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A Bench-to-Bedside Story: The Development of a Treatment for Postpartum Depression

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I will never forget the call I received from my patient, telling me how she was so depressed that she was afraid she was going to hurt her month-old daughter. She was plagued with a deep, inexorable hopelessness. She could barely get up the initiative to call me. I got her straight to an emergency room where she was admitted — and then spent the next two months in the hospital as the inpatient team tried everything they could to help her recover.

Postpartum depression, which can happen to mothers within a few weeks to a few months after giving birth, is a terrifying illness and is often difficult to treat. Until now, there has not been any treatment specifically approved for postpartum depression. That’s why the news that the FDA has approved brexanolone is so important for the 1 in 9 women in the United States who experience symptoms of postpartum depression and their families.

The approval of brexanolone is also a cause for celebration for psychiatric neuroscience, as it represents a true bench-to-bedside success for our field. The promise of basic neuroscience to provide truly novel and effective treatments for psychiatric disorders has for a long time been only that: a promise. But not anymore.

The story begins in the early 1940s. Hans Selye, Ph.D., a biochemist at McGill University, discovered and characterized a class of molecules related to progesterone that appeared to affect the central nervous system and were capable of producing sleep and anesthesia. The subsequent recognition that naturally occurring metabolites of progesterone were actively produced in the brain intensified efforts to understand how these neurosteroids exerted their effects.

Enter National Institute of Mental Health (NIMH) scientists Maria D. Majewska, Ph.D., and Steven M. Paul, M.D. Together with others in the NIMH and National Institute of Neurological Disorders and Stroke Intramural Research Programs, they showed that these neurosteroids induced anesthesia by enhancing the actions of GABA, the principal inhibitory neurotransmitter in the brain. Subsequent research showed that there were several naturally produced neurosteroids that all work through GABA receptors, some of which enhance GABA action and others which reduce it.

These basic neuroscience studies established the what and how of neurosteroids: What do neurosteroids do? They modulate brain activity. How do they do it? By acting on GABA receptors.

Dr. Paul, having been trained by the incredible Nobel-prize winning NIMH scientist Julius Axelrod, Ph.D., knew next to ask the why question: Why does the brain produce neurosteroids? Since steroid hormones, in general, are often produced during stressful periods, he decided to test whether neurosteroids were themselves induced by stress.

In a series of papers that came out of his lab at NIMH, Dr. Paul and others showed that production of neurosteroids was indeed induced by stress. Subsequent work came from multiple laboratories, including Dr. Paul’s and those of Istvan Mody, Ph.D., and Charles Zorumski, M.D., NIMH-funded investigators at the University of California, Los Angeles, and Washington University in St. Louis, respectively. They demonstrated that certain inhibitory neurosteroids, including one called allopregnanolone, were important for reducing the adverse effects of stress on the behavior and physiology of laboratory animals. Together, these findings suggested that neurosteroids like allopregnanolone were part of the brain’s response to stressful events, helping the brain respond adaptively to the myriad challenges we face in life.

These findings moved neurosteroids from molecules of interest to scientists to compounds of potential use in the clinic. Neurosteroids had entered the realm of translational neuroscience. But it was still unclear how they might be used to help patients. A final series of studies pointed in the direction of postpartum depression. Progesterone is a steroid hormone whose levels rise throughout pregnancy and drop rapidly at the time of birth. The same is true for the various neurosteroids that are metabolized from progesterone, including allopregnanolone. Dr. Mody and others hypothesized that these changes might play a role in postpartum depression and found evidence in support of this hypothesis in laboratory animal models. Moreover, they could “treat” these animals with drugs that mimicked allopregnanolone.

The stage was now set. Decades of careful basic science and some clever translational work led to a specific hypothesis that could be tested in a clinical trial: that allopregnanolone might be an effective treatment for postpartum depression. Re-enter Dr. Paul, who in the intervening years had left NIMH to work in the pharmaceutical industry, eventually starting a company called Sage Therapeutics. Sage Therapeutics set out to test the allopregnanolone hypothesis, and just this year completed a pair of randomized, placebo-controlled clinical trials of brexanolone, an intravenous formulation of allopregnanolone, in women hospitalized for postpartum depression. And guess what? The drug worked. It made a big difference, leading to remission in some women, responses in most.

Treatment development in psychiatry still has a long way to go. The road from basic science discoveries to novel therapies is long and winding. But here we have evidence that it sometimes leads to success. The FDA recently approved brexanolone as the first drug known to target postpartum depression. And for many women, this is good news. Very good news indeed.

References:

Gordon, J. A. (2002). Anxiolytic drug targets: beyond the usual suspects. The Journal of Clinical Investigation, 110, 915–917.

Kanes, S., Colquhoun, H., Gunduz-Bruce, H., Raines, S., Arnold, R., Schacterle, A., … & Meltzer-Brody, S. (2017). Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. The Lancet, 390, 480-489.

Majewska, M. D., Harrison, N. L., Schwartz, R. D., Barker, J. L., & Paul, S. M. (1986). Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science, 232, 1004-1007.

Meltzer-Brody, S., Colquhoun, H., Riesenberg, R., Epperson, C. N., Deligiannidis, K. M., Rubinow, D. R., … & Kanes, S. (2018). Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet, 392, 1058-1070.

Paul, S. M. & Purdy, R. H. (1992). Neuroactive Steroids. The FASEB Journal, 6, 2311-2322.

Purdy, R. H., Morrow, A. L., Moore, P. H., & Paul, S. M. (1991). Stress-induced elevations of y-aminobutyric acid type A receptor-active steroids in the rat brain. Proceedings of the National Academy of Sciences, 88, 4553-4557.

Selye, H. (1941). Anesthetic effect of steroid hormones. Experimental Biology and Medicine, 46, 116–121.