Brexanolone for PTSD
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Yale University
Must not be taking: Anxiolytics, Antidepressants, Opioids, Benzodiazepines
Disqualifiers: Schizophrenia, Bipolar, Substance use, others
No Placebo Group
Breakthrough Therapy
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This trial tests the safety and feasibility of using brexanolone, given through an IV, for people with both PTSD and AUD. The medication aims to balance brain chemicals to improve mood and reduce stress.
Will I have to stop taking my current medications?
The trial requires that participants stop using psychoactive drugs, including anxiolytics (anti-anxiety medications) and antidepressants, for at least 30 days before joining. It also excludes those taking opioids or other central nervous system depressants like benzodiazepines.
What data supports the effectiveness of the drug Brexanolone for PTSD?
Brexanolone is effective for postpartum depression (PPD), significantly reducing depression scores in women with moderate to severe PPD. However, there is no direct evidence supporting its effectiveness for PTSD, and a similar drug, ganaxolone, did not show significant benefits for PTSD in a clinical trial.
12345Is Brexanolone safe for human use?
Brexanolone, also known as Zulresso, has been approved by the FDA for the treatment of postpartum depression, indicating it has been evaluated for safety in humans. While it is generally well-tolerated, the treatment involves a lengthy infusion time and can be costly. There is no specific safety data for its use in PTSD, but its approval for postpartum depression suggests a level of safety in human use.
12467How is the drug Brexanolone unique for treating PTSD?
Brexanolone is unique because it is an intravenous drug that acts as a neuroactive steroid, specifically targeting GABAA receptors in the brain, which is different from most oral medications used for PTSD. It was originally developed for postpartum depression, highlighting its novel mechanism of action compared to traditional PTSD treatments.
13458Eligibility Criteria
This trial is for adults aged 21-55 with PTSD and AUD who drink heavily but don't have severe mental illnesses, other substance use disorders (except tobacco), or are using psychoactive drugs. Pregnant/nursing women or those not on birth control are excluded, as well as anyone with serious health issues like heart problems, liver disease, seizures, or seeking AUD treatment.Inclusion Criteria
I have been diagnosed with PTSD in the last 6 months.
Provision of signed and dated informed consent form
I am a man who drinks more than 14 times a week and has more than 5 drinks at least once a week.
+4 more
Exclusion Criteria
I have been diagnosed with schizophrenia, bipolar disorder, or another severe mental illness.
I have severe kidney disease or am taking opioids or drugs like Xanax.
I do not have any major health issues like heart problems, kidney or liver disease, seizures, or HIV.
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
1 visit (in-person)
Treatment
Participants receive brexanolone as a continuous IV infusion over 20 hours
1 day
1 visit (in-person)
Laboratory Session
Participants complete a laboratory session with personalized imagery and a 2-hour alcohol self-administration period
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness, including assessments of alcohol use, PTSD symptoms, and side effects
4 weeks
Weekly visits (virtual or in-person)
Participant Groups
The study tests the safety and feasibility of Brexanolone in individuals with PTSD and AUD. It aims to see if this medication can reduce stress-induced alcohol consumption among men and women meeting specific drinking criteria related to their conditions.
1Treatment groups
Experimental Treatment
Group I: BrexanaoloneExperimental Treatment1 Intervention
In this single-arm study, participants will be administered brexanolone as a continuous IV infusion over 20 hours (titrated up to 90mcg/kg/hour).
Brexanolone is already approved in United States for the following indications:
🇺🇸 Approved in United States as Zulresso for:
- Postpartum Depression
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Yale School of MedicineNew Haven, CT
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Who Is Running the Clinical Trial?
Yale UniversityLead Sponsor
National Institute on Alcohol Abuse and Alcoholism (NIAAA)Collaborator
Sage TherapeuticsIndustry Sponsor
References
Brexanolone: First Global Approval. [2020]Brexanolone (ZULRESSO™) is an intravenously administered, small molecule, neuroactive steroid GABAA receptor positive allosteric modulator that was developed by Sage Therapeutics under license to the University of California for the treatment of postpartum depression (PPD). The formulation is a mixture of allopregnanolone, an endogenous inhibitory pregnane neurosteroid, and sulfobutylether-beta-cyclodextrin (a solubilizing agent). In mid-March 2019 brexanolone received its first global approval in the USA for the treatment of PPD in adult women. This article summarizes the milestones in the development of brexanolone leading to its first approval for the treatment of adult women with PPD.
A randomized controlled trial of ganaxolone in posttraumatic stress disorder. [2018]Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.
