Enhancing Week-long Psychological Treatment for PTSD With Ketamine

NCT05737693 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 1509016530_aR61MH129559
• Study Type: interventional
• Target: 162
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Posttraumatic Stress Disorder

Keywords

PTSD; ketamine; midazolam

Outcome Measures

Primary Outcomes (3)

• Amygdala activation to trauma memory (Phase 1; R61)

  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)

  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)

  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 Outcomes (2)

• Change from baseline to 90 days post treatment in Beck Depression Inventory (BDI-II)

  Baseline, 7 days, 30 days and 90 days

• Measure the changes in psychophysiological distress to trauma reminders as a result of the proposed intervention

  Baseline, 7 days and 30 days

Study Arms (3)

0.2mg/kg ketamine with psychotherapy

EXPERIMENTAL

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

0.5mg/kg ketamine with psychotherapy

EXPERIMENTAL

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

Midazolam with psychotherapy

ACTIVE COMPARATOR

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

Interventions

Ketamine DRUG

Week-long exposure therapy with ketamine infusion on day 2 and 4 of the psychotherapy

Also known as: Ketalar

0.2mg/kg ketamine with psychotherapy; 0.5mg/kg ketamine with psychotherapy

Midazolam DRUG

Week-long exposure therapy with midazolam infusion on day 2 and 4 of the psychotherapy

Also known as: Versed

Midazolam with psychotherapy

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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); 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.

Sponsors & Collaborators

• Yale University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (2)

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

RECRUITING

Tel Aviv University

Tel Aviv, Israel

RECRUITING

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic

Interventions

Ketamine; Midazolam

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ilan Harpaz-Rotem, PhD ABPP

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Charles Gordon, MA

CONTACT

(203)937-4760; ptsd.stress.lab@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2023
• First Posted: February 21, 2023
• Study Start: August 21, 2023
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2031
• Last Updated: May 7, 2025

Record last verified: 2025-05

Locations

IL (1); US (1)