Brief on the New Postpartum Depression Medications ZURZUVAE (Zuranolone) and ZULRESSO (Brexanolone)
Dr. Haya Zedan, MPH, PhD, PMH-C*
August 7th, 2023
With the announcement by the US FDA of the approval of the new wonder treatment for postpartum depression, there has been a mix of reactions, ranging from excitement to relief. In the interest of clearing up some key issues, I have extensively researched the available information and summarized it below:
What is Perinatal Depression?
Maternal mental health conditions are a leading cause of maternal morbidity and mortality. PPD is among the most common complications during and after pregnancy. Around 1 in 8 women experience symptoms of PPD but less than half of PPD cases go undiagnosed without appropriate screening, and less than 20% receive treatment and support. Symptoms of PPD include depressed mood, loss of interest in activities, changes in sleep patterns and appetite, decreased energy, feelings of guilt or worthlessness, trouble concentrating and in extreme cases suicidality. Diagnosis for PPD must meet established criteria according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) and is not a casual consideration. Screening, evaluation and diagnosis must be conducted with an experienced medical professional, preferably a psychologist or psychiatrist.
Distinction from Major Depressive Disorder MDD
The differences center around the peripartum onset (around the end of pregnancy or within 4 weeks after childbirth) and the impact on maternal morbidity and mortality, the mother-infant bond and long-term child development.
What are the medications that have been approved?
ZURZUVAE (Zuranolone) and ZULRESSO (Brexanolone), have been developed and tested by Sage Therapeutics and Biogen, for treatment of severe depression.
ZURZUVAE is a rapid-acting neuroactive steroid given as a14-day course of treatment (once-a-day pill), easy to take. ZULRESSO is delivered intravenously (via IV drip) is difficult to access, must be taken as inpatient, treatment course/program takes 60 hours of infusion, and its expensive. Both medications are controlled substances, to be given only as prescription from a licensed medical professional, preferably an experienced psychiatrist (not an OB/Gyn or Midwife), and to be taken under close supervision.
What are the medications supposed to do?
Both medications mimic a derivative of progesterone, levels of which may fluctuate after childbirth. The medications are part of an emerging class of drugs called Neurosteroids, which stimulate different brain pathways than other antidepressants that target serotonin. (The links between serotonin levels and depression have been under increasing scrutiny in the past few years, with several studies now finding there is not enough evidence of the biochemical basis for depression, so scientists are seeking alternatives).
ZURZUVAE targets the GABA-A receptors in the brain with effects seen within three days. The GABA system is the major inhibitory signalling pathway of the brain and central nervous system which contributes to regulating brain function. The medication is expected to rapidly rebalance dysregulated neuronal networks responsible for mood, arousal, behaviour, and cognition.
Randomized clinical trials showed significant improvement in depressive symptoms for patients with severe MDD. Efficacy of ZURZUVAE for treatment of PPD in adults was tested in two randomized, double-blind, placebo-controlled, multi-center studies.
In Study 1: 543 patients with severe MDD were divided into two groups. One was given 50 mg of ZURZUVAE, and the other group was given a placebo (a dummy pill with no medication) once daily in the evening for 14 days. The patients did not know which group they were in or if they were given the actual medication or not. In Study 2: 196 patients were given ZURZUVAE or placebo, also for 14 days. Researchers monitored the patients in both studies for four weeks after they completed the 14-day treatment. Researchers measured changes in depressive symptoms using the total score from the 17-item Hamilton depression rating scale (HAMD-17) at days 3,15,28. Researchers measured changes in depressive symptoms using the total score from the 17-item Hamilton depression rating scale (HAMD-17) at days 3,15,28. Effects of the treatment were still apparent at Day 42—(four weeks) after the last dose of ZURZUVAE.
There is no information on follow-up from these studies or the pharmaceutical companies; or knowledge of what happens to patients after that (a few months after completing the treatment), if there is risk of relapse, and the issues associated with that or if they may need continued or periodic courses of treatment.**
Medication as the Solution – or the “Easy” Way Out?
Prescription Medications are prescribed to manage symptoms of illness and reduce impact on functioning health and quality of life. When prescribing medication, qualified professionals assess symptom presentation including onset, duration and intensity, along with multiple other factors. This should also include careful assessment of the suitability of the medication to the patients lifestyle and environment, short and long-term use vs. evidence on efficacy.
Metabolism and Withdrawal methods of these medications need to be carefully studied and advised by medical professionals, and patients should be fully informed and guided on how to do so safely to minimize the risks of relapse. There was no available information on how these studies would follow-up on the enrolled patients or guidance for withdrawal or stopping the medication.
Side effects: The FDA announcement also mentions that the use of ZURZUVAE may cause suicidal thoughts and behaviour, and that it may cause fetal harm if the woman is pregnant. The FDA has also stated that ZULRESSO administration must be under the supervision of a healthcare provider in a certified healthcare facility, due to the need for continuous pulse oximetry monitoring, the risks of sudden loss of consciousness, and potential for excessive sedation. Additionally, the FDA issued a complete response letter (CRL) for ZURZUVAE to treat adults with major depressive disorder (MDD), stating that the application for approval by Sage Therapeutics did not provide substantial evidence of effectiveness to support the approval and additional studies are needed.
