Towards a Post-exposition Pharmacological Prophylaxis for Post-traumatic Stress Disorder

Study Overview
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Brief Summary
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In this study, we investigate the role that deep sleep plays in the prevention of posttraumatic stress disorder after someone has been exposed to a trauma by boosting deep sleep with two drug conditions compared to placebo condition. Each volunteer in the study goes through all three conditions. The quantity of intrusive memories of the trauma will be compared between the three conditions.

Detailed Description
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The present study seeks to investigate the potential to pharmacologically modulate slow-wave sleep in the acute aftermath of an experimentally-induced trauma in the interest of developing a secondary prevention of posttraumatic stress disorder. The effects of a GABAergic compound will be compared with that of a noradrenergic compound. Memory, sleep and stress-related immune response factors will be quantified and compared across drug conditions.

Official Title
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Pharmacological Prevention of Post-traumatic Intrusions in Healthy Volunteers - Towards a Post-exposition Prophylaxis for Post-traumatic Stress Disorder

Conditions
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Intrusive Thought, Psychological Trauma, Inflammatory Response, Physiological Stress

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Gamma-Hydroxybutyrate
* Drug: Placebo
* Behavioral: Experimental Model Trauma Film


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Speaks and understands German BMI 18.5 -< 25 Non-smoker status Habitual 5 or fewer alcoholic beverages / week Habitual 3 or fewer caffeinated beverages / day Habitual average sleep duration 7-9 h / night Normal or corrected-to-normal vision Insomnia Severity Index score between 8-14 Exclusion Criteria: Travel across 3 or more time zones within 3 months of study start Habitual napping Extreme chronotype, determined by Morningness-Eveningness Questionnaire History of or presence of a trauma- or stressor-related disorder History of or presence of neurological disorder, psychiatric disorder or head injury History of or presence of a sleep disorder History of or presence of cardiovascular disorder Use of illicit drugs Atypical preference for excessively violent portrayals Faints at the site of blood or brutality Has participated in a study < 30 days or a study such as this (i.e., experimental trauma) at all.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine<br>Sublingual dose of dexmedetomidine | Drug: Dexmedetomidine<br>* Volunteers receive a single dose of dexmedetomidine sublingually at scheduled bedrest in the sleep laboratory<br>* Other names: Dexdor;Drug: Placebo<br>* Volunteers receive an oral (saline) or sublingual (orodispersible tablet) at scheduled bedrest in the sleep laboratory<br>Behavioral: Experimental Model Trauma Film<br>* Each volunteer views experimental model trauma film before scheduled bedrest in the sleep laboratory. This video is ca. 15 minutes in duration and is composed of short (a few seconds to a few minutes) individual and unrelated scenes of violent death and injury of varying description. Six versions of the film without re-occurring scenes will be presented in balanced order across drug order conditions.<br>|
| Active Comparator: Gamma-hydroxybutyrate<br>Oral dose of gamma-hydroxybutyrate | Drug: Gamma-Hydroxybutyrate<br>* Volunteers receive a single oral dose of gamma-hydroxybutyrate at scheduled bedrest in the sleep laboratory<br>* Other names: Xyrem;Drug: Placebo<br>* Volunteers receive an oral (saline) or sublingual (orodispersible tablet) at scheduled bedrest in the sleep laboratory<br>Behavioral: Experimental Model Trauma Film<br>* Each volunteer views experimental model trauma film before scheduled bedrest in the sleep laboratory. This video is ca. 15 minutes in duration and is composed of short (a few seconds to a few minutes) individual and unrelated scenes of violent death and injury of varying description. Six versions of the film without re-occurring scenes will be presented in balanced order across drug order conditions.<br>|
