Post Traumatic Stress Disorder
Conditions
Keywords
startle response, fear conditioning, PTSD
Brief summary
Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large cities in the U.S., increases the likelihood that people will experience a traumatizing event in their lifetime. About 1 in 10 people who survive such events will develop PTSD, while most people will get better over time. This suggests that some people may have biological vulnerabilities that make it harder for them to recover. One of these biological risk factors may be related to how stress hormones work in people who get sick. Another is how people react to things that make them afraid or nervous, investigators have found that PTSD patients have higher than normal fear reactions. The part of the brain that reacts to fearful stimulation is linked to stress hormones; the purpose of this study is to examine how these systems interact. The study will suppress stress hormones (cortisol) production in one group of participants, while another will get a placebo. When their cortisol is suppressed, the participants will undergo a startle study to see if their fear responses are decreased. Investigators expect that people PTSD will show a normal fear response when their cortisol levels are reduced, similar to people without PTSD. This research can help discover new medicines for people with PTSD.
Detailed description
The proposed study will provide innovative tools to tease apart the relationship between amygdala-dependent neurophysiology and HPA-axis sensitivity in a human clinical population. Investigators have discovered that cortisol suppression reduces fear responses in PTSD coupled with the development of new fear conditioning paradigms, providing a unique opportunity to interrogate amygdala-HPA interactions to determine aspects of the neurobiological underpinnings of PTSD-related pathology. Aim 1a will examine baseline and fear-potentiated startle (FPS) response, as well as cognitive awareness in PTSD patients and traumatized Non-PTSD controls during a fear conditioning experiment 10 hours after dexamethasone administration in a double-blind, placebo controlled crossover design. Aim 1b will examine the above outcome measures in PTSD patients and controls during a fear conditioning experiment 1 hour after dexamethasone administration in order to control for direct effects of dexamethasone. Aim 2a will examine fear-potentiated startle (FPS) response in PTSD patients and traumatized Non-PTSD controls during fear extinction, when the fear is acquired 10 hours after dexamethasone administration in a double-blind, placebo controlled crossover design. Aim 2b will examine the same outcome measures in PTSD patients and controls, when the fear is acquired 1 hour after dexamethasone administration in order to control for direct effects of dexamethasone.
Interventions
DRUGDexamethasone
One tablet of 0.5 mg dexamethasone will be taken ten hours prior to completing study assessments.
DRUGPlacebo
One placebo tablet will be taken ten hours prior to completing study assessments.
Sponsors
National Institute of Mental Health (NIMH)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Able to give informed consent * Willing to participate in initial assessment and 2 full days of interviews and imaging visit * Able to understand English and no obvious deficit in comprehension or following directions * 18-65 years old
Exclusion criteria
* Mental Retardation (per clinical judgment of study physician) * Psychotic Disorder (per clinical judgment of study physician) * Acute suicidal ideation * Pregnancy * Positive urine drug screen * Active medical disorders contributing to psychiatric sx e.g. hypo or hyperthyroidism, SLE, advanced cirrhosis, etc. (per clinical judgment of study physician)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Baseline Startle Magnitude During Fear Conditioning | 10 hours after drug administration | The study measured the acoustic startle response magnitude to a sudden noise using electromyography of the eyeblink muscle. This response magnitude was used as the individual's baseline to compare to the startle magnitude to the danger signal to see if fear conditioning had occurred. |
| Mean Startle Magnitude to Danger Signal During Fear Conditioning | 10 hours after drug administration | The acoustic startle response magnitude was measured using electromyography recordings of the eyeblink muscle when a sudden tone was delivered through headphones in the presence of a stimulus that was paired with an aversive outcome (i.e. the danger signal). If an individual showed successful fear learning, then startle to the danger signal would be greater than baseline startle. |
| Mean Fear-potentiated Startle to Danger Signal During Early Extinction | 10 hours after drug administration | Fear-potentiated startle was measured as a difference score between the startle to danger signal and the baseline. This difference score reflects the degree of fear response at the beginning of extinction. |
| Mean Fear-potentiated Startle to Danger Signal During Late Extinction | 10 hours after drug administration | This measures the level of fear-potentiated startle (the difference between startle magnitude to the danger signal and baseline startle magnitude) at the end of extinction. Because the danger signal is no longer paired with the aversive stimulus like it was during the conditioning phase, the fear response should decrease from early to late extinction in individuals who show intact extinction learning. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from Grady Memorial Hospital in Atlanta, Georgia.
