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Psychopharmacology Bulletin logoLink to Psychopharmacology Bulletin
. 2021 Mar 16;51(2):115–130.

Brexanolone to Treat Postpartum Depression in Adult Women

Elyse M Cornett 1, Lauren Rando 1, Austin M Labbé 1, Wil Perkins 1, Adam M Kaye 1, Alan David Kaye 1, Omar Viswanath 1, Ivan Urits 1
PMCID: PMC8146562  PMID: 34092826

Abstract

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.

Keywords: ZULRESSO, brexanolone, postpartum depression, major depressive disorder, GABA

Introduction

Postpartum depression (PPD) may be diagnosed in women experiencing depressive symptoms manifesting as cognitive, behavioral, or emotional disturbances beginning as early as the third trimester to 4 weeks following delivery.1 Efforts to elucidate the cause of PPD have been largely inconclusive with hormonal and genetic etiologies presumed.2,3 Preclinical evidence indicates the possible role of GABAAR deficits and hypothalamic-pituitary-adrenal axis (HPA axis) dysfunction in contributing to depressive symptoms in PPD.2 Historically, PPD was treated similar to Major Depressive Disorder (MDD) with selective serotonin reuptake ihibitors (SSRIs), tricyclic antidepressants (TCAs) or electroconvulsive therapy (ECT).3 However, treatment with SSRIs or other antidepressants has been inadequate in controlling PPD. Consequentially, this can influence family dynamics and result in lasting adverse effects on the family, such as cognitive, behavioral, and emotional disturbances in the child.2 ZULRESSO (Brexanolone) is the first drug approved by the Food and Drug Administration (FDA) to be clinically indicated for the treatment of moderate-to-severe PPD. Brexanolone acts by mimicking allopregnanolone, a metabolite of progesterone, that rises throughout pregnancy and falls precipitously after delivery, and increases the activity of GABAA receptors.4 In clinical trials Brexanolone rapidly reduces depressive symptoms with relatively mild side effects.3,4 It is administered intravenously and monitored in an inpatient setting due to the risk of excessive sedation and loss of consciousness.4 Oral formulations are currently being studied to improve accessibility and cost.2

PPD Epidemiology/Pathophysiology/Risk Factors/Presentation

PPD Epidemiology

Postpartum depression is similar to MDD and may be diagnosed in women experiencing depressive symptoms within the third trimester of pregnancy and up to four weeks following delivery. PPD is the most prevalent complication of childbirth.2 It may affect between 11.5%–20% of women.1,3,5 PPD is often underreported in the literature due to lack of patient screening and the stigma associated with the diagnosis.2 There is a lack of consensus regarding the pathophysiology of PPD, which is a likely barrier to proper diagnosis in patients.5 Additionally, rates of PPD vary worldwide, suggesting PPD diagnosis can be influenced by social and environmental factors.6 PPD is associated with an increased risk of self-harm, suicide, child abuse and infanticide.5,7 Furthermore, PPD poses an important threat to the health of women in the postpartum period with suicide accounting for 15%–20% of deaths.2,3 Untreated PPD is associated with increased risk of maternal substance abuse, pre-eclampsia, preterm delivery, and low infant birthweight.5 Considering these factors, PPD is a significant concern to public health.

Pathophysiology

The etiology of PPD is unknown, but there are several possible causes including hormonal and genetic etiologies, neuroinflammation, and neurotransmitter alterations.2,3 It may seem intuitive that fluctuations in gonadal steroid hormones such as estradiol and progesterone may precipitate PPD symptoms. However, studies show mixed results, and effects may only be seen in susceptible populations.2,8 The role of altered receptor sensitivity, rather than absolute hormone levels, has also been speculated in producing PPD symptoms.2

Allopregnanolone is a hormone derived from progesterone which rises during pregnancy, begins to fall during the third trimester, and drops precipitously after delivery. Downregulation of GABAA receptors in response to falling hormone levels is believed to contribute to symptoms of PPD.3 GABAA receptors contain several subunits and unique combinations of these subunits may induce phasic or tonic inhibition.2,9 However, interestingly decreased allopregnanolone levels alone do not correlate with depressive symptoms and development of PPD.9 Brexanolone mimics the action of allopregnanolone by increasing the activity of GABAA receptors.4 The recent success of brexanolone in the treatment of PPD fortifies the importance of neurosteroids in the treatment of PPD despite the unknown etiology of disease.2