| Placebo Comparator: Placebo<br>Oral (saline) and sublingual (orodispersible tablet) doses | Drug: Dexmedetomidine<br>* Volunteers receive a single dose of dexmedetomidine sublingually at scheduled bedrest in the sleep laboratory<br>* Other names: Dexdor;Drug: Placebo<br>* Volunteers receive an oral (saline) or sublingual (orodispersible tablet) at scheduled bedrest in the sleep laboratory<br>Behavioral: Experimental Model Trauma Film<br>* Each volunteer views experimental model trauma film before scheduled bedrest in the sleep laboratory. This video is ca. 15 minutes in duration and is composed of short (a few seconds to a few minutes) individual and unrelated scenes of violent death and injury of varying description. Six versions of the film without re-occurring scenes will be presented in balanced order across drug order conditions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of intrusive memories | The number of intrusive memories of the experimental model trauma film experienced. The number of intrusive memories will be recorded in a diary by participants. | Three weeks | 
| Emotional valence of intrusive memories | The emotional valence will be recorded in a diary after experiencing an intrusive memory in an integer scale. The integer scale will range from 1 to 10, where 1 indicates the lowest and 10 indicates the highest. | Three weeks | 
| Personal significance of intrusive memories | Personal significance of intrusive memories will be recorded in a diary after experiencing an intrusive memory in an integer scale. The integer scale will range from 1 to 10, where 1 indicates the lowest and 10 indicates the highest. | Three weeks | 
| Oscillatory delta power in the sleep electroencephalogram (EEG) during non rapid eye movement (REM) sleep stages N2 and N3 | Power in units microvolts squared will be quantified by fast Fourier transform in 4 second segment length in EEG sleep recordings in the delta frequency bin (0.5 - 4.5 Hz).Higher value of delta power indicates greater homeostatic sleep pressure, i.e., the feeling of need for sleep. | Four nights, each night a week apart, spanning one month | 
| Oscillatory theta power in the sleep electroencephalogram (EEG) during non rapid eye movement sleep stages N2 and N3 | Power in units microvolts squared will be quantified by fast Fourier transform in 4 second segment length in EEG sleep recordings in the theta frequency bin (6 - 9 Hz). Higher value of theta power indicates greater homeostatic sleep pressure, i.e., the feeling of need for sleep. | Four nights, each night a week apart, spanning one month | 
| EEG measures of sleep quality: distribution of N2 and N3 sleep stages. | Number of non-REM sleep stages N2 and N3. Greater number of stages N2 and N3 indicate greater homeostatic sleep pressure, i.e., the feeling of need for sleep. | Four nights, each night a week apart, spanning one month | 
| EEG measures of sleep quality: number of arousals | Number of arousals Arousals are defined by the American Academy of Sleep Medicine as an increase in EEG frequency at least 3 seconds in NREM sleep in alpha, theta or higher frequencies, excluding spindles; must be accompanied by a minimum of 1 second of muscle activity during REM sleep. The greater the number of arousals indicates the lower homeostatic sleep pressure is in healthy individuals. Normal number of arousals for a healthy adult is ca. 80 per 8 hour sleep episode. | Four nights, each night a week apart, spanning one month | 
| EEG measures of sleep quality: sleep onset latency | Sleep onset latency represents elapsed time from intention to initiate sleep until sleep is initiated (defined as the occurrence of any stage of sleep by the AASM). Longer latencies indicate lower homeostatic sleep pressure or some maladaptive, e.g., rumination, stress, or pathological state, e.g., insomnia, posttraumatic stress. Normal latencies for healthy adults is 10 - 20 minutes. | Four nights, each night a week apart, spanning one month | 
| EEG measures of sleep quality: sleep duration | Sleep duration represents the duration in time of a sleep episode excluding any intervening stages of waking. Typical sleep duration in the healthy adult population is ca. 8 hours. Extreme sleep durations (<5 or <6 hr or >10 hr) have been associated with cardiometabolic illness risk. | Four nights, each night a week apart, spanning one month | 
