Enhancing Week-long Psychological Treatment for PTSD With Ketamine

April 8, 2024 updated by: Yale University

Posttraumatic Stress Disorder (PTSD) Treatment: Using Ketamine to Enhance Memory Reconsolidation and Extinction of Overgeneralized Fear in Individuals Diagnosed With PTSD

The purpose of this study is to test if the combination of ketamine, vs midazolam, with an intensive trauma-focused psychotherapy will be more effective in relieving post-traumatic stress disorder (PTSD). This week-long treatment has the potential to produce a significant therapeutic effect that otherwise would take months to occur. The study will also focus on learning about the neurophysiological changes produced by the proposed clinical trial.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Based on the current research findings on the therapeutic effectiveness of trauma focus psychotherapy and of ketamine combining the two treatments may yield a promising new rapid week-long treatment for PTSD. As PTSD symptoms' structure is comprised of several unique clusters which include re-experiencing, avoidance, depression and hypervigilance the investigators hypothesize that by combining Ketamine with trauma-focused psychotherapy the proposed intervention can address these PTSD symptoms clusters more effectively than existing treatments. This proposed clinical trial has the potential to produce a significant therapeutic effect that otherwise would take months to occur by tapping on the enhanced neuroplasticity and the antidepressant effect of ketamine (which lasts between 24hrs to 7 days), to promote rapid changes in learning and memory when applying psychotherapy within a unique "window of opportunity" of neurophysiological changes produced by the investigative drug.

During the first visit participants will undergo a clinical interview to establish a PTSD diagnosis and other eligibility criteria. If found eligible participants will be invited to take part in this 7-day rapid treatment trial for PTSD.

On the first therapy visits, participants will be educated about the psychological treatment that will be provided and the potential benefit of ketamine or midazolam that may enhance the psychotherapy outcomes.

On the second day of the study, participants will receive an infusion of ketamine or midazolam and will undergo a magnetic resonance imaging (MRI) to assess their brain reactivity to PTSD before the treatment.

On days 3-6 participants will attend a 60-90 minutes psychotherapy session to address their PTSD symptoms.

A second ketamine or midazolam infusion will take place on day 4 of the study to enhance the drug therapeutic effect for the study duration.

Day 7 will include another MRI scan to assess treatment effect on PTSD.

Participants will need to attend one follow up MRI scan and clinical evaluation at 30 days and then a clinical evaluation at 90 days post-treatment to assess the long-term effectiveness of the intervention.

Study Type

Interventional

Enrollment (Estimated)

162

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Male or female between the ages of 21-70 years. This age range was chosen to fit with prior samples in which no adverse effects of ketamine have been observed. Adults in the 18-20 ranges have been eliminated because previous experience indicates that they often lack the maturity to participate effectively in similar protocols. Females will be included if they are not pregnant and agreed to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.
  • Must not have a medical/neurological problem or use medication that would render ketamine unsafe by history or medical evaluation.
  • Diagnosis of chronic PTSD with a score of 25 or higher (i.e. severe PTSD) on the Clinician-Administered PTSD Scale (CAPS-5) at screening. PTSD symptoms must have persisted for >1 year post-trauma exposure to meet the DSM-5 definition of chronic.
  • Subjects on FDA-approved antidepressant, trazodone, atypical neuroleptic, prazosin, or clonidine may enter the study if they have been on a stable treatment, as determined by the study clinician, for at least 4 weeks prior to randomization. Following randomization, small changes to doses may be allowable at the PI's discretion.
  • Able to provide written informed consent.
  • Able to read and write English.

Exclusion Criteria:

  • Patients with a diagnostic history of borderline personality disorder, obsessive compulsive disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as determined by the Structured Clinical Interview for DSM (SCID) (First, et al. 2010); dementia or suspicion thereof, are excluded. Patients with history of bipolar disorder will be included only if they have not experienced a manic or hypomanic episode in the 30 days prior to enrollment. Other DSM Axis I disorders are permitted as long as they are not considered primary disorders.
  • Patients with a history of antidepressant-induced hypomania or mania as determined by open-ended psychiatric interview.
  • Current, ongoing serious suicidal risk as assessed by evaluating investigator based on the Columbia-Suicide Severity Rating Scale (C-SSRS).
  • Moderate severity or greater Substance Use Disorder (excepting Alcohol and Marijuana Use Disorder) during the 3 months prior to randomization, as determined by the SCID.

