Gepirone (EXXUA): A Questionable Depression Drug With a Protracted FDA-Approval Path

In September 2023 the Food and Drug Administration (FDA) approved the oral, once-daily, extended-release drug gepirone (EXXUA) to treat major depressive disorder (MDD) in adults.[1]

MDD is a debilitating condition characterized by having five or more key symptoms for at least two weeks that are not attributed to other underlying health issues.[2] These symptoms include depressed mood, inability to feel joy or pleasure, low energy, poor concentration, agitation or psychomotor retardation (slowed thinking or speech, or decreased body movement), sleeplessness or oversleeping, thoughts of worthlessness or guilt, a change in appetite or weight, and repeated thoughts about death or suicide.

When it announced the FDA approval, gepirone’s current manufacturer (Fabre-Kramer Pharmaceuticals) hailed the drug as the “first and only approved antidepressant with a novel mechanism of action that selectively targets the serotonin 1A receptor…[and that it] relieves depressive symptoms with an acceptable side effect profile [and] provides an important new treatment option for patients.”[3]

However, neither the announcement nor the drug labeling[4] mentions that the FDA had previously declined to approve gepirone three times since 2002 or that most of the preapproval trials failed to demonstrate any benefit for the drug. Although having negative studies for approved drugs is not uncommon, gepirone has by far the highest number of such failed studies among 16 new psychiatric drugs that the FDA approved from 2013 to 2024, according to a 2025 analysis published in JAMA Network Open.[5]

In a December 2015 testimony before an FDA advisory committee of external scientific experts, Public Citizen’s Health Research Group urged the FDA not to approve gepirone without additional robust evidence of effectiveness.[6] Moreover, the advisory committee voted 9 to 4 that the manufacturer did not provide substantial evidence of effectiveness for gepirone.[7]

We have designated gepirone as Do Not Use due to the above concerns about its effectiveness, in addition to the lack of data about its long-term benefit and the fact that it has unique serious risks and monitoring requirements, as discussed below.

Priced at nearly $1,800 per month without insurance, gepirone is not currently approved for use outside the United States.

Limited benefit

According to the FDA, only two of 17 randomized, double-blind phase 2 or 3 controlled preapproval trials for gepirone showed statistically significant benefits on their primary endpoints.[8] Less than 1% of the participants in the two positive trials were 65 years of age or older.

The two positive trials lasted for only eight weeks and enrolled adults with MDD whose mean age was 39 years. The final analytic sample in the first trial involved 204 participants and the second involved 238 participants. Half of the participants in both trials received flexible doses of gepirone, and the remaining participants received a placebo.

By the end of follow-up, gepironetreated participants in both trials had a statistically significant larger reduction (by an average of 2.5 points) from baseline in their depression scores than participants in the placebo group. The depression scores were measured using the Hamilton depression rating scale, a 17-item clinician-administered tool with values ranging from zero to 52; lower scores indicate fewer depressive symptoms, and higher scores indicate severe symptoms over the last week. However, the 2.5-point difference in the depression scores in favor of gepirone is likely too small to reflect meaningful improvement to most MDD patients.[9] Notably, FDA officials had flipflopped on their assessment of the two positive trials. Initially, they determined that the trials might represent chance findings. However, after gepirone’s manufacturer submitted a formal dispute resolution request, a senior FDA official determined that the statutory standard for substantial evidence of effectiveness was met, which paved the way for the approval decision.

Notably, the manufacturer conducted a single long-term relapse prevention, placebo-controlled trial involving 250 participants with MDD, which lasted for up to 44 weeks.[10] However, the FDA characterized the trial as “insufficiently [designed] to yield interpretable evidence” due to problems with defining relapse. The agency scientists also did not accept attempts by the manufacturer to salvage the trial by changing the relapse criteria after the trial was completed.

Key safety profile

Gepirone has similar risks to other serotonergic antidepressants. For example, gepirone’s labeling includes a prominent (boxed) warning regarding an increased risk of suicide and suicidal ideation, especially in children and young adults. Based on clinical trials, treatment with gepirone in patients under the age of 25 years was associated with an excess risk of 19 cases of suicide or suicidal ideation per 1,000 cases compared with patients who took a placebo.

Gepirone’s labeling also carries general warnings regarding activation of mania (with symptoms that may include unusually increased energy, severe problems sleeping, racing thoughts and an elevated or irritable mood) or hypomania (a milder, shorter version of mania symptoms) in people with bipolar disorder. There also is a warning about an increased risk of serotonin syndrome, which is a potentially fatal condition characterized by agitation, confusion, hallucinations, fast heartbeat, high fever, shivering, sweating, nausea, vomiting, diarrhea, and muscle rigidity or twitching. In severe cases, this syndrome can lead to seizures and coma.

Importantly, gepirone has higher rates of certain adverse effects and monitoring requirements than other
antidepressants. Specifically, based on pooled data from the two positive trials, the drug causes dizziness, nausea and headache in 49%, 35% and 31%, respectively, of its users, which are higher rates than those for participants who took a placebo. The drug also causes higher rates of insomnia (trouble sleeping), abdominal pain and dyspepsia (upset stomach).