Brexanolone for Postpartum Depression: Clinical Evidence and Practical Considerations. [2020]Our aim was to review the efficacy, safety, and pharmacology of brexanolone (Zulresso), a new antidepressant with a novel mechanism of action, in the treatment of postpartum depression (PPD). Pertinent data and information were obtained via PubMed (1993 to August 2018). Articles published in English that evaluated the safety and efficacy of brexanolone and other off-label PPD treatments were included. Literature regarding epidemiology and pathophysiology of PPD was also selected. Brexanolone, administered as an intravenous infusion over 60 hours, produced a statistically significant and clinically meaningful reduction in Hamilton Depression Rating Scale (HAM-D) scores compared with placebo at both 60 and 90 μg/kg/hour in patients with moderate to severe PPD. Brexanolone groups had higher response and remission rates compared with placebo. Common adverse effects were somnolence, dizziness, and headache. A small percentage (4%) of patients required cessation of therapy due to excessive sedation or loss of consciousness. Although the evidence for brexanolone as a novel treatment for PPD looks promising, a Risk Evaluation and Mitigation Strategies (REMS) program requirement and the logistics of prolonged infusions serve as barriers to treatment. A discussion of these obstacles as well as pharmacokinetics, monitoring, and dosing is provided. Brexanolone is a novel antidepressant indicated for the treatment of PPD. Clinical trials demonstrated that brexanolone significantly reduces depression scores in women with moderate to severe PPD. Due to risk of oversedation and loss of consciousness, a REMS program will be put in place to mitigate the risk of adverse events.
Barbiturates and pyrazolopyridines for the treatment of postpartum depression-repurposing of two drug classes. [2023]Zulresso (brexanolone) is an aqueous formulation of the neurosteroid, allopregnanolone, and the only FDA-approved medication for the treatment of postpartum depression (PPD). While brexanolone is effective for the treatment of PPD, lengthy infusion time and high cost can be prohibitive. Failure of GABAA receptors to adapt to fluctuating neurosteroid levels is considered to predispose women to mood disorders in the postpartum period. Brexanolone is thought to act via stimulation of δ subunit-containing GABAA receptors, which are extrasynaptic and localized to particular brain regions. Neurosteroid stimulation of δ subunit-containing GABAA receptors leads to sustained inhibition (hyperpolarization) of GABAergic neurons, which makes δ subunit-containing GABAA receptors a potentially important pharmacologic target. Barbiturates and pyrazolopyridines are potent stimulators of δ subunit-containing GABAA receptors and therefore potentially cost-effective treatments for PPD. Barbiturates are often not prescribed, owing to risk of dependence and respiratory depression. The pyrazolopyridines were tested several decades ago for anxiety and depression but never developed commercially. Herein we use the FDA-approved dosing schedule of brexanolone and GABAA receptor binding data from various animal models to examine the safety, efficacy, and potential clinical utility of barbiturates and pyrazolopyridines for the treatment of PPD. We suggest consideration of repurposing barbiturates and pyrazolopyridines as safe and readily available treatment alternatives for PPD.
Postmarketing safety profile of brexanolone: a pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS). [2023]Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug reactions (ADRs) associated with its use is limited. The main aim of this study was to explore the postmarketing safety profile of brexanolone.
Design, synthesis and characterizations of prodrugs of brexanolone. [2023]A series of prodrugs of brexanolone, the synthetic version of the endogenously produced γ-aminobutyric acid A receptors positive allosteric modulator allopregnanolone, were designed, synthesized, and evaluated in vitro and in vivo. The effect of different function groups connecting to brexanolone C3 hydroxyl as well as those at the chain terminals of prodrug moieties were explored. Through these efforts, prodrugs that can efficiently release brexanolone in vitro and in vivo, and possess a potential for sustained delivery of a long acting brexanolone were discovered.
Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease. [2020]For several years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone) may have therapeutic potential for treatment of various stress-related diseases including post-traumatic stress disorder (PTSD), depression, alcohol use disorders (AUDs), as well as neurological and psychiatric conditions that are worsened in the presence of stress, such as multiple sclerosis, schizophrenia, and seizure disorders. In this review, we make the argument that the pleiotropic actions of allopregnanolone account for its ability to promote recovery in such a wide variety of illnesses. Likewise, the allopregnanolone precursors, pregnenolone and progesterone, share many actions of allopregnanolone. Of course, pregnenolone and progesterone lack direct effects on GABAA receptors, but these compounds are converted to allopregnanolone in vivo. This review presents a theoretical framework for understanding how endogenous neurosteroids that regulate 1) γ-aminobutyric acid (GABA)A receptors, 2) corticotropin releasing factor (CRF) and 3) pro-inflammatory signaling in the innate immune system and brain could play a key role in both the prevention and treatment of stress-related disease. We further discuss cautions and limitations of allopregnanolone or precursor therapy as well as the need for more clinical studies.
Brexanolone to Treat Postpartum Depression in Adult Women. [2023]ZULRESSO (Brexanolone) is a novel FDA-approved treatment for moderate-to-severe postpartum depression. Postpartum depression may be diagnosed in women experiencing depressive symptoms which can manifest as cognitive, behavioral, or emotional disturbances as early as the third trimester to 4 weeks following delivery. The efficacy of brexanolone suggests that neurosteroids such as allopregnanolone are important to treat PPD. However, it is currently unclear if brexanolone provides lasting relief of depressive symptoms at or beyond 30 days following administration. Further studies are necessary to make this determination.