
Chest Pain	2/38 (5.3%)		3/31 (9.7%)
Ear and labyrinth disorders
Ringing in ears	5/38 (13.2%)		1/31 (3.2%)
Eye disorders
Blurred vision	15/38 (39.5%)		6/31 (19.4%)
Gastrointestinal disorders
Diarrhea	3/38 (7.9%)		2/31 (6.5%)
Dry Mouth	10/38 (26.3%)		4/31 (12.9%)
Nausea/Vomiting	10/38 (26.3%)		0/31 (0%)
General disorders
Difficulty sleeping	3/38 (7.9%)		3/31 (9.7%)
Sleeping too much	2/38 (5.3%)		1/31 (3.2%)
Anxiety	5/38 (13.2%)		1/31 (3.2%)
Poor concentration	4/38 (10.5%)		6/31 (19.4%)
General malaise	3/38 (7.9%)		1/31 (3.2%)
Restlessness	13/38 (34.2%)		4/31 (12.9%)
Fatigue	10/38 (26.3%)		6/31 (19.4%)
Decreased energy	6/38 (15.8%)		3/31 (9.7%)
Nervous system disorders
Headace	8/38 (21.1%)		4/31 (12.9%)
Tremors	0/38 (0%)		1/31 (3.2%)
Poor coordination	7/38 (18.4%)		1/31 (3.2%)
Dizziness	14/38 (36.8%)		9/31 (29%)
Renal and urinary disorders
Difficulty urinating	0/38 (0%)		3/31 (9.7%)
Painful urination	2/38 (5.3%)		1/31 (3.2%)
Frequent urination	2/38 (5.3%)		4/31 (12.9%)
Skin and subcutaneous tissue disorders
Rash	1/38 (2.6%)		0/31 (0%)
Increased perspiration	3/38 (7.9%)		1/31 (3.2%)
Itching	1/38 (2.6%)		0/31 (0%)
Dry skin	2/38 (5.3%)		1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/31 (0%)

Limitations/Caveats

Several patients did not receive a second infusion per protocol because of sustained reduction in PTSD symptom levels . The study also does not address the safety or efficacy of ketamine in combination with other psychotropic medications in PTSD.

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.