Brexanolone, a First‐In‐Class Neurosteroid Medication: Mechanism of Action, Clinical, and Translational Science

ABSTRACT

Given the increasing prevalence of postpartum depression (PPD) and the stigma associated with this condition, it is essential to address this significant health concern. Brexanolone is an FDA‐approved treatment for PPD that works by positive‐allosteric modulation of type A γ‐aminobutyric acid (GABA_A) receptors. As an intravenous version of allopregnanolone, brexanolone is known for its rapid onset of action and lasting impact on depressive symptoms in patients with PPD, with significant reductions in depressive symptoms observed by the end of the 60‐h infusion and improvements maintained through Day 30 of follow‐up. The quick onset is particularly important as traditional first‐line treatment for PPD can take up to several weeks to produce observable improvements. Despite its efficacy, the clinical use of brexanolone is limited by the need for a continuous 60‐h intravenous infusion and mandatory enrollment in Risk Evaluation and Mitigation Strategy (REMS) program due to risks of excessive sedation and sudden loss of consciousness. Brexanolone is metabolized through non‐CYP‐mediated pathways, including keto‐reduction, glucuronidation, and sulfation; therefore, no dose adjustments are required in patients with mild to severe renal impairment (eGFR 15–89 mL/min/1.73 m²). However, its use should be avoided in end‐stage renal disease (eGFR < 15 mL/min/1.73 m²) due to potential accumulation of its solubilizing vehicle, betadex sulfobutyl ether sodium. While primarily indicated for PPD, brexanolone is under investigation for post‐traumatic stress disorder, alcohol use disorder, postpartum psychosis, and tinnitus. Future research focusing on alternative delivery methods and expanded therapeutic indications could make brexanolone more accessible and broaden its clinical utility.

Clinical & Translational Card for Brexanolone.

• ○ Mechanism of Action: positive allosteric modulator of GABA_A receptors.
• ○ Indication(s): treatment of postpartum depression in patients ≥ 15 years of age.
• ○
  Dosage and Administration: continuous IV infusion for 60 h which is 2.5 days.

  • 0 to 4 h: Initiate dose of 30 μg/kg/h.
  • 4 to 24 h: Increase dose to 60 μg/kg/h.
  • 24 to 52 h: Increase dose to 90 μg/kg/h, consider dose reduction to 60 μg/kg/h if poorly tolerated.
  • 52 to 56 h: Decrease dose to 60 μg/kg/h.
  • 56 to 60 h: Decrease the dose to 30 μg/kg/h.
• ○ Major Metabolic Pathway: keto‐reduction, glucuronidation, sulfation.
• ○ Key Pharmacokinetics Characteristics: volume of distribution of ~3 L/kg, plasma protein binding > 99%, geometric mean AUC_0‐60 of ~3516 ng·h/mL, C_max of ~79 ng/mL at 90 μg/kg/h, t_1/2 of ~9 h; clearance of ~1 L/h/kg, primarily excreted as metabolites (47% in feces and 42% in urine) with < 1% as unchanged drug.

1. Introduction

Postpartum depression (PPD) is defined by the Diagnostic and Statistical Manual, 5th edition (DSM‐5) as a major depressive disorder (MDD) episode in childbearing females, with an onset as early as the third trimester of pregnancy and as late as 4 weeks after delivery [1]. PPD is a growing public health concern, as it affects approximately 17% of women during pregnancy or after giving birth globally [2]. PPD is often underdiagnosed and untreated [3], and associated with adverse maternal and infant outcomes including increased maternal morbidity, reduced breastfeeding rates, impaired maternal–infant bonding, and increased risk for developmental delays in the children [4]. In severe cases, untreated PPD may lead to suicide, emphasizing the critical need for effective treatment [4].

The pathophysiology of PPD is not entirely understood; however, it is related to a variety of biologic factors, such as a previous history of mental health disorders and fluctuations in estrogen and progesterone concentrations, as well as different environmental factors, including emotional stressors and social relationships [1]. Selective serotonin reuptake inhibitors (SSRIs) have been considered the standard, traditional first‐line pharmacotherapy for PPD before the discovery of brexanolone [1]. However, SSRIs are associated with limitations including delayed onset of action, concerns about lactation safety, and suboptimal response rate [1]. Brexanolone (Zulresso or SAGE‐547) is the first drug approved to treat moderate to severe PPD [5]. Brexanolone is an exogenous, pharmaceutical‐grade formulation that is chemically identical to the endogenous neurosteroid allopregnanolone as shown in figure 1 [6]. The rapid postpartum decrease in allopregnanolone has been proposed as a contributing factor in the pathophysiology of PPD [7, 8, 9]. Brexanolone is administered to combat this neurosteroid withdrawal and to resume normal receptor activity. This article will review brexanolone and its role in treating PPD, in addition to its potential in treating other disorders, including super refractory status epilepticus (SRSE), postpartum psychosis, tinnitus, and COVID‐19‐associated acute respiratory distress syndrome (ARDS).

