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Inflammation and Threat Sensitivity in PTSD (K01)

Primary Purpose

Posttraumatic Stress Disorder

Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Typhoid Vi Polysaccharide Vaccine
Placebo
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Posttraumatic Stress Disorder

Eligibility Criteria

30 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

All Subjects:

  • Veterans aged 30-60.

PTSD Subjects:

  • Positive for current chronic moderate to severe PTSD symptoms of at least three months duration as indexed by the Clinically Administered PTSD Scale for DSM 5 (CAPS-5).

Control Subjects:

  • Negative for lifetime PTSD.
  • Negative for lifetime diagnosis of Mood Disorders, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder and Panic Disorder.

Exclusion Criteria:

All Subjects:

  • Lifetime history of any psychiatric disorder with psychotic features, bipolar disorder, panic disorder, obsessive-compulsive disorder, alcohol or substance dependence, or a history of alcohol or substance abuse within the past 2 years.
  • Currently exposed to recurrent trauma or have been exposed to a traumatic event within the past 3 months.
  • Diagnosis of neurologic disorder, systemic illness affecting central nervous system function, and/or anemia.
  • Prominent suicidal or homicidal ideation.
  • Current and planned ongoing use of medications that impact inflammation or immune function, or use of such medications in the past 6 months.
  • Subjects currently receiving serotonin reuptake inhibitors (SSRIs), benzodiazepine or benzodiazepine receptor agonists, anticonvulsants, atypical antipsychotic medication, any antidepressant medication including trazodone.
  • Termination of SSRIs, benzodiazepine or benzodiazepine receptor agonists, anticonvulsants, atypical antipsychotic medication, any antidepressant medication including trazodone in the last month or plans to start these medications during the course of the study.
  • Contraindications to Magnetic Resonance Imaging (MRI), which include claustrophobia severe enough to prevent MRI examination and presence of ferrometallic objects in the body that would interfere with MR examination and/or cause a safety risk (e.g., pace makers, implanted stimulators, pumps).
  • Contraindications to typhoid vaccine, which include acute febrile illness within the past two weeks, disorders characterized by a deficiency in ability to mount a humoral or cell-mediated immune response, use of anti-malarial medications in past six months, antibiotics in past three months, a history of hypersensitivity to typhoid vaccine or any other vaccine, previous immunization with whole-cell typhoid or live, oral typhoid vaccine, vaccination with the polysaccharide version of the typhoid vaccine within the past 3 year, coagulation disorders and thrombocytopenia.
  • Conditions or use of substances that may be associated with inflammation independent of trauma and PTSD, including chronic physical disease.
  • History of neurologic disorders, traumatic brain injury (TBI), brain tumor, brain hemorrhage, or head injury with loss of consciousness.
  • Women who are currently, or are planning to become, pregnant during the study.

The investigators will not exclude PTSD patients who are receiving psychotherapy, but will apply the following criteria: patients must have been in treatment for 6 months, meet symptomatic criteria for inclusion, and do not have plans to discontinue treatment during the course of the study.

Sites / Locations

  • San Francisco Veterans Affairs Medical Center
  • University of California, San Francisco

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Typhoid Vi Polysaccharide Vaccine

Placebo

Arm Description

Patients will receive one intramuscular 0.5 mL injection of Typhoid Vi Polysaccharide Vaccine containing 0.025 mg purified Vi polysaccharide.

Patients will receive one intramuscular 0.5 mL injection of saline placebo.

Outcomes

Primary Outcome Measures

Neural activity to threat as assessed with functional magnetic resonance imaging
On visits 1 (baseline) and 2 (post-vaccine or post-placebo administration), participants will perform computerized threat and reward tasks and investigators will measure and compare neural activity between groups (PTSD vs. control) and condition (endotoxin vs. placebo).

Secondary Outcome Measures

Threat sensitivity
Participants will perform computerized tasks designed to assess threat sensitivity.

Full Information

First Posted
February 2, 2017
Last Updated
May 11, 2021
Sponsor
University of California, San Francisco
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT03048929
Brief Title
Inflammation and Threat Sensitivity in PTSD
Acronym
K01
Official Title
Effects of Inflammation on Neural Mechanisms of Threat Sensitivity in Posttraumatic Stress Disorder
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
April 1, 2019 (Actual)
Primary Completion Date
March 30, 2020 (Actual)
Study Completion Date
March 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
The overall goals of this study are to examine the relationship between chronic inflammation and threat and reward sensitivity, and to determine the effects of acute inflammation on threat sensitivity, in individuals with and without moderate to severe PTSD symptoms. The investigators will first conduct an observational study to examine the relationship between chronic inflammation and neural and behavioral measures of threat sensitivity. Then, the investigators will conduct a randomized, double-blind, placebo-controlled, between-subjects study to examine the effects of acute inflammation on neural and behavioral measures of threat sensitivity.
Detailed Description
Posttraumatic stress disorder (PTSD) is a disabling chronic psychiatric disorder that affects more than 8% of the population. New treatments for PTSD symptoms are desperately needed because current pharmacologic and behavioral treatments for PTSD are inadequate or they have low uptake. Accumulating evidence supports elevated inflammation as a new potential treatment target for PTSD. Inflammation is increased in PTSD, and can promote threat sensitivity, a core mechanism underlying several PTSD symptoms. Two major gaps in knowledge prevent progress towards effective anti- inflammatory treatments for PTSD symptoms. First, researchers know little about the relationship between chronic inflammation and exaggerated threat sensitivity. Second, no studies have directly examined the effects of acute inflammation on neural and behavioral measures of threat sensitivity in PTSD. The objective of this study is to uncover the effects of chronic and acute inflammation on neural mechanisms and behavioral measures of threat sensitivity in individuals with and without PTSD symptoms. The central hypothesis is that both chronic and acute inflammation will be associated with exaggerated threat sensitivity overall, with particularly strong relationships in PTSD. The scientific rationale is that establishing a link between elevated inflammation and threat sensitivity in both observational and experimental studies in individuals with and without PTSD symptoms will drive progress towards a targeted approach to identifying effective anti- inflammatory treatments for PTSD symptoms. In particular, this work has the potential to identify a target for clinical trials of anti-inflammatory interventions in PTSD. Guided by preliminary data, hypotheses will be tested by pursuing two specific aims: 1) Examine the association of chronic inflammation with threat sensitivity; and 2) Determine the effects of an acute inflammatory challenge on threat sensitivity. To achieve these aims, 40 participants with moderate to severe PTSD symptoms and 40 age- and body mass index-matched trauma-exposed participants with no history of PTSD will be recruited. The investigators will assess chronic resting levels of inflammation (Aim 1) and will randomize participants to placebo or inflammatory challenge using polysaccharide typhoid vaccine (i.e., endotoxin) (Aim 2) and will use validated functional MRI paradigms and behavioral tasks to assess threat sensitivity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Posttraumatic Stress Disorder