Additionally, alterations in the hypothalamic-pituitary-adrenal axis (HPA axis) has been indicated as a possible contributor to PPD. Increased cortisol secretion is reported in patients with depressive symptoms who also experience PPD or MDD.2,10 Therefore, PDD may result as an outcome of an inability to suppress the HPA axis.7 Yet, the data involving the HPA axis and hypercortisolemia do not yield a causal relationship to the development of PPD. Finally, preclinical evidence suggests that allopregnanolone may regulate the HPA axis. Therefore, the relationship between these neurosteroids, GABA, the HPA axis, and PPD must be further explored.2

Risk Factors

There are many identified risk factors for PPD. Genetics and heritability account for 40% of PPD cases.1 Other risk factors for PPD include low socioeconomic status, poor social support, prior psychiatric illness, hormonal fluctuations, sleep deprivation, marital conflict, stress and adverse life events.1,2,5,10

A decline in gonadal steroid hormones such as estradiol and progesterone, and neurosteroid hormones like allopregnanolone demonstrate depressive and angiogenic symptoms in animal models and susceptible individuals.8

A systematic review surveying over 50 countries found higher rates of PPD in countries with high levels of income inequality, maternal mortality, infant mortality, and women of childbearing age working greater than forty hours per week.6 Additionally, variation may be seen between countries with similar economic status.6 These findings are suggestive of possible environmental factors predisposing the development of PPD.

Presentation

The presentation of PPD varies widely with respect to both the severity of symptoms and the time of onset. Women suffering from PPD may present with a variety of symptoms ranging from subjective changes in mood such as irritability, anxiety, and sadness to significant functional impairment, distress, and suicidality.8 Symptoms may manifest as disturbances in sleep, concentration, or appetite resulting in weight loss or gain.1 Additionally, excessive concern for the well-being of the child is a common symptom.11 Symptoms may begin prior to delivery for some women and after for others. These symptoms must be persistent for greater than two weeks in order to differentiate from “baby blues” which is common to new mothers and often resolves within this time frame.7 Additionally, the presentation of PPD is clinically distinct from postpartum psychosis which is characterized by the presence of hallucinations or delusions.11 PPD has historically been treated based off of knowledge of MDD due to similarities in presentation. Unfortunately, this has resulted in inadequate treatment and management of symptoms. As many as 30% of women with PPD reported continued symptoms at one year postpartum.12

Current Treatment of Brexanolone Complications/Side Effects

Brexanolone is associated with serious side effects which include excessive sedation and a sudden loss of consciousness, sleepiness, dry mouth, and flushing of the skin or face. With regard to excessive sedation, healthcare providers should check patients every two hours for signs of excessive sleepiness while they are awake and receiving the infusion. Patients should also immediately notify their healthcare provider if they feel faint during the infusion, which could be an indication that the infusion dose needs to be lowered. Patients must also have alternative care options for family members or children under their care while receiving the infusion. All of which suggest that the risk of sedation during an infusion is an important consideration. In the event that a patient does exhibit loss of consciousness or excessive sleepiness the healthcare provider should stop the infusion until the symptoms go away, or adjust the dose of the infusion.13

It is currently unknown whether Brexanolone will harm unborn babies, therefore it is recommended that patients tell their healthcare providers if they are pregnant, breastfeeding, or planning to become pregnant. Sage Therapeutics has created a registry for females who are exposed to Brexanolone during pregnancy to collect information about babies who are exposed to the drug. Brexanolone does pass into breastmilk, however, it is advised that patients and healthcare providers discuss the risk-benefit options of taking Brexanolone while breastfeeding.13

Brexanolone can interact with other drugs. For example, other antidepressants, opioids, or central nervous system depressants (e.g. benzodiazepines) should all be disclosed to the patients healthcare provider. Furthermore, alcohol usage and any pre existing kidney conditions, especially end-stage renal disease, should also be disclosed. Alcohol is a depressant and can increase the likelihood of loss of consciousness in the presence of Brexanolone. With regard to the kidneys, the solubilizing agent in Brexanolone, betadex sulfobutyl ether sodium, can accumulate in the body and potentially adversely affect the liver.14,15

