Brexanolone (Zulresso)

Number: 0951

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Note: Requires Precertification:

Precertification of brexanolone (Zulresso) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of brexanolone (Zulresso), call (866) 752-7021 or fax (888) 267-3277.

  1. Criteria for Initial Approval

    Aetna considers 1 infusion of brexanolone (Zulresso) injection medically necessary for the treatment of moderate to severe postpartum depression (PPD) in members 15 years of age or older when all of the following criteria are met:

    1. Member has moderate to severe PPD and had a major depressive episode that began no earlier than the third trimester of pregnancy and no later than the first 4 weeks following delivery, documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.); and
    2. Diagnosis is verified by a psychiatrist; and
    3. Member is 6 months postpartum or less; and
    4. Lactation has ceased or breastmilk produced will not be used for feedings during the infusion and up to 4 days following infusion completion; and
    5. Member will not receive more than one infusion per pregnancy/childbirth.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).  

Dosage and Administration

Brexanolone (Zulresso) for injection is available as 100 mg/20 mL (5 mg/mL) single-dose vial which must be diluted, administered and continuously monitored on-site by a healthcare provider, who can intervene as necessary for the duration of the infusion.  Healthcare providers must assess for excessive sedation every 2 hours during planned, non-sleep periods.

Administered as a continuous intravenous infusion over 60 hours (2.5 days) as follows:

  • 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour
  • 4 to 24 hours: Increase dosage to 60 mcg/kg/hour
  • 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (alternatively consider a dosage of 60 mcg/kg/hour for those who do not tolerate 90 mcg/kg/hour)
  • 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour
  • 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour.

If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve.  The infusion may be resumed at the same or lower dose as clinically appropriate.

For women whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors, consider changing the therapeutic regimen, including discontinuing Zulresso.

Avoid use of Zulresso in those with estimated glomerular filtration rate (eGFR) of less than 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium.

Source: Sage Therapeutics, 2022

Experimental and Investigational

Aetna considers more than one brexanolone (Zulresso) infusion per pregnancy/childbirth experimental and investigational because the safety and efficacy have not been established in the peer-reviewed published literature.

Aetna considers brexanolone (Zulresso) experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established: 

  • Anxiety disorders
  • Mood disorders other than moderate to severe postpartum depression
  • Neurodegenerative disorders
  • Status epilepticus.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Other CPT codes related to the CPB :

96365 - 96368 Intravenous infusion administration

HCPCS codes covered if selection criteria are met:

J1632 Injection, brexanolone, 1 mg

ICD-10 codes covered if selection criteria are met:

F53.0 Postpartum depression

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

F34.0 - F39 Mood disorders
F41.0 - F41.9 Other anxiety disorders
G10 - G14 Systemic atrophies primarily affecting the central nervous system
G20 - G26 Extrapyramidal and movement disorders
G30.0 - G32.89 Other degenerative diseases of the nervous system
G35 - G37.9 Demyelinating diseases of the central nervous system
G40.001 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, with status epilepticus
G40.011 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, with status epilepticus
G40.101 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, with status epilepticus
G40.111 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, with status epilepticus
G40.201 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, with status epilepticus
G40.211 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, with status epilepticus
G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus
G40.311 Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus
G40.401 Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus
G40.411 Other generalized epilepsy and epileptic syndromes, intractable, with status epilepticus
G40.501 Epileptic seizures related to external causes, not intractable, with status epilepticus
G40.801 Other epilepsy, not intractable, with status epilepticus. Other epilepsy without intractability with status epilepticus
G40.803 Other epilepsy, intractable, with status epilepticus
G40.811 Lennox-Gastaut syndrome, not intractable, with status epilepticus
G40.813 Lennox-Gastaut syndrome, intractable, with status epilepticus
G40.821 Epileptic spasms, not intractable, with status epilepticus
G40.823 Epileptic spasms, intractable, with status epilepticus
G40.901 Epilepsy, unspecified, not intractable, with status epilepticus
G40.911 Epilepsy, unspecified, intractable, with status epilepticus
G40.A01 Absence epileptic syndrome, not intractable, with status epilepticus
G40.A11 Absence epileptic syndrome, intractable, with status epilepticus
G40.B01 Juvenile myoclonic epilepsy, not intractable, with status epilepticus
G40.B11 Juvenile myoclonic epilepsy, intractable, with status epilepticus
G60.0 - G65.2 Polyneuropathies and other disorders of the peripheral nervous system
G70.00 - G73.7 Diseases of myoneural junction and muscle
G80.0 - G80.9 Cerebral palsy