2. Drug‐Regulatory Approval

Brexanolone was developed by Sage Therapeutics under license to the University of California for the treatment of PPD. Brexanolone became the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for PPD on March 19, 2019 [5].

3. Mechanism of Action

During the 3rd trimester of pregnancy, maternal progesterone concentrations rise markedly, leading to increased production of the neuroactive steroid (neurosteroid) allopregnanolone, which is one of the major metabolites of progesterone [9]. This increase in hormonal activity is accompanied by a reduction in tonic inhibition currents mediated by GABA_A receptors [9]. After childbirth, there is a rapid postpartum decline of progesterone and neurosteroids, otherwise known as neurosteroid withdrawal, as well as a delay in GABA_A receptors resuming normal activity [9]. This leads to neuronal hyperexcitability and depressive symptoms. By restoring allopregnanolone‐like activity during this vulnerable period, brexanolone is thought to rapidly normalize GABAergic signaling and restore network balance [7, 8]. Brexanolone is chemically identical to allopregnanolone (Figure 1), a neuroactive steroid that acts primarily as a positive allosteric modulator of GABA_A receptors. As illustrated in Figure 2, Brexanolone binds allosterically to GABA_A receptors, resulting in increased chloride ion (Cl⁻) conductance and enhancing inhibitory neurotransmission. Consequently, it is believed that this mechanism alleviates the hormonal and neurochemical imbalance associated with PPD and reverses the reduction in tonic inhibition currents experienced during the 3rd trimester. The exact downstream neural circuit dynamics responsible for its uniquely rapid and sustained clinical efficacy in PPD remain an area of ongoing investigation.

FIGURE 1.

Structural identity of commercial and endogenous neurosteroids. The chemical structure of brexanolone (a, PubChem CID 92786, PubChem SID 49836635) is chemically identical to the endogenous neurosteroid allopregnanolone (b, also PubChem CID 92786), a major metabolite of progesterone.

FIGURE 2.

Proposed mechanism of action of Brexanolone in postpartum depression (PPD). Brexanolone is a synthetic compound of allopregnanolone and acts as a positive allosteric modulator of GABA_A receptors. Postpartum withdrawal of progesterone‐derived neurosteroids is associated with reduced GABAergic tone and increased excitability within corticolimbic and stress‐regulatory circuits. Brexanolone is proposed to restore inhibitory–excitatory balance through enhancement of GABAergic signaling.

4. Pharmacokinetic/Pharmacodynamic (PK/PD) Characteristics

4.1. Pharmacokinetics

After a continuous IV infusion of brexanolone to female patients with PPD over 60 h (hours 0 to 4: 30 μg/kg/h; hours 4 to 24: 60 μg/kg/h; hours 24 to 52: 90 μg/kg/h; hours 52–56: 60 μg/kg/h; hours 56 to 60: 30 μg/kg/h), the Area Under the Concentration‐Time Curve from Time Zero to 60 Hours (AUC_0‐60) was determined to be approximately 3516 ng·h/mL [10]. Brexanolone is exclusively administered by intravenous infusion because of its poor oral bioavailability (< 5%) resulting from extensive first‐pass metabolism [7, 8]. Across studies, brexanolone demonstrated generally consistent pharmacokinetic exposure, with inter‐individual variability characterized in integrated clinical pharmacology analyses submitted to the FDA (NDA 211,371) [11]. Overall, brexanolone shows a consistent pharmacokinetic profile across infusion regimens, with relatively low pharmacokinetic variability [10].

Based on population pharmacokinetic modeling, the steady‐state volume of distribution (V_ss) for brexanolone is estimated to be approximately 587 L, consistent with its highly lipophilic profile and extensive tissue disribution [10]. Brexanolone is also highly protein‐bound in plasma, with a binding fraction over 99% [10]. While such high plasma binding typically confines a drug to the vascular space, brexanolone's high affinity for lipids allows the free, unbound fraction to readily cross the blood–brain barrier. This strong lipid partitioning continuously draws the drug out of the plasma compartment and into central nervous system tissues, explaining its extensive volume of distribution despite the high plasma protein binding property. Brexanolone can be excreted into breast milk; however, the amount found in breast milk is relatively low, and the amount decreases rapidly after the infusion ends [10]. Furthermore, infant exposure is limited due to its poor oral bioavailability (< 5%) [10].

