The year 2025 has seen several setbacks in the development of new treatments for depression, with multiple high-profile clinical trials failing to achieve their intended outcomes. The process of developing drugs for central nervous system (CNS) disorders remains difficult, as evidenced by an estimated 85% failure rate for CNS drugs in Phase II and III trials, according to WCG Clinical Services. Between 2009 and 2025, only 15 medications for depressive disorders have received FDA approval, despite major depression affecting more than 8% of the U.S. population each year.
Myles Minter, a partner at William Blair, discussed the ongoing efforts in this field. “You’ve got 21 million patients in the U.S. and around 50% of them get treated,” he said. “But, of these, there are 8 million that really don’t respond after several lines of therapy, including all the relapses.” He cited factors such as side effects, lack of efficacy, and time to efficacy—selective serotonin reuptake inhibitors (SSRIs) can take about six weeks to show results and only work half the time—as contributing to unmet needs.
Minter also identified placebo response as a significant barrier to successful clinical development in depression. Because depression trials rely on patient self-reported outcomes, there is a higher chance that patients receiving placebos will report improvements.
This issue was evident when Johnson & Johnson discontinued its Phase III trial for aticaprant earlier this year due to insufficient efficacy compared to placebo in major depressive disorder (MDD). Minter described this as "the most significant trial failure in recent years," noting its impact on expectations for kappa opioid receptor (KOR) antagonists.
Neumora Therapeutics experienced similar challenges with its KOR antagonist navacaprant. In January, Neumora reported that its first Phase III trial did not show statistically significant improvement over placebo. However, unlike J&J, Neumora chose not to discontinue development but instead made changes to two ongoing studies by reducing the number of sites involved and adding new monitoring procedures. “We believe these changes strengthen the studies and look forward to delivering topline data in 2026,” said Neumora CEO Paul Berns during a business update.
Alto Neuroscience’s ALTO-203 also failed to significantly improve mood in MDD patients during an exploratory trial reported in June. Despite this result, Alto highlighted other positive treatment outcomes such as improved sustained attention and wakefulness that could support further research. Alto’s previous asset targeting the BDNF protein had also failed mid-stage trials less than a year prior.
Patient adherence emerged as another challenge for these trials; Minter noted that up to 30% of participants assigned Alto’s study drug did not take it as directed during one trial phase.
Supernus Pharmaceuticals faced difficulties with SPN-820, an oral activator of mTORC protein designed for treatment-resistant depression (TRD). A Phase IIb trial failed both primary and secondary endpoints earlier this year. Although Supernus had previously seen positive results from an earlier study in MDD patients, CEO Jack Khattar stated that they would continue analyzing data before determining next steps regarding TRD.
Neurocrine Biosciences encountered issues with NBI-1070770 (‘770’), which missed its primary endpoint in a Phase II study evaluating its effect on depression severity. Neurocrine CMO Sanjay Keswani commented there are “aspects of the data that warrant further exploration,” indicating further analysis before future decisions are made.
Despite these failures, some treatments have achieved regulatory approval—such as J&J’s esketamine-based Spravato—and have been recognized by clinicians for their importance in treating severe cases where traditional therapies fail. As Minter concluded regarding Spravato: “Most people say the product is literally a lifesaver because you don’t know when that patient is coming back. If you can’t treat a depressive episode, then that may be the last time you see them.”