U.S. Food and Drug Administration (FDA)-Approved Indications

  • Treatment of postpartum depression (PPD) in patients 15 years and older

Brexanolone injection is available as Zulresso (Sage Therapeutics, Inc.). Brexanolone, a schedule IV controlled substance, is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator. The mechanism of action of brexanolone in the treatment of PPD in adults is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors. 

Zulresso carries a black box warning for excessive sedation and sudden loss of consciousness during administration. In clinical studies, Zulresso caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of Zulresso-treated patients compared to 0% of placebo-treated patients). Some patients were also reported to have loss of consciousness or altered state of consciousness during the Zulresso infusion (4% of the Zulresso-treated patients compared with 0% of the placebo-treated patients). Time to full recovery from loss or altered state of consciousness, after dose interruption, ranged from 15 to 60 minutes.Other labeled warnings and precautions include suicidal thoughts and behaviors. The most common adverse reactions (incidence 5% or more and at least twice the rate of placebo) include  sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. In pregnancy, Zulresso may cause fetal harm. Avoid use in patients with end stage renal disease (ESRD) (Sage Therapeutics, 2019).

Postpartum Depression (PPD)

Postpartum depression (PPD) is associated with moderate to severe depressive symptoms (or episodes) that can be emotionally and physically debilitating for some women after childbirth. If left untreated, PPD can result in adverse consequences for the mother and infant (e.g., impaired maternal functioning, impaired child development) (Viguera, 2018). PPD goes beyond the postpartum blues, or “baby blues”, which consists of mild depressive symptoms that are generally self-limited. PPD is more intense, lasts longer and often requires treatment (APA, 2017; Viguera, 2018). Per CDC, about 1 in 9 women in the United States experience symptoms of PPD; however, prevalence can vary by state and can be as high as 1 in 5 women (CDC, 2017).

Although PPD appears to refer to “after childbirth”, onset of symptoms can occur in women peripartum. The American Psychiatric Association's Diagnostic and Statistical Manual, Fifth Edition (DSM-5) “does not recognize PPD as a separate diagnosis; rather, patients must meet the criteria for a major depressive episode and the criteria for the peripartum-onset specifier. The definition is therefore a major depressive episode with an onset in pregnancy or within 4 weeks of delivery” (Epocrates, 2019).

Peripartum hormonal changes (e.g., progesterone) are thought to contribute to the development of PPD, although the precise pathogenesis is unknown. Kanes et al. (2017b) states there is some evidence which indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes that may trigger PPD in some women. Thus, failure of type A gamma-aminobutyric acid (GABAA) receptors to adapt to abrupt changes in allopregnanolone levels at parturition may play a part in triggering PPD (Kanes et al, 2017a). The authors postulated that  “women with onset of severe depressive symptoms in the third trimester or triggered by childbirth—often associated with rapid fluctuations in gonadal steroids— are more likely to have a hormone-responsive form of post-partum depression that could respond to therapeutic doses of neuroactive steroids, such as allopregnanolone”.

Standard of care for the treatment of PPD has consisted of pharmacologic regimens, such as selective serotonin reuptake inhibitor (SSRI) antidepressants, psychotherapy, and in in treatment refractory patients, electroconvulsive therapy (ECT) (Viguera, 2018).  Although SSRIs are commonly used as first‐line PPD treatment, there is limited evidence for their use in the postpartum period specifically, and the proportion of PPD patients treated successfully with SSRIs has a wide range (Kanes et al, 2017a).

Brexanolone (formerly SAGE‐547 Injection) is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator, that is chemically identical to endogenous allopregnanolone, a hormone produced by progesterone. The mechanism of action of brexanolone in the treatment of PPD in adults is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors (Sage Therapeutics, 2022).

