- Email: [email protected]
Brexanolone For Postpartum Depression: A Novel Approach and a Call for Comprehensive Postpartum Care
Clinical Therapeutics/Volume xxx, Number xxx, xxxx
Brexanolone For Postpartum Depression: A Novel Approach and a Call for Comprehensive Postpartum Care Angela F. Jarman, MD, MPH1; Joanna V. MacLean, MD2; Rebecca J. Barron, MD, MPH3; Rachel S. Wightman, MD4,5; and Alyson J. McGregor, MD, MA4 1
Department of Emergency Medicine, University of California Davis, Sacramento, CA, USA; Department of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Providence, RI, USA; 3Department of Emergency Medicine, Portsmouth Regional Hospital, Portsmouth, NH, USA; 4Department of Emergency Medicine, Alpert Medical School, Brown University, Providence, RI, USA; and 5Division of Medical Toxicology, Alpert Medical School, Brown University, Providence, RI, USA 2
ABSTRACT Brexanolone recently became the first medication to be approved by the US Food and Drug Administration specifically for treating postpartum depression. In contrast to traditional antidepressants, however, brexanolone is a neurosteroid that is believed to mimic allopregnanolone, a product of endogenous progesterone. Although early clinical trials have shown success, the medication remains largely unavailable due to its extremely high cost and formulation (it must be given as a continuous intravenous infusion over 3 days in a monitored, inpatient setting). The efficacy data surrounding brexanolone are encouraging; there is also evidence, however, that postpartum depression may be mitigated by a number of social policies that provide support to new parents. We suggest a comprehensive approach to postpartum wellness that includes investing in evidence-based social interventions that may be much more accessible to the millions of Americans experiencing postpartum mood disturbance. (Clin Ther. xxxx;xxx:xxx) © 2019 Elsevier Inc. All rights reserved. Keywords: Postpartum depression, Brexanolone, Social determinants, Pharmacotherapy.
On March 19, 2019, brexanolone [*Trademark: Zulresso™ (Sage Therapeutics, Cambridge, Massachusetts)] received approval from the US Food
▪▪▪ xxxx
and Drug Administration (FDA) as the first drug specifically targeted to treat postpartum depression (PPD) in women in the United States.1 PPD, a major depressive mood disorder that starts within 1 month of childbirth (termed major depressive disorder with peripartum onset according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders),2 occurs in 10%e20% of new mothers.3e5 In addition to the effects on patients, PPD is associated with detrimental effects on infant and child development. PPD can lead to decreased mothereinfant attachment and difficulty breastfeeding. It is also associated with delayed motor development, behavioral inhibition, externalizing disorders, and poor emotion regulation in young children.6 In addition, it can have devastating negative effects on patients and their families, potentially even leading to maternal suicide, which is among the leading causes of death in the postpartum period.7 The pathophysiology of PPD is complex and incompletely understood. Several models have suggested a role not only for pregnancy hormones but also for a number of neurohormones, including thyroglobulin cortisol, and modulation of the entire hypothalamicepituitary axis.8e10 The most well
Accepted for publication November 11, 2019 https://doi.org/10.1016/j.clinthera.2019.11.005 0149-2918/$ - see front matter © 2019 Elsevier Inc. All rights reserved.