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Typhoid Vi Polysaccharide Vaccine
Arm Type
Active Comparator
Arm Description
Patients will receive one intramuscular 0.5 mL injection of Typhoid Vi Polysaccharide Vaccine containing 0.025 mg purified Vi polysaccharide.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will receive one intramuscular 0.5 mL injection of saline placebo.
Intervention Type
Biological
Intervention Name(s)
Typhoid Vi Polysaccharide Vaccine
Intervention Description
Salmonella typhi capsular polysaccharide vaccine (Typhoid Vi Polysaccharide Vaccine): Each dose of 0.5ml Salmonella typhi capsular polysaccharide vaccine (Sanofi Pasteur, SA) is formulated to contain 25μg of purified Vi polysaccharide in a colorless isotonic phosphate buffered saline (pH 7±0.3), 4.150mg of sodium chloride, 0.065mg of disodium phosphate, 0.023mg of monosodium phosphate and 0.5ml of sterile water for injection. It is indicated for use by humans aged 2 years and older for protection against typhoid fever.
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
The placebo injection will consist of 0.5mL of saline.
Primary Outcome Measure Information:
Title
Neural activity to threat as assessed with functional magnetic resonance imaging
Description
On visits 1 (baseline) and 2 (post-vaccine or post-placebo administration), participants will perform computerized threat and reward tasks and investigators will measure and compare neural activity between groups (PTSD vs. control) and condition (endotoxin vs. placebo).
Time Frame
Change from Visit 1 (baseline) to Visit 2 (within two weeks of baseline)
Secondary Outcome Measure Information:
Title
Threat sensitivity
Description
Participants will perform computerized tasks designed to assess threat sensitivity.
Time Frame
Change from Visit 1 (baseline) to Visit 2 (within two weeks of baseline)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: All Subjects: Veterans aged 30-60. PTSD Subjects: Positive for current chronic moderate to severe PTSD symptoms of at least three months duration as indexed by the Clinically Administered PTSD Scale for DSM 5 (CAPS-5). Control Subjects: Negative for lifetime PTSD. Negative for lifetime diagnosis of Mood Disorders, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder and Panic Disorder. Exclusion Criteria: All Subjects: Lifetime history of any psychiatric disorder with psychotic features, bipolar disorder, panic disorder, obsessive-compulsive disorder, alcohol or substance dependence, or a history of alcohol or substance abuse within the past 2 years. Currently exposed to recurrent trauma or have been exposed to a traumatic event within the past 3 months. Diagnosis of neurologic disorder, systemic illness affecting central nervous system function, and/or anemia. Prominent suicidal or homicidal ideation. Current and planned ongoing use of medications that impact inflammation or immune function, or use of such medications in the past 6 months. Subjects currently receiving serotonin reuptake inhibitors (SSRIs), benzodiazepine or benzodiazepine receptor agonists, anticonvulsants, atypical antipsychotic medication, any antidepressant medication including trazodone. Termination of SSRIs, benzodiazepine or benzodiazepine receptor agonists, anticonvulsants, atypical antipsychotic medication, any antidepressant medication including trazodone in the last month or plans to start these medications during the course of the study. Contraindications to Magnetic Resonance Imaging (MRI), which include claustrophobia severe enough to prevent MRI examination and presence of ferrometallic objects in the body that would interfere with MR examination and/or cause a safety risk (e.g., pace makers, implanted stimulators, pumps). Contraindications to typhoid vaccine, which include acute febrile illness within the past two weeks, disorders characterized by a deficiency in ability to mount a humoral or cell-mediated immune response, use of anti-malarial medications in past six months, antibiotics in past three months, a history of hypersensitivity to typhoid vaccine or any other vaccine, previous immunization with whole-cell typhoid or live, oral typhoid vaccine, vaccination with the polysaccharide version of the typhoid vaccine within the past 3 year, coagulation disorders and thrombocytopenia. Conditions or use of substances that may be associated with inflammation independent of trauma and PTSD, including chronic physical disease. History of neurologic disorders, traumatic brain injury (TBI), brain tumor, brain hemorrhage, or head injury with loss of consciousness. Women who are currently, or are planning to become, pregnant during the study. The investigators will not exclude PTSD patients who are receiving psychotherapy, but will apply the following criteria: patients must have been in treatment for 6 months, meet symptomatic criteria for inclusion, and do not have plans to discontinue treatment during the course of the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aoife S O'Donovan, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
San Francisco Veterans Affairs Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94121
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Inflammation and Threat Sensitivity in PTSD

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