Brexanolone Drug Info

Brexanolone is a novel drug developed by Sage Therapeutics with the specific indication to treat adult women with postpartum depression, which is defined as an episode of major depression that begins in the third trimester or less than 4 weeks after delivery. Brexanolone is an aqueous and chemically identical formulation of endogenous allopregnanolone, a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor modulator. The medication is given as an infusion administered intravenously in a healthcare facility over a 60-hour period. Evidence of Brexanolone as an efficacious immediate treatment for PPD was first shown in a series of randomized, double-blind, controlled clinical trials which gave participants a 60 hour infusion of either the drug or placebo and then followed them for 4 weeks, measuring their response to treatment using the Hamilton Depression Rating Scale (HAM-D).16,17 In these studies, Brexanolone demonstrated superior reduction in HAM-D scores at the end of the infusion and the end of the follow up period.16,17 Based on the promising evidence, Brexanolone was given priority review and breakthrough therapy designations before gaining FDA approval on March 19th, 2019. Brexanolone is the first drug to be approved by the FDA specifically for post-partum depression. It is currently available only through a restricted registry as it carries a black box warning for somnolence and excessive sedation. The price of treatment is currently listed at approximately $34,000 before discounts or insurance reimbursements. Sage Therapeutics does offer financial assistance programs for women who qualify.

Mechanism of Action

Brexanolone is an aqueous formulation of the steroid allopregnanolone, a progesterone metabolite produced by the brain, corpus luteum, and placenta during pregnancy.18 Allopregnanolone plasma concentrations are known to increase throughout the duration of pregnancy, peaking around delivery before dropping rapidly upon parturition.19 Previous research has shown that PPD symptoms are associated with allopregnanolone levels, leading researchers to hypothesize that a deficit could contribute to the incidence of PPD and providing a possible target for pharmacotherapy.20,21 This relationship between allopregnanolone and PPD symptoms provided the theoretical basis for drug research and development. Although the exact mechanism is still unknown, the proposed mechanisms for the efficacy of Brexanolone involve the GABAA receptor.

Positive Allosteric Modulation

Allopregnanolone is classified as a neuroactive steroid (neurosteroid), which is defined as a steroid which alters neuron excitability via interaction with cell-surface receptors, most commonly, ligand-gated ion channels. Neurosteroids can be further classified into subgroups based on their function. Allopregnanolone is an inhibitory neurosteroid, defined by its action of positive allosteric modulation of GABAA receptors in the central nervous system.22 This positive modulation of the GABAA receptor is mediated by the binding of allopregnanolone to an allosteric site on the receptor complex. Once bound, it induces a conformational change which increases the conductance of Cl- ions through the membrane pore, thus hyperpolarizing the cell. Therefore, Brexanolone potentiates the GABAA mediated hyperpolarization of a neuron, resulting in a net inhibitory effect on neurotransmission as excitatory neurotransmitters become less likely to depolarize the membrane and generate and action potential. Allopregnanolone has activity on all GABAA receptor isoforms, but has the greatest potentiation of those containing a d subunit.23 Animal studies have shown that female mice with decreased d-subunit-containing GABAA receptors develop depression-like behaviors and deficits in maternal care which closely mimic PPD. Using this animal model, a 2008 study demonstrated improved PPD behaviors following the administration of drugs which potentiate GABAA receptors.24 Because GABA is the major inhibitory neurotransmitter in the central nervous system, positive modulation of the associated GABAA receptor results in a net inhibitory effect on neurotransmission. It is believed that this modulation mediates the therapeutic effects of Brexanolone.