1
Clinical Therapeutics studied among these models, which is the target of brexanolone, is that of the withdrawal of pregnancy hormones. During pregnancy, levels of progesterone and its metabolites increase to reach peak concentrations in the third trimester and then decline abruptly after childbirth. However, studies have failed to find an unequivocal association between maternal hormone concentrations and PPD. It has been postulated that multiple PPD phenotypes may exist, with a subgroup of women who are sensitive to hormonal fluctuations that may trigger affective dysregulation with resultant depressive and anxiety symptoms.8 Despite PPD being historically understood as biological in the United States, some suggest that this framework may reflect a false dichotomy between the “normal” overjoyed new mother and the pathologically affected victim of depression.11 Interestingly, the prevalence of depression in women of reproductive age outside the perinatal period is similar to that of PPD, leading physicians to question if it is, in fact, a distinct pathophysiologic process.12 Many of the risk factors associated with PPD are social determinants of health, including poor partner/social support, adolescent age, socioeconomic status, psychosocial stressors, marital conflict, preterm infant, or complicated delivery.5,12 In addition, the prevalence of PPD between countries across the world shows great heterogeneity. In a global systematic review, for example, rates of PPD varied from as low as 3% (Singapore) to as high as 38% (Chile), underscoring the possibility that this may reflect the sociocultural aspects of childbearing.12 Although the diagnostic criteria for PPD are clear, there are logistical barriers to making this diagnosis in a timely manner. To date, there is no universal screening policy in the peripartum period, and the responsibility for screening, diagnosing, and caring for patients with PPD is shared among obstetricians, general practitioners, and mental health professionals. The American College of Obstetrics and Gynecology recommends that all mothers be screened for peripartum depression and that new mothers would “ideally” have a postpartum visit within 3 weeks of giving birth, which may obviate the need for selfreferral during the first month of the child's life.13,14 Treatment for PPD is selected based on the presenting symptoms and their severity. Although
2
nonpharmacologic therapies such as cognitive behavioral therapy have been shown to be effective for women with mild to moderate PPD, selective serotonin reuptake inhibitors are often chosen in more moderate to severe cases, for which they have shown efficacy.15 More studies are needed to compare the efficacy of antidepressant medications versus psychotherapy and to confirm that treatment with antidepressant medications leads to improvement in maternal functioning and infant and child development. Brexanolone has been celebrated as the first medication ever approved specifically to treat PPD. It is not a traditional antidepressant but is an intravenous formulation of synthetic allopregnanolone, the major active metabolite of progesterone.16 It is believed to provide postpartum mothers with doses of allopregnanolone equivalent to endogenous third-trimester concentrations.10 In animal models, allopregnanolone modulates neuronal excitability through direct action on g-aminobutyric acid type A receptors, whose endogenous ligand, gaminobutyric acid, acts as the main inhibitory neurotransmitter in the central nervous system.17 Fluctuations in allopregnanolone exhibit profound effects on anxiety- and depression-like behavior in these animal models and seem to modulate affective changes via the hypothalamic-pituitary-adrenal axis in the peripartum period.18 The FDA's approval of brexanolone, which is its first globally, is based on a series of recently published clinical trials.10,19,20 In these, a total of 3 multicenter, randomized, double-blind, placebocontrolled trials were conducted in women (aged 18e45 years) with moderate and severe PPD, and they have been methodologically reviewed in detail elsewhere.21 These studies found reductions in the degree of depression (the primary outcome) as measured by using the Hamilton Rating Scale for Depression compared with placebo. Although this outcome was not shown in each individual trial, in a composite end point that included data from all 3 studies, the effect was significant at both the end of the 60-h infusion and was maintained at 30 days.20 It is worth noting that in these trials, brexanolone was efficacious much more quickly than traditional antidepressants, which typically take up to 4 weeks to have clinically significant effects. In fact, in each clinical trial of brexanolone, investigators found a
Volume xxx Number xxx
