Anxiety Disorder, Depression, PTSD, Stress Disorders, Post-Traumatic
Conditions
Keywords
Stress Disorders, Post-Traumatic, PTSD, anxiety disorder, ketamine, depression, depressed mood
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.
Interventions
DRUGMidazolam
single dose 0.045 mg/kg IV infused over 40 minutes
DRUGKetamine
Single dose 0.5 mg/kg IV (in the vein) infused over 40 minutes
Sponsors
United States Department of Defense
Dennis Charney
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Then Midazolam 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 | 22 |
| Midazolam the Ketamine 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 | 19 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| no Infusion at Week 1 | delayed-onset sedation | 0 | 1 |
| no Infusion at Week 1 | Lost to Follow-up | 0 | 1 |
| no Infusion at Week 1 | low baseline PTSD symptoms level | 0 | 1 |
| no Infusion at Week 1 | Withdrawal by Subject | 0 | 1 |
| Second Infusion at 2 Weeks | Protocol Violation | 0 | 1 |
| Second Infusion at 2 Weeks | pt felt uncomfortable after infusion | 0 | 1 |
Baseline characteristics
| Characteristic | Ketamine Then Midazolam | Midazolam the Ketamine | Total |
|---|---|---|---|
| Age, Continuous | 36.4 years STANDARD_DEVIATION 10.8 | 35.7 years STANDARD_DEVIATION 10 | 36.05 years STANDARD_DEVIATION 10.3 |
| Clinician-Administered PTSD Scale (CAPS) score (past month) | 82.5 units on a scale STANDARD_DEVIATION 14.1 | 77.1 units on a scale STANDARD_DEVIATION 11.8 | 80.0 units on a scale STANDARD_DEVIATION 13 |
| Duration of PTSD | 14.2 years STANDARD_DEVIATION 12.3 | 11.9 years STANDARD_DEVIATION 14 | 13.1 years STANDARD_DEVIATION 13.1 |
| Education high school graduate | 3 participants | 3 participants | 6 participants |
| Education less than high school | 1 participants | 0 participants | 1 participants |
| Education more than 4 years of college | 5 participants | 2 participants | 7 participants |
| Education some college | 12 participants | 14 participants | 26 participants |
| Education unknown | 1 participants | 0 participants | 1 participants |
| History of treatment with psychotropic medication | 50 percentage of participants | 42.1 percentage of participants | 92.1 percentage of participants |
| Percentage Unemployed | 50 percentage of participants | 73.7 percentage of participants | 123.7 percentage of participants |
| Primary Trauma Accident or fire | 1 participants | 3 participants | 4 participants |
| Primary Trauma Combat exposure | 2 participants | 0 participants | 2 participants |
| Primary Trauma Physical assault or abuse | 4 participants | 7 participants | 11 participants |
| Primary Trauma Sexual assault or molestation | 9 participants | 0 participants | 9 participants |
| Primary Trauma Unknown | 0 participants | 4 participants | 4 participants |
| Primary Trauma Witnessed 9/11 terrorist attacks | 2 participants | 0 participants | 2 participants |
| Primary Trauma Witnessed violent assault or death | 4 participants | 5 participants | 9 participants |
| Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) score | 12.4 units on a scale STANDARD_DEVIATION 5.2 | 11.3 units on a scale STANDARD_DEVIATION 5.6 | 11.9 units on a scale STANDARD_DEVIATION 5.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 12 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) White | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 13 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 31 |
| other Total, other adverse events | 0 / 38 | 0 / 31 |
| serious Total, serious adverse events | 33 / 38 | 31 / 31 |
Outcome results
Primary
Impact of Event Scale - Revised (IES-R)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Impact of Event Scale - Revised (IES-R) | 25.76 units on a scale | Standard Deviation 19.4 |
| Midazolam | Impact of Event Scale - Revised (IES-R) | 36.32 units on a scale | Standard Deviation 13.73 |
Secondary
Clinician-Administered PTSD Scale (CAPS)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Clinician-Administered PTSD Scale (CAPS) | 54 units on a scale | Standard Deviation 23.63 |
| Midazolam | Clinician-Administered PTSD Scale (CAPS) | 65.69 units on a scale | Standard Deviation 16.36 |
Secondary
Hopkins Verbal Learning Test (HVLT)
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
Population: data not collected
Secondary
Montgomery-Asberg Depression Rating Scale (MADRS)
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Montgomery-Asberg Depression Rating Scale (MADRS) | 12.6 units on a scale | Standard Deviation 7.9 |
| Midazolam | Montgomery-Asberg Depression Rating Scale (MADRS) | 10.1 units on a scale | Standard Deviation 9.7 |
Secondary
Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR)
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) | 12.4 units on a scale | Standard Deviation 5.2 |
| Midazolam | Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) | 11.3 units on a scale | Standard Deviation 5.6 |