Know Limitations of the New Antidepressant Gepirone

Gepirone ER tabs (Exxua) will be the first selective serotonin 1A receptor agonist approved for depression.

Think of it as working similarly to the anxiety med buspirone.

But don’t get too excited...gepirone has a checkered history.

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FDA rejected it 3 times over 20 years...due to a stack of studies that don’t find any benefit compared to other meds or placebo.

Now it’s approved for adults with depression based on 2 studies showing efficacy at 8 weeks. But there aren’t good data showing long-term efficacy. And it doesn’t seem effective in kids, based on data so far.

Plus there are other downsides. For example, about a third or more of patients taking gepirone report dizziness, nausea, or headache.

Also, gepirone seems to prolong the QT interval more than other antidepressants, such as citalopram. And ECG monitoring is recommended before starting gepirone and periodically during treatment.

On top of that, gepirone will likely cost at least $500/month versus about $15 for generic first-line meds (SSRIs, SNRIs, etc).

Expect to hear that gepirone doesn’t carry a warning about sexual dysfunction. But there’s no good evidence that sexual dysfunction is less...and any difference may not matter if the med isn’t effective.

Don’t jump to gepirone.

If meds are preferred for depression, continue to rely on first-line options instead...such as an SSRI, SNRI, bupropion, or mirtazapine.

Tailor based on symptoms, comorbidities, med side effects, etc.

For example, consider bupropion or mirtazapine if sexual side effects are a concern. But advise caution with bupropion in patients with anxiety...and avoid mirtazapine if there’s concern about weight gain.

Explain that it may require trial and error...since less than one-third of patients achieve remission with the first antidepressant.

Recommend SWITCHING antidepressants if patients don’t respond after 4 to 6 weeks at an optimized dose...or it’s not tolerated.

With a partial response, individualize options to AUGMENT...based on side effects, interactions, etc.

Consider adding a second antidepressant from a different class. Often suggest bupropion or mirtazapine PLUS an SSRI or SNRI.

Or consider adding an atypical antipsychotic. Several are FDA approved...but lean toward aripiprazole due to tolerability and cost.

Review our resource, Choosing and Switching Antidepressants, for more med considerations and strategies to taper, switch, etc.

Key References

  • FDA. Drug Approval Package: Exxua. November 28, 2023. (Accessed April 18, 2024).
  • Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252.
  • Kovich H, Kim W, Quaste AM. Pharmacologic Treatment of Depression. Am Fam Physician. 2023 Feb;107(2):173-181.
  • Keam SJ. Gepirone Extended-Release: First Approval. Drugs. 2023 Dec;83(18):1723-1728.
Pharmacist's Letter. May 2024, No. 400501

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