Brexanolone is mainly biotransformed through non‐CYP pathways including keto‐reduction, glucuronidation, and sulfation. The resulting inactive metabolites undergo dual clearance routes, with 47% eliminated in the feces and 42% excreted in the urine; notably, less than 1% is renally cleared as the unchanged parent compound [11]. As a result, no dose adjustments are recommended for patients with mild (eGFR 60–89 mL/min/1.73m²), moderate (eGFR 30–59 mL/min/1.73m²), or severe (eGFR 15–29 mL/min/1.73m²) renal impairment. However, its clinical use must be avoided in patients with end‐stage renal disease (eGFR < 15 mL/min/1.73m²) mainly due to potential accumulation of the solubilizing vehicle, betadex sulfobutyl ether sodium [12]. Under the approved 60‐h intravenous infusion regimen (titrated to a maximum of 90 μg/kg/h), the clearance is approximately 1.1 L/h/kg [a coefficient of variation (CV) of 21%] and the terminal half‐life is approximately nine hours (CV of 21% to 30%) [11].

4.2. Pharmacodynamics

Brexanolone is a synthetic compound of allopregnanolone that acts as a positive allosteric modulator of GABA_A receptors, enhancing inhibitory neurotransmission [7, 8, 9]. It is associated with adverse events (Table 1), including sedation/somnolence, dizziness, loss of consciousness, dry mouth, fatigue, nausea, and infusion site pain. Due to its noted adverse events, brexanolone is administered only under supervision as part of a Risk Evaluation and Mitigation Strategy (REMS) program to mitigate potential risks [12].

TABLE 1.

Commonly reported adverse effects associated with brexanolone.

Adverse event	Frequency (approx%)
Sedation/Somnolence	11%–24% [7, 8, 12]
Dizziness	7%–15% [7, 8, 12]
Loss of Consciousness	3%–8% [7, 8, 12]
Dry Mouth	~10% [7, 8, 12]
Fatigue	~6% [7, 8, 12]
Nausea	2%–10% [7, 8, 12]
Infusion Site Pain	~2% [7, 8, 12]

Rapid symptom control is often critical when managing patients with PPD. Brexanolone demonstrates a rapid onset of action and shows antidepressant effects within 2–3 days of administration, whereas traditional SSRIs may take 2–6 weeks to show noticeable clinical improvement [7, 8]. Additionally, brexanolone consistently produces a rapid onset of action within hours to days that is largely maintained through 30 days, which may reduce the burden of long‐term treatment for PPD [7, 8]. It is important to note, however, that when administered alongside other antidepressants, careful monitoring is recommended as concomitant use has been shown to increase the likelihood or intensity of sedation‐related adverse events [12].

5. Key Clinical Trials

As of June 2025, six completed clinical trials have assessed brexanolone's pharmacokinetics, pharmacodynamics, and efficacy in the treatment of PPD. A summary of the clinical trials is presented in Table 2. These studies demonstrate its rapid onset of action, lasting effects, and manageable safety profile, leading to its FDA approval in 2019.

TABLE 2.

Summary of completed clinical trials investigating brexanolone for postpartum depression and other conditions.

