Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD

Boston University

Status and phase: Enrolling; Phase 2

Conditions: Post Traumatic Stress Disorder

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

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04468360

H-40643

R01MH122867 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 256 estimated patients

Sex: All

Ages: 18 to 55 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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256 participants in 4 patient groups, including a placebo group

IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)

Experimental group

Description:

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.

Treatment:

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

IV Placebo for Extinction Retention (Expt. 1)

Placebo Comparator group

Description:

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.

Treatment:

Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm

Other: Matching IV Placebo

IV Allo for Reconsolidation Blockade (Expt. 2)

Experimental group

Description:

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+).

Treatment:

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

IV Placebo for Reconsolidation Blockade (Expt. 2)

Placebo Comparator group

Description:

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+).

Treatment:

Behavioral: 3-day differential fear conditioning, extinction, and extinction retention testing paradigm

Other: Matching IV Placebo