In 2015, an initial evaluation on the use of brexanolone to target allopregnanolone was studied as a treatment option for PPD. Kanes and colleagues (2017a) initiated an open‐label, proof‐of‐concept study which enrolled 4 women (18-45 years of age) with severe PPD (HAM-D score greater than or equal to 20). Brexanolone dosing was chosen to target allopregnanolone exposure in the third trimester. Participants were allowed to continue their dose of antidepressants if they were taking a stable dose for longer than 2 weeks. In addition, all women participated in psychotherapy. Permanent weaning from breastfeeding prior to Visit 1 was required. Primary outcomes were safety and tolerability measures. Secondary outcomes were assessments of efficacy. Adverse events (AEs) were reported by all four patients, although none serious. Three participants had precautionary dosage adjustments due to mild or moderate AEs. Sedation was reported by two patients. This preliminary study found that participants achieved rapid reduction of symptoms based on HAM-D and CGI‐I scores, with clinically relevant improvements from baseline beginning at the first assessment post infusion initiation (Hour 12) and continuing through Hour 84. Three of the 4 participants continued psychotropic medications during the trial, thus the effect of the brexanolone administration alone cannot be excluded. The authors concluded that even though the limitations include an open‐label design and relatively short treatment and assessment period, this small exploratory study suggests that brexanolone, and by extension positive allosteric GABAA receptor modulation with neuroactive steroids, may be an important therapeutic modality in PPD (Kanes et al. 2017a).

Kanes et al (2017b) reported on a double-blind, randomized, placebo-controlled, phase 2 trial which investigated brexanolone infusion for the treatment of severe PPD from 4 hospitals in the USA between December 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). Twenty-one women were randomized (1:1) to receive brexanolone (n=10) or placebo (n=11) for 60 hours. The primary efficacy endpoint was the change from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score at 60 h.  The participants received the following dosing schedule for the 60 hours during inpatient care: 30 μg/kg per h (0–4 h); 60 μg/kg per h (4–24 h); 90 μg/kg per h (24–52 h); 60 μg/kg per h (52–56 h); 30 μg/kg per h (56–60 h). After dosing was complete, patients were followed with clinical and safety assessments, which were done at days 7 and 30. The most frequently reported AE in the brexanolone group were dizziness and somnolence. Moderate treatment-emergent AEs were reported in two participants in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1). No deaths, serious AEs, or discontinuations because of AEs were reported.  The authors found that a larger proportion of participants in the brexanolone group than in the placebo group achieved HAM-D remission at each time point after 2 h. The difference was found to be significant at 24 h (p=0.0561), 48 h (p=0.0897), 60 h (p=0.0449), and 72 h (p=0.0364), as well as at day 7 (p=0.0449) and day 30 (p=0.0449). The authors concluded that their results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with PPD, and that a pivotal clinical investigation was underway. Limitations include the 30 day follow-up period, possible respondent fatigue in HAM-D assessment from frequent administration, and the inability (because of the small study size) to stratify patients on the basis of previous history of PPD.

Brexanolone infusion was further studied as a treatment option for moderate to severe PPD in two multicenter, randomized, double-blind, placebo-controlled phase 3 trials. Both trials enrolled ambulatory female participants (Study 1, n=138; Study 2, n=108) aged 18-45 years who had an onset of a major depressive episode no earlier than the third trimester of pregnancy and no later than 4 weeks after delivery (as determined by DSM-IV Axis I Disorders (SCID-I)), had a qualifying HAM-D total score (≥26 for study 1 for severe PPD; 20–25 for study 2 for moderate PPD), were 6 months postpartum or less at screening, and had stopped lactating or ceased breastfeeding while receiving the study drug until 4 days after the end of the infusion. Participants were excluded if they had hemoglobin less than 10 g/dL, renal failure requiring dialysis, fulminant hepatic failure, active psychosis, medical history of schizophrenia, bipolar disorder, or schizoaffective disorder, had attempted suicide during the current episode of PPD, a history of alcohol or drug abuse in the previous 12 months, or electroconvulsive (ECT) therapy within last 14 days before screening. Participants taking prescribed psychotropic medication at baseline were required to be at a stable dose 14 days before screening until completion of the 72 h assessments (Melzer-Brody et al, 2018).

