madman
Super Moderator
ABSTRACT
Introduction: Postpartum depression (PPD) is a serious and common complication of childbirth that can have deleterious effects not only on the mother but on the cognitive and behavioral development of exposed children. Brexanolone is a novel, soluble synthetic formulation of the natural hormone allopregnanolone and acts as a positive allosteric modulator of the gamma-aminobutyric acid A receptor (GABAA). Allopregnanolone levels dramatically decrease during the postpartum time period and some studies indicate lower serum levels of allopregnanolone during pregnancy in women that go on to develop PPD.
Areas covered: The author provides an overview of brexanolone as a treatment option for PPD including coverage of its pharmacokinetics, efficacy, safety, and tolerability. Furthermore, the author gives her expert perspectives on its use and its standing in the treatment armamentarium moving forward.
Expert opinion: Brexanolone represents a breakthrough for psychiatry due to its novel mechanism of action, its rapid onset of action, and its sustained effects without continued administration. It is appropriate for use in women with moderate to severe PPD. Experience with the medication and further research is needed to clarify whether the currently recommended dosing regimen is required for efficacy.
1. Introduction
Postpartum depression (PPD) is one of the most common complications of childbirth and is associated with significant adverse outcomes for the mother, the child, and the family as a whole [1,2]. Prevalence in the general population is approximately 10–15% [1,2] but is higher in women with a history of a preexisting mood disorder. The risk for PPD has been shown to be increased in women with a history of major depression [3], bipolar disorder [4], and PPD following previous pregnancies [5]. Repercussions of PPD are not insignificant. Suicides account for up to 20% of all postpartum deaths and represent one of the leading causes of peripartum mortality [6]. PPD has also been associated with impaired bonding [7] and negatively affects parenting behavior [8,9]. Finally, PPD has significant negative effects on infant development, including lower IQ, slower language development, and increases in adverse childhood behavioral issues [10]. Thus, adequate treatment of PPD is imperative – not only for maternal outcomes but for child outcomes as well.
*Clinically, PPD is essentially a major depressive episode that occurs during the immediate postpartum time period, a period that has been demonstrated to have an elevated risk for the development of a major depressive episode [13]. A major depressive episode is defined as 2 weeks or longer of 5 or more of the following symptoms: persistent depression or low mood, anhedonia, change in appetite, sleep disturbance, psychomotor retardation or agitation, loss of energy, feelings of worthlessness or hopelessness, poor concentration, and thoughts of death or suicide [12]. PPD, then, meets criteria for a major depressive episode with symptom onset during pregnancy or in the immediate postpartum time-period.
The exact pathophysiology underlying PPD remains unclear and is likely multifactorial with genetics/epigenetics, neuroendocrine changes, inflammation, neurotransmitter changes, and environmental risk factors all playing a role [14]. Further, PPD is likely heterogeneous as a diagnosis and different pathophysiological mechanisms may be at play in different women. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been proposed as an underlying mechanism for PPD and preclinical work has demonstrated that HPA axis dysfunction induces postpartum depression-like behaviors in animal models (reviewed in [15]). The major inhibitory neurotransmitter system in the brain, the gamma-aminobutyric acid (GABA) system tightly regulates neurons in the hypothalamus via neurosteroid-sensitive GABA-A (GABAA) receptors. During pregnancy and the postpartum time period, there are significant changes in HPA axis functioning, neuroactive steroids, and GABAA receptors. Animal models have demonstrated that reduced GABAA receptor functioning is associated with depression-like behavior and abnormal maternal behavior in the postpartum period (reviewed in [15]). Thus, GABAergic hypo functioning coupled with HPA axis overactivity, potentially triggered in susceptible women by pregnancy-induced changes in the GABA system, neurosteroid levels, and the HPA axis, may underlie at least some cases of PPD.