ZULRESSO (Brexanolone) Original Use

ZULRESSO (Brexanolone) is the first drug approved by the FDA to be clinically indicated for the treatment of moderate to severe PPD. In two double blind clinical trials, brexanolone was shown to reduce depressive symptoms, demonstrated by reduced Hamilton Depression Rating Scale (HAM-D) scores, following a 60 hour infusion period compared to placebo groups.4,16 It is unclear whether these effects are lasting due to conflicting data between trials at 30 days following administration.3 Brexanolone, a mimic of the neurosteroid allopregnanolone, was speculated for use in the treatment of PPD due to its activity on GABAA receptors. Increased activity of GABAA receptors is known to produce a potent anxiolytic and antidepressant response.2,8 The binding site of allopregnanolone on GABAA receptors is distinct from that of benzodiazepines.25 The action of allopregnanolone is diverse and may exert its effects as an antidepressant by neuroprotective mechanisms and by reducing the inflammatory response.2,8 Brexanolone has been shown in clinical trials to rapidly and effectively reduce symptoms of PPD. There is no significant delay required to achieve remission of symptoms, unlike with SSRIs where it may take as long as four to six weeks.16,26 This is an important factor to take into consideration as prolonged symptoms may present undue risk of harm to the mother and child.16 The efficacy of brexanolone in the treatment of PPD provides support for the role of neurosteroids in treating PPD.26 As shown in clinical trials, this treatment is generally well tolerated without any associated deaths or adverse events.16 However, there is an increased risk for sedation and loss of consciousness especially in the setting of concurrent SSRI administration.4

Pharmacokinetics and Pharmacodynamics

Dosing

Brexanolone is rapidly cleared in the blood and has an oral bioavailability of less than 5%, making intravenous administration of this drug necessary. To maintain a steady-state therapeutic plasma concentration, Brexanolone has been formulated as an isotonic solution of 5 mg/ml allopreganolone buffered in 250 mg/ml sulfobutylether-B-cyclodextrin and is administered over 60 hours. Dosing is weight-based and infusion should obey the recommended dosing schedule as follows

0 – 4 hours: Initiate infusion at 30 mcg/kg/hr.

4 – 24 hours: Increase dosage to 60 mcg/kg/hr.

24 – 52 hours: Increase dosage to 90 mcg/kg/hr.

52 – 56 hours: Decrease dosage to 60 mcg/kg/hr.

56 – 60 hours: Decrease dosage to 30 mcg/kg/hr.

It should be noted that a dose reduction to 60 mcg/kg/hr may be considered for patients who do not tolerate 90 mcg/kg/hr.

Pharmacodynamics

Brexanolone is an analog of the endogenous hormone allopregnanolone, a progesterone metabolite. Brexanolone acts by positive allosteric modulation of GABAA receptors expressing all subunit isoforms but has a greater effect on those expressing a δ subunit. According to the FDA-approved prescribing information, Brexanolone potentiated a GABA-mediated current from recombinant GABAA receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits. In a Phase 1 randomized, placebo-controlled crossover study, the effect of Brexanolone on the QT interval was evaluated on 30 healthy adults. At almost twice the maximum recommended infusion rate, it was not found to prolong the QT interval. Presently, Brexanolone exposure-response relationships and the time course of pharmacodynamics response are unknown. More research is required to elucidate the pharmacodynamics of Brexanolone.27

Pharmacokinetics

In clinical trials, Brexanolone exhibited dose proportional pharmacokinetics throughout the range of 30 mcg/kg/hr (initiation dose) to 270 mcg/kg/hr (three times the maximum recommended dose). The mean steady state exposure of the drug was found to be 52 ng/mL at the dosage of 60 mcg/kg/hr and 79 ng/mL at the dosage of 90 mcg/kg/hr. The volume of distribution of Brexanolone is approximately 3 L/kg. Plasma protein binding is > 99% and independent of plasma concentrations.27 The drug half-life is approximately 9 hours and total plasma clearance is approximately 1 L/h/kg. Metabolism follows 3 main, non-CYP based routes: keto-reduction, glucuronidation and sulfation. 3 major metabolites circulate; however, they are pharmacologically inactive and do not contribute to the efficacy of the drug. No studies have specifically evaluated the effects of other drugs on Brexanolone, but in-vitro studies showed little evidence of cytochrome P450 inhibition. The only CYP enzyme which had any evidence of inhibition by Brexanolone was CYP2C9, and even then there were no clinically significant differences in phenytoin pharmacokinetics (a CYP2C9 substrate) when it was used with Brexanolone.17

Brexanolone excretion is distributed fairly evenly between the feces and urine, with 47% of radiolabeled drug (mostly metabolites) recovered in feces and 42% in urine. The pharmacokinetics of Brexanolone did not differ significantly when studied in renal or hepatic impairment, however the effect of end-stage renal disease on Brexanolone was not studied and so the drug should be avoided in patients with ESRD. 1 to 2% of Brexanolone enters breast milk but no data available has suggested a significant risk of adverse reactions in breastfed infants.27

Clinical Studies: Safety and Efficacy

Many studies have investigated both the safety and clinical efficacy of Brexanolone in the treatment of PPD.

