What's Up With Zuranolone for PPD?
Authored by:
Anna Glezer, M.D.
In this article, we will discuss the new FDA-approved medication for postpartum depression called Zuranolone. Zuranolone is the first medication approved by the FDA with a specific indication for postpartum depression, which is unique because it works quite quickly.
The Science Behind Zuranolone
Zuranolone is a medication similar to Brexanolone. Brexanolone was the medication first approved back in 2019 that is specifically for postpartum depression, but it is an IV form that needs to be infused over the course of 60 hours.It also has a REMS, which is a risk mitigation and evaluation strategy, meaning that the medication is considered to be a slightly higher risk and additional guidelines and training are involved for those who administer the medication (i.e., the organization, the hospital, and the clinicians). Brexanolone is a neuroactive steroid with allosteric modulation of GABA receptors. The most recent drug, Zuranolone, is also a neuroactive steroid with this allosteric modulation of GABA-A receptors, increasing activity at the GABA A receptor site.
GABA-A receptors are a class of receptors that respond to the neurotransmitter GABA or gamma-aminobutyric acid. There are two types, GABA-A and GABA-B. You may have heard of GABA-A receptor medications often used for anxiety but can have issues with dependence and tolerance (like benzodiazepines).
Zuranolone works through allopregnanolone, a progesterone metabolite. It has the same mechanism of allosteric modulation at that GABA receptor site as some other anti anxiety medications, but without the same issues related to dependence and tolerance. Brexanolone is essentially a synthetic version of Allopregnanolone, the progesterone metabolite, the neuroactive steroid. And as is Zuranolone, but in an oral form.
What Zuranolone Is Used For
The FDA approved zuranolone for postpartum depression. Now interestingly, the company that makes the medication also sought approval for major depressive disorder - MDD - but the FDA requested additional information before they will able to approve it for that particular indication. Right now, the only indication is for postpartum depression.
Postpartum depression, according to the diagnostic classification system, is a subtype of MDD—a subtype of major depressive disorder. In most mental health clinics and organizations, clinicians who diagnose individuals with mental illness or mental health conditions use the DSM, the diagnostic and statistical manual. To qualify for that, you must meet the criteria for regular major depressive disorder, with the additional qualifier that the symptoms began within three months before delivery or within four weeks postpartum.
However, our diagnostic criteria are not perfect, and many people are outside of the box of the DSM.
We've looked at the science behind the medication and the indication according to the FDA. Now, let's look at the research study that led to this.
The Approval of Zuranolone
The original study (you can find the published comprehensive article in the American Journal of Psychiatry) was a phase three trial, which means it was a randomized control trial. The study was double-blind and placebo-controlled, which means that both the individuals in the study and the clinicians administering the medication were blind to whether or not the individual was receiving a placebo or the medication. Placebo-controlled means that one group received the medication alone (in this case, at 50 milligrams), and the other group received a placebo.
Now, something must be said about the placebo effect - I am actually a fan. Many individuals out there might take a placebo and find improvement in symptoms, and they might also have side effects. That really speaks to the power of the mind, which we notice in many of our medications, even some of the older medications that we classically use for conditions like anxiety and depression. For example, the SSRI medications like fluoxetine and sertraline have a pretty high percentage of their effect related to the placebo effect. The placebo effect is not something to dismiss. It can actually be quite valuable.
This particular study was a double-blind, placebo-controlled study involving 200 women. All of the women were less than six months postpartum, and they had the diagnosis of postpartum depression, which means major depressive disorder with the postpartum specifier that symptoms began in the third trimester or within four weeks postpartum.
All of these patients were noted to have severe postpartum depression. They used a questionnaire called the HAM-D (Hamilton Depression Rating), and everyone had a score of at least 26 or more. They were separated into either the placebo or the medication arm, and they did try to include some diversity as well. In this particular study, about 25% of the individuals self-identified as black, and about 34% self-identified as Hispanic. What they found was a significant difference between those who received zuranolone, which was 98 individuals, and those who received the placebo.
If you look at the published article, there is a graph that paints a very interesting picture demonstrating the amount of improvement from the baseline, which actually means a reduction in the HAM-D score in the score of depression over time. And what they found was that the zuranolone begins to separate from the placebo arm as early as three days. That is notable for this particular medication because it works quite quickly.
That separation continues to be significant at day 15 and up to day 45, which was the duration of this particular study. They also looked at the difference between response and remission in this specific group, and the response really refers to an improvement in symptoms, whereas remission means that symptoms have mostly been alleviated. They found that within the first few days, there was a significant difference in response between the zuranolone and the placebo group. And then, as time passed, there was a significant difference in remission between the two by day 45.
There are several caveats to keep in mind. The first is, like all medications, there can be the potential for some side effects. The most common side effects in this particular group were somnolence, which is sleepiness or sedation, dizziness, and some GI symptoms.
There are some other things that we need more information about as we think about who will be the ideal candidate for this type of medication. There are four specific aspects that I want to emphasize: the first is that the women in these trials in this study were asked to forego breastfeeding. Now this is something that many individuals who are postpartum would really prefer to avoid as they want to continue to breastfeed their baby.
Many of my patients would like to continue to breastfeed, and this does not mean you cannot breastfeed on this medication. It just means that we do not currently have the appropriate data to be able to advise women, one way or the other. We need more data about breastfeeding in the context of taking this medication and how much of it ends up in the breast milk.
The second interesting aspect is this study was a placebo-controlled trial. One thing to keep in mind is that these days we do have a lot of different kinds of treatments for postpartum depression, including medications like SSRIs such as fluoxetine and sertraline, as well as different kinds of psychotherapies and other types of interventions. We have a lot of different kinds of treatments for postpartum depression and this study didn't actually compare this medication and how it works compared to other types of treatments for postpartum depression. It really just compared it to a placebo, which is essentially no treatment. It would be valuable to consider how this medication compares to our current first-line treatment tools for postpartum depression, including differences in efficacy and the frequency of side effects.
The third outstanding question to be answered is what is the longevity of the improvement? This particular study continued for 45 days. It would be fascinating to see the response and remission continue to be ongoing beyond that short window of time.
And finally, the patient population in this particular study was noted to have severe postpartum depression. While I definitely work with a number of patients who struggle with severe postpartum depression, I also have patients who have mild to moderate postpartum depression, as well as symptoms of postpartum anxiety. And so, it will be really interesting to learn more about how this medication particularly impacts this patient population.
While we need a little more information on this medication regarding breastfeeding and how it compares to current treatments, the longevity of the effect, and the way that it can help mild to moderate symptoms, it is really great news to have a new type of medication, a new mechanism, a new type of treatment that works quickly and works effectively to help those really struggling with symptoms of postpartum depression. I am that the FDA approved this medication and that it is going to be administered orally
If you are someone who is struggling with postpartum depression, I would encourage you to connect with a clinician, hopefully, someone who has experience in reproductive mental health, and they will be able to help guide you in the different treatment options available out there, including this new one.
Please note that while I am a clinical doctor, this article is not a substitute, and no one should be taken as medical advice. No specific health advice is being given in this article, and no physician-client relationship is created by you reading this article; all information provided in this article is for informational purposes only.