2. Overview of the market
3. Introduction to the compound
Brexanolone is a soluble synthetic formulation of the naturally occurring neuroactive steroid allopregnanolone that can be administered intravenously to produce stable physiological serum concentrations. It acts on the gamma-aminobutyric acid A receptor (GABAA) and was originally developed by SAGE Therapeutics for the treatment of status epilepticus [20] but was also simultaneously developed for the treatment of PPD. It is the first FDA-approved medication for PPD and was approved in March of 2019 after being granted a Priority Review and a Breakthrough Therapy designation by the FDA. It is administered as a 60-h stepped dosage infusion from 30 µg/kg/hour up to a high of 90 µg/kg/hour, though available studies have demonstrated efficacy with a 60 µg/kg/hour dosage as well. Remarkably, brexanolone results in rapid treatment response, with a significant decrease in depressive symptoms (and separation from placebo) as early as 24 hours after the start of the infusion and can therefore be classified as a Rapidly Acting Antidepressant with a similar timing of response as ketamine and esketamine. However, unlike ketamine’s generally brief response, based on the available data, response to brexanolone appears to be maintained for at least 30 days after the infusion despite discontinuation of the medication. In addition, like ketamine and esketamine, brexanolone has a novel mechanism of action that is unique since most other antidepressant medications work via the monoamine neurotransmitter systems. Thus, brexanolone is the first treatment approved specifically for PPD and has a novel mechanism of action, a rapid onset of action, and a sustained response despite discontinuation of the medication.
4. Chemistry
Brexanolone is chemically identical to endogenous allopregnanolone and, like allopregnanolone, acts as a positive allosteric modulator of the gamma-aminobutyric acid A receptor (GABAA) in the brain. GABA acts as an inhibitory neurotransmitter, and GABAA receptors are five-unit transmembrane ion channels that are found in intrasynaptic and extrasynaptic sites as well as on glial cells. The number of preclinical and clinical studies have implicated reduced neuroactive steroid levels, in particular allopregnanolone, in mood and anxiety disorders (reviewed in [21,22]). For example, in animal models, neuronal levels of allopregnanolone rise during acute stress, but chronic stress decrease and correlate with depressive and anxiety-like behaviors [22]. Allopregnanolone levels rise across the course of pregnancy and precipitously drop after delivery and some [23,24] but not all studies [25] have found that lower levels of allopregnanolone in pregnancy are associated with the development of PPD. Brexanolone is thus thought to target the decreased levels of allopregnanolone following childbirth, which may trigger a depressive episode in susceptible women, thus alleviating their depressive symptoms.
5. Pharmacodynamics
Brexanolone potentiates GABA-mediated currents by acting on the GABAA receptor and enhancing the receptor’s function, potentiating GABA transmission. As noted above, The GABAergic system tightly regulates the HPA axis and inhibits HPA activity. Thus, brexanolone is thought to correct HPA axis dysfunction by targeting the GABAergic system. The exposure-response relationship of brexanolone and the time course of pharmacodynamic response are unknown, and thus, the requirement for a 60-h continuous infusion is solely based on the previous study designs and currently available data.
(1) Pharmacokinetics and metabolism [26]
Brexanolone is administered as a stepped intravenous infusion over 60 hours. The starting dose is 30 µg/kg/hour for the first 4 hours, then 60 µg/kg/hour for hours 4–24 and then 90 µg/kg/hour for hours 24–52. The dose is then lowered to 60 µg/kg/hour for the next 4 hours (hours 52–56) and finally to 30 µg/kg/hour for the last 4 hours
Brexanolone exhibits dose-proportional pharmacokinetics from 30 µg/kg/hour to 270 µg/kg/hour and the mean steady-state exposure at 60 µg/kg/hour was approximately 52 ng/mL and for 90 µg/kg/hour was 79 mg/mL. The volume of distribution was approximately 3 L/kg which suggests an extensive tissue distribution. Plasma protein binding is greater than 99%, independent of plasma concentration. For elimination, the terminal half-life is approximately 9 hours and the total plasma clearance is approximately 1 L/h/kg. Brexanolone is extensively metabolized by non-CYP pathways including ketoreduction, glucuronidation, and sulfation. Brexanolone has three major circulating metabolites that are pharmacologically inactive and do not contribute to efficacy. Brexanolone is primarily excreted in feces (47%) and urine (42%) with less than 1% unchanged. Importantly, no clinically significant differences in pharmacokinetics were observed in populations with renal or hepatic impairment. Although the effect of end-stage renal disease on brexanolone pharmacokinetics is unknown, it is recommended that brexanolone not be used in this population because the solubilizing agent, betadex sulfobutyl ether sodium, can accumulate in these patients. There have been no studies to evaluate the effects of other drugs on brexanolone. No clinically significant differences in the pharmacokinetics of phenytoin were observed with the concomitant use of brexanolone.
