Allopregnanolone for PTSD

Recruiting at 1 trial location

Overseen By Seth Norrholm, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Boston University

Must not be taking: Hormonal contraceptives

Disqualifiers: Bipolar, Schizophreniform, Substance use, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 3 days

256 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 6 7}

How 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. ^{1 3 8 9 10}

Research Team

Ann M Rasmusson, MD

Principal Investigator

Boston University School of Medicine, Dept of Psychiatry

Eligibility 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

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

Treatment Details

Interventions

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

Trial Overview 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.

Participant Groups

Group I: IV Allopregnanolone (Allo) for Extinction Retention (Expt. 1) Experimental Treatment 2 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 Treatment 2 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 Group 2 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 Group 2 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+).

Who Is Running the Clinical Trial?

Boston University

Lead Sponsor

Trials

494

Recruited

9,998,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

Deficient levels of GABAergic neurosteroid metabolites, such as allopregnanolone and pregnanolone, may contribute to PTSD symptoms, suggesting a potential target for treatment development.

Research indicates that administering these neurosteroids at specific times could enhance memory extinction and prevent the reconsolidation of traumatic memories, offering a promising avenue for improving PTSD therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder. Rasmusson, AM., Pineles, SL., Brown, KD., et al.[2023]

A double-blind, placebo-controlled trial involving 62 participants with and without PTSD showed that dexamethasone administration significantly improved fear extinction and safety discrimination in individuals with PTSD, reversing deficits seen in the placebo condition.

Dexamethasone appears to effectively suppress hyperactivity of the HPA axis, which is linked to exaggerated fear responses in PTSD, suggesting it could be a promising new treatment for reducing fear expression in affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study. Michopoulos, V., Norrholm, SD., Stevens, JS., et al.[2021]

In a study involving 18 trauma-exposed women (9 with PTSD and 9 without), it was found that higher levels of the neurosteroids allopregnanolone (Allo) and pregnanolone (PA) were positively associated with better retention of extinction learning in women with PTSD during the mid-luteal phase of their menstrual cycle.

The research suggests that women with PTSD may have a reduced ability to convert progesterone into these beneficial neurosteroids, which could contribute to their difficulties in retaining extinction learning, indicating a potential therapeutic target for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity. Pineles, SL., Nillni, YI., Pinna, G., et al.[2022]

In a study involving 90 individuals with PTSD, both hydrocortisone (HC) and D-Cycloserine (DCS) were found to enhance fear extinction learning, as indicated by reduced skin conductance responses during extinction learning compared to a placebo.

These findings suggest that pharmacological agents like glucocorticoids and NMDA receptor agonists could be promising adjuncts to prolonged exposure therapy for improving treatment outcomes in PTSD, although further clinical implications need to be explored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. Inslicht, SS., Niles, AN., Metzler, TJ., et al.[2022]

Administering glucocorticoids immediately after reactivating a fear memory in rodents significantly reduces the recall of that memory, suggesting a potential treatment strategy for anxiety disorders like PTSD.

Glucocorticoids not only diminish fear memory retrieval but also enhance the extinction of fear memories, indicating their dual role in managing established anxiety disorders in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postreactivation glucocorticoids impair recall of established fear memory. Cai, WH., Blundell, J., Han, J., et al.[2019]

Allopregnanolone, a neurosteroid that modulates GABAA receptors, is linked to PTSD symptoms, with lower levels correlating with increased re-experiencing and depressive symptoms in patients, suggesting its potential as a biomarker for diagnosis and treatment.

In rodent models of PTSD, decreased allopregnanolone synthesis is associated with heightened fear responses and impaired fear extinction, indicating that treatments targeting allopregnanolone or its analogs could help improve PTSD symptoms and facilitate recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone. Pinna, G.[2023]

Glucocorticoid receptor agonists, like dexamethasone, enhance the extinction of conditioned fear in rats in a dose-dependent manner, indicating their potential role in fear memory processing.

The effectiveness of dexamethasone in facilitating fear extinction is linked to its action on amygdaloid glucocorticoid receptors, as blocking these receptors with mifepristone inhibited the extinction process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear. Yang, YL., Chao, PK., Lu, KT.[2019]

In men with PTSD, lower levels of the neurosteroids allopregnanolone and pregnanolone (allo + pregnan) in cerebrospinal fluid were strongly associated with higher PTSD symptoms, indicating their potential role in mood regulation.

The study suggests that the synthesis of these neurosteroids may be blocked by specific enzymes, with implications for developing targeted neurosteroid-based treatments for PTSD that consider sex differences and PTSD severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD. Rasmusson, AM., King, MW., Valovski, I., et al.[2020]

Allopregnanolone, an endogenous neuroactive steroid, was administered to 16 women with premenstrual dysphoric disorder (PMDD) and 12 healthy controls, but it did not significantly affect the startle response or prepulse inhibition, indicating no anxiolytic effect in this context.

Despite increasing self-rated sedation levels in both groups, the study found that PMDD patients had lower serum concentrations of allopregnanolone compared to healthy controls, suggesting a potential difference in neuroactive steroid levels between these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls. Kask, K., Bäckström, T., Lundgren, P., et al.[2014]

Allopregnanolone, a metabolite of progesterone, was found to have anxiolytic effects when infused into the amygdala of rats, indicating this brain region plays a significant role in mediating anxiety relief.

The study showed that while allopregnanolone was effective in the amygdala and partially effective in the medial prefrontal cortex, it had no anxiolytic effect in the hippocampus, suggesting that different brain regions have varying sensitivities to this compound's effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anxiolytic-like effects of allopregnanolone vary as a function of intracerebral microinfusion site: the amygdala, medial prefrontal cortex, or hippocampus. Engin, E., Treit, D.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Postreactivation glucocorticoids impair recall of established fear memory. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls. [2014]

10. England pubmed.ncbi.nlm.nih.gov

The anxiolytic-like effects of allopregnanolone vary as a function of intracerebral microinfusion site: the amygdala, medial prefrontal cortex, or hippocampus. [2013]