Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD
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): 1. promotes consolidation of extinction learning (sub-study 1) or 2. 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.
- Post Traumatic Stress Disorder
- Eligible Ages
- Between 18 Years and 55 Years
- Eligible Genders
- Accepts Healthy Volunteers
- Posttraumatic Stress Disorder
- Bipolar I disorder, schizophreniform disorder, or substance use disorder within 3 months of study entry - 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) - 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. - Females: pregnant, breastfeeding, or if of childbearing potential, unwilling to use two forms of effective birth control for one week before and one month after study drug administration - Wear hearing aids or fail hearing test (not applicable to PK study)
- Phase 2
- Study Type
- Intervention Model
- Parallel Assignment
- Intervention 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.
- Primary Purpose
- Basic Science
- Triple (Participant, Investigator, Outcomes Assessor)
- Masking Description
- In this double-blind, placebo controlled, randomized trial, active drug and matching placebo will be supplied by the research pharmacy. Participants, assessors, and the investigators will be blind to treatment condition.
IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)
|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.||
IV Placebo for Extinction Retention (Expt. 1)
|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.||
IV Allo for Reconsolidation Blockade (Expt. 2)
|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+).||
IV Placebo for Reconsolidation Blockade (Expt. 2)
|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+).||
- Boston University
Study ContactAnn M Rasmusson, MD
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.