https://www.scientificamerican.com/article/an-entirely-new-type-of-antidepressant-targets-postpartum-depression/

An Entirely New Type of Antidepressant Targets Postpartum Depression

The steroid drug is intended to help women who suffer from the hormone-driven condition

Dana G. SmithAugust 15, 2018

Postpartum depression afflicts 10 to 20 percent of the nearly four million women who give birth in the U.S. every year. The condition hits at a vulnerable moment when mother and infant normally begin to bond. Depressed moms pay less attention to their newborns, so the critical attachment between mother and baby does not occur. For some women, postpartum depression can last for years, and the lack of maternal bonding can interfere with children’s development through adolescence.

“There’s a real need to identify women and treat them, and treat them quickly,” says Samantha Meltzer-Brody, director of the Perinatal Psychiatry Program at the University of North Carolina at Chapel Hill Center for Women’s Mood Disorders. “When mom is not doing well, it becomes a crisis for the whole family at this vulnerable time. But like many issues related to mental health, and specifically women’s mental health, it has been neglected.”

Despite the frequency of postpartum depression, no treatments specifically target it. Many women who suffer from the condition receive standard antidepressants like SSRIs (selective serotonin reuptake inhibitors, such as Prozac) but it is unclear how well these drugs work because the neurochemical serotonin may play only a secondary role in postpartum depression or may not be involved at all. Instead, researchers hypothesize that a shift in female reproductive hormones during pregnancy is the main cause. Now a new drug that has gone through late-stage clinical trials aims to correct the consequences of these hormonal changes, and early results in human trials suggest it may be working.

The reason for the drug’s possible efficacy has to do with the basic biology of pregnancy. An expectant mother experiences a dramatic rise in the reproductive hormones estrogen and progesterone. Accompanying that increase is a spike in the brain of a steroid called allopregnanolone. Allopregnanolone activates GABA receptors—a neurochemical that signals brain cells to stop firing. GABA activity, however, stays largely the same during pregnancy because most of its cellular receptors go dormant to avoid being activated by allopregnanolone. If they were not, too much GABA receptor activation would cause a pregnant woman to become virtually anesthetized.

Immediately following birth, estrogen, progesterone and allopregnanolone drop back to normal levels, after which GABA receptor levels rebound quickly. But in some new mothers the readjustment in GABA receptors takes longer. Researchers postulate this lag may underlie the depression some women experience postpartum. Low GABA activity is known to result in generalized depression and anxiety.

Istvan Mody, a professor of neurology and physiology at the University of California, Los Angeles, has studied this complex system of hormones, steroids and neurochemicals for many years. In 2008 he showed postpartum mice that had lower levels of GABA receptors provided poor care for their pups—in some cases, the mothers even ate their own babies. Mody gave the mothers a drug that activated the few available GABA receptors to increase their function. After just one day of the treatment Mody says the mice “no longer threw the pups around, they did not cannibalize them. They pretty much behaved like normal.”

Based on Mody’s research, a company called Sage Therapeutics has developed a new drug to treat postpartum depression. Administered intravenously, the medication elevates allopregnanolone. It does not target the GABA receptors directly but has a similar effect: Higher levels of the steroid help activate the receptors, keeping GABA at a healthy level. Two phase II clinical trials led by Meltzer-Brody at U.N.C. tested the new drug in severely depressed postpartum women and had successful outcomes, resulting in a significant improvement in the self-reported mood of 70 percent of the new mothers. Most striking, the effect occurred immediately after the drug was administered, and the benefits persisted for 30 days. The first two trials included a total of only 25 women but Sage has since conducted two phase III trials with a combined 246 postpartum women, and preliminary reports are promising. The drug, called Brexanolone, is now under review by the U.S. Food and Drug Administration. If approved, it would be one of the first antidepressants with a new mechanism of action developed in recent years.

Beyond postpartum depression, Mody hopes these drugs could treat other types of hormonal depression such as premenstrual dysphoric disorder—an extreme version of premenstrual syndrome (PMS)—and depression around the time of menopause. Mody is also looking into whether nonhormonal depression in women is influenced by this system. Women are twice as likely to suffer from generalized depression than men, so it is possible there is a hormonal component to their depression outside the established periods of extreme hormone fluctuation.

Not everyone is convinced, however, that this particular steroid pathway is the right target. Other hormones and neurochemicals—oxytocin, prolactin and norepinephrine—have also been implicated in postpartum depression. Joseph Lonstein, a professor of psychology at Michigan State University who was not involved in the research, says, “I very much doubt this is the only system that’s atypical in women [who] might suffer from postpartum depression or anxiety, but I think it’s a completely reasonable one, and I think that it does make a lot of sense.”

To Meltzer-Brody, a drug that engages any of these targets is better than none at all. She says there is a great need for new treatments developed based on the currently understood underlying pathophysiology of postpartum depression—or at least one contributor. “That would change the way we’re able to treat [these] women,” she notes. “We have to do better than we’re doing.”