Ketamine and Prolonged Exposure in PTSD

Repeated Sub-anesthetic Ketamine to Enhance Prolonged Exposure Therapy in Post-traumatic Stress Disorder: A Proof-of-concept Study

This study aims at investigating the effectiveness of the drug, Ketamine, in combination with Prolonged Exposure (PE) therapy for people suffering from PTSD. Participation in the study includes Ketamine infusions, which occur once a week for three weeks. PE therapy sessions will be scheduled one day after each infusion, and may continue up to 12 weeks. After completely therapy, there will be two monthly follow-up assessment visits.

Study Overview

• Status: Completed
• Conditions: Post-traumatic Stress Disorder
• Intervention / Treatment: Drug: ketamine-enhanced prolonged exposure

Detailed Description

Study location: Minneapolis VA Medical Center

The study is an open-label interventional study designed to inform and strengthen the feasibility of protocol implementation on sub-anesthetic doses of intravenous Ketamine as augmenting strategy of standardized, manually-driven Prolonged Exposure therapy in PTSD.

Timeline: Eligible individuals can expect their participation to last up to 5 months. Compensation will be given for participation per session that is attended. Potential participants will be provided with information about the study and asked a series of questions to determine if they meet basic inclusion/exclusion criteria (e.g., indicators of current PTSD). They will be informed that the treatment involves multiple infusions of sedatives at subanesthetic doses followed by PE therapy. Those interested will be scheduled for an in-person, baseline session.

Voluntary informed consent will be obtained in accordance with local IRB approvals. During the baseline, all assessments, computer tasks, and information on treatment will be explained. Participants will also undergo a urine toxicology analysis during this session. Ketamine infusions and PE therapy appointments will be scheduled within two weeks of the baseline.

The day of the infusion, patients will arrive in the morning after an overnight fast of at least 8 hours. An IV will be placed in the non-dominant arm for medication administration. Vitals will be recorded throughout the entire medication treatment. Subjects will then receive IV infusion of 0.5mg/Kg of ketamine hydrochloride solution over 40 minutes. The dose of ketamine will be calculated by ideal body weight. Any altered sensory or dissociative effects will be measured before and after each infusion. Vitals will be monitored for another hour, until all side-effects have subsided. Participants are required not to drive or use heavy machinery until the following morning.

One day after the infusion, patients will come back for study assessments and Prolonged Exposure therapy with a VA psychologist. PE is an evidence-based psychotherapy for PTSD that is based on the Emotional Processing Theory of PTSD; the four components of PE are: 1) exposure to safe situations, objects, or people that cause distress and are avoided because they are trauma reminders (in vivo exposure), 2) revisiting and processing of the trauma memory (imaginal exposure), 3) psycho-education about trauma-related symptoms, and 4) breathing retraining. Session 1 includes the presentation of treatment rationale and program overview, information gathering, and breathing retraining. Session 2 includes education about common reactions to trauma, rationale for in vivo exposure, and construction of an in vivo exposure hierarchy. The hierarchy includes safe or low-risk activities and situations that were avoided because of their association with the trauma. Throughout the treatment, participants will be assigned homework to confront items on the hierarchy in a gradual fashion, working up to the most anxiety-arousing situations. During Session 3, the rationale for confronting the trauma memory in imagination is presented and initiation of imaginal exposure and processing is conducted. In this procedure, participants will be asked to close their eyes, visualize the trauma, and recount it aloud in the present tense for 45-60 min. The memory recounting will be repeated if necessary to allow total reliving of 45-60 min. The exposure will be audiotaped; participants will be instructed to listen daily to the tape. Sessions 4-10 will be conducted in a similar fashion: therapists review homework, conduct imaginal exposure to trauma memory for 30-45 min, discuss the imaginal exposure, and assigned in vivo and imaginal exposure homework. In the final session, participants summarize learning in treatment, discuss their progress, plans, and relapse prevention.

