by Melanie Basnak
figures by Aparna Nathan

Emily gave birth to a healthy baby boy. But, soon after the delivery, she started to feel sad and constantly overwhelmed. She could easily get irritated and was often angry. She worried that something would happen to her baby, and this obsession kept her from sleeping. Even though she had lots of support from her partner and family, she felt anxious and helpless most of the time. These symptoms went on for months.

Emily doesn’t exist, but her condition is very much real: it is called postpartum depression (PPD), and it’s a mood disorder that impacts many women following childbirth. Currently, there is no available drug exclusively designed to treat PPD. This, however, will soon change. On March 19, 2019, the Food and Drug Administration (FDA) approved the drug brexanolone to be used for treatment of PPD in adult women. Brexanolone will be commercialized as of June in the US.

What are some potential causes for PPD? and how does the new drug work?

PPD affects about 1 in every 9 women in the US after childbirth (Figure 1), making it hard for them to care for themselves and others. The symptoms of PPD often include sleep disturbance, anxiety, irritability, extreme sadness and/or inability to experience pleasure and, in some cases, suicidal tendencies. PPD may resolve itself within weeks after its onset, but in about 20% of the cases, the depression persists for a year or more after delivery. Moreover, the condition is likely to come back in subsequent pregnancies: around 40% of women who suffered PPD will have a relapse.

Figure 1: PPD in numbers. PPD affects many women per year, and the percentage of women affected varies with factors such as age and race. A big number of those suffering from PPD will experience the symptoms for over a year, and even more will suffer a relapse in subsequent pregnancies.

The causes for PPD are not very clear, but some evidence suggest that it arises from sudden hormonal changes associated with childbirth. One of the hormones that has been linked to PPD is called allopregnanolone: reduced levels of this hormone in the blood have been linked to depression and anxiety in rodents and humans. Allopregnanolone is a molecule that binds, or physically attaches to, a type of receptor found on the surface of brain cells called GABA type A receptors. Receptors are molecules that, upon binding of the proper partner molecule, can initiate a biological signal. In the case of GABA A receptors, this biological signal is a physical change in the receptor’s shape that allows it to open, forming a pore or channel into the cell. Once open, molecules called chloride ions can circulate and generate changes in the activity of the cells they enter. When allopregnanolone binds to the GABA A receptors, it causes them to open for more time, allowing more chloride ions to flow through them. In normal conditions, this can help reduce the activity of our hormonal stress-response system, the hypothalamic-pituitary-adrenal (HPA) axis (Figure 2). If the levels of allopregnanolone are lower than usual after giving birth (i.e., abnormally low), this could decrease GABA A receptor activation in the brain. This, in turn, would lead to an increase in the activity of the HPA axis, which may lead to increases in anxiety and stress, contributing to PPD. Likewise, anomalies with the  GABA A receptor themselves (lower levels of them for example) can generate the same effects, and they have been linked to PPD in mice and human studies.

Because of the poorly understood causes of PPD, it has been treated with methods that were not designed exclusively to address it. Up to this point, PPD was only treated by counseling for moderate cases and using traditional anti-depressants for severe cases. Analyses of multiple studies using common anti-depressants show that they might not be very effective, and this is probably because they are not targeting the root causes of the disorder.

A new drug, brexanolone, might be a solution to this problem. It appears to be more effective than the treatments available so far, and this possibly arises from its mechanism of action. It is a synthetic compound that has a similar structure to that of the hormone allopregnanolone. The drug would act, as allopregnanolone, by increasing the activity of GABA A receptors upon binding to them (Figure 2).

Figure 2: Potential causes of PPD and mechanism of action of brexanolone. In normal conditions, GABA A is involved in the inhibition of the HPA axis, our stress-response system. It is thought that in women with PPD, a problem with GABA A-related signals may lead to a decreased inhibition of the HPA axis, resulting in increased depression and anxiety. Brexanolone would treat this by binding to GABA A receptors and increasing their activity, restoring control over the HPA axis.

Promising clinical trials

Brexanolone has been shown to be effective in two clinical trials involving 246 adult women with moderate and severe PPD. The participants were assessed for PPD by clinicians using a well-established tool called the Hamilton Depression Rating Scale (HAM-D), in which a higher score in the overall scale means higher depression. Eligible women were randomly assigned to receive a brexanolone infusion (blood injection) or a matching infusion of a placebo (a substance that has no therapeutic effect, used as a control in testing new drugs). The women’s HAM-D score was determined again 60 h after the infusion started, and 7 and 30 days after the treatment.

These studies showed a more significant reduction in the depression score from baseline in the drug-treated group when compared with the placebo group. By the end of the infusion, 51%-61% of the drug-treated patients showed no evidence of depression according to the scale vs 16%-38% of the placebo-treated patients. The effect of the drug was durable and sustained 30 days after infusion.

As for side effects, the drug produced headache, dizziness, or sleepiness in about 30% of the patients. Because of this, its administration will occur in health centers, with the patients being closely monitored by medical personnel.

Future directions

This new drug seems promising but is far from being the sole solution to the problem. Beyond the secondary effects mentioned previously, it didn’t work in all the women tested, and this treatment will be very expensive, averaging $34,000 per patient. The company that developed brexanolone is working on the pill version of this treatment, which has shown promising results in clinical trials when administering the drug for two weeks. The possibility of taking a pill instead of a 60-h infusion at a health center might bring the costs of the treatment down. Some alternative, non-pharmacological treatments are being tested as well. Some researchers studied the use of light therapy devices, glasses emitting a certain type of light, that might improve PPD symptoms by improving the women’s sleep schedule. Other treatments are based upon different types of therapy, including online cognitive behavioral therapy. A substantial amount of research is being conducted around PPD using non-human animals and humans to determine more of its underlying causes and explore other treatments. The promising results of brexanolone, combined with new insights into the mechanisms behind PPD and the role of alternative treatments, might lead to even better solutions in the future.

Melanie Basnak is a second-year Ph.D. student in the Program in Neuroscience who studies the neural bases of behavior using Drosophila melanogaster.

Aparna Nathan is a second year PhD student in the Bioinformatics and Integrative Genomics PhD program at Harvard University. You can find her on Twitter as @aparnanathan.

cover image: “the crying games”by vajlentka is licensed under CC BY-NC-SA 2.0

For more information:

  • To learn more about the overview, symptoms and risk factors of PPD, read this article from the National Institute of Health.
  • To learn more about the HPA axis, read this blog post.
  • To learn about the use of different animal models for the study of PPD, read this article.
  • To learn more about GABA signaling, watch this YouTube video.
  • To learn more about what are clinical trials and how they work, read this article.
  • To learn more about the FDA’s drug-approval process, read this post.

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