Study category	Study short title	Phase	Total N	Intervention arm and dosage	Results
PK/PD + Female Adults	PK/PD in Female Adults with PPD (NCT02285504) [7]	II	4	Single‐arm Brexanolone (N = 4): open‐label, 60‐h continuous IV infusion with a 12‐h titration phase (21.5 → 43 → 64.5 μg/kg/h), a 36 h maintenance infusion at 86 μg/kg/h, and a 12 h taper phase (64.5 → 43 → 21.5 μg/kg/h)	Met safety and PK objectives. The multi‐step infusion protocol was well‐tolerated with predictable PK parameters. Exploratory efficacy tracking demonstrated a rapid and substantial reduction in mean HAM‐D scores by Hour 60, which was sustained through the follow‐up period, providing foundational proof‐of‐concept for the dosing schedule.
Female Adults Women with Severe PPD	Proof‐of‐Concept Efficacy (NCT02614547) [7]	II	21	Two‐arm Placebo (N = 11): 60‐h continuous IV infusion of brexanolone‐matching placebo Brexanolone (N = 10): 60‐h continuous IV infusion of brexanolone (titrated up to a target maintenance dose of 90 μg/kg/h, followed by taper)	Met primary efficacy endpoint. Demonstrated a rapid, statistically superior reduction in HAM‐D scores at Hour 60 compared to placebo: mean reduction of −21.0 vs. −8.8; p = 0.0075 The protocol was well‐tolerated with no deaths or serious adverse events reported; common TEAEs were restricted to transient dizziness and somnolence.
HUMMINGBIRD study 1	Efficacy in Severe PPD (NCT02942004) [8]	III	138	Three‐arm Placebo (N = 46): 60‐h continuous IV infusion of brexanolone‐matching placebo 60 μg/kg/h brexanolone (N = 47): 60‐h continuous IV infusion of brexanolone [30 μg/kg/h (0‐4 h) → 60 μg/kg/h(4‐56 h) → 30 μg/kg/h (56‐60 h)] 90 μg/kg/h brexanolone (N = 45): 60‐h continuous IV infusion of brexanolone [30 μg/kg/h (0‐4 h) → 60 μg/kg/h(4‐24 h) → 90 μg/kg/h(24‐52 h) → 60 μg/kg/h (52–56 h) → 30 μg/kg/h (56‐60 h)]	Met primary efficacy endpoint. Both 60 & 90 μg/kg/h showed significant reduction in HAM‐D score at 60 h vs. placebo: [−19.5 (60 μg/kg/h) vs.‐17.7 (90 μg/kg/h) vs.‐14.0 (placebo)] Infusions were generally well‐tolerated with typical TEAEs restricted to transient headache, dizziness, and somnolence.
HUMMINGBIRD study 2	Efficacy in Moderate PPD (NCT02942017) [8]	III	108	Two‐arm Placebo (N = 54): 60‐h continuous IV infusion of brexanolone‐matching placebo Brexanolone (N = 54): 60‐h continuous IV infusion of brexanolone [30 μg/kg/h (0‐4 h) → 60 μg/kg/h(4‐24 h) → 90 μg/kg/h(24‐52 h) → 60 μg/kg/h (52–56 h) → 30 μg/kg/h (56‐60 h)]	Met primary efficacy endpoint. 90 μg/kg/h significantly improved HAM‐D score at 60 h compared to placebo (−14.6 vs.‐12.21; p = 0.016) Infusions were generally well‐tolerated with typical TEAEs restricted to transient headache and dizziness. One subject treated with brexanolone experienced severe treatment‐related altered consciousness and syncope.
CHICKADEE	PK/PD + Safety in Female Adolescents with PPD (NCT03665038) [13]	III	28	Three‐arm Placebo (N = 8): 60‐h continuous IV infusion of brexanolone‐matching placebo Brexanolone (N = 8): double‐blind, 60‐h continuous IV infusion of brexanolone (30 → 60 → 90 → 60 → 30 μg/kg/h) Brexanolone (N = 12): double‐blind, 60‐h continuous IV infusion of brexanolone (30 → 60 → 90 → 60 → 30 μg/kg/h)	PK parameters consistent with adult data: median AUC0‐inf of 4040 ng.h/mL, median Cmax of 83.5 ng/mL Most common TEAEs include somnolence, dizziness in adolescents (ages 15–17) were entirely consistent with adult data. Brexanolone treatment showed rapid, clinically meaningful reductions in HAM‐D scores: −17.6 at the end of the 60‐h infusion and −20.6 at Day 30
Mechanistic	Dynamic Neural Mechanisms of brexanolone‐induced antidepressant effects in postpartum depression (PPD) (NCT05543746) [14]	N/A	10	Single‐arm Brexanolone (N = 10): open label, 60‐h continuous intravenous (IV) infusion of brexanolone [30 μg/kg/h (0–4 h), 60 μg/kg/h (4–24 h), 90 μg/kg/h (24–52 h), 60 μg/kg/h (52–56 h), and 30 μg/kg/h (56–60 h)]	All participants completed treatment 100% Clinical Response Majority achieved full remission within 44 h All participants receiving multiple EEG recordings during administration of brexanolone to track acute neural circuit changes. Data hasn't been reported.
Feasibility and safe‐use of brexanolone in home setting	Assess The Safe‐Use Conditions For Administration of brexanolone in a Home Setting in adult women with PPD (NCT05059600) [15]	IV	42/52 completed	Single‐arm Brexanolone (N = 42): open label, 60‐h continuous intravenous (IV) infusion of brexanolone [30 μg/kg/h (0–4 h), 60 μg/kg/h (4–24 h), 90 μg/kg/h (24–52 h), 60 μg/kg/h (52–56 h), and 30 μg/kg/h (56–60 h)]	7.1% (3/42) of participants experienced a treatment‐emergent adverse event (TEAE) that led to dose interruption or discontinuation of brexanolone 42.9% (18/42) of participants experienced at least one TEAE during the study. 76.2% (32/42) of participants had at least one instance of nonadherence to the predefined safe‐use conditions required for home administration. Most deviations were related to operational or monitoring procedures rather than serious safety events. A total of 75 use‐related issues were reported during home administration with 13 critical use errors, 62 use difficulties, 0 close calls.