Alcohol or Marijuana Use Disorder may be allowed based on the judgment of study physician/APRN/clinician that patients can remain sober for all study visits.

  • Subjects on a prohibited medication (see Table 1). Patients will not be taken off medication for the purpose of this study.
  • History of traumatic brain injury (TBI) with loss of consciousness for more than 24 hours or posttraumatic amnesia for more than 7 days may be considered if the trauma occurred more than 1 year ago, and no more than minimal symptoms have persisted over the past year.
  • Positive pregnancy test at screening or prior to any study drug infusion.
  • Breathalyzer showing an alcohol level > 0% at screening, or at the discretion of the investigator, prior to any study drug infusion.
  • Resting blood pressure lower than 90/60 or higher than 150/90, or resting heart rate lower than 45/min or higher than 100/min.
  • Any significant history of serious medical or neurological illness.
  • Any signs of major medical or neurological illness on examination or as a result of ECG screening or laboratory studies.
  • Abnormality on physical examination. A subject with a clinical abnormality may be included only if the study physician considers the abnormality will not introduce additional risk factors and will not interfere with the study procedure.
  • A positive pre-study (screening) urine drug screen or, at the study physician's discretion on any drug screens given before the scans.
  • Pregnant or lactating women or a positive urine pregnancy test for women of child-bearing potential at screening or prior to any imaging day.
  • Any history indicating learning disability or mental retardation.
  • Known sensitivity to ketamine.
  • Body circumference of 52 inches or greater.
  • Body weight of 350 pounds or greater.
  • History of claustrophobia.
  • Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire.
  • Donation of blood in excess of 500 mL within 56 days prior to dosing.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Active engagement in trauma-focused CBT (TF cognitive-behavioral therapy) or any evidence-based PTSD psychotherapy (CPT, PE, EMDR) initiated within the past 3 months (continuation of established maintenance supportive therapy will be permitted
  • Enrollment in another research study testing an experimental/clinical/behavioral intervention intended to affect symptoms initiated within the last 2 months, or intended enrollment within the next 3 months

Table 1. Concomitant Treatments that are prohibited

MAOIs: 4-weeks off medication prior to randomization is required.

Memantine: 4-weeks of medication prior to randomization is required.

Long Acting Benzodiazepines -Chlordiazepoxide, Diazepam, Flurazepam: 2-weeks off medication prior to randomization is required.

Notes: As above, individuals who have used any of the prohibited medications within the "weeks off" time period will not be eligible for the study. Use of sedatives, hypnotics, benzodiazepines, sedating antihistamines or other psychotropic medications are not permitted within 8 hours of treatment sessions; except - at the discretion of the investigator - for medications that will result in discontinuation/withdrawal symptoms or that may alter the risk benefit ratio.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 0.2mg/kg ketamine with psychotherapy
Two infusions of low dose Ketamine combined with trauma-focused psychotherapy. Low dose ketamine infusion will take place on day 2 and day 4, of the psychotherapy intervention. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state of ketamine infusion of 0.2 mg/kg for 40 minutes.
Drug: Ketamine
Week-long exposure therapy with ketamine infusion on day 2 and 4 of the psychotherapy
Other Names:
  • Ketalar
Experimental: 0.5mg/kg ketamine with psychotherapy
2. Two infusions of Ketamine combined with trauma-focused psychotherapy. Low dose ketamine infusion will take place on day 2 and day 4, of the psychotherapy intervention. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state of ketamine infusion of 0.5 mg/kg for 40 minutes.
Drug: Ketamine
Week-long exposure therapy with ketamine infusion on day 2 and 4 of the psychotherapy
Other Names:
  • Ketalar
Active Comparator: Midazolam with psychotherapy
Midazolam combined with trauma-focused psychotherapy. Midazolam infusion procedure will take place on day 2 and day 4, of the psychotherapy intervention. A physician will oversee administer the Midazolam infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following midazolam infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady midazolam infusion at a rate 0.045 mg/kg for 40 minutes.
Drug: Midazolam
Week-long exposure therapy with midazolam infusion on day 2 and 4 of the psychotherapy
Other Names:
  • Versed