In both studies (Study 1 (NCT02942004), Study 2 (NCT02942017)), a total of 246 participants were treated in a medically-supervised setting for 72 h, which consisted of 60 hours of infusion and 12 additional hours for assessment completion.  Participants were randomized (1:1:1) to receive a single intravenous (IV)infusion of either brexanolone 90 μg/kg/h (BRX90) (n=45), brexanolone 60 μg/kg/h (BRX60) (n=47), or matching placebo (n=46) for 60-hours in study 1 (severe PPD), or (1:1) BRX90 (n=54) or matching placebo (n=54) for 60-hours in study 2 (moderate PPD). The primary efficacy endpoint in both studies was the change from baseline in depressive symptoms as measured by the HAM-D total score at the end of the infusion at hour 60. The secondary efficacy endpoint was the mean change from baseline in HAM-D total score during the inpatient stay and at follow-up on days 7 and 30.

In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19.5 points in the BRX60 group and 17.7 points in the BRX90 group compared with 14.0 points in the placebo group (p=0·0013 for the BRX60 group; p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14.6 points in the BRX90 group compared with 12.1 points for the placebo group (p=0·0160). The authors found that, in both studies, titration to a target dose of brexanolone 90 mcg/kg/hour was superior to placebo in improvement of depressive symptoms. In addition, outcomes in Study 1 showed that a titration to target dose of 60 mcg/kg/hour was also superior to placebo in improvement of depressive symptoms in a group of 38 participants.

Based on the results of Study 1 and Study 2, the U.S. Food and Drug Administration (FDA) approved brexanolone (Zulresso) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women, making Zulresso the first drug approved by the FDA specifically for PPD (FDA, 2019).

In June 2022, the FDA approved the supplemental New Drug Application for Zulresso to include patients 15 years of age and older with postpartum depression. Previously, the treatment was approved only for adults 18 years of age and older. The FDA's expanded approval was based on the safety data from an open-label study in patients 15 to 17 years. A titration to a target dosage of 90 mcg/kg/hour was evaluated in 20 patients with PPD. Patients were then followed for 4 weeks. Adverse reactions reported in the clinical study were generally similar to those observed in clinical studies of Zulresso in adults with PPD. Additionally, brexanolone pharmacokinetics in patients 15 to 17 years old were found to be comparable to those in adults (Park, 2022; Sage Therapeutics, 2022).

Anxiety Disorders

Rupprecht and colleagues (2021) noted that there is increasing evidence that neuroinflammatory processes may play a role in the pathophysiology of psychiatric disorders.  Recently, the complement protein C1q and the translocator protein (18 kDa) (TSPO) have attracted considerable interest in this context.  C1q is a small molecule which is involved into synaptic pruning mechanisms, increases during aging and may contribute to neurodegenerative disorders.  TSPO is a transmembrane channel protein, which mediates numerous biological functions such as bioenergetics and steroid synthesis.  Meanwhile, there is evidence that both C1q and TSPO may be elevated in psychiatric disorders (e.g., major depression).  Moreover, pre-clinical and first clinical studies suggested that TSPO ligands may exert anti-depressant and anxiolytic properties by promoting endogenous neuro-steroid synthesis.  Furthermore, certain neuro-steroids (e.g., allopregnanolone) are potent positive allosteric modulators of GABAA receptors and their composition is altered in depression and anxiety disorders.  Recently, neuro-steroid compounds (e.g., brexanolone and zuranolone) have been reported to reduce depressive and anxiety symptoms in PPD and major depressive disorder (MDD).  The authors concluded that compounds enhancing GABAergic neurotransmission such as neuro-steroids and TSPO ligands, which also may exert anti-inflammatory properties in concert with immunomodulators such as C1q may open new avenues for the treatment of psychiatric disorders.

Mood Disorders

Wilkinson and Sanacora (2019) stated that mood disorders represent the largest cause of disability worldwide.  The monoaminergic deficiency hypothesis, which has dominated the conceptual framework for researching the pathophysiology of mood disorders and the development of novel treatment strategies, cannot fully explain the underlying neurobiology of mood disorders.  Mounting evidence collected over the past 20 years suggested that the amino acid neurotransmitter systems (glutamate and γ-aminobutyric acid [GABA]) serve central roles in the pathophysiology of mood disorders.  These investigators reviewed progress in the development of compounds that act on these systems as well as their purported mechanisms of action.  They included glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.