Conditions Beyond PPD	Adjunctive Therapy and Dose‐Ranging Safety for Super‐Refractory Status Epilepticus (SRSE) (NCT02052739) [16]	I/II	22	Two‐arm Brexanolone standard dose (N = 19): IV loading infusion at 286.6 μg/kg/h for 1 h, followed by maintenance infusion at 86 μg/kg/h for 95 h, then three sequential 8‐h taper infusions at 64.5,43.0, and 21.5 μg/kg/h. Brexanolone high dose (N = 6): IV loading infusion at 286.6 μg/kg/h for 1 h, followed by maintenance infusion at 86 μg/kg/h for 23 h on Day 1 and 156 μg/kg/h for 72 h. then four sequential 6‐h taper infusions at 125, 94, 62, and 31 μg/kg/h	Demonstrated favorable safety and initial efficacy signals. Both dosing protocols successfully supported the weaning off background anesthetic comas while maintaining durable seizure control in a majority of ICU patients.77% (17/22) patients with SRSE successfully weaned off anesthetic third‐line agents (TLAs) before brexanolone tapering, and 73% (16/22) remained free of TLAs without seizure recurrence. PK analysis demonstrated predictable, dose‐proportional plasma clearance, establishing safety margins for subsequent Phase III evaluation. Brexanolone was well‐tolerated in complex ICU environments; no serious adverse events (SAEs) or deaths were determined by investigators to be directly attributable to the brexanolone. Six deaths occurred during the study, all attributed to underlying medical conditions rather than brexanolone.
	Efficacy in Super‐Refractory Status Epilepticus (SRSE) (NCT02477618) [17]	III	132	Two‐arm Brexanolone (N = 65): 6‐day (144 h) continuous IV infusion of brexanolone‐matching placebo Brexanolone (N = 67): 6‐day (144 h) continuous IV infusion starting with a 1 h loading dose of 300 μg/kg/h, followed by maintenance infusion at 90 μg/kg/h or open‐label rescue maintenance phase (up to 150 μg/kg/h for non‐responders), with stepwise taper down over the final 24 h	Failed to meet primary efficacy endpoint. Brexanolone therapy failed to show a statistically significant therapeutic difference compared to the control group for successfully weaning patients off third‐line anesthetics while keeping them seizure‐free for 24 h post‐infusion. The successful response rate at 7 days was 43.9% in the brexanolone cohort vs. 42.4% in the placebo group (p = 0.88) Rates of TEAEs, severe adverse events (SAEs), and mortality rates in these ICU settings were similar between the brexanolone and placebo treatment groups.
	Efficacy in Adult Postpartum Psychosis (NCT05314153) [18]	I	10	Single‐arm Brexanolone (N = 10): open‐label, 60‐h continuous IV infusion [30 μg/kg/h (0–4 h), 60 μg/kg/h (4–24 h), 90 μg/kg/h (24–52 h), 60 μg/kg/h (52–56 h), and 30 μg/kg/h (56–60 h)]	Designed as a proof‐of‐concept trial to determine if positive GABA‐A receptor modulation yields a rapid reduction in acute affective psychosis or mania symptoms similar to PPD protocols. Brexanolone treatment is associated with rapid and significant reduction in psychiatric symptoms via PANSS, YMRS, HAM‐D by Day 7 with sustained improvement to Day 90. Brexanolone was generally well tolerated; no new safety signals were identified. Adverse events were consistent with the known sedative and hemodynamic effects of IV neuroactive steroids, and no treatment‐related deaths were reported.
	Phase 2 Tinnitus Trial (NCT05645432) [19]	II	10	Single‐arm Brexanolone (N = 10): open‐label, 6‐h continuous IV infusion [30 μg/kg/h (30 min), 60 μg/kg/h (30 min), 90 μg/kg/h (300 min)]	Rapid, clinically meaningful drops in tinnitus loudness and distress were seen within 2 h of starting the infusion and lasted through the 1‐week follow‐up.
	Efficacy in COVID‐19‐associated ARDS (NCT04537806) [20]	III	29	Two‐arm Placebo (N = 15): matched 60‐h IV infusion of placebo with baseline standard of care. Brexanolone (N = 14): continuous 60‐h IV infusion protocol (70 μg/kg/h for 58 h, followed by a 2‐h taper at 35 μg/kg/h) in addition to baseline mechanical ventilation standard of care	Failed to demonstrate therapeutic benefit. The percentage of patients alive and ventilator‐free at Day 28 was identical between the brexanolone arm (23.1%, 3/13) and the placebo arm (23.1%, 3/13) Terminated early due to internal company decision
	Efficacy in Stress‐Induced Alcohol Use Disorder in PTSD/AUD (NCT05223829) [21]	I	25	Single‐arm Brexanolone (N = 25): open‐label, 20‐h continuous IV infusion titrated up to 90 μg/kg/h	Active, not recruiting Feasibility and safety of brexanolone administration; exploratory effects on alcohol consumption and PTSD symptoms
	Efficacy in PTSD and alcohol use in veterans (NCT06580444) [22]	II	40	Four‐arm, randomized, placebo‐controlled dose‐finding study Placebo: 20‐h continuous IV infusion of placebo Brexanolone 30 μg/kg/h: 20‐h continuous IV infusion Brexanolone 60 μg/kg/h: 20‐h continuous IV infusion Brexanolone 90 μg/kg/h: 20‐h continuous IV infusion	Active, not recruiting Evaluate safety and tolerability of brexanolone across dose levels.