A.F. Jarman et al. statistically significant improvement in symptoms at the completion of the 60-h infusion.19,20 Although we are certainly hopeful that brexanolone will be an effective treatment for the many women who experience PPD, there are a number of challenges to overcome before this treatment can be available to all patients who may benefit from it. The medication is extremely expensive ($34,000 for the medication alone), and it is not yet clear how many private insurers will cover the cost. Some insurance providers have created policies by which patients who meet strict criteria may be covered, but patients will need to work with their physicians on a case-by-case basis to determine if they are eligible.22,23 The manufacturer also offers a financial assistance program that may be helpful to some underinsured and uninsured patients, but cost is likely to remain a significant barrier for many patients.24 Brexanolone must also be administered in an inpatient, monitored setting over a total of 60 h. This requirement is due to concern for potential side effects that include dizziness, sedation, and loss of consciousness, which resulted in its approval through the Risk Evaluation and Mitigation Program.25 In addition to further safety studies, efficacy data will need to be independently validated. Development of an oral formulation is ongoing and may make the medication more widely available. It is also unclear how and whether new mothers may breastfeed while taking this medication, and although the manufacturers state that available data “do not suggest a significant risk of adverse events to breastfed infants” there is insufficient data for physicians to make informed recommendations and will require further study. The Drugs and Lactation Database (LactMed) recommendation states: “Because of the low amounts of brexanolone in the milk and low oral bioavailability, brexanolone would not be expected to cause any adverse effects in breastfed infants.”26,27 This recommendation is based on scant data, which do not include milk concentrations or milk-to-plasma ratios.28 Furthermore, the effects of any dose of brexanolone on infants are unknown. Although the pathophysiology of PPD and the in vivo mechanism of action of brexanolone are incompletely understood and would benefit from further study, we should also consider the contribution of social determinants of health. The
▪▪▪ xxxx
transition to motherhood is a difficult one for many women, made more difficult by cultural expectations and policies surrounding childbirth. For example, the United States is the only industrialized country that does not provide paid maternity (or paternity) leave.29 Among women who took maternity leave of 12 weeks, shorter leave was associated with increased risk of PPD symptoms.30 Conversely, when paternity leave leads to increased paternal involvement (as it seems would naturally be the case), mothers are less depressed.31 Studies have also observed higher PPD rates in countries where reproductive-aged women worked >40 h per week, noting that working full-time while caring for children can cause stress linked to PPD.12 The US Preventive Services Task Force recently issued a recommendation that clinicians provide or refer pregnant and postpartum patients at increased risk for PPD to counseling interventions, perhaps reflecting increased recognition of the role of nonpharmacologic interventions in the prevention and treatment of PPD.5 PPD is a common condition in the United States that causes harm to entire families. Brexanolone represents a mechanistically novel approach to the treatment of PPD that has shown initial efficacy data that are encouraging. In its current formulation, however, brexanolone will not be available to many of the patients for whom it may provide relief. Clinicians and patients will benefit from additional studies of the drug, including validation of the initial results. As we await additional safety and efficacy data on this pharmacologic treatment, our patients would also benefit from efforts focused on social policies that mitigate the burden of the peripartum period. Instituting policies that are more supportive of growing families may help combat feelings of isolation, lack of support, and fatigue that are associated with PPD and could augment the effects of medication treatment or even obviate the need for it. Callister et al32 provide examples of cultural practices across the world viewed as nurturing of women's postpartum mental health, including postpartum social structure, a period of recuperation from giving birth, and protective measures that recognize the vulnerability of women in the postpartum period (eg, assistance with chores). Despite daily advances in our scientific
3
Clinical Therapeutics understanding of PPD and its treatment, screening should encompass a holistic perspective that includes the myriad sociocultural contributions to patient's health.
CONFLICTS OF INTEREST Alyson J. McGregor is a Topic Editor for Clinical Therapeutics. She was not involved in the peer review or editorial decision-making for this article. The other authors have no conflicts of interest to disclose.
ACKNOWLEDGMENTS Drs. Jarman and McGregor conceived, outlined, and edited the work. Drs. Barron, MacLean, and Wightman contributed substantially by writing sections of the manuscript. All authors critically revised the work for intellectual content and approved the final version as submitted.
