Gepirone: A New Extended-Release Oral Selective Serotonin Receptor Agonist for Major Depressive Disorder

Abstract

Objective: To evaluate the safety, efficacy, and tolerability of gepirone (Exxua) in the treatment of adult patients with major depressive disorder. Data Sources: A literature search was performed through PubMed, Embase, and PsycINFO using the following terms: Exxua, gepirone, depression, major depressive disorder, anxiety, and anxiety disorders. Study Selection and Data Extraction: Articles that were selected included English-language dominant studies, or studies that could be translated into English by the authors, with terms associated with the safety, efficacy, and/or tolerability of gepirone. Data Synthesis: Gepirone exhibits its antidepressant activity through agonism of 5HT_1A serotonin receptors. Phase 3 clinical trials showed that gepirone at a dose of 20 to 80 mg was proven to be effective in the treatment of major depressive disorder in adult patients. Common adverse effects reported in clinical trials included dizziness, nausea, headache, fatigue, and insomnia. Conclusion: This review evaluates the pharmacokinetic, pharmacologic, efficacy, and safety profile of gepirone and includes a discussion on its place in therapy for the treatment of major depressive disorder. Most clinical guidelines recommend second-generation antidepressants consisting of selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors as first-line therapy options. Gepirone is expected to receive greater clinical relevance and recommendations when compared to other azapirone medications (buspirone) within practice guidelines. Gepirone could be considered as either an alternative option for patients failing first-line therapies or for initial use to avoid unwanted side effects of other therapy options in the treatment of adult patients with major depressive disorder.

Introduction

Major depressive disorder (MDD), commonly referred to as unipolar depression, affects approximately 3.8% (280 million) of the global population, and approximately 8.3% (21 million) of adults in the United States.^1,2 Major depressive disorder was the largest contributor to nonfatal health loss globally in 2015. ³ In the United States alone, the total economic burden of MDD increased from $236.6 billion in 2010 to $326.2 billion in 2018, an increase of 37.9%. ⁴ Despite the economic burden and disability associated with MDD, many individuals remain untreated or undertreated. ⁵

The underlying cause of depression is not fully elucidated. One of the leading hypotheses is the monoamine hypothesis, describing the cause of depression to be due to a lack or imbalance of monoamine neurotransmitters, mainly serotonin, norepinephrine, and dopamine.^{6 -8} The relative efficacy of medication classes, such as tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs), supports this hypothesis. On the contrary, the lack of generalized success, observed through delayed onset of action and common non-responses to antidepressant therapy, suggest that the monoamine hypothesis is part of a larger, unknown etiology. ⁸ The most studied serotonin receptor subtype is the 5HT_1A receptor. Experimental evidence from preclinical studies suggests that 5HT_1A receptor-mediated transmission in the hippocampus is increased with long-term antidepressant treatment to alleviate symptoms, such as impaired memory and concentration. ⁹ The 5HT_1A agonists have struggled to gain traction in depression treatment having less robust coverage of serotonin modulation due to the 5HT_1A specificity. For example, buspirone agonizes 5HT_1A receptors but lacks a Food and Drug Administration (FDA) indication for MDD and is more so considered for its anxiolytic properties.

Gepirone extended release (ER) is the first 5HT_1A receptor agonist approved by the US FDA with an indication for MDD. ¹⁰ For historical context, gepirone has been undergoing clinical trials for the treatment of MDD dating back to the early 1990s. Despite multiple FDA rejections and transitions between pharmaceutical companies, gepirone was finally approved in September 2023. It is the first unique approach for the pharmacological treatment of MDD to be approved in decades. ¹¹ The purpose of this review is to describe the pharmacology, pharmacokinetics, efficacy, and safety of gepirone ER in the treatment of MDD.

Data Selection

A literature search was performed utilizing PubMed, Embase, and PsycINFO using the following search terms: Exxua, gepirone, depression, major depressive disorder, anxiety, and anxiety disorders. The search was conducted with an end search date of March 31, 2024. All English-language dominant studies, or studies that could be translated into English by the authors, with the associated search terms were included and analyzed.

Pharmacology and Pharmacokinetics

Pharmacology

Gepirone is a 5HT_1A receptor agonist, which exerts its actions both pre-synaptically and post-synaptically. While the full mechanism of action is not completely understood, it is believed that the normalization of serotonin levels resulting from autoreceptor desensitization and agonism at postsynaptic 5HT_1A receptors plays a part in the antianxiety and antidepressant properties of gepirone. ¹² The parent drug, as well as both active metabolites 3’-OH-gepirone and 1-PP, are responsible for its pharmacologic activity. ¹³ Gepirone is classified as an azapirone with a structure similar to buspirone, however, has minimal affinity for the dopamine receptor.^14,15

