Dopamine Enhancement of Fear Extinction Learning in PTSD (1R21MH108753)

Sponsor
University of Wisconsin, Madison (Other)
Overall Status
Completed
CT.gov ID
NCT02560389
Collaborator
(none)
103
1
3
26
4

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate a new use for a medication called levodopa (L-DOPA). L-DOPA has been approved for use in Parkinson 's disease, but not for Posttraumatic Stress Disorder (PTSD). L-DOPA is thought to enhance certain cognitive abilities that the investigators believe may be affected among women with PTSD. It is hypothesized that L-DOPA may enhance fear extinction learning to a conditioned fear stimulus. If this is true, L-DOPA may improve outcomes for those undergoing certain types of therapy for PTSD, though that aim is beyond the scope of this project. Additionally, the investigators are testing whether an individual's genetic profile affects how well L-DOPA works to enhance cognitive abilities.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Current state-of-the art treatments for posttraumatic stress disorder (PTSD) are lacking in efficacy. There are two main evidence-based psychological treatments for PTSD. Prolonged Exposure (PE) is a largely-exposure based intervention that has been found efficacious for the reduction of PTSD symptoms; however, PE is associated with post-treatment remission rates of only ~53-60%. Cognitive Processing Therapy (CPT) is also a widely studied and efficacious psychological treatment for PTSD, which focuses both on exposure to the trauma memory as well as cognitive therapy techniques. As with PE, post-treatment remission rates for CPT are only ~53-60%, thus also indicating need for improvement in overall efficacy and consistency of response across individuals.

There is emerging research demonstrating that dopamine is critical to the consolidation and subsequent recall of fear extinction learning. A recent study of healthy adult humans demonstrated that oral administration of 150 mg L-DOPA after fear extinction learning led to decreased fear responding, even when tested in a new context. Further, this study also found that resting-state functional connectivity, measured ~45 minutes after post-extinction learning L-DOPA administration, between the ventral tegmental area (VTA) and mPFC was correlated with magnitude of medial prefrontal cortex (mPFC) recruitment during recall of the fear extinction learning. This latter finding suggests that the mechanism by which L-DOPA boosts consolidation of fear extinction learning is through acutely reorganized dopaminergic resting-state networks. Indeed, other studies have demonstrated an acute effect of L-DOPA administration on resting-state functional connectivity within dopaminergic neural networks. Thus, agents that increase dopamine transmission acutely during the post-extinction learning consolidation window, and thereby acutely altering organization of dopaminergic neural networks, show promise for boosting the consolidation of fear extinction memories and decreasing fear responding.

Genetic variation is a primary contributor to individual differences in baseline dopamine neurotransmission. Individuals with specific alleles in genes coding for high baseline dopamine demonstrate better performance on tasks probing working memory, cognitive control, and social cognition. Genetic variants in baseline dopamine neurotransmission would therefore be expected to modulate performance-enhancing effects of L-DOPA, such that individuals with low endogenous would be expected to have increased performance upon exogenously increasing dopamine neurotransmission; whereas individuals with high endogenous dopamine would be expected to have performance deteriorate from exogenously increasing dopamine neurotransmission. In support of this hypothesis, a recent study found an interaction between L-DOPA administration and endogenous dopamine neurotransmission (as indicated by a polygenic score pooled across catechol-O-methyltransferase (COMT), dopamine transporter protein (DAT), dopamine D1 receptor (DRD1-3)) on motor learning performance, such that individuals with a combination of alleles coding for higher baseline dopamine demonstrated a weaker learning benefit from L-DOPA, whereas individuals with a combination of alleles coding for lower baseline dopamine demonstrated a stronger learning benefit from L-DOPA. These data demonstrate the non-linear relationship between performance and dopamine levels, suggesting that any investigation of potential effects of boosting dopamine neurotransmission as a means of boosting learning needs to account for baseline dopamine neurotransmission.

Overall, the proposed project seeks to demonstrate the engagement of post-extinction dopamine neurotransmission and downstream acute reorganization of dopaminergic resting-state neural networks as a means of increasing consolidation of generic fear extinction learning in adult women with PTSD.