In a randomized, double‐blind, placebo‐controlled Phase 2 trial (NCT02614547), 21 women with severe PPD received a 60‐h continuous IV infusion of brexanolone (titrated to a target of 90 μg/kg/h) or brexanolone‐matched placebo (see Table 2) [7]. Brexanolone produced a significantly greater reduction in 17‐item Hamilton Depression Rating Scale (HAM‐D‐17) total score at 60 h compared with placebo (−21.0 vs. −8.8 points; p = 0.0075) [7]. Among the ten participants who received brexanolone, four reported side effects, with sedation being the most common [7]. An earlier open‐label proof‐of‐concept study (NCT02285504) also supported the antidepressant effects of brexanolone in severe PPD [7]. No serious adverse events were noted, and a reduction in suicidal ideation was observed (75% pre‐infusion vs., 25% post‐infusion) [7].

The two pivotal Phase 3 HUMMINGBIRD trials [NCT02942004 (Study 1) and NCT02942017 (Study 2)] evaluated the efficacy and safety of a 60‐h continuous intravenous brexanolone infusion (using the standard titration regimen of 30 → 60 → 90 μg/kg/h) in adult women with moderate‐to‐severe postpartum depression. In Study 1, 138 women were randomized to brexanolone 60 μg/kg/h (BRX60, n = 47), brexanolone 90 μg/kg/h (BRX90, n = 45), or placebo (n = 46). In Study 2, 108 women were randomized to brexanolone 90 μg/kg/h (BRX90, n = 54) or placebo (n = 54) (Table 2) [8]. Both trials met the primary endpoint, demonstrating statistically significant reductions in HAM‐D‐17 total score at the end of the 60‐h infusion compared with placebo [Study 1: −19.5 points (BRX60) and −17.7 points (BRX90) versus −14.0 points (placebo), p < 0.05; Study 2: −14.6 points (BRX90) versus −12.1 points (placebo), p = 0.025] (Table 2) [8]. Improvements were rapid in onset and generally sustained through Day 30. Brexanolone was generally well tolerated, with common adverse events including headache, dizziness, and somnolence (Table 1) [8].

The Phase 3, Open‐Label CHICKADEE Study (NCT03665038) evaluated the safety, tolerability, and pharmacokinetics of brexanolone in adolescent females (aged 15–17 years) with PPD. 19 of 20 patients completed the 60‐h continuous IV infusions of brexanolone (titrated up to 90 μg/kg/h) [13]. Brexanolone effectively alleviated the depression, with a mean change from baseline in HAMD‐17 total score of −17.6 at the end of the 60‐h infusion and −20.6 at Day 30 (Table 2) [13]. These improvements are consistent with those observed in the pivotal adult Phase 3 HUMMINGBIRD trials, where brexanolone produced mean HAM‐D‐17 reductions of approximately 14.6–19.5 points at 60 h (Table 2) [8]. Safety was also comparable to the adult population: 40% of patients reported at least one treatment‐emergent adverse event (TEAE, mostly mild), with the most common (≥ 10%) being dizziness (15%), infusion site pain (15%), nausea (10%), and sedation (10%). One patient experienced transient serious adverse events (dizziness and loss of consciousness) that resolved rapidly after temporary infusion interruption; the patient resumed treatment and completed the study [13]. Systemic exposures in the adolescent population were consistent with adult data, with the median maximum plasma concentration (C_max) of 83.5 ng/mL (range 63.4–102 ng/mL) and the median AUC_0‐inf of 4040 ng·h/mL (range 3090–5010 ng·h/mL) [13]. While the purpose of this study was to analyze the PK and pharmacodynamics (PD) of brexanolone, it established the safety and pharmacokinetic profiles of brexanolone in adolescent populations. These data were subsequently evaluated by the FDA to support the label expansion for adolescent patients aged 15–17 years [14].