REFERENCES 1. Sage Therapeutics. Sage Therapeutics Announces FDA Approval of ZULRESSO™ (Brexanolone) Injection, the First and Only Treatment Specifically Indicated for Postpartum Depression. Press Release; Mar 19 2019. https://investor.sagerx.com/newsreleases/news-release-details/sage-therapeutics-announcesfda-approval-zulressotm-brexanolone. Accessed April 15, 2019. 2. American Psychiatric Association, DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5™. 5th ed. Arlington, VA, US: American Psychiatric Publishing, Inc; 2013. https://doi.org/10.1176/ appi.books.9780890425596. 3. Dave S1, Petersen I, Sherr L, Nazareth I. Incidence of maternal and paternal depression in primary care: a cohort study using a primary care database. Arch Pediatr Adolesc Med. 2010 Nov;164:1038e1044. 4. Holopainen A, Hakulinen T. New parents' experiences of postpartum depression: a systematic review of qualitative evidence. JBI Database Syst Rev Implement Rep. 2019;17: 1731e1769. 5. US Preventive Services Task Force. Interventions to prevent perinatal depression: US preventive Services Task Force recommendation statement. JAMA. 2019;321:580e587. https://doi.org/10.1001/jama.2019.0007. 6. Suri R, Lin AS, Cohen LS, Altshuler LL. Acute and long-term behavioral outcome of infants and children exposed in utero to either maternal depression or antidepressants: a review of the literature. J Clin Psychiatry. 2014;75: e1142ee1152.
4
7. Wisner KL, Sit DKY, McShea MC, et al. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. JAMA Psychiatry. 2013;70:490e498. 8. Schiller CE, Meltzer-Brody S, Rubinow DR. The role of reproductive hormones in postpartum depression. CNS Spectr. 2015;20:48e59. https://doi.org/10.1017/ S1092852914000480. 9. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157: 924e930. 10. 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. 2017;32, e2576. 11. Lee C. Social context, depression and the transition to motherhood. Br J Health Psychol. 1997;2:93e108. 12. Hahn-Holbrook J, Cornwell Hinrichs T, Anaya I. Economic and health predictors of national postpartum depression prevalence: a systematic review, meta-analysis, and metaregression of 291 studies from 56 countries. Front Psychiatry. 2018;8:248. https://doi.org/10.3389/fpsyt.2017.00248. 13. Committee on Obstetric Practice. The American College of obstetricians and gynecologists committee opinion no. 630. Screening for perinatal depression. Obstet Gynecol. 2015 May;125:1268e1271. https://doi.org/10.1097/ 01.AOG.0000465192.34779. dc. 14. ACOG Committee Opinion No. 736. Optimizing postpartum care. Obstet Gynecol. 2018 May;131:e140ee150. https:// doi.org/10.1097/AOG.0000000000002633. 15. Molyneaux E, Howard LM, McGeown HR, et al. Antidepressant treatment for postnatal depression. Cochrane Database Syst Rev. 2014;9:CD002018. 16. Nonacs RA. Primer on Brexanolone (Zulresso) for Postpartum Depression. MGH Center for Women’s Mental Health; Mar 28 2019. https://womensmentalhealth.org/posts/aprimer-on-brexanolone-zulresso-for-postpartumdepression/. Accessed April 15, 2019. 17. Mel on L, Hammond R, Lewis M, Maguire J. A novel, synthetic, neuroactive steroid is effective at decreasing depression-like behaviors and improving maternal care in preclinical models of postpartum depression. Front Endocrinol (Lausanne). 2018;9:703. 18. Mel on LC, Hooper A, Yang X, Moss SJ, Maguire J. Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice. Psychoneuroendocrinology. 2017;90:182e193. 19. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;309:480e489.