Pre-assignment details
Of the 165 participants enrolled, 91 met the inclusion criteria and began the study. Sixty three participants completed all study visits for which data were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| PTSD Negative: Placebo First, Then Dexamethasone Participants who do not have PTSD received placebo then dexamethasone for the duration of two consecutive study visits separated by at least one month.
Placebo: One placebo tablet was taken ten hours prior to completing study assessments.
Dexamethasone: One tablet of 0.5 mg dexamethasone was taken ten hours prior to completing study assessments. | 16 |
| PTSD Negative: Dexamethasone First, Then Placebo Participants who do not have PTSD received dexamethasone then placebo for the duration of two consecutive study visits separated by at least one month.
Dexamethasone: One tablet of 0.5 mg dexamethasone was taken ten hours prior to completing study assessments.
Placebo: One placebo tablet was taken ten hours prior to completing study assessments. | 20 |
| PTSD Positive: Placebo First, Then Dexamethosone Participants with PTSD received placebo then dexamethasone for the duration of two consecutive study visits separated by at least one month.
Placebo: One placebo tablet was taken ten hours prior to completing study assessments.
Dexamethasone: One tablet of 0.5 mg dexamethasone was taken ten hours prior to completing study assessments. | 16 |
| PTSD Positive: Dexamethasone First, Then Placebo Participants with PTSD received dexamethasone then placebo for the duration of two consecutive study visits separated by at least one month.
Dexamethasone: One tablet of 0.5 mg dexamethasone was taken ten hours prior to completing study assessments.
Placebo: One placebo tablet was taken ten hours prior to completing study assessments. | 11 |
| Total | 63 |
Baseline characteristics
| Characteristic | PTSD Negative: Placebo First, Then Dexamethasone | PTSD Negative: Dexamethasone First, Then Placebo | PTSD Positive: Placebo First, Then Dexamethosone | PTSD Positive: Dexamethasone First, Then Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.13 years STANDARD_DEVIATION 3.13 | 43.10 years STANDARD_DEVIATION 2.8 | 43.067 years STANDARD_DEVIATION 3.237 | 45.46 years STANDARD_DEVIATION 3.78 | 42.4 years STANDARD_DEVIATION 11.8 |
| Race/Ethnicity, Customized African American | 16 participants | 18 participants | 14 participants | 10 participants | 58 participants |
| Race/Ethnicity, Customized Other | 0 participants | 2 participants | 2 participants | 1 participants | 5 participants |
| Region of Enrollment United States | 16 participants | 20 participants | 16 participants | 11 participants | 63 participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 14 Participants | 7 Participants | 47 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 2 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 33 | 0 / 20 | 0 / 13 |
| other Total, other adverse events | 0 / 25 | 0 / 33 | 0 / 20 | 0 / 13 |
| serious Total, serious adverse events | 0 / 25 | 0 / 33 | 0 / 20 | 0 / 13 |
Outcome results
Primary
Mean Baseline Startle Magnitude During Fear Conditioning
The study measured the acoustic startle response magnitude to a sudden noise using electromyography of the eyeblink muscle. This response magnitude was used as the individual's baseline to compare to the startle magnitude to the danger signal to see if fear conditioning had occurred.
