Allopregnanolone for PTSD
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byAnn M Rasmusson, MD
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Boston University
Must not be taking: Hormonal contraceptives
Disqualifiers: Bipolar, Schizophreniform, Substance use, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial requires that participants not be on any medications that could affect the study outcomes or increase the risk of side effects from the study drug. If you are taking such medications, you may need to stop them to participate.
What data supports the effectiveness of the drug Allopregnanolone for PTSD?
Research suggests that Allopregnanolone, a neurosteroid, may help with PTSD by improving the brain's ability to forget fear-related memories. This is supported by studies showing that similar neurosteroids can aid in the extinction of fear responses, which is a key challenge in PTSD treatment.
12345Is Allopregnanolone safe for use in humans?
The research does not provide specific safety data for Allopregnanolone in humans, but it discusses its potential therapeutic role in PTSD and related conditions.
12367How is the drug Allopregnanolone used in PTSD treatment different from other treatments?
Allopregnanolone is unique because it targets GABA receptors in the brain to help with learning and memory processes critical for PTSD recovery, such as extinction retention, which is not a focus of most traditional PTSD treatments.
138910Eligibility Criteria
This trial is for individuals with PTSD who are not at immediate risk to themselves or others, and do not have a severe traumatic brain injury, bipolar I disorder, schizophreniform disorder, or recent substance use disorder. Women must not be pregnant or breastfeeding and should agree to use two forms of birth control.Inclusion Criteria
I have been diagnosed with Posttraumatic Stress Disorder.
I have been diagnosed with Posttraumatic Stress Disorder.
Exclusion Criteria
I have had a moderate to severe brain injury.
You have tried to harm or kill yourself in the past year.
Imminent risk to self or others or require clinical intervention to maintain safety
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pharmacokinetic Studies
Pharmacokinetic studies are conducted in a small group of individuals with PTSD to confirm the selected IV Allo dose increases blood Allo levels as expected
1 week
Treatment
Participants undergo a 3-day laboratory psychophysiology paradigm with startle testing and receive either IV Allo or placebo
3 days
3 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests if an IV dose of Allopregnanolone (Allo) can help with PTSD by either making it easier to learn that something isn't scary anymore (extinction learning), or by blocking the body's stress response when remembering trauma compared to a placebo.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1)Experimental Treatment2 Interventions
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.
Group II: IV Allo for Reconsolidation Blockade (Expt. 2)Experimental Treatment2 Interventions
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+).
Group III: IV Placebo for Extinction Retention (Expt. 1)Placebo Group2 Interventions
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.
Group IV: IV Placebo for Reconsolidation Blockade (Expt. 2)Placebo Group2 Interventions
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+).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Wayne State UniversityDetroit, MI
Boston University School of MedicineBoston, MA
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Who Is Running the Clinical Trial?
Boston UniversityLead Sponsor
National Institute of Mental Health (NIMH)Collaborator
References
A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder. [2023]Trauma-focused psychotherapies show general efficacy in post-traumatic stress disorder (PTSD), although outcomes vary substantially among individuals with PTSD and many patients do not achieve clinically meaningful symptom improvement. Several factors may contribute to poor treatment response, including genetic or environmental (e.g., stress) effects on neurobiological factors involved in learning and memory processes critical to PTSD recovery. In this review, we discuss the relationship between deficient GABAergic neurosteroid metabolites of progesterone, allopregnanolone (Allo) and pregnanolone (PA), and PTSD symptoms in men and women or PTSD-like behavioral abnormalities observed in male rodent models of PTSD. We also review the role and molecular underpinnings of learning and memory processes relevant to PTSD recovery, including extinction, extinction retention, reconsolidation of reactivated aversive memories and episodic non-aversive memory. We then discuss preclinical and clinical research that supports a role in these learning and memory processes for GABAergic neurosteroids and sulfated metabolites of Allo and PA that allosterically antagonize NMDA receptor function. Studies supporting the possible therapeutic impact of appropriately timed, acutely administered Allo or Allo analogs to facilitate extinction retention and/or block reconsolidation of aversive memories are also reviewed. Finally, we discuss important future directions for research in this area. Examining the varied and composite effects in PTSD of these metabolites of progesterone, as well as neuroactive derivatives of other parent steroids produced in the brain and the periphery, will likely enable a broadening of targets for treatment development. Defining contributions of these neuroactive steroids to common PTSD-comorbid psychiatric and medical conditions, as well as subpopulation-specific underlying dysfunctional physiological processes such as hypothalamic-pituitary-adrenal axis and immune system dysregulation, may also enable development of more effective multisystem precision medicines to prevent and treat the broader, polymorbid sequelae of extreme and chronic stress.
Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study. [2021]Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p
Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity. [2022]Several studies have demonstrated poor retention of extinction learning among individuals with posttraumatic stress disorder (PTSD). Gonadal hormone signaling in brain appears to influence the retention of extinction learning differently in women with and without PTSD. Women with PTSD, compared to trauma-exposed women without PTSD, show relative deficits in extinction retention during the mid-luteal phase (mLP) of the menstrual cycle, compared to the early follicular phase (eFP). A PTSD-related reduction in conversion of progesterone to its GABAergic metabolites allopregnanolone (Allo) and pregnanolone (PA) may contribute to these findings. The current study in trauma-exposed women with (n = 9) and without (n = 9) PTSD investigated associations between extinction retention and plasma Allo + PA levels, as well as the ratio of Allo + PA to 5α-dihydroprogesterone (5α-DHP), the immediate steroid precursor for Allo. The study also investigated the relationship between extinction retention and the ratio of Allo + PA to dehydroepiandrosterone (DHEA), an adrenally-derived GABAA receptor antagonist. Study participants completed differential fear-conditioning during both the eFP and mLP of the menstrual cycle. Analyses revealed a strong positive relationship between resting plasma Allo + PA levels and extinction retention during the mLP in the women with, but not without, PTSD (e.g., diagnosis X Allo + PA interaction controlling for early extinction: β = -.0008, p = .003). A similar pattern emerged for the Allo + PA to 5α-DHP ratio (β = -.165, p = .071), consistent with a PTSD-related block in production of Allo and PA at the enzyme 3α-hydroxysteroid dehydrogenase. The ratio of Allo + PA to DHEA appeared to influence extinction retention only during the eFP when Allo + PA and DHEA levels are comparable and thus may compete for effects on GABAA receptor function. This study aligns with male rodent PTSD models linking experimental reductions in brain Allo levels to deficits in extinction retention and suggests that targeting PTSD-related deficits in GABAergic neurosteroid synthesis may be therapeutic.
Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. [2022]Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS- skin conductance response (SCR) compared to placebo (b = -0.19, CI = -0.01 to -37, p = 0.042 and b = -0.25, CI = -08 to -0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS- SCR in the DCS group, compared to placebo, (b = -0.25, CI = 0.04 to -0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.
Postreactivation glucocorticoids impair recall of established fear memory. [2019]Pavlovian fear conditioning provides one of the best rodent models of acquired anxiety disorders, including posttraumatic stress disorder. Injection of a variety of drugs after training in fear-conditioning paradigms can impair consolidation of fear memories. Indeed, early clinical trials suggest that immediate administration of such drugs after a traumatic event may decrease the risk of developing posttraumatic stress disorder in humans (Pitman et al., 2002; Vaiva et al., 2003). The use of such a treatment is limited by the difficulty of treating every patient at risk and by the difficulty in predicting which patients will experience chronic adverse consequences. Recent clinical trials suggest that administration of glucocorticoids may have a beneficial effect on established posttraumatic stress disorder (Aerni et al., 2004) and specific phobia (Soravia et al., 2006). Conversely, glucocorticoid administration after training is known to enhance memory consolidation (McGaugh and Roozendaal, 2002; Roozendaal, 2002). From a clinical perspective, enhancement of a fear memory or a reactivated fear memory would not be desirable. We report here that when glucocorticoids are administered immediately after reactivation of a contextual fear memory, subsequent recall is significantly diminished. Additional experiments support the interpretation that glucocorticoids not only decrease fear memory retrieval but, in addition, augment consolidation of fear memory extinction rather than decreasing reconsolidation. These findings provide a rodent model for a potential treatment of established acquired anxiety disorders in humans, as suggested by others (Aerni et al., 2004; Schelling et al., 2004), based on a mechanism of enhanced extinction.
Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone. [2023]Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%-13% of the general population and 20%-30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABAA receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABAA receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.
Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear. [2019]We examined the effect of glucocorticoid agonists on the extinction of conditioned fear in rats by using fear-potentiated startle. Systemic injection of glucocorticoid receptor agonists dexamethasone (DEX) (0.1, 0.5, and 1.0 mg/kg) and intra-amygdala infusion of RU28362 (0.5, 1.0, and 3.0 ng/side) prior to extinction training facilitated extinction of conditioned fear in a dose-dependent manner. Extinction of conditioned fear and circulating corticosterone levels were attenuated by administration of corticosteroid synthesis inhibitor metyrapone (25 mg/kg s.c.) 90 min before extinction training. The facilitation effect of DEX was dependent on repeated presentation of the conditioned stimulus rather than exposure to the experimental context, indicating this effect did not result from impaired expression of conditioned fear or accelerated forgetting. Intra-amygdaloid administration of the glucocorticoid receptor antagonist mifepristone (0.1, 0.2, and 0.5 ng/side, bilaterally) blocked extinction of conditioned fear and the facilitation effect of DEX in a dose-dependent manner. Mifepristone (2 ng/side) did not affect extinction but blocked the facilitating effect of DEX. Systemic administration of DEX after extinction training also facilitated extinction, suggesting that DEX may influence the memory consodilation phase of extinction. The Dose of dexamethsone or metyrapone used here did not influence fear-potentiated startle when administered before testing. Thus, it is unlikely that these drugs influenced extinction by increasing or disrupting CS processing. All results suggested that amygdaloid glucocorticoid receptors were involved in the extinction of conditioned fear.
Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD. [2020]Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABAA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.
Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls. [2014]Allopregnanolone is an endogenous neuroactive steroid which, through the binding to the GABA(A) receptor, enhances inhibitory neurotransmission and exerts anxiolytic, sedative and antiepileptic effects. Following acute administration, allopregnanolone reliably acts as an anxiolytic compound. The primary aim of this study was to investigate if allopregnanolone, administered to healthy women and women with premenstrual dysphoric disorder (PMDD), would have an anxiolytic effect, expressed as a decreased startle response.
The anxiolytic-like effects of allopregnanolone vary as a function of intracerebral microinfusion site: the amygdala, medial prefrontal cortex, or hippocampus. [2013]Allopregnanolone is a 5alpha-reduced metabolite of progesterone that potentiates gamma-aminobutyric acid type-A (GABA(A)) receptor activity and produces anxiolytic effects in animal models. Little is, however, known about the brain regions that mediate its anxiolytic effects. In this study Sprague-Dawley rats were microinfused with allopregnanolone into the amygdala, medial prefrontal cortex, or hippocampus--brain regions that have been previously implicated in the control of anxiety in animal models. After the microinfusion, the animals were tested on the elevated plus-maze and the shock-probe burying test. In the amygdala, allopregnanolone produced anxiolytic-like effects in both tests; in the medial prefrontal cortex, allopregnanolone produced anxiolytic effects restricted to the plus-maze test; in the hippocampus, allopregnanolone was ineffective in both tests. The results were discussed in terms of differences in the control of specific fear reactions within subregions of each brain area, differences in the 'sensitivity' of behavioral tests to the anxiolytic effects of allopregnanolone, and finally, regional differences in the subunit composition of GABA(A) receptors and their possible relationship to the relative efficacy of steroidal and nonsteroidal GABA(A) agonists.