An electrocardiogram (ECG) reading is required before initiating treatment with gepirone, during dosage titration and periodically thereafter because the drug can cause a heart-rhythm problem called QT interval prolongation, which can lead to fainting and irregular heartbeat.

Similarly, blood tests are required to check (and correct, if necessary) the level of certain body salts (electrolytes), including low blood levels of magnesium (hypomagnesemia) or potassium (hypokalemia), before and during treatment with gepirone.

Instead of not approving gepirone because of the above serious risks, the FDA decided that these risks can be mitigated by adding warnings to the drug label.

Gepirone’s manufacturer claims that, unlike other antidepressants (such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors), gepirone is not associated with unwanted adverse effects, such as weight gain or a decrease in sexual function. However, FDA scientists noted that gepirone’s studies did not provide sufficient data regarding sexual dysfunction and that, compared with placebo, there appears to be some weight gain associated with its use.

Future studies

As a post-marketing requirement, the FDA mandated gepirone’s manufacturer to conduct a multipledose study to examine gepirone’s effects on QT interval prolongation using ECG readings in healthy subjects. Other requirements include collecting pregnancy-related registry data and conducting an additional pregnancy study to assess pregnancy complications as well as major congenital malformations and other birth outcomes.

Furthermore, the manufacturer committed to conducting a placebocontrolled, randomized-withdrawal trial to evaluate the long-term effectiveness of gepirone among participants who previously benefited from the drug. However, results of this study are not expected until early 2030.

What You Can Do

If you have mild to moderate MDD, seek nondrug treatment options, including psychotherapy (such as cognitive behavioral therapy) and physical activity, as first-line treatments. If you need treatment with antidepressant therapy, consider older approved options and do not take gepirone.

If you are currently taking gepirone or any other antidepressant, do not change your dose or stop taking it without consulting your clinician.

Call your clinician or get emergency medical help right away if you experience new or sudden changes in behavior, mood, thoughts or feelings, or if you develop suicidal thoughts or actions while taking any antidepressant. You also can call, text or chat online with the 9-8-8 Suicide & Crisis Lifeline, which is free and confidential, anytime if you are facing mental health struggles or just need to talk to someone.[11]

References

[1] Food and Drug Administration. NDA approval letter re. Gepirone (Exxua). September 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/021164Orig1s000ltr.pdf. Accessed September 8, 2026. 

[2] Rush AJ. Major depressive disorder in adults: Approach to initial management. UpToDate. July 2026.  

[3] Fabre-Kramer Pharmaceuticals announces FDA approval of EXXUA, the first and only oral selective 5HT1a receptor agonist for the treatment of major depressive disorder in adults. PR Newswire. September 28, 2023. https://www.prnewswire.com/news-releases/fabre-kramer-pharmaceuticals-announces-fda-approval-of-exxua-the-first-and-only-oral-selective-5ht1a-receptor-agonist-for-the-treatment-of-major-depressive-disorder-in-adults-301941467.html. Accessed September 8, 2026. 

[4] Fabre-Kramer. Label: Gepirone (EXXUA). September 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021164s000lbl.pdf. Accessed September 8, 2026.

[5] Ahn-Horst RY, Turner EH, Kesselheim AS. Characteristics of trials preceding FDA approval of novel psychiatric drugs. JAMA Netw Open. 2025;8(1):e2456588. 

[6] Public Citizen. Testimony before the FDA’s Psychopharmacologic Drugs Advisory Committee regarding gepirone. December 1, 2015. https://www.citizen.org/article/testimony-before-the-fdas-psychopharmacologic-drugs-advisory-committee-regarding-gepirone/. Accessed September 8, 2026.

[7] Food and Drug Administration. Summary Minutes Meeting of the Psychopharmacologic Drugs Advisory Committee December 1, 2015, meeting regarding gepirone. December 1, 2015. https://fda.report/media/95048/Minutes-for-the-December-1--2015-Meeting-of-the-Psychopharmacologic-Drugs-Advisory-Committee-%28PDAC%29.pdf. Accessed September 8, 2026. 

[8] Food and Drug Administration. NDA multidisciplinary review and evaluation NDA 021164, Gepirone. December 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/021164Orig1s000MultidisciplineR.pdf. Accessed September 8, 2026.

[9] Turner EH, Powers JH, Ahn-Horst RY, Kesselheim AS. Assessing drug efficacy after multiple negative trials—gepirone’s journey through the FDA. JAMA Psychiatry. 2026;83(8):864-869.

[10] Food and Drug Administration. NDA multidisciplinary review and evaluation NDA 021164, Gepirone. December 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/021164Orig1s000MultidisciplineR.pdf. Accessed September 8, 2026. 

[11] Substance Abuse and Mental Health Services Administration. 988 lifeline. https://988lifeline.org/. Accessed September 8, 2026.