Upon PE completion, participants are asked to come back for 2 follow-up sessions over two months. Familiar study and PTSD assessments will be administered during this time.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Minneapolis VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of chronic (minimum of three months) PTSD (Clinician-Administered PTSD Scale for DSM-5 -CAPS-5 score>33).
2. Voluntarily eligible to participate in PE.
3. Severity of PTSD symptoms defined by PCL-5>33.
4. Psychotropic medications on stable doses (no dosing adjustments/changes for ≥4 weeks; ≥6 weeks for fluoxetine) prior to prior to beginning of the study.

Exclusion Criteria:

1. Unwillingness/unable to sign informed consent.
2. Previous or current participation in trauma-exposed therapy and/or ketamine treatment.
3. Evidence of mental retardation, pervasive developmental disorder and/or moderate/severe cognitive impairment (MMSE scores ≤27).
4. Any unstable medical or non-psychiatric CNS condition.
5. Lifetime history of psychosis-related disorder, bipolar disorder I or II disorder, or any condition other than PTSD judged to be the primary presenting psychiatric diagnosis.
6. Moderate to severe traumatic brain injury (mental status change or loss of consciousness>30 min; Glasgow Coma Scale <13; post-traumatic amnesia>24hours; visible lesion on CT/MRI brain scan).
7. Active alcohol/illicit substance use disorder within 6 months of initial assessment; presence of illicit drugs by positive urine toxicology.
8. For women: pregnancy (confirmed by lab test), initiation of female hormonal treatments within 3 months of screening, or inability/ unwillingness to use a medically accepted contraceptive method during the study.
9. Imminent risk of suicidal/homicidal ideation and/or behavior with intent and/or plan

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ketamine and PE; ketamine treatment followed by a standardized prolonged exposure session for the first 3 weeks; then, weekly prolonged exposure as usual.

Drug: ketamine-enhanced prolonged exposure; Subjects will receive a single infusion of racemic ketamine at 0.5mg/kg (ideal body weight) for 40 minutes. The next day, patients will have a standardized prolonged exposure session which lasts approximately 90 minutes. This co-jointed intervention will be repeated for 3 weeks. Then, patients will continue with therapy sessions to complete a total of 10-12 sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Severity of Post-traumatic Stress Disorder (PTSD) Symptoms	The overall severity of PTSD symptoms would be measured by the mean change in the Past Month (current) total scores on the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (CAPS-5) from baseline to post-treatment (10 weeks). The CAPS-5 is a structured interview with higher values representing worse outcomes. The CAPS-5 total symptom severity score ranges from 0 to 80 and it is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms.	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Severity of Depressive Symptoms	Total score on the Montgomery- Åsberg Depression Rating Scale , a semi- structured 10-item scale. Range 0-60. Higher values represent worse outcomes. The total score is obtained by summing the severity score of each item.	10 weeks
Change in PTSD Symptoms for DSM-5	The PTSD Checklist for DSM-5 (PCL5) is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. Range from 0-80. Higher values represent worse outcomes.	10 weeks

Collaborators and Investigators

• Sponsor: Minneapolis Veterans Affairs Medical Center
• Investigators: Principal Investigator: Paulo R Shiroma, MD, Minneapolis Veterans Affairs Medical Center

Publications and helpful links

General Publications

• Shiroma PR, Thuras P, Wels J, Erbes C, Kehle-Forbes S, Polusny M. A Proof-of-Concept Study of Subanesthetic Intravenous Ketamine Combined With Prolonged Exposure Therapy Among Veterans With Posttraumatic Stress Disorder. J Clin Psychiatry. 2020 Nov 10;81(6):20l13406. doi: 10.4088/JCP.20l13406. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2019
• Primary Completion (Actual): November 18, 2019
• Study Completion (Actual): December 4, 2019

Study Registration Dates

• First Submitted: May 20, 2019
• First Submitted That Met QC Criteria: May 21, 2019
• First Posted (Actual): May 23, 2019

Study Record Updates

• Last Update Posted (Actual): March 22, 2021
• Last Update Submitted That Met QC Criteria: March 19, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Trauma and Stressor Related Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: VAM-18-00333

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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