Althaus and colleagues (2020) noted that zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABAA receptor (GABAAR) positive allosteric modulator (PAM) designed with the pharmacokinetic properties to support oral daily dosing. In-vitro, zuranolone enhanced GABAAR current at 9 unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extra-synaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, α1β2γ2, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the 2 classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABAARs to the cell surface. In-vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABAARs in the central nervous system (CNS) after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data established zuranolone as an effective neuro-active steroid GABAAR PAM with drug-like properties and CNS exposure in pre-clinical models. Recent clinical data supported the therapeutic promise of neuro-active steroid GABAAR-positive modulators for treating mood disorders; brexanolone was the 1st therapeutic approved specifically for the treatment of PPD. Zuranolone is currently under clinical investigation for the treatment of bipolar depression, major depressive episodes in major depressive disorder, and PPD.

Neurodegenerative Disorders

Belelli and colleagues (2020) stated that in the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, effective PAMs of the GABAAR.  These reports were followed by the discovery that such steroids may be synthesized not only in peripheral endocrine glands, but locally in the CNS, to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine-tuning neuronal inhibition.  These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and examine if their levels may be perturbed in particular psychiatric and neurological disorders.  In pre-clinical studies the GABAAR-active steroids were reported to exhibit anxiolytic, anti-convulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anesthesia.  Collectively, these findings encouraged efforts to examine the therapeutic potential of neurosteroids and related synthetic analogs.  However, following over 30 years of research, realizing their possible medical potential has proved challenging.  The recent FDA approval of brexanolone for the treatment of PPD should trigger renewed enthusiasm for neurosteroid research.  The authors focused on the influence of neuroactive steroids on GABA-ergic signaling and on the challenges faced in developing such steroids as anesthetics, sedatives, analgesics, anti-convulsants, anti-depressants as well as treatments for neurodegenerative disorders.

Status Epilepticus

Rosenthal and colleagues (2017) noted that super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment.  These researchers conducted a multi-center, phase-I/II clinical trial in SRSE patients to evaluate the safety and tolerability of brexanolone; secondary objectives included pharmacokinetic assessment and open-label evaluation of brexanolone response during and after anesthetic third-line agent (TLA) weaning.  Patients receiving TLAs for SRSE control were eligible for open-label, 1-hour brexanolone loading infusions, followed by maintenance infusion.  After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance.  After 4 days, the brexanolone dose was tapered.  Safety and functional status were assessed over 3 weeks of follow-up.  A total of 25 patients received open-label study drug.  No serious AEs (SAEs) were attributable to study drug, as determined by the Safety Review Committee; 16 patients (64 %) experienced greater than or equal to 1 SAE; 6 patient deaths occurred, all deemed related to underlying medical conditions; 22 patients underwent greater than or equal to 1 TLA wean attempt; 17 (77 %) met the response end-point of weaning successfully off TLAs before tapering brexanolone; 16 (73 %) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours.  The authors concluded that in an open-label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning.  These researchers stated that these findings demonstrated that brexanolone may offer a new approach as adjunctive therapy to TLAs in the management of children and adults with SRSE; and this hypothesis is being tested in a larger, controlled trial that is currently ongoing in 15 countries.

Allen and Vespa (2019) stated that seizures and status epilepticus are very common diagnoses in the critically ill patient and are associated with significant morbidity and mortality.  There is an abundance of research on the utility of anti-seizure medications in this setting, but limited randomized-controlled trials (RCTs) to guide the selection of medications in these patients.  These investigators examined the current guidelines and treatment strategies for status epilepticus and provided an update on newer anti-seizure medications in the critical care settings.  They noted that delays in treatment correspond with worsened outcomes; and establishing standardized protocols within a health system, including pre-hospital treatment, may lead to improved outcomes.  Once RSE is established, continuous deep sedation with IV anesthetic agents should be effective.  In cases that prove highly refractory, novel approaches should be considered, with recent data suggesting multiple recently approved anti-seizure medications, appropriate therapeutic options, as well as novel approaches to up-regulate extra-synaptic GABA channels with brexanolone.  The authors concluded that although there are many new treatments to consider for seizures and status epilepticus in the critically ill patient, the most important predictor of outcome may be rapid diagnosis and treatment.  There are multiple new and established medications that can be considered in the treatment of these patients once status epilepticus has become refractory, and a multi-drug regimen will often be necessary.