One study investigated four women in an open-label trial. Brexanolone was administered as a single infusion over the course of three days. On the first day, the dose was titrated up in four-hour increments. A maintenance dosing followed for the next 36 hours to achieve steady state plasma levels of allopregnanolone consistent with a third trimester pregnancy (around 150 nM). The infusion was then titrated down in four-hour increments. HAM-D scores were reassessed every twelve hours. The four participants had a mean baseline HAM-D score of 26.5 before the infusion was begun. All four patients reported statistically significant reductions in HAM-D score from the first reassessment, and this was maintained for all of the HAM-D measurements. At hour 60, the mean HAM-D score was 1.8 ± 1.5 and at hour 84 it was 5.3 ± 2.9 (p < 0.001 when compared to baseline). Every patient achieved remission of the depressive episode by hour 24 and maintained remission through all of the following reassessments. Since the patients were allowed to remain on any antidepressant they may have been taking, these results are unable to be confirmed to be due exclusively to the infusion. All patients were able to complete the infusion, with no reports of serious adverse events. Two patients reported sedation, with all other adverse effects being reported by one patient. This included dizziness, flushing, injection site pain/redness, and an increase in TSH levels. All reported adverse events were considered mild or moderate; however, three patients required dose adjustments secondary to side effects. The biggest limitation of this study was the small sample size of four patients. Additionally, the open-label study design limited generalizability of the data.28 Table 1.

Table 1. Clinical Efficacy and Safety of Brexanolone.

Author (Year) Groups Studied and Intervention Results and Findings Conclusions
Study 1: Kanes et al. (2017)28 4 females with a severe PPD episode (HAM-D score of at least 20). Mean HAM-D was 1.8 ± 1.5 at hour 60.
Mean HAM-D was 5.3 ± 2.9 at hour 84.
HAM-D scores were below 7 (indicating remission) but hour 24.
AEs: sedation, flushing, dizziness, injection site pain, increased TSH.
Brexanolone may have an effect in PPD, but small sample size and concomitant use of antidepressants are limitations.
Study 2: Kanes et al. (2017)16 21 female patients with a baseline HAM-D score of at least 26.
Treatment: 10 patients.
Dose titrated up to 90 μg/kg, maintained, then tapered down.
Placebo: 11 patients.
Treatment group saw reduction in mean HAM-D score of 21.0 points.
Placebo group saw decrease in mean HAM-D score of 8.8 points.
AEs: somnolence, dizziness, sedation, sinus tachycardia, insomnia, headache, infusion site pain.
Brexanolone infusion lead to a rapid onset, significant, and durable response in PPD, which is in stark contrast to traditional antidepressant treatment.
Study 3: Meltzer-Brody et al. (2018)17 138 female patients with a baseline HAM-D score of at least 26.
BRX60: 38 patients; Dose titrated up to 60 μg/kg, maintained, then tapered down.
BRX 90: 41 patients; Dose titrated up to 90 μ/kg, maintained, then tapered down.
Placebo: 43 patients.
BRX60: Reduction in mean HAM-D score by 19.5 points.
BRX90: reduction in mean HAM-D score by 17.7 points.
Placebo: reduction in mean HAM-D score by 14.0 points.
AEs: Headache, dizziness, somnolence, suicidal ideation, attempted overdose, loss of consciousness.
Brexanolone infusions produced a rapid onset, significant, and sustained reduction in depressive symptoms.
Study 4: Meltzer-Brody et al. (2018)17 108 female patients with a baseline HAM-D score of 20–25.
BRX90: 51 patients, dose titrated up to 90 μg/kg, then titrated down.
Placebo: 53 patients.
BRX90: reduction in mean HAM-D score by 14.6 points.
Placebo: reduction in mean HAM-D score by 12.1 points.
AEs: Headache, dizziness, somnolence, altered consciousness, syncope, fatigue, presyncope.
Brexanolone might have a more generalizable effect on all cases of PPD, not only in cases of severe PPD.

