Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD

Study Overview
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Brief Summary
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Purpose: About 6.4% of the U.S. population suffers from posttraumatic stress disorder (PTSD). Trauma-focused psychotherapies are generally effective in PTSD, but responses vary greatly across individuals and PTSD subpopulations. Neurobiological factors impacted by life experiences, stress, and genetics can affect treatment responses. These factors can alter brain capacities needed to reprocess traumatic memories prevent them from triggering intensely distressing, disruptive, out-of-place responses. For example, during psychotherapy for PTSD, trauma memory activation engages two competing brain processes that affect recovery: extinction versus reconsolidation of trauma-related emotional, physiological, and behavioral responses. This study tests whether a single intravenous (IV) dose of allopregnanolone (Allo) compared to placebo (which is non-active): promotes consolidation of extinction learning (sub-study 1) or blocks reconsolidation physiological responses triggered by aversive memories (sub-study 2). The study also tests whether Allo compared to placebo affects retention of non-aversive memories.

Detailed Description
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Background: Allo is a neurosteroid (hormone) produced from progesterone by the brain, adrenal glands, testes, and ovaries. Production of Allo and its equally powerful, structurally similar, stereoisomer pregnanolone (PA) is stimulated when certain neurons in the brain are activated and when stress activates the adrenal glands. Allo and PA markedly increase effects of gamma-amino-butyric acid (GABA; an inhibitory neurotransmitter) in the brain, thereby regulating arousal and responses to stress. Allo and PA also influence processes that strengthen or weaken memories. Basic research suggests that several factors can reduce production of Allo: exposure to chronic or extreme stress, prolonged social isolation, chronic intermittent heavy alcohol use, certain oral contraceptives, chronic use of some psychiatric medications or other substances used to manage PTSD such as nicotine, exposure to environment toxins, and genetic predisposition. Research shows that Allo and PA production is reduced in a large subpopulation of women and men with PTSD. Reduced Allo and PA is strongly associated with severity and poor retention of extinction learning-both of which contribute to chronic PTSD. The proposed study thus will be conducted in adult men and women with chronic PTSD. Women will be studied during two distinct phases of the menstrual cycle because progesterone levels (and therefore levels of Allo and PA) change markedly across the menstrual cycle, as do problems with extinction retention. Study Procedures: Eligible participants will take part in a widely used, standardized 3-day laboratory psychophysiology paradigm during which activation of the sympathetic nervous system (fight/flight system) is monitored via small electrode patches placed on the skin. The paradigm involves startle testing on Days 1, 2 and 3. During startle testing, participants will hear sudden bursts of white noise through headphones, see colored shapes on a computer screen, and feel sudden (not painful) blasts of air to the neck. The electrodes record participants' eye blinks, skin conductance, and heart rate. The startling sounds will be about as loud as a train but last only a fraction of a second. Participants will sit quietly with their eyes open as they listen. On study Day 2, participants are randomized by luck of the draw or chance to receive either IV Allo or placebo. On study Days 2 and 3, a brief memory test also will be conducted. Blood is collected each day for measurement of Allo, PA and other neurobiological factors that may affect the potential beneficial effects of Allo. Before starting the above studies, the investigators will conduct pharmacokinetic (PK) studies in a small group of individuals with PTSD to confirm that the selected IV Allo dose increases blood Allo levels as expected. Implications: These studies may help us understand treatable factors that increase risk for chronic or treatment-resistant PTSD and PTSD-related depression. They may also tell us whether treatments that increase Allo might help prevent or treat PTSD. IV Allo (at much higher doses than used in this study) is currently FDA-approved for treatment of postpartum depression-supporting the potential for this research to spur development of Allo as a new PTSD treatment. Study Population 256 individuals with PTSD (about 85 males and 170 females) will be recruited to participate in these studies. Half of the women will be studied during the follicular phase of the menstrual cycle (after onset of menses) and half during the luteal phase (after ovulation). The study is being conducted at Boston University School of Medicine in Boston, Massachusetts, and half at Wayne State University School of Medicine in Detroit, Michigan.