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A.F. Jarman et al. 20. Meltzer-Brody S, Colquhoun H, Reisenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392:1058 e1070. 21. Cirino N. Brexanolone for Postpartum Depression: Promising, but Will it Deliver? Relias Media; Mar 1 2019. Abstract & Commentary https://www. reliasmedia.com/articles/144003brexanolone-for-postpartumdepression-promising-but-will-itdeliver. Accessed April 15, 2019. 22. Blue Cross Blue Shield of North Carolina. Brexanolone corporate medical policy. https://www. bluecrossnc.com/sites/default/files/ document/attachment/services/ public/pdfs/medicalpolicy/ brexanolone_zulresso.pdf. Accessed October 11, 2019. 23. Health Partners. Brexanolone. https://www.healthpartners.com/ public/coverage-criteria/policy.html? contentid¼ENTRY_210232. Accessed October 11, 2019. 24. Sage Therapeutics. Sage central financial assistance programs. https://www.zulressohcp.com/ access-and-support/rems/. Accessed October 11, 2019. 25. US Food and Drug Administration. FDA Approves First Treatment for Postpartum Depression. FDA News Release; Mar 19 2019. https://www.fda.gov/ NewsEvents/Newsroom/ PressAnnouncements/ucm633919. htm?utm_campaign¼FDA% 20approves%20first%20treatment% 20for%20post-partum% 20depression&utm_ medium¼email&utm_ source¼Eloqua. Accessed April 15, 2019. 26. US National Library of Medicine. Toxicology data network. Brexanolone. https://toxnet.nlm.nih.
27.
28.
29.
30.
31.
32.
gov/cgi-bin/sis/search2. Accessed April 15, 2019. Sage Therapeutics. Zulresso: full prescribing information. https:// www.zulressohcp.com/aboutzulresso/safety/. Accessed December 2, 2019. Hoffmann E, Wald J, Colquhoun H. Evaluation of breast milk concentrations following brexanolone IV administration to healthy lactating women. Am J Obstet Gynecol. 2019;220:S554. https:// doi.org/10.1016/ j.ajog.2018.11.873. Abstract. World Policy Analysis Center. Is paid leave available to mothers and fathers of infants?. https://www. worldpolicycenter.org/policies/ispaid-leave-available-to-mothers-andfathers-of-infants/is-paid-leaveavailable-for-mothers-of-infants. Accessed April 15, 2019. Kornfeind KR, Sipsma HL. Exploring the link between maternity leave and postpartum depression. Womens Health Issues. 2018;28:321e326. https://doi.org/10.1016/ j.whi.2018.03.008. Sejourne N, Beaume M, Vaslot V, Chabrol H. Effect of paternity leave on maternal postpartum depression. Gynecol Obstet Fertil. 2012;40:360 e364. https://doi.org/10.1016/ j.gyobfe.2011.08.033. Callister LC, Beckstrand RL, Corbett C. Postpartum depression and culture: pesado corazon. MCN Am J Matern Child Nurs. 2010;35:254 e261.
Address correspondence to: Angela F. Jarman, 4150 V St, PSSB #2100, Sacramento, CA, 95817, USA. E-mail: [email protected]
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5
Brexanolone For Postpartum Depression: A Novel Approach and a Call for Comprehensive Postpartum Care Angela F. Jarman, MD, MPH1; Joanna V. MacLean, MD2; Rebecca J. Barron, MD, MPH3; Rachel S. Wightman, MD4,5; and Alyson J. McGregor, MD, MA4 1
Department of Emergency Medicine, University of California Davis, Sacramento, CA, USA; Department of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Providence, RI, USA; 3Department of Emergency Medicine, Portsmouth Regional Hospital, Portsmouth, NH, USA; 4Department of Emergency Medicine, Alpert Medical School, Brown University, Providence, RI, USA; and 5Division of Medical Toxicology, Alpert Medical School, Brown University, Providence, RI, USA 2
ABSTRACT Brexanolone recently became the first medication to be approved by the US Food and Drug Administration specifically for treating postpartum depression. In contrast to traditional antidepressants, however, brexanolone is a neurosteroid that is believed to mimic allopregnanolone, a product of endogenous progesterone. Although early clinical trials have shown success, the medication remains largely unavailable due to its extremely high cost and formulation (it must be given as a continuous intravenous infusion over 3 days in a monitored, inpatient setting). The efficacy data surrounding brexanolone are encouraging; there is also evidence, however, that postpartum depression may be mitigated by a number of social policies that provide support to new parents. We suggest a comprehensive approach to postpartum wellness that includes investing in evidence-based social interventions that may be much more accessible to the millions of Americans experiencing postpartum mood disturbance. (Clin Ther. xxxx;xxx:xxx) © 2019 Elsevier Inc. All rights reserved. Keywords: Postpartum depression, Brexanolone, Social determinants, Pharmacotherapy.
