Antidepressant Approvals Could Herald New Era in Psychiatric Drugs

From The Scientist, 1 October 2019:

As droughts go, the one plaguing the antidepressant drug development landscape for the past few decades has been noteworthy. Since the advent of serotonin and norepinephrine reuptake inhibitors in the 1980s and 1990s, there has been a dearth of new pharmacological therapies for mood disorders, says psychiatrist Samantha Meltzer-Brody, director of the University of North Carolina’s Perinatal Psychiatry Program. “The same medications largely that were there when I went to medical school a long time ago were still the ones we’ve been using.”

Given this state of affairs, Meltzer-Brody says she had the “most modest” of expectations a few years ago when she got involved in the first clinical trial testing a new drug, SAGE-547, for postpartum depression. Developed by Massachusetts-based Sage Therapeutics, SAGE-547 is a solution of allopregnanolone, a neuroactive metabolite of the sex hormone progesterone, which plays key roles in the female reproductive system.

Progesterone and allopregnanolone levels peak during the third trimester of pregnancy, then crash immediately after delivery. Preclinical data suggested the drop in allopregnanolone could be a trigger for postpartum depression in some women. The company-funded trial involved administering SAGE-547 to a handful of patients with postpartum depression as an intravenous infusion over 48 hours.

The response in the first patient treated with SAGE-547 was dramatic. From being withdrawn and depressed with no appetite before treatment, she began smiling, talking, eating, and interacting, Meltzer-Brody says. “After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.” Three more patients were treated, with similar results. Known by the generic name brexanolone, the drug sped through Phase 2 and Phase 3 trials before being approved by the US Food and Drug Administration (FDA) on March 19.

Now marketed by Sage Therapeutics as Zulresso, the therapy is the vanguard of a new wave of antidepressants. Although the path to market hasn’t been straightforward for all drug candidates, these treatments are known for being fast-acting and effective, and have fewer side effects than previous therapies. These improvements are reflected in the price tag: the first of these new antidepressants to reach the market—Zulresso and Janssen Pharmaceuticals’ Spravato (esketamine), approved just two weeks earlier for major depressive disorder—cost up to tens of thousands of dollars for a course of treatment. Read more.