Official Title
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Facilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD

Conditions
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Post Traumatic Stress Disorder

Intervention / Treatment
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* Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm
* Drug: Allopregnanolone (Allo) with Dexolve in 0.9% saline for injection manufactured by University of California, Davis
* Other: Matching IV Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic Posttraumatic Stress Disorder Generally healthy and not on any prohibited medications (that could affect study outcomes) Willing to abstain from alcohol for 2 weeks and from nicotine, marijuana or illicit drugs for 4 weeks before experimental procedures and throughout the study Females: must have a menstrual cycle and not be on hormonal birth control (with a few exceptions; see below) If gender non-conforming: must not be on hormone therapy Exclusion Criteria: Bipolar I disorder, schizophreniform disorder, or clinically significant psychotic symptoms apart from the presence of trauma-related sensory hallucinations or negative beliefs Moderate or severe substance use disorder within three months of screening Sleep Apnea History of a suicide attempt within 1 year of enrolling Imminent risk to self or others or require clinical intervention to maintain safety Unstable medical condition or condition that may affect outcomes Moderate or severe traumatic brain injury (TBI) (mild TBI acceptable; moderate TBI allowed for PK study) Using any medications or substances (by self-report or toxicology testing) that may increase the risk of the side effects of IV Allo or affect the experimental results. Unable to tolerate IV placement or blood drawing by needle stick Wear hearing aids or fail hearing test (not applicable to PK study) Females: pregnant, breastfeeding, or if of childbearing potential, unwilling to use two forms of effective birth control (except for hormonal contraceptives, unless intrauterine device [IUD] or a device like NuvaRing) for one week before and one month after study drug administration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Active drug vs. placebo will be administered in two separate experiments to a population of medically healthy, non-medicated patients with PTSD stratified by sex and by menstrual phase within female sex.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)<br>Arm 1 of Expt. 1 includes women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV Allo immediately after completion of extinction training. | Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm<br>* Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.<br>Drug: Allopregnanolone (Allo) with Dexolve in 0.9% saline for injection manufactured by University of California, Davis<br>* Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of Allo will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at  1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of Allo will be infused over 30 minutes immediately following presentation of a single CS+.<br>* Other names: U.S. P. equivalent: brexanolone (SAGE Therapeutics) (IV Allopregnanolone with Captisol);|
| Placebo Comparator: IV Placebo for Extinction Retention (Expt. 1)<br>Arm 2 of Expt. 1 includes women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV placebo immediately after completion of extinction training. | Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm<br>* Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.<br>Other: Matching IV Placebo<br>* Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of the matching placebo formulation will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at  1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of the matching placebo formulation will be infused over 30 minutes immediately following presentation of a single CS+.<br>|
| Experimental: IV Allo for Reconsolidation Blockade (Expt. 2)<br>Arm 1 of Expt. 2 will include women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV Allo immediately after reactivation of the conditioned fear memory by exposure to one conditioned stimulus (CS+). | Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm<br>* Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.<br>Drug: Allopregnanolone (Allo) with Dexolve in 0.9% saline for injection manufactured by University of California, Davis<br>* Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of Allo will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at  1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of Allo will be infused over 30 minutes immediately following presentation of a single CS+.<br>* Other names: U.S. P. equivalent: brexanolone (SAGE Therapeutics) (IV Allopregnanolone with Captisol);|
