A new oral medication, zuranolone, was developed to treat depressive disorders and recently underwent review by the U.S. Food and Drug Administration (FDA). The drug was under consideration for two different conditions: postpartum depression (PPD) and major depressive disorder (MDD). The medical community and patient populations awaited the FDA’s decision, given the drug’s potential to offer a new type of treatment for these widespread conditions.
The FDA’s Ruling on Zuranolone
The FDA announced its decision on August 4, 2023, approving zuranolone, under the brand name Zurzuvae, for the treatment of postpartum depression in adults. This marked the arrival of the first oral medication specifically approved for PPD. Until this decision, the only PPD-specific treatment was an intravenous injection requiring administration in a healthcare facility. The approval of an oral, 14-day treatment course is a step forward in making care more accessible for women with PPD.
In the same announcement, the FDA issued a Complete Response Letter (CRL) for the New Drug Application for zuranolone in major depressive disorder, meaning the drug was not approved for this condition. A CRL is the FDA’s official communication indicating that an application cannot be approved in its current state. The letter details specific deficiencies and requires the drug’s developers, Sage Therapeutics and Biogen, to conduct additional studies to provide more robust data on its effectiveness and safety for MDD.
How Zuranolone Works
Zuranolone functions as a neuroactive steroid that can rapidly influence brain activity. It works as a positive allosteric modulator of GABA-A receptors. The GABA system is the primary inhibitory signaling pathway in the brain, responsible for calming neural activity. By binding to a distinct site on the GABA-A receptor, zuranolone helps the brain’s main calming neurotransmitter, GABA, work more efficiently.
This mechanism can be thought of as rebalancing brain circuits that have been disrupted by depression. This mode of action differs from more common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), which target the serotonin system and can take four to six weeks to produce an effect. Zuranolone is designed as a short-term, 14-day treatment intended to provide rapid relief from depressive symptoms.
Reviewing the Clinical Trial Data
The FDA’s divergent decisions were based on data from several clinical trials. For postpartum depression, the approval was supported by two Phase 3, randomized, double-blind, placebo-controlled studies, including the SKYLARK Study. In these trials, women with PPD who received a daily 50 mg dose of zuranolone showed a statistically significant reduction in their depressive symptoms by day 15. This was measured by the 17-item Hamilton Depression Rating Scale (HAMD-17) compared to those who received a placebo, and the rapid improvement was a factor in the approval.
The application for major depressive disorder was supported by data from studies including the WATERFALL and CORAL trials. While these studies reportedly met their primary goals, the FDA’s Complete Response Letter indicated the submitted data were not sufficient. The agency concluded that the information did not establish a favorable benefit-risk profile for MDD. This suggests that while some positive effects were observed, they were not strong or consistent enough to warrant approval without further investigation.
What This Means for Depression Treatment
The approval of zuranolone for postpartum depression changes how the condition can be treated. It provides a fast-acting, oral medication that can be taken at home for 14 days. This offers new mothers the possibility of rapid symptom relief without the logistical challenges of intravenous infusions or the long wait times associated with traditional antidepressants. The recommended dose is 50 mg taken once daily in the evening with a fatty meal.
For major depressive disorder, the future of zuranolone is less clear. The rejection means its developers, Sage Therapeutics and Biogen, must review the FDA’s feedback. They will likely need to conduct at least one more large-scale clinical trial to generate the additional evidence the agency requires. This process will delay any potential approval for MDD by several years.