Another study consisted of a double-blind, randomized, placebo-controlled trial from December 2015 to May 2016. Twenty-one eligible patients completed the trial and there were no withdrawals. Again, Brexanolone was administered as a single continuous infusion over the course of 60 hours. The dose was 30 μg/kg per hour for the first four hours. The dose was increased to 60 μg/kg per hour for the next 20 hours and increased again to 90 μg/kg per hour for the following 28 hours. The dosing was then decreased to 60 and then 30 μg/kg per hour in four-hour increments to finish the infusion. The trial patients were followed for 30 days to monitor maintained improvement. In addition to using the HAM-D scale to asses severity of depression, the Montgomery-Asberg Depression Rating Scale (MADRS) was monitored as a secondary endpoint. All patients had a baseline HAM-D score of at least 26 at the onset of infusion. In the treatment group, there was a mean decrease in HAM-D score was 21.0 points as compared to an 8.8-point reduction in the control group. The secondary measure of the MADRS showed similar improvements in depression severity. Seven out of ten patients in the treatment group achieved remission in depressive symptoms at the end of the 60-hour infusion. Only one patient in the placebo group out of eleven achieved remission after the infusion. Over the entire course of treatment and follow-up, more patients achieved a 50% or more reduction in depressive symptoms in the treatment group as compared to placebo. This difference reached statistical significance at 72 hours and at day seven. Again, there were no reported serious adverse events with Brexanolone and all patients were able to complete the infusion and the follow up. Four out of ten patients in the treatment group reported adverse events as opposed to eight out of eleven in the placebo group. The most reported side effects in the treatment group were somnolence and dizziness, both reported by two patients each. One patient in the treatment group reported sedation. Three patients in the control group reported dizziness, no patients in the control group reported somnolence nor sedation. One patient in the placebo group had a severe adverse effect of insomnia. Moderate adverse events in the treatment group included sinus tachycardia (one patient), and headache (one patient) and pain at infusion site (one patient) in the control group. The study had a couple of limitations. Limitations of particular importance include a small sample size and the strict participant criteria.16 Table 1.

The third study ran from August 2016 to October 2017 and was a phase three randomized, placebo-controlled trial which investigated various dosages of Brexanolone. Patients were randomly divided into two treatment groups: a 60 μg/kg per hour group (BRX60) and a 90 μg/kg per hour group (BRX90). There was also a corresponding placebo group. To be enrolled in the study, patients needed to have a baseline HAM-D score of at least 26. All three groups received either treatment or placebo over the course of a single, 60-hour infusion. Each of the infusions were increased stepwise in dosages in a manner similar to the previous studies. Once again, the main efficacy measure was the change from baseline HAM-D score over the course of the infusion. Additionally, patients were followed for 30 days post-infusion. 45 patients received the BRX90 group, 47 patients were in the BRX60 and 46 patients received placebo. 25 patients did not complete the trial, mostly due to not receiving the infusion, failing to follow-up, or withdrawing consent. Mean scores in HAM-D were reduced by 19.5 points in the BRX60 group. The BRX90 group had a mean reduction in HAM-D of 17.7 points. The placebo group had a mean reduction in HAM-D score of 14.0 points. The reduction in scores in the treatment groups were maintained at the end of the 30-day follow-up period. Furthermore, the reductions seen in the treatment groups were larger than those seen in the placebo group. There were more patients achieving remission in both treatment groups compared to the control group. Secondary measurements in efficacy consisted of changes in Clinical Global Impression-Improvement (CGI-I). Both treatment groups reported statistically significant responses according to the CGI-I scale compared to the placebo. In this study, mirroring the previous studies performed, there were minimal adverse effects. Headache was reported by seven BRX60 patients, six BRX90 patients, and seven placebo patients. Dizziness (six patients in both BRX60 and BRX90 groups and one patient in the placebo group) and somnolence (seven patients in the BRX60 group, two patients in the BRX 90 group, and three patients in the placebo group) were also commonly reported. All of these adverse effects were considered to be mild and self-limiting. One patient with a history of suicide attempts had two serious adverse effects, suicidal ideation and attempting to overdose. Another patient had severe adverse effects of somnolence and loss of consciousness. Both of these patients were in the BRX60 treatment group. There were no reported deaths nor unexpected adverse effects.17 Table 1.