| EEG measures of sleep quality: sleep efficiency | Sleep efficiency represents how efficient a given sleep episode is and is defined as the duration of sleep (i.e., time spent in all NREM and REM sleep stages) divided b by the total time spent in bed and multiplied by 100. Normal sleep efficiency is 80% or greater. Efficiencies less than this value could raise questions of sleep satiety, maladaptive behavior (e.g., alcohol consumption, caffeine consumption, sleep at incongruent circadian phase) or pathological health conditions (e.g., restless legs, disordered breathing, insomnia). | Four nights, each night a week apart, spanning one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physiological stress: circulating cortisol | Cortisol (nmol/l) is a marker of stress activation and will be quantified by salivary assay. Greater values indicate greater stress response. Salivary cortisol concentrations vary by sex; in males it ranges under normal conditions from 1-50 nmol/l. | Four nights, each morning a week apart, spanning one month | 
| Physiological stress: electrocardiogram (ECG) heart rate (HR) | Average resting ECG HR during waking in healthy adult males is 75 bpm (range: 60 - 100 bpm). Higher HR from an individual's baseline HR during and after experimental model trauma will be indicative of increases in sympathetic activation of heart function. | Four nights, each night a week apart, spanning one month | 
| Physiological stress: respirometry respiration rate | Resting respiration rate of an adult male is 12 - 16 breaths per minute. Increases in the number of breaths per minute will indicate increase in sympathetic activation of the autonomic system. | Four nights, each night a week apart, spanning one month | 
| Physiological stress: electrocardiogram (ECG) heart rate variability (HRV) | Heart rate variability will be quantified by measuring inter-beat intervals of the ECG. The normal-to-normal interval will be taken, which is the interpolated interval between normal R peaks of the QRS wave complex of the ECG. HRV values indicate performance of the autonomic nervous system in a given context. Higher values of sympathetic activation will be expected during experimental model trauma film exposure. | Four nights, each night a week apart, spanning one month | 
| Physiological stress: inflammatory immune factors (cytokines and kynurenines) | Lower concentration values of immune factors will be expected in GHB or DMTN conditions compared to placebo conditions. | Four mornings, each morning a week apart, spanning one month | 
| Subjective ratings of mood: Positive and Negative Affect Scale (PANAS) | The PANAS scale assesses affect and is comprised of a positive affect subscales and a negative affect subscale. The range of scores of either are 10 - 50. Higher scores in the positive subscale indicate higher (i.e., better) mood; lower scores in the negative affect subscale indicate lower (i.e., worse) mood. Mean (i.e., scores for normal healthy adults) respective scores for the positive and negative subscales are 33.3 (standard deviation [SD] = 7.2) and 17.4 (SD = 6.2). | Four nights, each night a week apart, spanning one month | 
| Subjective ratings of mood: State Trait Anxiety Inventory (STAI) | The STAI assesses anxiety and is composed of a state and a trait scale. Scores in either can range from 20 - 80, and higher scores indicate greater anxiety. Mean scores for healthy adult males of the state and trait scales are, respectively 35.7 (SD = 10.4) and 34.9 (SD = 9.2). | Four nights, each night a week apart, spanning one month | 
| Awakening response: cortisol | Salivary cortisol samples will be taken at regular intervals each morning in the lab to assess the awakening response. Higher values of cortisol concentrations indicate an stronger signal in this process of gaining alertness after sleep. | Four mornings, each morning a week apart, spanning one month | 
| Awakening response: Psychomotor Vigilance Task (PVT) | To assess behavioral response to awaking after sleep, a simple 10 minute reaction time task at the computer called the PVT will be administered. Typical reaction times for an adult are < 500 ms from stimulus presentation. Higher values will be expected for greater degree of sleep inertia after awakening. | Four mornings, each morning a week apart, spanning one month | 
| Sleep inertia Questionnaire - Acute (SIQ - Acute) | The SIQ - Acute assesses the subjective experience of the process of regaining alertness after waking from a sleep episode. Scores range from -66 to +66, higher scores indicating greater difficulty in regaining normal levels of alertness. | Four mornings, each morning a week apart, spanning one month |