FDA Approves New Antidepressant That Does Not Work

It failed in 11 of 13 trials, and ekes out the smallest effect size in the history of psychiatric approvals. Why?

STUDY: Turner EH et al, JAMA Psychiatry 2026

STUDY TYPE: Review

FUNDING: Arnold Ventures (philanthropic)

Background

The FDA approved gepirone XR (Exxua) for major depressive disorder in September 2023. Like its anxiolytic cousin buspirone, gepirone is a serotonin-1A agonist. This paper traces its three-decade path to approval, which included four rejections, an Advisory Committee vote against it, and a final approval that overrode years of internal FDA skepticism.

The Study

• The authors reviewed all FDA documents from the gepirone approval package, including clinical reviews, administrative correspondence, and the 2015 Advisory Committee materials.
• They analyzed 13 trials reviewed by the FDA, nearly all of which have not been published or made available to the public.

Results

Of the 12 short-term trials, only 2 were positive. The other 10 failed to beat placebo. In 3 of those, gepirone performed worse than the active comparator (fluoxetine or paroxetine). The single maintenance trial was also negative.

When all 12 trials were pooled, the overall drug-placebo difference was less than half a point on the HAMD-17 — not statistically significant (p = .09), and well below the 2-point threshold the sponsor itself cited as clinically meaningful. For comparison, FDA-reviewed antidepressant trials typically show a drug-placebo difference of about 2.5 points.

The sponsor achieved a statistically significant result only by excluding several trials it labeled as lacking “assay sensitivity.” The FDA’s own leadership found that argument unconvincing. Why? Some of these supposedly insensitive trials did indeed detect a difference; they found that SSRIs outperformed gepirone.

The Advisory Committee voted 9 to 4 that efficacy had not been demonstrated. FDA leadership nonetheless approved the drug in 2023. The product label mentions only the 2 positive trials; the other 11 are not discussed.

Gepirone is now commercially available as Exxua. Its selling point is that it does not cause sexual side effects (along with bupropion, mirtazapine, the off-label pramipexole, and possibly trazodone and vortioxetine). Its downside is that it does not have a meaningful or lasting benefit and requires and ECG before starting (due to QTc prolongation).

Practice Implications

1. Before the 1960s, the American Medical Association regulated medication approvals, but they lost the public’s trust by earning advertising money from the companies whose drugs they approved.
2. The FDA took over in 1963. Now they are burning the trust they earned with industry-friendly approvals, incentivized by a revolving door that rewards FDA employees with high paying jobs at the industries they once “regulated.”
3. Learn more about gepirone, and how it compares to buspirone.

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

What’s Your Take? Share in Comments