The recent open‐label pilot study (NCT05543746) analyzed the feasibility of repeated electroencephalogram (EEG) recordings in women with moderate‐to‐severe PPD [14]. Ten enrolled women received the standard 60‐h continuous intravenous brexanolone infusion. All participants achieved clinical response, with most reaching remission within 44 h of treatment initiation. Symptom improvement was broad and rapid, with no single symptom consistently drove the affective shift. Significant improvements were observed across key domains, including anhedonia (89% reduction), rumination (29% reduction), and maternal functioning (56% increase), and all of which were sustained at 30‐day follow‐up. Notably, the timing of maximal subjective mood satisfaction often diverged from changes captured by standard depression rating scales, highlighting the individualized and dynamic nature of antidepressant response to brexanolone.

A clear dose‐dependent response was not consistently observed across brexanolone clinical trials. In the Phase 2 randomized controlled trial (NCT02614547), a single target dose of 90 μg/kg/h produced a strong antidepressant effect. In the pivotal Phase 3 HUMMINGBIRD Study 1 (NCT02942004), both the 60 μg/kg/h and 90 μg/kg/h regimens (using the standard titration schedule) were superior to placebo on the primary endpoint (HAM‐D‐17 change at 60 h), but the 60 μg/kg/h arm showed numerically greater improvement (−19.5 points) than the 90 μg/kg/h arm (−17.7 points) [8]. In HUMMINGBIRD Study 2 (NCT02942017), only the 90 μg/kg/h regimen was tested and was superior to placebo (−14.6 vs. −12.1 points) [8]. The open‐label studies (NCT02285504 [7], NCT03665038 [13], and NCT05543746 [14]) used only the standard titration to 90 μg/kg/h and were not designed to evaluate dose–response. No dedicated exposure‐response (E‐R) analyses for efficacy were reported in the primary publications. Pharmacokinetics were dose‐proportional across the studied range, and some safety findings (e.g., sedation/somnolence) showed modest exposure‐dependence at higher doses.

6. Clinical Efficacy and Safety

Brexanolone is an effective treatment option for PPD due to its rapid onset of action and sustained therapeutic effects. It is a compelling option for those with moderate to severe PPD, those that feel that their quality of life is significantly impacted by PPD, or those with inadequate responses to conventional oral antidepressants [9]. However, because of the risk of sudden, severe sedation/somnolence (11%–24%), dizziness (7%–15%), and loss of consciousness (3%–8%) (Table 1), brexanolone is subject to a strict Risk Evaluation and Mitigation Strategy (REMS) program. As a result, brexanolone can only be administered at certified healthcare facilities where the patient can be continuously monitored over the course of the mandatory 60‐h continuous intravenous infusion [12]. These requirements create significant barriers to access, making the therapy entirely impractical or unavailable for patients who cannot accommodate a prolonged inpatient stay or who lack access to a certified treatment center.

The efforts have been made to expand administration beyond inpatient settings. A phase 4 single‐arm, open‐label feasibility/safety study (NCT05059600) assessed the feasibility and safety of administering the standard 60‐h continuous intravenous brexanolone infusion in the home setting [15]. Among the 42 participants who completed the study, 42.9% (18/42) experienced at least one treatment‐emergent adverse event (TEAE), whereas TEAEs leading to dose interruption or discontinuation occurred in only 7.1% (3/42) participants. However, nonadherence to predefined safe‐use conditions was common (76.2%; 32/42), and the study reported 13 critical use errors and 62 instances of use difficulties, highlighting the practical challenges in implementing REMS‐aligned protocols outside supervised healthcare facilities [15]. In addition, the expanded access study (NCT03924492) provided brexanolone to adult women with PPD who had limited treatment options, further supporting efforts to improve access to this therapy [23].