6. Clinical efficacy
7. Safety and tolerability
8. Regulatory affairs
9. Conclusion
Brexanolone (Box 1) has been found to be rapidly effective in the treatment of PPD (defined as beginning no earlier than the third trimester of pregnancy and no later than 12 weeks after delivery) and was generally well tolerated with the most common side effect being sedation. Both response and remission rates were higher in the brexanolone treated groups as compared to placebo based on the primary outcome measure of the least-squares mean reduction in HAM-D score from baseline to 60 hours after the start of the infusion. For psychiatry in general, brexanolone’s new mechanisms of action targeting GABAA receptors are exciting and open up a new avenue to explore in the treatment of major depression in general and PPD specifically. Brexanolone is also rapidly acting and has a sustained response for at least 30 days after infusion and therefore represents a new direction in psychiatric care that heretofore has been limited to the rapidly acting, but short-lived response to ketamine injection. In summary, brexanolone is an exciting opportunity for psychiatry in terms of research as well as clinical care.
10. Expert opinion
Brexanolone is clearly a breakthrough for psychiatry both in terms of identifying a novel mechanism of action that has not been directly targeted before in the treatment of major depressive episodes and its rapid onset of action and its sustained effects after discontinuation of the medication. It is also, the first medication to be FDA approved for the treatment of PPD, an important common variant of major depression that occurs after the birth of a child. The medication is generally well-tolerated, and there do not appear to be lasting side effects.
Downsides of brexanolone include the fact that it needs to be administered in an inpatient setting that has been REMS approved and requires constant pulse oximetry monitoring and discontinuation of the drug in the setting of oversedation. These conditions make brexanolone difficult to administer on psychiatry inpatient units, and many sites are administering brexanolone in medical and obstetrics units instead. Given its rapid onset of action and short course of therapy, brexanolone should be attractive to women experiencing PPD though some may be reluctant to agree to an inpatient stay away from their new child or may not have access to alternative child care arrangements. Brexanolone is also expensive (approximately 34,000 USD plus the costs of inpatient care) and therefore obtaining insurance coverage may be difficult in some cases. That being said, when one considers the costs associated with PPD, the need for long-term treatment with standard antidepressants, and the effects of PPD on infant development and IQ, brexanolone and its rapid and sustained response may ultimately be more cost-effective.
Introduction: Postpartum depression (PPD) is a serious and common complication of childbirth that can have deleterious effects not only on the mother but on the cognitive and behavioral development of exposed children. Brexanolone is a novel, soluble synthetic formulation of the natural hormone allopregnanolone and acts as a positive allosteric modulator of the gamma-aminobutyric acid A receptor (GABAA). Allopregnanolone levels dramatically decrease during the postpartum time period and some studies indicate lower serum levels of allopregnanolone during pregnancy in women that go on to develop PPD.
Areas covered: The author provides an overview of brexanolone as a treatment option for PPD including coverage of its pharmacokinetics, efficacy, safety, and tolerability. Furthermore, the author gives her expert perspectives on its use and its standing in the treatment armamentarium moving forward.
Expert opinion: Brexanolone represents a breakthrough for psychiatry due to its novel mechanism of action, its rapid onset of action, and its sustained effects without continued administration. It is appropriate for use in women with moderate to severe PPD. Experience with the medication and further research is needed to clarify whether the currently recommended dosing regimen is required for efficacy.
1. Introduction
Postpartum depression (PPD) is one of the most common complications of childbirth and is associated with significant adverse outcomes for the mother, the child, and the family as a whole [1,2]. Prevalence in the general population is approximately 10–15% [1,2] but is higher in women with a history of a preexisting mood disorder. The risk for PPD has been shown to be increased in women with a history of major depression [3], bipolar disorder [4], and PPD following previous pregnancies [5]. Repercussions of PPD are not insignificant. Suicides account for up to 20% of all postpartum deaths and represent one of the leading causes of peripartum mortality [6]. PPD has also been associated with impaired bonding [7] and negatively affects parenting behavior [8,9]. Finally, PPD has significant negative effects on infant development, including lower IQ, slower language development, and increases in adverse childhood behavioral issues [10]. Thus, adequate treatment of PPD is imperative – not only for maternal outcomes but for child outcomes as well.