On March 19, 2019, brexanolone [*Trademark: Zulresso™ (Sage Therapeutics, Cambridge, Massachusetts)] received approval from the US Food
▪▪▪ xxxx
and Drug Administration (FDA) as the first drug specifically targeted to treat postpartum depression (PPD) in women in the United States.1 PPD, a major depressive mood disorder that starts within 1 month of childbirth (termed major depressive disorder with peripartum onset according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders),2 occurs in 10%e20% of new mothers.3e5 In addition to the effects on patients, PPD is associated with detrimental effects on infant and child development. PPD can lead to decreased mothereinfant attachment and difficulty breastfeeding. It is also associated with delayed motor development, behavioral inhibition, externalizing disorders, and poor emotion regulation in young children.6 In addition, it can have devastating negative effects on patients and their families, potentially even leading to maternal suicide, which is among the leading causes of death in the postpartum period.7 The pathophysiology of PPD is complex and incompletely understood. Several models have suggested a role not only for pregnancy hormones but also for a number of neurohormones, including thyroglobulin cortisol, and modulation of the entire hypothalamicepituitary axis.8e10 The most well
Accepted for publication November 11, 2019 https://doi.org/10.1016/j.clinthera.2019.11.005 0149-2918/$ - see front matter © 2019 Elsevier Inc. All rights reserved.
1
Clinical Therapeutics studied among these models, which is the target of brexanolone, is that of the withdrawal of pregnancy hormones. During pregnancy, levels of progesterone and its metabolites increase to reach peak concentrations in the third trimester and then decline abruptly after childbirth. However, studies have failed to find an unequivocal association between maternal hormone concentrations and PPD. It has been postulated that multiple PPD phenotypes may exist, with a subgroup of women who are sensitive to hormonal fluctuations that may trigger affective dysregulation with resultant depressive and anxiety symptoms.8 Despite PPD being historically understood as biological in the United States, some suggest that this framework may reflect a false dichotomy between the “normal” overjoyed new mother and the pathologically affected victim of depression.11 Interestingly, the prevalence of depression in women of reproductive age outside the perinatal period is similar to that of PPD, leading physicians to question if it is, in fact, a distinct pathophysiologic process.12 Many of the risk factors associated with PPD are social determinants of health, including poor partner/social support, adolescent age, socioeconomic status, psychosocial stressors, marital conflict, preterm infant, or complicated delivery.5,12 In addition, the prevalence of PPD between countries across the world shows great heterogeneity. In a global systematic review, for example, rates of PPD varied from as low as 3% (Singapore) to as high as 38% (Chile), underscoring the possibility that this may reflect the sociocultural aspects of childbearing.12 Although the diagnostic criteria for PPD are clear, there are logistical barriers to making this diagnosis in a timely manner. To date, there is no universal screening policy in the peripartum period, and the responsibility for screening, diagnosing, and caring for patients with PPD is shared among obstetricians, general practitioners, and mental health professionals. The American College of Obstetrics and Gynecology recommends that all mothers be screened for peripartum depression and that new mothers would “ideally” have a postpartum visit within 3 weeks of giving birth, which may obviate the need for selfreferral during the first month of the child's life.13,14 Treatment for PPD is selected based on the presenting symptoms and their severity. Although
2
