In this video, Dr. Chris Aiken, Editor-in-Chief of The Carlat Psychiatry Report, provides a comprehensive review of Gepirone, also known as Exxua, a newly FDA-approved antidepressant for major depressive disorder in adults. Gepirone is unique due to its classification as an azipirone, a class of medications that work as serotonin 5-HT1A receptor agonists. 

Unlike other antidepressants, Gepirone's mechanism brings both advantages and new concerns. We’ll start by diving into how Exxua works compared to familiar antidepressants like Buspirone, its predecessor. Interestingly, Gepirone has three times higher affinity for the 5-HT1A receptor than Buspirone, and its extended release formula enables once-daily dosing. This is unlike Buspirone, which requires multiple daily doses due to its shorter half-life. However, while Gepirone aims to treat depression, it also carries risks, particularly its potential to cause QTC prolongation, a serious cardiac side effect.

The FDA has issued a warning recommending ECGs during treatment, something no other antidepressant requires. The FDA's approval of Gepirone came after 25 years of rejections and controversy, as 13 clinical trials for depression were negative, leading to earlier denials. However, its eventual approval was based on positive results from a few well-conducted trials. Despite these controversies, Gepirone has shown some promise in improving depressive symptoms, with efficacy comparable to lower-performing antidepressants, boasting a number needed to treat of 6-8 for response and 7 for remission.

In addition to its antidepressant use, Gepirone is being studied for generalized anxiety disorder (GAD) and sexual dysfunction, both areas where Buspirone has shown utility. In GAD, Exxua appears to be effective, though possibly less so than Buspirone. When it comes to sexual side effects, Gepirone may offer relief, improving sexual function in both men and women with depression. A key benefit of Exxua is its minimal sexual side effects and lack of weight gain, unlike many other antidepressants. This makes it comparable to medications like Bupropion, Vilazodone, and possibly Vortioxetine, which also avoid these common side effects.

Despite these advantages, the cardiac risks associated with QTC prolongation pose significant challenges. An ECG is required before and during treatment, which may deter many prescribers. In this detailed breakdown, we’ll explore Gepirone's efficacy, side effects, and how it fits into the broader landscape of antidepressant treatments. We’ll compare it to other 5-HT1A agonists like Vortioxetine, Lurasidone, and Aripiprazole, and weigh its clinical use given the FDA's controversial approval. We’ll also cover its interactions with alpha-2 agonists such as Guanfacine and Clonidine, which could lead to canceled effects due to Gepirone’s alpha-2 antagonism. Given the high rate of negative trials—87% compared to 49% for most approved antidepressants—many clinicians may be hesitant to prescribe Gepirone.

While it spares patients from weight gain and sexual dysfunction, the QTC prolongation risks make its use questionable, especially when other safer and more effective options, such as MAO inhibitors, tricyclics, and ketamine, are available. Ultimately, while Gepirone represents a novel addition to the antidepressant market, its cardiac risks, limited efficacy, and FDA warnings make it unlikely to become a first-line treatment. It may, however, find use in specific cases where its unique mechanism offers benefits that outweigh the risks. For more insights and updates on Gepirone and other psychiatric treatments, stay tuned to the Carlat Psychiatry Report and subscribe to the channel for more in-depth reviews.

Related:

• An Antidepressant Diet (Related Podcast Episode)
• TMS Treatment for Depression: An Update
• Optimal Antidepressant Doses in Major Depression
• Webinar: How to Treat Depression in Older Adults