Arya and Rotenberg (2019) summarized the evidence regarding dietary, immunological, surgical, and other emerging treatments for RSE/SRSE.  Hypothermia and brexanolone were tested in RCTs for RSE/SRSE management, while other interventions have only limited evidence for their safety and efficacy.  Clinical trials including the HYBERNATUS study found the efficacy of therapeutic hypothermia to be no better than placebo for RSE/SRSE, and raised concerns about its safety.  Ketogenic diet has shown possible efficacy in RSE/SRSE in several case series, with electrographic seizure resolution within 7 days in 20 % to 90 % patients in larger (n = 8 to 17) reports.  A review of 37 pediatric patients reported seizure control with immunotherapy in only 7 patients.  A double-blind, phase-III clinical trial showed that brexanolone was no better than placebo for successful weaning of TLAs and freedom from RSE for greater than or equal to 24 hours.  Epilepsy surgery has been reported to successfully control seizures in small series; however, pre-surgical evaluation was confounded by ongoing ictal activity and anesthetic infusions.  Vagus nerve stimulation (VNS) was reported to be associated with cessation of RSE/SRSE in 21/28 patients in a review of anecdotal reports.  There was no evidence for use of pyridoxine and magnesium outside of specific indications.  The authors concluded that there was only anecdotal evidence for dietary, immunological, surgical, and other treatments for RSE/SRSE, often confounded by multiple concurrent treatments, and heterogeneity in their use and assessment of outcomes; and clinical trials for therapeutic hypothermia and brexanolone have not shown a significant advantage over comparators.


Depressive Symptoms Measurement Scales (not an all-inclusive list)


The above policy is based on the following references:

  1. Allen B, Vespa PM. Antiseizure medications in critical care: An update. Curr Opin Crit Care. 2019;25(2):117-125.
  2. Althaus AL, Ackley MA, Belfort GM, et al. Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology. 2020;181:108333.
  3. American Psychiatric Association (APA). Postpartum depression: What is postpartum depression? Washington, DC: APA; reviewed March 2017.
  4. Arya R, Rotenberg A. Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus. Seizure. 2019;68:89-96.
  5. Belelli D, Hogenkamp D, Gee KW, Lambert JJ. Realising the therapeutic potential of neuroactive steroid modulators of the GABA A receptor. Neurobiol Stress. 2019;12:100207.
  6. Centers for Disease Control and Prevention (CDC). Reproductive health: Depression among women. CDC [online]. Atlanta, GA: CDC; reviewed December 2017.
  7. Epocrates, Inc. Postpartum depression. Epocrates [online serial]. San Francisco, CA: Epocrates; 2019. Available at: Accessed March 22, 2019.
  8. Kanes s, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: A randomised controlled trial. Lancet. 2017b;390(10093):480-489.
  9. Kanes SJ, Colquhoun H, Doherty J, et al. Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum Psychopharmacol. 2017a;32(2):e2576.
  10. Meltzer-Brody S, Colquhoun H, Riesenberg, et al. Brexanolone injection in post-partum depression: Two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392 (10152):1058-1070.
  11. Park B. Zulresso indication expanded to include younger patients with postpartum depression. MPR [online]. June 21, 2022. Available at: Accessed July 7, 2022.
  12. Rosenthal ES, Claassen J, Wainwright MS, et al. Brexanolone as adjunctive therapy in super-refractory status epilepticus. Ann Neurol. 2017;82(3):342-352.
  13. Rupprecht R, Rupprecht C, Di Benedetto B, Rammes G. Neuroinflammation and psychiatric disorders: Relevance of C1q, translocator protein (18 kDa) (TSPO), and neurosteroids. World J Biol Psychiatry. 2021 Sep 10; 1-7. 
  14. Sage Therapeutics, Inc.  Zulresso (brexanolone) injection, for intravenous use, [controlled substance schedule pending]. Prescribing Information.  Reference ID: 4405779. Cambridge, MA: Sage; revised June 2022.
  15. U.S. Food and Drug Administration (FDA). FDA approves first treatment for post-partum depression. FDA News Release. Silver Spring, MD: FDA; March 19, 2019.
  16. Viguera A. Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDtae; reviewed November 2018.
  17. Wilkinson ST, Sanacora G. A new generation of antidepressants: An update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2019;24(2):606-615.