Post-partum depression is common. Ten to twenty percent of women experience significant depressive symptoms after the birth of a child. Of these, 5 to 10% experience severe depressive symptoms, meaning that about 1% of women develop a severe depression after childbirth.

Many hormonal changes occur during pregnancy. Allopregnanolone is a steroid derived from progesterone (and hence from cholesterol) that is made in the body and brain. Both progesterone and allopregnanolone levels change substantially during pregnancy, increasing up to 30-fold and then rapidly returning to normal levels at the time of delivery. Allopregnanolone is also synthesized by cells in the brain, including excitatory neurons, in response to stress, and it has direct effects on GABA receptors in the brain. (GABA is the most common inhibitory neurotransmitter in the brain. An inhibitory neurotransmitter diminishes the responsiveness of various brain cells to other neurotransmitters.) Allopregnanolone enhances the effects of GABA at a specific class of GABA receptors. Because it is made in the brain and affects the activity of the brain, allopregnanolone is classified as a “neurosteroid,” which is a subset of the broader class of “neuroactive steroids,” steroids that can either be made in the body or synthesized chemically that alter brain function.

When allopregnanolone levels drop dramatically after delivery, the nerve cells containing GABA take a while to adjust to the decrease. It is thought that this delay might trigger depressive symptoms in some women.

In the journal Lancet, Stephen Kanes and colleagues recently described the results of a phase II, double-blind, placebo-controlled study of 21 participants treated with a potential new drug for severe post-partum depression. The drug they tested is called brexanolone, a formulation of allopregnanolone that can be administered intravenously. A 60-hour infusion of this compound can temporarily return the level of allopregnanolone to pre-delivery levels, thus allowing the brain to adjust to a more gradual decrease in this steroid’s levels.

The results at the end of the 60-hour infusion were dramatic. Seven of the 10 women treated with the active drug had a marked response – full remission of symptoms – in comparison to 1 of 10 women who were treated with placebo. Importantly, the benefits of the drug were still apparent 30 days after the beginning of the infusion. The treatment was also well tolerated. The phase II study was a follow-up to an earlier open label study of four women with severe post-partum depression treated with brexanolone, all of whom achieved remission of depressive symptoms.

The rationale and design of this study make sense. Some of the authors work for Sage Therapeutics, the company that developed the drug, but the oversight and design of the study looks appropriate.

A phase II study typically involves a small number of patients and is intended to test for possible effectiveness of the drug and to carefully monitor for possible side effects. Dramatic results are uncommon in phase II studies of treatments for serious mental disorders. We will have to wait to see if the results from this study are reproducible in an ongoing, larger, phase III study.   

ClinicalTrials.gov is a government-run website that lists all ongoing drug trials. This website reports that a 120-participant, phase III trial of brexanolone in post-partum depression is in progress. It is likely that this larger trial will be completed in early 2018. Interestingly, Sage has another small phase II trial underway of another drug for the treatment of post-partum depression. This new drug has been formulated in such a way that it can be taken orally, and it is also being examined in women and men with (non-post-partum) major depression.

If the results of the phase III trial of brexanolone reproduce the results of the smaller phase II trial, it would be exciting for two reasons. It would give clinicians a new tool to help women with severe post-partum depression. In addition, it would introduce a new class of compounds, neuroactive steroids, for investigation as potential treatments for other psychiatric disorders. Brexanolone infusions are also being tested in a phase III trial for super-refractory status epilepticus (SRSE), a dire state of continuous seizures that is life-threatening and very difficult to treat. If brexanolone proves effective in both severe neurological conditions such as SRSE and severe major depression, it would be a step toward uncovering unique ways by which brain function can be regulated across a range of neuropsychiatric illnesses.

This article was written by Eugene Rubin MD, PhD and Charles Zorumski MD. 

NOTE: In full disclosure, one of us (CZ) studies the cellular mechanisms of neuroactive steroids, the class of molecules described in this post. He is also a member of the Scientific Advisory Board of Sage Therapeutics and a shareholder in the company. The potential therapeutic agent discussed here is being developed by Sage Therapeutics, and Sage Therapeutics funded the study.

References

Kanes, S., Colquhoun, H., Gunduz-Bruce, H., Raines, S., Arnold, R., Schacterle, A., Doherty, J., et al. (2017). Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. Published online June 12, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31264-3.

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