| Placebo Comparator: IV Placebo for Reconsolidation Blockade (Expt. 2)<br>Arm 2 of Expt. 2 will include will include women in the early follicular or mid-luteal phase of the menstrual cycle and men with PTSD who receive IV placebo immediately after reactivation of the conditioned fear memory by exposure to one conditioned stimulus (CS+). | Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm<br>* Day 1: Fear acquisition involving the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a conditioned stimuli (CS) (Expts. 1 and 2). The CS will be different colored shapes appearing on a computer monitor. An auditory stimulus will serve as the startle probe. Day 2: Either extinction training (Expt. 1) or fear memory reactivation by a single CS+ with no US (Expt. 2) will occur followed by IV Allo vs. IV placebo administration. Day 3: The effects of IV Allo vs. IV placebo (administered on Day 2) on extinction retention (Expt. 1) or reconsolidation blockade (Expt. 2), as well as reinstatement of conditioned fear (Expts. 1 and 2) will be assessed.<br>Other: Matching IV Placebo<br>* Expt. 1 (extinction retention): On Day 2, a 1.7 ug/kg IV bolus of the matching placebo formulation will be administered over 5 minutes at the completion of extinction training and continued as a 5-hour drip to maintain resting plasma Allo levels at  1500 pg/ml. Expt. 2 (reconsolidation blockade): On Day 2, a 28 ug/kg IV bolus of the matching placebo formulation will be infused over 30 minutes immediately following presentation of a single CS+.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extinction retention in Expt. 1 | To determine extinction retention, the difference between the average SCR to the first 4 fear conditioned stimuli (CS+) trials and the average SCR to first 4 neutral conditioned stimuli (CS-) trials on Day 3 will be calculated. Extinction retention for SCR will be defined as this differential SCR minus differential SCR for Day 2 (calculated as the difference between the average SCR to the last 4 CS+ trials and average SCR for last 4 CS- trials-the index of Day 2 extinction). For Fear-Potentiated Startle (FPS), the degree of FPS to the CS+ during the first 4 CS+ trials on Day 3 will be examined and compared to the FPS for the last 4 CS+ trials during extinction. Lower scores indicate better extinction retention. | Day 3 | 
| Reconsolidation blockade in Expt. 2 | Reconsolidation blockade on Day 3 will be assessed by a) comparing the difference between the average SCR to the first 4 CS+ trials minus the average SCR to the first 4 CS- trials, and b) calculating the average FPS to the first 4 CS+ trials. Lower scores indicate better reconsolidation blockade. | Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fear acquisition in Expt. 1 | Fear acquisition will be defined as the difference between the average SCR to the last 4 CS+ and average SCR to the last 4 CS- trials during the acquisition phase (i.e., differential SCR). For FPS, the last 4 trials of acquisition for each CS will be examined. Since FPS is calculated as the difference between startle to the CSs compared to Noise Alone (NA) trials, the standard is to use FPS to CS+ trials as the dependent variable rather than the difference between FPS to CS+ versus CS- as is typically done for SCR. Higher scores indicate greater conditioned fear acquisition. | Day 1 | 
| Fear acquisition in Expt. 2 | Fear acquisition will be defined as the difference between the average SCR to the last 4 CS+ and average SCR to the last 4 CS- trials during the acquisition phase (i.e., differential SCR). For FPS, the last 4 trials of acquisition for each CS will be examined. Since FPS is calculated as the difference between startle to the CSs compared to NA trials, the standard is to use FPS to CS+ trials as the dependent variable rather than the difference between FPS to CS+ versus CS- as is typically done for SCR. Higher scores indicate greater conditioned fear acquisition. | Day 1 | 
| Reinstatement of Conditioned Fear in Expt. 1 | Reinstatement of conditioned fear will be defined as the average SCR to the last 4 CS+ trials minus the average SCR to the last 4 CS- trials. For FPS, the last 4 CS+ trials will be examined. Higher scores indicate greater reinstatement of conditioned fear. | Day 3 | 
| Reinstatement of Conditioned Fear in Expt. 2 | Reinstatement of conditioned fear will be defined as the average SCR to the last 4 CS+ trials minus the average SCR to the last 4 CS- trials. For FPS, the last 4 CS+ trials will be examined. Higher scores indicate greater reinstatement of conditioned fear. | Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extinction retention, Reconsolidation blockade, Fear conditioning paradigm, Conditioned threat stimulus (CS+), Allopregnanolone (Allo), Refractory PTSD, Trauma-focused therapy