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

• ClinicalTrials.gov Identifier: NCT00749203
• Recruitment Status: Completed
• First Posted: September 9, 2008
• Results First Posted: February 14, 2018
• Last Update Posted: February 14, 2018
• Sponsor: Dennis Charney
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Dennis Charney, Icahn School of Medicine at Mount Sinai

Tracking Information

• First Submitted Date: September 5, 2008
• First Posted Date: September 9, 2008
• Results First Submitted Date: April 12, 2017
• Results First Posted Date: February 14, 2018
• Last Update Posted Date: February 14, 2018
• Study Start Date: January 2009
• Actual Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2018)

Impact of Event Scale - Revised (IES-R) [ Time Frame: 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)

• Original Primary Outcome Measures (submitted: September 8, 2008): Score on Impact of Events Scale [ Time Frame: two weeks ]

Current Secondary Outcome Measures (submitted: February 13, 2018)

• Clinician-Administered PTSD Scale (CAPS) [ Time Frame: 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.
• Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) [ Time Frame: 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.
• Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: 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.
• Hopkins Verbal Learning Test (HVLT) [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketamine as a Rapid Treatment for Post-traumatic Stress Disorder (PTSD)
• Official Title: Ketamine as a Rapid Treatment for Post-traumatic Stress Disorder
• 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.

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Stress Disorders, Post-Traumatic
• PTSD
• Depression
• Anxiety Disorder

Intervention

• Drug: Midazolam
  single dose 0.045 mg/kg IV infused over 40 minutes
• Drug: Ketamine
  Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes
  Other Name: Racemic ketamine hydrochloride

Study Arms

• Experimental: Ketamine
  Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes
  Intervention: Drug: Ketamine
• Active Comparator: Midazolam
  single dose 0.045 mg/kg IV infused over 40 minutes
  Intervention: Drug: Midazolam

Publications *

• 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. doi: 10.1001/archpsyc.63.8.856.
• 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. doi: 10.1016/s0006-3223(99)00230-9.
• Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, Kirkwood K, Aan Het Rot M, Lapidus KA, Wan LB, Iosifescu D, Charney DS. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014 Jun;71(6):681-8. doi: 10.1001/jamapsychiatry.2014.62.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 13, 2018): 41
• Original Estimated Enrollment (submitted: September 8, 2008): 40
• Actual Study Completion Date: September 2013
• Actual Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00749203
• Other Study ID Numbers: GCO 07-1199; PT074949; IF1554104; A-15236 ( Other Identifier: USAMRMC ORP HRPO )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dennis Charney, Icahn School of Medicine at Mount Sinai
• Original Responsible Party: Dennis Charney, MD, Mount Sinai School of Medicine
• Current Study Sponsor: Dennis Charney
• Original Study Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: United States Department of Defense

Investigators

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

• PRS Account: Icahn School of Medicine at Mount Sinai
• Verification Date: February 2018