Time frame: 10 hours after drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Baseline Startle Magnitude During Fear Conditioning | Placebo | 48.401 microvolts | Standard Error 30.001 |
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Baseline Startle Magnitude During Fear Conditioning | Dexamethasone | 42.842 microvolts | Standard Error 16.371 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Baseline Startle Magnitude During Fear Conditioning | Dexamethasone | 72.072 microvolts | Standard Error 12.141 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Baseline Startle Magnitude During Fear Conditioning | Placebo | 56.595 microvolts | Standard Error 26.42 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Baseline Startle Magnitude During Fear Conditioning | Placebo | 115.778 microvolts | Standard Error 29.538 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Baseline Startle Magnitude During Fear Conditioning | Dexamethasone | 45.000 microvolts | Standard Error 14.511 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Baseline Startle Magnitude During Fear Conditioning | Placebo | 57.684 microvolts | Standard Error 35.624 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Baseline Startle Magnitude During Fear Conditioning | Dexamethasone | 59.534 microvolts | Standard Error 16.371 |
Primary
Mean Fear-potentiated Startle to Danger Signal During Early Extinction
Fear-potentiated startle was measured as a difference score between the startle to danger signal and the baseline. This difference score reflects the degree of fear response at the beginning of extinction.
Time frame: 10 hours after drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Placebo | 29.211 microvolts | Standard Deviation 10.046 |
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Dexamethasone | 18.715 microvolts | Standard Deviation 8.9 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Dexamethasone | 25.119 microvolts | Standard Deviation 7.708 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Placebo | 17.328 microvolts | Standard Deviation 9.17 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Placebo | 33.404 microvolts | Standard Deviation 10.046 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Dexamethasone | 42.511 microvolts | Standard Deviation 8.9 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Placebo | 37.099 microvolts | Standard Deviation 11.731 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Early Extinction | Dexamethasone | 21.250 microvolts | Standard Deviation 9.951 |
Primary
Mean Fear-potentiated Startle to Danger Signal During Late Extinction
This measures the level of fear-potentiated startle (the difference between startle magnitude to the danger signal and baseline startle magnitude) at the end of extinction. Because the danger signal is no longer paired with the aversive stimulus like it was during the conditioning phase, the fear response should decrease from early to late extinction in individuals who show intact extinction learning.
Time frame: 10 hours after drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Placebo | 1.620 microvolts | Standard Error 17.839 |
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Dexamethasone | -1.867 microvolts | Standard Error 6.114 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Dexamethasone | -10.440 microvolts | Standard Error 5.295 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Placebo | -7.824 microvolts | Standard Error 16.285 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Placebo | 30.858 microvolts | Standard Error 17.839 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Dexamethasone | 2.253 microvolts | Standard Error 6.114 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Placebo | 13.369 microvolts | Standard Error 20.832 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Fear-potentiated Startle to Danger Signal During Late Extinction | Dexamethasone | 0.897 microvolts | Standard Error 6.836 |
Primary
Mean Startle Magnitude to Danger Signal During Fear Conditioning
The acoustic startle response magnitude was measured using electromyography recordings of the eyeblink muscle when a sudden tone was delivered through headphones in the presence of a stimulus that was paired with an aversive outcome (i.e. the danger signal). If an individual showed successful fear learning, then startle to the danger signal would be greater than baseline startle.
Time frame: 10 hours after drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Placebo | 98.734 microvolts | Standard Error 31.926 |
| PTSD Negative: Placebo First, Then Dexamethasone | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Dexamethasone | 80.825 microvolts | Standard Error 24.892 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Dexamethasone | 113.208 microvolts | Standard Error 18.461 |
| PTSD Negative: Dexamethasone First, Then Placebo | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Placebo | 94.912 microvolts | Standard Error 28.556 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Placebo | 143.360 microvolts | Standard Error 31.926 |
| PTSD Positive: Placebo First, Then Dexamethosone | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Dexamethasone | 84.133 microvolts | Standard Error 22.065 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Placebo | 76.294 microvolts | Standard Error 38.505 |
| PTSD Positive: Dexamethasone First, Then Placebo | Mean Startle Magnitude to Danger Signal During Fear Conditioning | Dexamethasone | 88.079 microvolts | Standard Error 24.892 |