A Statement from Biogen and Sage Therapeutics: “Drug development and commercialization involve a high degree of risk and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented.”
Price points are as yet unclear, but Sage Therapeutics have stated the list price for ZULRESSO around “$7,450 per vial/dose, or $34,000 per patient for the entire course of therapy, before discounts”. There is still no information on the unit price of ZURZUVAE. (Addendum: it was announced on 7 Nov. 2023 that the wholesale cost of ZURZUVAE is $15,900 for the 14-day treatment cycle.) Of course, it is also important to consider if any insurance plans will cover some of this cost.
Breastfeeding: The statements from Biogen and Sage Therapeutics clearly state that ZURZUVAE and ZULRESSO passes into breast milk, and it is not known if it can harm your baby, which means that women who take these medications should not breastfeed. This is also a serious consideration.
Peripartum depression happens at a critical time when mothers and babies are establishing their bond and can affect this negatively. Mothers and families may feel pressured and want quick resolutions to this issue, and these medications may present themselves as a quick fix. But there is a need to exercise caution in prescribing, ensuring accurate diagnosis and assessment for depression severity, and the importance of fully understanding all aspects surrounding the use of these medications, and making informed decisions.
The Roots of maternal mental health issues (and mental health issues in general) are more and more understood to be the result of external factors placing the brain and the body under stress, in conjunction with genetic vulnerabilities, neurochemical variabilities and psychological vulnerabilities. Plainly put, medication may only work on modifying brain function temporarily, but it won’t fix the other issues, such as the real-life circumstances.
Consider the context: the American Medical Model is historically heavily dependent on drug treatment regimens with insufficient emphasis on medication harms associated with their use. The BBC has recently filmed a documentary on antidepressant use which provides in-depth analysis of the interplay between pharmaceutical companies and the science capitalizing on trends for medical and psychosocial vulnerabilities, and sheds light on the long-term effects of anti-depressant use.
Bottom line: Read the fine print, research carefully and ask questions before prescribing or taking a new medication, consider all factors, weigh risks vs. benefits for the mother, her baby, and her family, and remember there is no magic bullet or shortcut that solves mental health problems and helps avoid having to do the hard work with a qualified therapist to fully resolve psychological and social issues.
Further Reading and References:
1) U.S. Food and Drug Administration (2023) FDA Approves First Oral Treatment for Postpartum Depression: FDA News Release [04 August 2023] https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression?emci=dfcf75a2-2e33-ee11-a3f1-00224832eb73&emdi=cb00c66a-3033-ee11-a3f1-00224832eb73&ceid=8675835
2) Clayton, Anita H, et al. “Zuranolone for the Treatment of Adults with Major Depressive Disorder: A Randomized, Placebo‐Controlled Phase 3 Trial.” American Journal of Psychiatry, 3 May 2023, https://doi.org/10.1176/appi.ajp.20220459. Accessed 11 July 2023.
3) Deligiannidis, Kristina M, et al. “Zuranolone for the Treatment of Postpartum Depression.” American Journal of Psychiatry, 26 July 2023, https://doi.org/10.1176/appi.ajp.20220785. Accessed 7 Aug. 2023.
4) Blank, C. (2019) New Postpartum Drug Comes at a High Price. Formulary Watch https://www.formularywatch.com/view/new-postpartum-drug-comes-high-price?emci=dfcf75a2-2e33-ee11-a3f1-00224832eb73&emdi=cb00c66a-3033-ee11-a3f1-00224832eb73&ceid=8675835
5) Formulary Watch (2023) FDA Approves Oral Treatment for Postpartum Depression. https://www.formularywatch.com/view/fda-approves-oral-treatment-for-postpartum-depression
6) Biogen (2023) FDA Approves ZURZUVAE™ (Zuranolone), the First and Only Oral Treatment Approved for Women with Postpartum Depression, and Issues a Complete Response Letter for Major Depressive Disorder: News Release [04 August 2023] https://investors.biogen.com/news-releases/news-release-details/fda-approves-zurzuvaetm-zuranolone-first-and-only-oral-treatment
7) Zulresso (2023) https://www.zulresso.com/?emci=dfcf75a2-2e33-ee11-a3f1-00224832eb73&emdi=cb00c66a-3033-ee11-a3f1-00224832eb73&ceid=8675835
8) BBC (2023) The Antidepressant Story. https://www.bbc.co.uk/programmes/m001n39z
9) Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01661-0
10) Policy Center for Maternal Mental Health (2023) Insurance Coverage of ZURZUVAE™ – What We Know Right Now. https://www.2020mom.org/blog/2023/11/15/insurance-coverage-of-zurzuvae-what-we-know-right-now
*Dr. Haya Zedan is a licensed perinatal psychologist from Saudi Arabia. She is a fellow of the American Psychological Association (APA), and a member of the American Psychiatric Association (APA), Postpartum Support International (PSI), among several other professional associations both internationally and within the Kingdom of Saudi Arabia.
**Access to the full two articles describing the randomized clinical trials was restricted to the abstracts of the studies on the website of the American Psychiatric Association and the American Journal of Psychiatry, despite the presence of a full membership.
استجابات