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Amygdala activation to trauma memory (Phase 1; R61)
Time Frame: Changes from baseline to 30-day post-treatment in amygdala activation to the trauma memory

Phase 1 (R61) investigators will analyze the first 60 participants (20 per arm). Using MRI scan data, the investigators will compare changes in the amygdala bold activation from baseline to 30-day post treatment in response to the trauma scripts between the the 3 study arm. Greater activation of the amygdala is an indicator of a greater distress.

Investigators will also measure the effect size resulting from the mean changes in amygdala activation from pre to post treatment between each of the experimental groups and the active comparator to determine the dose that will be carried to phase 2.
Changes from baseline to 30-day post-treatment in amygdala activation to the trauma memory
To determine if ketamine + exposure therapy results in clinical improvement in PTSD symptoms which are significantly greater than midazolam + exposure therapy (Phase 2; combined R61/R33 data)
Time Frame: Baseline, 7 days, 30 days and 90 days

Change in PTSD symptoms from baseline up to 90-day post treatment. PTSD Symptoms severity will be evaluated overtime using PTSD Check List (PCL-5).

Evidence for the PCL suggests that 10 points difference in the measure is a reliable indicator for a clinically meaningful change. The PCL scores ranges from 0 (no symptoms) to a maximum score of 80 (PCL Score > 33 indicates probable PTSD diagnosis).
Baseline, 7 days, 30 days and 90 days
To determine if ketamine + exposure therapy results in more profound changes in task-based connectivity in region of interest than midazolam + exposure therapy (Phase 2; combined R61/R33 data)
Time Frame: Baseline, 7 days and 30 days (no MRI scan at 90 days post-treatment)
Using MRI brain activation data, the investigators will compare changes in the connectivity between participants' different brain regions (brain network connectivity) from baseline to end of treatment and 30-day post treatment. Investigators will examine the neural connectivity between the amygdala, hippocampus, prefrontal cortex, striatum and insula and other major brain areas associated with PTSD.
Baseline, 7 days and 30 days (no MRI scan at 90 days post-treatment)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline to 90 days post treatment in Beck Depression Inventory (BDI-II)
Time Frame: Baseline, 7 days, 30 days and 90 days
The self-report BDI-II will be used to assess severity of depressive symptoms. A higher score is associated with higher severity of depression. The score is interpreted as follows: 0-13 indicates minimal depression, 14-19 indicates mild depression, 20-28 indicates moderate depression and 29-63 indicates severe depression
Baseline, 7 days, 30 days and 90 days
Measure the changes in psychophysiological distress to trauma reminders as a result of the proposed intervention
Time Frame: Baseline, 7 days and 30 days
Using wrist mobile galvanic skin responses (GSR) device the investigators will measure changes in GSR from pre to post treatment during exposure to avoidance cue. Investigators will compare the magnitude of these changes between the study arms. Higher GSR indicate a greater level of distress.
Baseline, 7 days and 30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Ilan Harpaz-Rotem, PhD ABPP, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 21, 2023

Primary Completion (Estimated)

August 1, 2030

Study Completion (Estimated)

August 1, 2031

Study Registration Dates

First Submitted

February 1, 2023

First Submitted That Met QC Criteria

February 10, 2023

First Posted (Actual)

February 21, 2023

Study Record Updates

Last Update Posted (Actual)

April 9, 2024

Last Update Submitted That Met QC Criteria

April 8, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1509016530_a
  • R61MH129559 (U.S. NIH Grant/Contract: NIH)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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