Gepirone Offers New Option for Major Depressive Disorder

In September 2023, the FDA granted approval to gepirone hydrochloride extended-release tablets (Exxua; Fabre-Kramer Pharmaceuticals) for the treatment of major depressive disorder (MDD) in adults. The medication represents a pioneering class of antidepressants that selectively target 5HT1A receptors, thereby displaying a more favorable adverse effects profile. Anticipated to arrive in pharmacies early in 2024, gepirone offers a promising option for those seeking relief from depression without the unwanted adverse effects of sexual dysfunction or weight gain.¹

Gepirone, an azapirone compound, serves as a pharmacological counterpart to buspirone, exerting its specific action on both pre- and post-synaptic 5HT1A receptors. In contrast to buspirone, gepirone exhibits higher effectiveness in stimulating the 5-HT1A receptor and displays minimal binding affinity for the D2 receptor, with a substantially lower affinity compared to buspirone.^2,3

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Initial clinical trials demonstrated promising outcomes for gepirone; however, its immediate-release tablet formulation required frequent dosing intervals due to its brief half-life. It was not until an extended-release variant of gepirone became accessible that it emerged as a potential candidate for a new antidepressant, offering an improved dosing schedule.⁴

Approval of the medication was granted on the basis of data obtained from two 8-week clinical trials that were randomized, double-blinded, placebo-controlled, and utilized flexible dosing. These trials involved outpatients aged 18 to 69 who met the DSM-IV criteria for Major Depressive Disorder (MDD). In both trials, gepirone extended release demonstrated its superiority to the placebo, as assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17).³

In the initial trial, individuals receiving gepirone extended release displayed more substantial enhancements in their depression scores after 8 weeks compared to those in the placebo group, with a mean difference of -2.47 (P=0.013). The second trial yielded comparable results.^3,5

Subsequently, in a maintenance study, patients diagnosed with MDD who had previously responded positively to gepirone extended release during the open-label treatment phase were randomized to either continue the medication for a duration of up to 12 months or switch to a placebo. It was observed that the treatment group experienced a statistically significant lower rate of relapse when contrasted with the placebo group (24% vs. 38.7%).³

Extended-release tablets will be available in 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg. The recommended starting dose is 18.2 mg and may be increased after 7 days of use.⁶

Like many other antidepressants, this medication has a black box warning regarding an elevated risk of suicidal thoughts and behaviors in young adults.6 Contraindications include known hypersensitivity to gepirone, prolonged QTc interval > 450 msec at baseline, congenital long QT syndrome, concomitant use of strong CYP3A4 inhibitors, severe hepatic impairment, and use with an MAOI or within 14 days of stopping treatment with gepirone. Recommended to do not use gepirone within 14 days of discontinuing an MAOI. Warnings and precautions include recommendations to monitor for QTc prolongation, serotonin syndrome if used with other serotonergic agents, and screening for bipolar disorder.⁶

Gepirone could be a viable alternative to selective serotonin reuptake inhibitors (SSRIs) for the treatment of psychiatric disorders, as it doesn't induce sexual dysfunction, a common limitation associated with SSRIs.³

References

1. Biospace. 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. https://www.biospace.com/article/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/?s=74. Accessed on November 7, 2023.

2. Jenkins SW, Robinson DS, Fabre LF Jr, et al. Gepirone in the treatment of major depression. J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):77S-85S. doi: 10.1097/00004714-199006001-00014.

3. Kaur Gill A, Bansal Y, Bhandari R, et al. Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties. Drugs Today (Barc). 2019 Jul;55(7):423-437. doi: 10.1358/dot.2019.55.7.2958474. PMID: 31347611.

4. Robinson DS, Sitsen JM, Gibertini M. A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone. Clin Ther. 2003 Jun;25(6):1618-33. doi: 10.1016/s0149-2918(03)80159-5.

5. Alpert JE, Franznick DA, Hollander SB, et al. Gepirone extended-release treatment of anxious depression: evidence from a retrospective subgroup analysis in patients with major depressive disorder. J Clin Psychiatry. 2004 Aug;65(8):1069-75. PMID: 15323591.

6. Exxua (gepirone hydrochloride extended-release tablets). [prescribing information]. September 2023.