On September 28, 2023, the FDA approved gepirone (Exxua) for major depressive disorder in adults. The medication is unlike any other antidepressant, and its approval process was unparalleled as well. In this article, I’ll look at what gepirone brings to the table.

How it works

Gepirone is an azapirone, a class of medications that work as agonists at the serotonin 5-HT1A receptor. Buspirone was the original azapirone (Eison AS, J Clin Psychopharmacol 1990;10(3 Suppl):2S–5S). Compared to buspirone, gepirone has three times higher affinity for 5-HT1A, but otherwise the two are close pharmacologic relatives. Tandospirone is another sibling, an azapirone approved for both depression and anxiety in Asia. Other 5-HT1A agonists that are not in the azapirone class include vortioxetine, lurasidone, and aripiprazole.

Gepirone and buspirone also produce an active metabolite (1-PP) that may contribute to their anxiolytic effects. 1-PP is an alpha-2-antagonist, a mechanism shared by prazosin and mirtazapine, as well as yohimbine, a once-popular treatment for erectile dysfunction from the pre-Viagra era. This alpha-2-antagonism may create a drug interaction with alpha-2-agonists like guanfacine and clonidine, something that has been suggested by animal studies but is unexplored in humans.

Most azapirones have short half-lives, but gepirone has overcome its five-hour half-life through extended-release coating, allowing once-a-day dosing. Buspirone, with a half-life of two to three hours, is dosed two to three times a day.

A controversial approval

The FDA rejected gepirone three times over the past 25 years before finally giving it a pass. What changed? It wasn’t the data. The FDA requires two positive results from well-designed, adequately sized, randomized trials to earn approval, and gepirone has met that standard since 2008 (Bielski RJ et al, J Clin Psychiatry 2008;69(4):571–577; Feiger AD et al, J Clin Psychiatry 2003;64(3):243–249). But gepirone also has 13 trials in depression that were not positive, and that is why the FDA rejected it in the past. During the recent approval, the negative data were given a different weight.

The manufacturer (Fabre-Kramer Pharmaceuticals) did not respond to requests for scientific information, but a summary of the FDA’s decision categorizes those unlucky 13 trials as follows:

• Seven negative, including four involving an active comparator where gepirone performed worse than placebo and the active comparator surpassed the placebo on the 17-item Hamilton Depression Rating Scale
• Three failed but “uninformative”
• Two excluded for using dosages outside the usual range
• One excluded due to data manipulation (a relapse prevention trial where 40 patients were removed after the blind was broken) (www.­tinyurl.com/2s4dmyez)

Negative trials are common for antidepressants, but not at this rate. Among 74 trials reviewed by the FDA for approved antidepressants, 49% were negative, compared to 87% for gepirone (Turner EH et al, N Engl J Med 2008;358(3):252–260).

Turning to its positive studies, gepirone separated from placebo by three to four weeks, with continued improvement up to the eight-week end point. Its efficacy was similar to that seen in published trials of other antidepressants, albeit at the lower end of that range, with a number needed to treat of 6–8 for response and 7 for remission (www.tinyurl.com/3z6fkx72).

Gepirone’s antidepressant effects do find further support in six other controlled trials, but most of these had limitations that excluded them from the FDA’s consideration, such as a small sample size or a focus on specific subtypes like anxious or atypical depression.

Overall, the evidence supporting gepirone in depression is weak but positive and in the same league as that for buspirone. Buspirone was explored as monotherapy for depression in the 1990s and was effective in four industry-sponsored placebo-controlled trials, although most of them enrolled patients with high levels of anxiety (Kishi T et al, Psychol Med 2014;44(11):2255–2269). In contrast to these monotherapy depression trials, buspirone actually failed in most of the antidepressant augmentation trials where it is often used. This may be because augmentation trials involve a more difficult-to-treat population. Gepirone has not been tested as antidepressant augmentation.

Other uses

Gepirone is being explored for generalized anxiety disorder (GAD) and sexual dysfunction. Only a few studies are available for GAD. There, gepirone appears to work, though it may be less effective than buspirone (Rossano F et al, Eur Neuropsychopharmacol 2023;76:23–51). In sexual dysfunction, the data are suggestive but far from definitive. Specifically, gepirone improved sexual function in women and men with depression—this was a secondary finding in some of the large trials where it failed to work as an antidepressant (Fabre LF et al, J Sex Med 2012;9(3):821–829).

Side effects

Gepirone’s main advantage over other antidepressants is its lack of weight gain and sexual side effects. However, there are other medication options that are free from those problems as well, such as bupropion, trazodone, vilazodone, and possibly vortioxetine (mirtazapine also spares libido but is not weight neutral)—all have a more reliable track record in treating depression.

Like buspirone, gepirone is well tolerated, with common side effects of dizziness, headache, and gastrointestinal distress. It is weight-neutral and nonsedating. Unlike buspirone, it comes with a warning about QTc prolongation and a recommendation to “perform an ECG prior to initiation, during dosage titration, and periodically during treatment.” The risk here is a potentially fatal arrhythmia (torsades de pointes) and is greater in patients with electrolyte disturbances.

No other antidepressant comes with that mandate. The reason is that gepirone prolongs the QTc by an average of 18 msec at a high dose (100 mg instant release). A similar degree of prolongation caused the FDA to restrict citalopram’s dosing to 40 mg. What is missing from the FDA’s report is how much gepirone prolongs the QTc in normal doses (≤72.6 mg extended release). Likely it is less, but an accidental glass of grapefruit juice could send the serum level higher (see drug interactions in the “Gepirone Quick Facts” table).

When to use gepirone

With the cardiac risks of a tricyclic and the efficacy of buspirone (rough comparisons), gepirone is not first-line for depression. Most patients who move to second- and third-line options need something more effective, like a monoamine oxidase inhibitor, a tricyclic, or ketamine, so it’s hard to find a place for gepirone there. Perhaps there are patients who will benefit from the azapirone mechanism, but it’s hard to justify the cardiac risks when a safer option with comparable antidepressant data exists: buspirone. Buspirone also has an intriguing synergy with melatonin (see the “Buspirone-Melatonin Combo” sidebar). 

Gepirone should be dosed with a meal, as food increases its levels by 20%–30%, based on area under the curve (AUC). The average dose in the trials was 70 mg/day (range 55–85 mg/day), but the FDA-approved max is 72.6 mg. A lower maximum dose is suggested for the elderly (36.3 mg) because they achieve higher serum levels of the drug.

CARLAT TAKE

Gepirone brings new risks and questionable efficacy to the treatment of depression, while sparing patients from weight gain and sexual side effects.