Study Design

Study Type:
Interventional
Actual Enrollment :
103 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Other
Official Title:
Dopamine Enhancement of Fear Extinction Learning in PTSD (1R21MH108753)
Study Start Date :
Mar 1, 2016
Actual Primary Completion Date :
May 1, 2018
Actual Study Completion Date :
May 1, 2018

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo

Placebo administered in pill form once by mouth

Drug: Placebo
Sugar pill packaged to resemble levodopa

Active Comparator: 100mg L-DOPA

100mg levodopa administered in pill form once by mouth

Drug: Levodopa
EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
Other Names:
  • L-DOPA
  • Larodopa
  • Active Comparator: 200mg L-DOPA

    200mg levodopa administered in pill form once by mouth

    Drug: Levodopa
    EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
    Other Names:
  • L-DOPA
  • Larodopa
  • Outcome Measures

    Primary Outcome Measures

    1. Galvanic Skin Response [Within 30 days of the MRI]

      Differential galvanic skin response will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential galvanic skin response between the placebo, 100 mg, and 200 mg L-DOPA groups.

    Secondary Outcome Measures

    1. Percentage Change in Functional Activation of Amygdala [Within 30 days of the MRI]

      Amygdala is the part of the brain which controls emotions, survival instincts, and memory. PTSD patients exhibit hyperactivity in the amygdala in response to stimuli. Differential functional activation of the amygdala will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential functional activation between the placebo, 100 mg, and 200 mg L-DOPA groups.

    2. Functional Activation of Anterior Cingulate Cortex [Within 30 days of the MRI]

      Differential functional activation of the anterior cingulate cortex will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential functional activation between the placebo, 100 mg, and 200 mg L-DOPA groups.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    25 Years to 50 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • 25-50 years of age

    • PTSD related to physical or sexual assault

    • Medically healthy

    • English speaking

    Exclusion Criteria:
    • Claustrophobia, or the inability to lie still in a confined space

    • Major medical disorders (e.g., HIV, cancer)

    • Magnetic metallic implants (such as screws, pins, shrapnel remnants, aneurysm clips, artificial heart valves, inner ear (cochlear) implants, artificial joints, and vascular stents)

    • Electronic or magnetic implants, such as pacemakers

    • Permanent makeup or tattoos with metallic dyes

    • Currently pregnant

    • A self-reported history of loss of consciousness (greater than 10 minutes)

    • Physical disabilities that prohibit task performance (such as blindness or deafness)

    • Psychotic disorders (e.g., schizophrenia)

    • Any other condition that the investigator believes might put the participant at risk

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Arkansas for Medical Sciences Little Rock Arkansas United States 72205

    Sponsors and Collaborators

    • University of Wisconsin, Madison

    Investigators

    • Principal Investigator: Josh Cisler, PhD., University of Wisconsin, Madison

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Wisconsin, Madison
    ClinicalTrials.gov Identifier:
    NCT02560389
    Other Study ID Numbers:
    • 204583
    First Posted:
    Sep 25, 2015
    Last Update Posted:
    Jun 25, 2019
    Last Verified:
    Jun 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by University of Wisconsin, Madison
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 103 participants enrolled but only 91 started in the study. 12 participants did not start in the study (6 did not show up, 3 were claustrophobic, 1 was too large to fit in MRI scanner and 2 were tested positive for having used cannabis)
    Arm/Group Title Placebo 100mg L-DOPA 200mg L-DOPA
    Arm/Group Description Placebo administered in pill form once by mouth Placebo: Sugar pill packaged to resemble levodopa 100mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. 200mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
    Period Title: Overall Study
    STARTED 34 28 29
    COMPLETED 33 25 27
    NOT COMPLETED 1 3 2

    Baseline Characteristics

    Arm/Group Title Placebo 100mg L-DOPA 200mg L-DOPA Total
    Arm/Group Description Placebo administered in pill form once by mouth Placebo: Sugar pill packaged to resemble levodopa 100mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. 200mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. Total of all reporting groups
    Overall Participants 33 25 27 85
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    33.7
    (9)
    35.1
    (9.7)
    33.9
    (8.4)
    34.23
    (9.03)
    Sex: Female, Male (Count of Participants)
    Female
    33
    100%
    25
    100%
    27
    100%
    85
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    3%
    0
    0%
    0
    0%
    1
    1.2%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    3
    9.1%
    8
    32%
    4
    14.8%
    15
    17.6%
    White
    25
    75.8%
    15
    60%
    22
    81.5%
    62
    72.9%
    More than one race
    2
    6.1%
    0
    0%
    0
    0%
    2
    2.4%
    Unknown or Not Reported
    2
    6.1%
    2
    8%
    1
    3.7%
    5
    5.9%
    Region of Enrollment (participants) [Number]
    United States
    33
    100%
    25
    100%
    27
    100%
    85
    100%