The fourth study was performed from July 2016 to October 2017 and ivestigated Brexanolone at 90 μg/kg dose compared to placebo. Out of a total of 108 participants, 54 were randomly placed in the BRX90 group with the remaining 54 were in the placebo group. Eight patients in this study discontinued the study before completion, mainly due to not receiving the infusion, not adhering to follow-up, or removing consent. As in the other trials, the infusion was given as a single dose over 60 hours. As in the previous study, efficacy was measured by reduction in HAM-D score during the infusion and for 30 days of follow up. Secondary efficacy measurements were accomplished via CGI-I assessment. The mean reduction in HAM-D score for the treatment group was 14.6 points as compared to a 12.1-point reduction in the control group. The difference between the treatment and control groups reached statistical significance at the 48-hour reassessment. There was no return to baseline in the treatment group throughout the duration of the follow-up period. In fact, at the 30-day mark, the mean decrease in HAM-D score was similar to that seen at the end of the infusion period. At the end of the 60-hour infusion, more patients in the treatment group saw a larger number of participants reporting a CGI-I improvement as compared to the placebo group. These results were sustained throughout the follow-up period. There were minimal adverse effects reported during this trial as well, as has been a trend with previous Brexanolone trials. Headache was reported by nine patients in the treatment group and six patients in the placebo group. Dizziness was reported by five BRX90 group members as opposed to four control group members. Somnolence was the third of the most common adverse effects reported, with four patients in the BRX90 treatment group and two patients in the control group endorsing the adverse effect. One patient in the BRX90 group reported two serious side effects, alterations in consciousness and syncope. These were determined to be of moderate severity and were tied to the treatment. There were two patients in the BRX90 group which experienced severe adverse reactions, one being fatigue and the other being presyncope. There were no deaths and none of the adverse effects were considered unexpected. This study and the study before it were limited by unknown generalizability of the data.17 Table 1.

A secondary meta-analysis was conducted using the data from the previous three randomized controlled trials for brexanolone. Upon statistical analysis of the data, the study found that treatment infusion resulted in a significant response by the 24-hour mark. This effect reached a peak at hour 36 and was maintained until the seventh day. Treatment infusion was also shown to result in short-term remission of depressive symptoms which began at 24 hours and lasted until 72 hours. Brexanolone infusion resulted in rapid-onset, clinically significant, and durable reductions in HAM-D scores as compared to placebo. In terms of adverse events, no difference in rates of adverse events were found between infusion groups and placebo. Since there were only three randomized controlled trials available, the meta-analysis was unable to perform certain analyses. Additionally, there are no studies comparing brexanolone infusion to standard antidepressant treatment. Finally, all of the studies used in the meta-analysis had rather strict criteria for participant entry; that is, required HAM-D score was mainly for moderate and severe depression.29 Table 2.

Table 2. Comparative Studies of Brexanolone.

Author (Year) Groups Studied and Intervention Results and Findings Conclusions
Study 1: Zheng et al. (2019)29 Data from the three randomized clinical trials (studies 2, 3, 4) Clinically significant reduction in HAM-D scores in the treatment groups compared to placebo. When looking at three RCTs as a whole, brexanolone infusions produced a clinically significant reduction in depressive symptoms compared to placebo with no increase in adverse events.

Conclusion

Brexanolone is a novel treatment, approved by the FDA in March of 2019, for moderate to severe postpartum depression. It provides prompt and effective resolution of depressive symptoms. The efficacy of Brexanolone provides support for the role of neurosteroids like allopregnanolone in the treatment of PPD. However, the role of GABAA is likely only a partial contributor to the underlying etiology of PPD. Other probable factors including genetics, stress, and environmental factors should not be overlooked. It is unclear whether treatment with Brexanolone provides lasting relief of depressive symptoms at or beyond 30 days following administration. Further studies may be indicated to make this determination. Limitations to the use of this medication include the requirement for hospitalization, intravenous administration, risk of sedation or loss of consciousness, and high cost. Despite this, the use of brexanolone offers a positive risk-benefit ratio in the treatment of moderate-to-severe PPD and offers exciting potential for improvements in maternal health during the postpartum period. In a broader sense, effective treatment of PPD may enhance public health by improving family dynamics, bonding, and childhood development. Research is currently being done to develop oral formulations in an effort to make effective treatment for PPD more readily available. Further studies may elucidate the pathophysiology of PPD leading to identification of at-risk patients, accurate diagnoses, and consequently better, more accessible treatment.

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