Pharmacokinetics

Gepirone is 14% to 17% bioavailable, and maximal concentrations (C_max) are reached within 6 hours after oral administration. Results of 2 studies comparing gepirone administered in a fasting state versus post-prandially demonstrated the (C_max and area under the curve (AUC) of gepirone were significantly higher in patients who took gepirone 15 minutes after a meal.^16,17 Thus, it is recommended gepirone be taken with food at the same time each day. Gepirone is 72% bound to plasma proteins and has a volume of distribution of approximately 94.5 L.^13,14 Renal impairment (creatinine clearance [CrCl] < 50 mL/min) and hepatic impairment (Child-Pugh Classes B and C) have been shown to increase the C_max and AUC; thus, specific dosing requirements are required for such situations. Gepirone is primarily metabolized by CYP3A4. Dose reductions are required in patients taking moderate CYP3A4 inhibitors and its use is contraindicated in patients taking strong CYP3A4 inhibitors. The elimination half-life is roughly 5 hours with steady-state concentrations achieved within 2 to 4 days.^13,14

Clinical Trials

There are a multitude of development studies evaluating the use of ER gepirone in the treatment of MDD.^11,18 However, only a handful of phase 3 studies yielded interpretable results and are included in the analysis below. ¹⁹

Trial Number 134001²⁰

Bielski and colleagues designed a multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and tolerability of gepirone ER 20 to 80 mg/day in the treatment of MDD over an 8-week treatment period. Subjects between the ages of 18 and 70 years of age with a Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) diagnosis of moderate to severe MDD, significant dysphoria for the past 4 weeks prior to screening, and a Hamilton Depression Rating Scale-17 (HAMD-17) total score of ≥ 20 were included. The primary endpoint was the change from baseline in the HAMD-17 total score at the conclusion of the study (week 8 or last visit) for the intention-to-treat (ITT) study population. Secondary endpoints included change from baseline in additional scales and scoring systems evaluating depression and/or anxiety. After study initiation and randomization, a total of 204 subjects encompassed the ITT population. Slightly higher rates of dropout occurred in the gepirone ER group due to adverse effects, such as dizziness, nausea, headache, somnolence, insomnia, and diarrhea. In the study population, 66% were on the prescribed dose of 80 mg once daily at study endpoint. Significant differences in the primary endpoint between the gepirone ER and placebo groups were found at both week 3 (P = 0.013) and study conclusion (P = 0.018). Results regarding secondary endpoints favored gepirone ER at all study visits with a significant difference at study endpoint. The authors concluded that there is strong evidence supporting the therapeutic use of gepirone ER for the treatment of adult patients with MDD.

A follow-up study (Trial Number 134002) evaluating the same endpoints with a similar study design aimed to reinforce the efficacy of gepirone ER in treating MDD. ¹⁹ In contrast to the previous study, the primary endpoint analysis revealed gepirone ER did not produce significant results. However, positive trends for the secondary endpoints were noted in the study results.

Trial Number FKGBE007 ²¹

Feiger and colleagues conducted a multicenter, randomized, double-blind, placebo-controlled study evaluating gepirone ER for the treatment of MDD. After a 4-day to 7-day washout period via placebo, 209 subjects were randomized to receive either placebo or gepirone ER (20-80 mg) once daily for 8 weeks. Inclusion/exclusion criteria and primary/secondary endpoints were similar to the previously mentioned studies, with the exception of the age range of included patients (18-64 years of age). Similar dropout rates were seen between the gepirone ER and placebo groups, attributable to adverse effects, lack of efficacy, and other reasons, leaving the ITT population consisting of 204 patients (101 in gepirone ER and 103 in placebo groups, respectively). In the study population, 66% were on the prescribed dose of 80 mg once daily at study endpoint. Use of gepirone ER produced significant changes in the primary endpoint at weeks 4, 6, and conclusion of the study (week 8 or last visit). Furthermore, results of the secondary endpoints favored gepirone ER over placebo. With these results, the authors concluded that this study provides strong evidence supporting the use of gepirone ER for the treatment of adult patients with MDD.

A follow-up study (Trial Number FKGBE008) evaluated the therapeutic efficacy of gepirone ER versus placebo in adult patients with MDD with a similar study design but smaller sample size. ¹⁹ This study evaluated the same endpoints, however, use of gepirone did not produce significant results. In contrast, data trends suggested that gepirone had a beneficial effect on MDD symptoms.