    Outcome Measures

    1. Primary Outcome
    Title Galvanic Skin Response
    Description Differential galvanic skin response will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential galvanic skin response between the placebo, 100 mg, and 200 mg L-DOPA groups.
    Time Frame Within 30 days of the MRI

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Placebo 100mg L-DOPA 200mg L-DOPA
    Arm/Group Description Placebo administered in pill form once by mouth Placebo: Sugar pill packaged to resemble levodopa 100mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. 200mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
    Measure Participants 33 25 27
    Mean (Standard Deviation) [Unitless]
    .37
    (0.05)
    .29
    (0.06)
    .36
    (0.05)
    2. Secondary Outcome
    Title Percentage Change in Functional Activation of Amygdala
    Description Amygdala is the part of the brain which controls emotions, survival instincts, and memory. PTSD patients exhibit hyperactivity in the amygdala in response to stimuli. Differential functional activation of the amygdala will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential functional activation between the placebo, 100 mg, and 200 mg L-DOPA groups.
    Time Frame Within 30 days of the MRI

    Outcome Measure Data

    Analysis Population Description
    fMRI data was excluded for following number of participants due to artifacts caused by excessive head motion during the scan. Placebo n=4 participants, 100mg L-DOPA n=3 participants, 200mg L-DOPA n=3 participants
    Arm/Group Title Placebo 100mg L-DOPA 200mg L-DOPA
    Arm/Group Description Placebo administered in pill form once by mouth Placebo: Sugar pill packaged to resemble levodopa 100mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. 200mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
    Measure Participants 29 22 24
    Mean (Standard Deviation) [Percentage change]
    -0.1
    (0.05)
    -0.06
    (0.04)
    -0.05
    (0.04)
    3. Secondary Outcome
    Title Functional Activation of Anterior Cingulate Cortex
    Description Differential functional activation of the anterior cingulate cortex will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential functional activation between the placebo, 100 mg, and 200 mg L-DOPA groups.
    Time Frame Within 30 days of the MRI

    Outcome Measure Data

    Analysis Population Description
    Data was excluded for following number of participants due to artifacts caused by excessive head motion during the scan. Placebo n=4 participants, 100mg L-DOPA n=3 participants, 200mg L-DOPA n=3 participants
    Arm/Group Title Placebo 100mg L-DOPA 200mg L-DOPA
    Arm/Group Description Placebo administered in pill form once by mouth Placebo: Sugar pill packaged to resemble levodopa 100mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. 200mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
    Measure Participants 29 22 24
    Mean (Standard Error) [percentage change]
    0.08
    (0.07)
    0.09
    (0.04)
    0.07
    (0.05)

    Adverse Events

    Time Frame 2 days
    Adverse Event Reporting Description Non-systematic
    Arm/Group Title Placebo 100mg L-DOPA 200mg L-DOPA
    Arm/Group Description Placebo administered in pill form once by mouth Placebo: Sugar pill packaged to resemble levodopa 100mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth. 200mg levodopa administered in pill form once by mouth Levodopa: EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
    All Cause Mortality
    Placebo 100mg L-DOPA 200mg L-DOPA
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/33 (0%) 0/25 (0%) 0/27 (0%)
    Serious Adverse Events
    Placebo 100mg L-DOPA 200mg L-DOPA
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/33 (0%) 0/25 (0%) 0/27 (0%)
    Other (Not Including Serious) Adverse Events
    Placebo 100mg L-DOPA 200mg L-DOPA
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/33 (0%) 0/25 (0%) 0/27 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Josh Cisler
    Organization University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison
    Phone 608-263-6100
    Email jcisler2@wisc.edu
    Responsible Party:
    University of Wisconsin, Madison
    ClinicalTrials.gov Identifier:
    NCT02560389
    Other Study ID Numbers:
    • 204583
    First Posted:
    Sep 25, 2015
    Last Update Posted:
    Jun 25, 2019
    Last Verified:
    Jun 1, 2019