*Clinically, PPD is essentially a major depressive episode that occurs during the immediate postpartum time period, a period that has been demonstrated to have an elevated risk for the development of a major depressive episode [13]. A major depressive episode is defined as 2 weeks or longer of 5 or more of the following symptoms: persistent depression or low mood, anhedonia, change in appetite, sleep disturbance, psychomotor retardation or agitation, loss of energy, feelings of worthlessness or hopelessness, poor concentration, and thoughts of death or suicide [12]. PPD, then, meets criteria for a major depressive episode with symptom onset during pregnancy or in the immediate postpartum time-period.
The exact pathophysiology underlying PPD remains unclear and is likely multifactorial with genetics/epigenetics, neuroendocrine changes, inflammation, neurotransmitter changes, and environmental risk factors all playing a role [14]. Further, PPD is likely heterogeneous as a diagnosis and different pathophysiological mechanisms may be at play in different women. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been proposed as an underlying mechanism for PPD and preclinical work has demonstrated that HPA axis dysfunction induces postpartum depression-like behaviors in animal models (reviewed in [15]). The major inhibitory neurotransmitter system in the brain, the gamma-aminobutyric acid (GABA) system tightly regulates neurons in the hypothalamus via neurosteroid-sensitive GABA-A (GABAA) receptors. During pregnancy and the postpartum time period, there are significant changes in HPA axis functioning, neuroactive steroids, and GABAA receptors. Animal models have demonstrated that reduced GABAA receptor functioning is associated with depression-like behavior and abnormal maternal behavior in the postpartum period (reviewed in [15]). Thus, GABAergic hypo functioning coupled with HPA axis overactivity, potentially triggered in susceptible women by pregnancy-induced changes in the GABA system, neurosteroid levels, and the HPA axis, may underlie at least some cases of PPD.
2. Overview of the market
3. Introduction to the compound
Brexanolone is a soluble synthetic formulation of the naturally occurring neuroactive steroid allopregnanolone that can be administered intravenously to produce stable physiological serum concentrations. It acts on the gamma-aminobutyric acid A receptor (GABAA) and was originally developed by SAGE Therapeutics for the treatment of status epilepticus [20] but was also simultaneously developed for the treatment of PPD. It is the first FDA-approved medication for PPD and was approved in March of 2019 after being granted a Priority Review and a Breakthrough Therapy designation by the FDA. It is administered as a 60-h stepped dosage infusion from 30 µg/kg/hour up to a high of 90 µg/kg/hour, though available studies have demonstrated efficacy with a 60 µg/kg/hour dosage as well. Remarkably, brexanolone results in rapid treatment response, with a significant decrease in depressive symptoms (and separation from placebo) as early as 24 hours after the start of the infusion and can therefore be classified as a Rapidly Acting Antidepressant with a similar timing of response as ketamine and esketamine. However, unlike ketamine’s generally brief response, based on the available data, response to brexanolone appears to be maintained for at least 30 days after the infusion despite discontinuation of the medication. In addition, like ketamine and esketamine, brexanolone has a novel mechanism of action that is unique since most other antidepressant medications work via the monoamine neurotransmitter systems. Thus, brexanolone is the first treatment approved specifically for PPD and has a novel mechanism of action, a rapid onset of action, and a sustained response despite discontinuation of the medication.
4. Chemistry
Brexanolone is chemically identical to endogenous allopregnanolone and, like allopregnanolone, acts as a positive allosteric modulator of the gamma-aminobutyric acid A receptor (GABAA) in the brain. GABA acts as an inhibitory neurotransmitter, and GABAA receptors are five-unit transmembrane ion channels that are found in intrasynaptic and extrasynaptic sites as well as on glial cells. The number of preclinical and clinical studies have implicated reduced neuroactive steroid levels, in particular allopregnanolone, in mood and anxiety disorders (reviewed in [21,22]). For example, in animal models, neuronal levels of allopregnanolone rise during acute stress, but chronic stress decrease and correlate with depressive and anxiety-like behaviors [22]. Allopregnanolone levels rise across the course of pregnancy and precipitously drop after delivery and some [23,24] but not all studies [25] have found that lower levels of allopregnanolone in pregnancy are associated with the development of PPD. Brexanolone is thus thought to target the decreased levels of allopregnanolone following childbirth, which may trigger a depressive episode in susceptible women, thus alleviating their depressive symptoms.