Notably, despite its demonstrated efficacy in clinical trials and efforts to broaden its use, the FDA withdrew approval of brexanolone effective April 14, 2025 at the Sage Therapeutics' request for commercial reasons. This regulatory action reflects the limited clinical uptake and substantial logistical constraints associated with its administration. Sage Therapeutics has shifted its focus to the oral neurosteroid zuranolone (Zurzuvae, approved 2023).

7. Future Prospects

Brexanolone has also been investigated in other clinical indications. One of the neurologic conditions the brexanolone has been investigated for is refractory and super‐refractory status epilepticus (SRSE). While the Phase 1/2 study (NCT02052739, see Table 2—conditions beyond PPD) demonstrated a promising 77% success rate in weaning patients with SRSE off third‐line anesthetic agents such as pentobarbital, midazolam, or propofol [16], these findings were not replicated in the larger Phase 3 STATUS trial (NCT02477618 [17], see Table 2—conditions beyond PPD). It highlights the inherent unpredictability of expanding a drug's indications.

Although the negative phase 3 trial in SRSE dampened initial enthusiasm for one potential indication, the encouraging results in postpartum psychosis may suggest that neuroactive steroid therapies may still have broader clinical applications. In a Phase 1 pilot study, 10 women with postpartum psychosis were treated with a single 60‐h intravenous infusion of brexanolone and followed through Day 90 (NCT05314153, table 2—conditions beyond PPD) [18]. Brexanolone infusion was associated with rapid improvements in psychotic and depressive symptoms. By Day 7, mean Positive and Negative Syndrome Scale (PANSS) scores decreased from 73 to 44 (p = 0.00006), Young Mania Rating Scale (YMRS) scores decreased from 17 to 7 (p = 0.01), and HAM‐D scores decreased from 19 to 11 (p = 0.0003) [18]. Symptom improvement began during the infusion and was maintained throughout the 90‐day follow‐up period [18]. Brexanolone was generally well tolerated, with no treatment‐related serious adverse events reported [18]. Although these findings are encouraging, the small sample size and open‐label design warrant confirmation in larger controlled studies.

Brexanolone has also been investigated in neuro‐otology as a potential therapeutic approach for tinnitus, based on the hypothesis that restoring inhibitory–excitatory balance within central auditory pathways may alleviate symptoms of tinnitus. A Phase 2, single‐arm, proof‐of‐mechanism study (NCT05645432, Table 2—conditions beyond PPD) evaluated brexanolone in ten adults with chronic, bilateral, moderate tinnitus using a shortened 6‐h intravenous infusion regimen (30 μg/kg/h for the first half hour, 60 μg/kg/h for the second half hour, and 90 μg/kg/h for the next 5 h) [19]. The study met its primary safety and tolerability endpoints, with all ten participants completing the treatment and only minor, non–treatment‐related adverse events reported [19]. This trial outcome suggested rapid, exposure‐related improvements in tinnitus severity. Reductions in self‐reported tinnitus loudness and annoyance were observed early during infusion and were generally sustained through short‐term follow‐up. These subjective improvements were supported by changes in audiometric loudness matching and were accompanied by reductions in validated functional outcome measures, including the Tinnitus Handicap Inventory and Tinnitus Functional Index at Day 7. Although limited by the small sample size and open‐label design, these findings provide preliminary evidence that GABAergic modulation may influence tinnitus‐related perceptual and functional outcomes.

The potential therapeutic use of brexanolone was evaluated in pulmonary critical care in a Phase 3 trial (NCT04537806) [20], which was designed to investigate brexanolone's efficacy in patients with COVID‐19‐associated acute respiratory distress syndrome (ARDS). No difference was observed between treatment and placebo groups in the primary outcome of survival free of respiratory failure at Day 28 (23% in both groups), suggesting a lack of efficacy in this clinical context (Table 2—conditions beyond PPD). The study was terminated early due to a strategic sponsor decision. Nevertheless, the study provides important information on safety, feasibility, and trial design considerations for evaluating neuroactive steroid modulation in systemic inflammatory conditions.

Beyond completed studies, brexanolone continues to be evaluated in ongoing clinical trials for a range of neurologic and neuropsychiatric conditions. Current investigations include trials in conditions characterized by network hyperexcitability and dysregulated inhibitory signaling, such as those registered under NCT05223829 [21] and NCT06580444 17 [22] (Table 2—conditions beyond PPD). At present, these trials remain active and not recruiting; however, they underscore the continued translational interest in neuroactive steroid modulation as a therapeutic strategy across neurological and neuropsychiatric disorders.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.