nonpharmacologic therapies such as cognitive behavioral therapy have been shown to be effective for women with mild to moderate PPD, selective serotonin reuptake inhibitors are often chosen in more moderate to severe cases, for which they have shown efficacy.15 More studies are needed to compare the efficacy of antidepressant medications versus psychotherapy and to confirm that treatment with antidepressant medications leads to improvement in maternal functioning and infant and child development. Brexanolone has been celebrated as the first medication ever approved specifically to treat PPD. It is not a traditional antidepressant but is an intravenous formulation of synthetic allopregnanolone, the major active metabolite of progesterone.16 It is believed to provide postpartum mothers with doses of allopregnanolone equivalent to endogenous third-trimester concentrations.10 In animal models, allopregnanolone modulates neuronal excitability through direct action on g-aminobutyric acid type A receptors, whose endogenous ligand, gaminobutyric acid, acts as the main inhibitory neurotransmitter in the central nervous system.17 Fluctuations in allopregnanolone exhibit profound effects on anxiety- and depression-like behavior in these animal models and seem to modulate affective changes via the hypothalamic-pituitary-adrenal axis in the peripartum period.18 The FDA's approval of brexanolone, which is its first globally, is based on a series of recently published clinical trials.10,19,20 In these, a total of 3 multicenter, randomized, double-blind, placebocontrolled trials were conducted in women (aged 18e45 years) with moderate and severe PPD, and they have been methodologically reviewed in detail elsewhere.21 These studies found reductions in the degree of depression (the primary outcome) as measured by using the Hamilton Rating Scale for Depression compared with placebo. Although this outcome was not shown in each individual trial, in a composite end point that included data from all 3 studies, the effect was significant at both the end of the 60-h infusion and was maintained at 30 days.20 It is worth noting that in these trials, brexanolone was efficacious much more quickly than traditional antidepressants, which typically take up to 4 weeks to have clinically significant effects. In fact, in each clinical trial of brexanolone, investigators found a
Volume xxx Number xxx
A.F. Jarman et al. statistically significant improvement in symptoms at the completion of the 60-h infusion.19,20 Although we are certainly hopeful that brexanolone will be an effective treatment for the many women who experience PPD, there are a number of challenges to overcome before this treatment can be available to all patients who may benefit from it. The medication is extremely expensive ($34,000 for the medication alone), and it is not yet clear how many private insurers will cover the cost. Some insurance providers have created policies by which patients who meet strict criteria may be covered, but patients will need to work with their physicians on a case-by-case basis to determine if they are eligible.22,23 The manufacturer also offers a financial assistance program that may be helpful to some underinsured and uninsured patients, but cost is likely to remain a significant barrier for many patients.24 Brexanolone must also be administered in an inpatient, monitored setting over a total of 60 h. This requirement is due to concern for potential side effects that include dizziness, sedation, and loss of consciousness, which resulted in its approval through the Risk Evaluation and Mitigation Program.25 In addition to further safety studies, efficacy data will need to be independently validated. Development of an oral formulation is ongoing and may make the medication more widely available. It is also unclear how and whether new mothers may breastfeed while taking this medication, and although the manufacturers state that available data “do not suggest a significant risk of adverse events to breastfed infants” there is insufficient data for physicians to make informed recommendations and will require further study. The Drugs and Lactation Database (LactMed) recommendation states: “Because of the low amounts of brexanolone in the milk and low oral bioavailability, brexanolone would not be expected to cause any adverse effects in breastfed infants.”26,27 This recommendation is based on scant data, which do not include milk concentrations or milk-to-plasma ratios.28 Furthermore, the effects of any dose of brexanolone on infants are unknown. Although the pathophysiology of PPD and the in vivo mechanism of action of brexanolone are incompletely understood and would benefit from further study, we should also consider the contribution of social determinants of health. The
▪▪▪ xxxx