5. Pharmacodynamics
Brexanolone potentiates GABA-mediated currents by acting on the GABAA receptor and enhancing the receptor’s function, potentiating GABA transmission. As noted above, The GABAergic system tightly regulates the HPA axis and inhibits HPA activity. Thus, brexanolone is thought to correct HPA axis dysfunction by targeting the GABAergic system. The exposure-response relationship of brexanolone and the time course of pharmacodynamic response are unknown, and thus, the requirement for a 60-h continuous infusion is solely based on the previous study designs and currently available data.
(1) Pharmacokinetics and metabolism [26]
Brexanolone is administered as a stepped intravenous infusion over 60 hours. The starting dose is 30 µg/kg/hour for the first 4 hours, then 60 µg/kg/hour for hours 4–24 and then 90 µg/kg/hour for hours 24–52. The dose is then lowered to 60 µg/kg/hour for the next 4 hours (hours 52–56) and finally to 30 µg/kg/hour for the last 4 hours
Brexanolone exhibits dose-proportional pharmacokinetics from 30 µg/kg/hour to 270 µg/kg/hour and the mean steady-state exposure at 60 µg/kg/hour was approximately 52 ng/mL and for 90 µg/kg/hour was 79 mg/mL. The volume of distribution was approximately 3 L/kg which suggests an extensive tissue distribution. Plasma protein binding is greater than 99%, independent of plasma concentration. For elimination, the terminal half-life is approximately 9 hours and the total plasma clearance is approximately 1 L/h/kg. Brexanolone is extensively metabolized by non-CYP pathways including ketoreduction, glucuronidation, and sulfation. Brexanolone has three major circulating metabolites that are pharmacologically inactive and do not contribute to efficacy. Brexanolone is primarily excreted in feces (47%) and urine (42%) with less than 1% unchanged. Importantly, no clinically significant differences in pharmacokinetics were observed in populations with renal or hepatic impairment. Although the effect of end-stage renal disease on brexanolone pharmacokinetics is unknown, it is recommended that brexanolone not be used in this population because the solubilizing agent, betadex sulfobutyl ether sodium, can accumulate in these patients. There have been no studies to evaluate the effects of other drugs on brexanolone. No clinically significant differences in the pharmacokinetics of phenytoin were observed with the concomitant use of brexanolone.
6. Clinical efficacy
7. Safety and tolerability
8. Regulatory affairs
9. Conclusion
Brexanolone (Box 1) has been found to be rapidly effective in the treatment of PPD (defined as beginning no earlier than the third trimester of pregnancy and no later than 12 weeks after delivery) and was generally well tolerated with the most common side effect being sedation. Both response and remission rates were higher in the brexanolone treated groups as compared to placebo based on the primary outcome measure of the least-squares mean reduction in HAM-D score from baseline to 60 hours after the start of the infusion. For psychiatry in general, brexanolone’s new mechanisms of action targeting GABAA receptors are exciting and open up a new avenue to explore in the treatment of major depression in general and PPD specifically. Brexanolone is also rapidly acting and has a sustained response for at least 30 days after infusion and therefore represents a new direction in psychiatric care that heretofore has been limited to the rapidly acting, but short-lived response to ketamine injection. In summary, brexanolone is an exciting opportunity for psychiatry in terms of research as well as clinical care.
10. Expert opinion
Brexanolone is clearly a breakthrough for psychiatry both in terms of identifying a novel mechanism of action that has not been directly targeted before in the treatment of major depressive episodes and its rapid onset of action and its sustained effects after discontinuation of the medication. It is also, the first medication to be FDA approved for the treatment of PPD, an important common variant of major depression that occurs after the birth of a child. The medication is generally well-tolerated, and there do not appear to be lasting side effects.
Downsides of brexanolone include the fact that it needs to be administered in an inpatient setting that has been REMS approved and requires constant pulse oximetry monitoring and discontinuation of the drug in the setting of oversedation. These conditions make brexanolone difficult to administer on psychiatry inpatient units, and many sites are administering brexanolone in medical and obstetrics units instead. Given its rapid onset of action and short course of therapy, brexanolone should be attractive to women experiencing PPD though some may be reluctant to agree to an inpatient stay away from their new child or may not have access to alternative child care arrangements. Brexanolone is also expensive (approximately 34,000 USD plus the costs of inpatient care) and therefore obtaining insurance coverage may be difficult in some cases. That being said, when one considers the costs associated with PPD, the need for long-term treatment with standard antidepressants, and the effects of PPD on infant development and IQ, brexanolone and its rapid and sustained response may ultimately be more cost-effective.