transition to motherhood is a difficult one for many women, made more difficult by cultural expectations and policies surrounding childbirth. For example, the United States is the only industrialized country that does not provide paid maternity (or paternity) leave.29 Among women who took maternity leave of 12 weeks, shorter leave was associated with increased risk of PPD symptoms.30 Conversely, when paternity leave leads to increased paternal involvement (as it seems would naturally be the case), mothers are less depressed.31 Studies have also observed higher PPD rates in countries where reproductive-aged women worked >40 h per week, noting that working full-time while caring for children can cause stress linked to PPD.12 The US Preventive Services Task Force recently issued a recommendation that clinicians provide or refer pregnant and postpartum patients at increased risk for PPD to counseling interventions, perhaps reflecting increased recognition of the role of nonpharmacologic interventions in the prevention and treatment of PPD.5 PPD is a common condition in the United States that causes harm to entire families. Brexanolone represents a mechanistically novel approach to the treatment of PPD that has shown initial efficacy data that are encouraging. In its current formulation, however, brexanolone will not be available to many of the patients for whom it may provide relief. Clinicians and patients will benefit from additional studies of the drug, including validation of the initial results. As we await additional safety and efficacy data on this pharmacologic treatment, our patients would also benefit from efforts focused on social policies that mitigate the burden of the peripartum period. Instituting policies that are more supportive of growing families may help combat feelings of isolation, lack of support, and fatigue that are associated with PPD and could augment the effects of medication treatment or even obviate the need for it. Callister et al32 provide examples of cultural practices across the world viewed as nurturing of women's postpartum mental health, including postpartum social structure, a period of recuperation from giving birth, and protective measures that recognize the vulnerability of women in the postpartum period (eg, assistance with chores). Despite daily advances in our scientific
3
Clinical Therapeutics understanding of PPD and its treatment, screening should encompass a holistic perspective that includes the myriad sociocultural contributions to patient's health.
CONFLICTS OF INTEREST Alyson J. McGregor is a Topic Editor for Clinical Therapeutics. She was not involved in the peer review or editorial decision-making for this article. The other authors have no conflicts of interest to disclose.
ACKNOWLEDGMENTS Drs. Jarman and McGregor conceived, outlined, and edited the work. Drs. Barron, MacLean, and Wightman contributed substantially by writing sections of the manuscript. All authors critically revised the work for intellectual content and approved the final version as submitted.
REFERENCES 1. Sage Therapeutics. Sage Therapeutics Announces FDA Approval of ZULRESSO™ (Brexanolone) Injection, the First and Only Treatment Specifically Indicated for Postpartum Depression. Press Release; Mar 19 2019. https://investor.sagerx.com/newsreleases/news-release-details/sage-therapeutics-announcesfda-approval-zulressotm-brexanolone. Accessed April 15, 2019. 2. American Psychiatric Association, DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5™. 5th ed. Arlington, VA, US: American Psychiatric Publishing, Inc; 2013. https://doi.org/10.1176/ appi.books.9780890425596. 3. Dave S1, Petersen I, Sherr L, Nazareth I. Incidence of maternal and paternal depression in primary care: a cohort study using a primary care database. Arch Pediatr Adolesc Med. 2010 Nov;164:1038e1044. 4. Holopainen A, Hakulinen T. New parents' experiences of postpartum depression: a systematic review of qualitative evidence. JBI Database Syst Rev Implement Rep. 2019;17: 1731e1769. 5. US Preventive Services Task Force. Interventions to prevent perinatal depression: US preventive Services Task Force recommendation statement. JAMA. 2019;321:580e587. https://doi.org/10.1001/jama.2019.0007. 6. Suri R, Lin AS, Cohen LS, Altshuler LL. Acute and long-term behavioral outcome of infants and children exposed in utero to either maternal depression or antidepressants: a review of the literature. J Clin Psychiatry. 2014;75: e1142ee1152.
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Address correspondence to: Angela F. Jarman, 4150 V St, PSSB #2100, Sacramento, CA, 95817, USA. E-mail: [email protected]
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