Trial Number 134023

This study was a multicenter, randomized, double-blind, placebo-controlled trial of gepirone ER in adult patients with MDD over the course of a 9-week treatment period. ¹⁹ After a 4-day to 14-day washout period with placebo, patients were randomized to receive either gepirone ER (20-80 mg/day) or placebo once daily and evaluated at weeks 1, 2, 3, 5, 7, and 9. Patients enrolled in the study were between 18 and 70 years of age with moderate to severe MDD (per DSM-IV), had experienced the current MDD episode and dysphoria the majority of the days for at least the previous calendar month, and had a Montgomery-Asberg Depression Rating Scale score ≥ 30. The primary outcome included the change in HAMD-17 total score by the end of the study (week 9 or last visit). Secondary outcomes included additional scales and scoring systems regarding depression. A total of 246 subjects (123 per group) were included in the ITT analysis. There were similar rates of drug discontinuation in both groups (26% vs 21.3%) with more dropouts due to adverse effects (9.4% vs 0.1%) yet less dropouts due to lack of efficacy (3.9% vs 5.5%) in the gepirone group compared to placebo. Use of gepirone ER versus placebo failed to produce significant results in both the primary and secondary outcomes. Interestingly, both groups experienced an 8-point reduction in HAMD-17 scores by study endpoint (P = 0.947). The authors concluded that while the study was adequately designed, the trial did not show therapeutic benefit of gepirone ER in the treatment of adults with MDD.

Keller 2005

This study evaluated the long-term efficacy and tolerability of gepirone ER on relapse prevention in adult patients with MDD. ²² This multicenter, randomized, placebo-controlled study included adult patients between 18 and 70 years of age with a diagnosis of recurrent MDD (per DSM-IV) and both a screening and baseline HAMD-17 total score ≥ 20. After completing a 3-day to 14-day washout period with placebo, patients were assigned to complete either an 8-week or a 12-week open-label treatment course of gepirone ER at a starting dose of 20 mg per day with further titration to 40 to 80 mg per day. Time to achieving remission, defined as a HAMD-17 total score ≤ 8, determined which treatment course duration patients were assigned. Patients who achieved remission were randomized and double-blinded to either continue their current gepirone ER treatment or provided a placebo for 40 to 44 weeks. The primary outcome of this study was a comparison in the rates of relapse, defined as a HAMD-17 total score ≥ 16 or discontinuation of the assigned treatment due to lack of efficacy, between gepirone ER and placebo groups. Of the 303 patients who completed treatment in the open label phase, 250 patients met the remission criteria to be randomized into the double-blind continuation phase. Use of gepirone ER led to significantly lower relapse rates compared with the placebo group (23% vs 34.7%; P = 0.024). During the open-label phase, the most common adverse effects included nausea (15.7%), dizziness (13.1%), headache (12.9%), insomnia (6.2%), and vertigo (6%). Adverse effects during the continuation phase were similar in presentation as well as frequency between the gepirone ER and placebo groups (43.7% vs 42.7%). Based on the results of this study, the authors concluded gepirone at a daily dose of 40 to 80 mg per day is effective for relapse prevention in adult patients with a diagnosis of MDD.

Adverse Effects and Safety

The most common adverse effects associated with gepirone (reported in ≥ 10% of patients in clinical trials) are dizziness, nausea, headache, somnolence, insomnia, and diarrhea.^{19 -22}Adverse effects that plague other treatments commonly used for depression, such as anticholinergic effects (constipation and dry mouth), sexual dysfunction, and weight gain, were rarely reported in clinical trials with gepirone.

Prior to initiating gepirone treatment, electrocardiogram (ECG) and electrolyte monitoring are required. Electrolyte abnormalities, specifically hypomagnesemia and hypokalemia, should be corrected prior to starting gepirone. In addition, electrolytes should be periodically monitored, especially in patients taking diuretics or glucocorticoids and those with a history of electrolyte imbalances. Gepirone prolongs the QTc interval and is thus contraindicated in patients with congenital long QTc syndrome. If the QTc interval exceeds 450 ms at baseline, the use of gepirone should be avoided. Periodic ECG monitoring should be conducted in patients taking other medications, which affect the QTc interval and in patients at risk of developing torsade de pointes. Dose increases should be avoided if the QTc interval exceeds 450 ms during treatment. ¹³

Similar to other antidepressants, a black box warning regarding suicidal thoughts and behaviors is included in the package insert for gepirone. Close monitoring of patients initiated on gepirone should occur, especially during the first several months of treatment and within at-risk populations. Patients should be periodically evaluated for the emergence of suicidal thoughts and behaviors as well as clinical worsening of their depression. ¹³

Drug Interactions

The main drug-drug interactions of concern are with other CYP3A4 substrates. Both CYP3A4 inhibitors and inducers can significantly affect the serum concentration of gepirone. Gepirone is contraindicated with concomitant use of strong CYP3A4 inhibitors (eg, ritonavir, ketoconazole) as this interaction can cause a five-fold increase in gepirone serum concentrations. Gepirone is also contraindicated with concomitant use of strong CYP3A4 inducers (eg, rifampin, phenytoin) as the serum concentration of gepirone can be reduced by as much as 29-fold. In addition, gepirone is contraindicated with concomitant use of MAOIs and requires a 14-day washout period prior to switching agents. The coadministration of gepirone with other serotonergic agents or QTc interval prolonging agents requires continuous monitoring throughout treatment. ¹³

Dosing and Administration

Gepirone is available in 18.2, 36.3, 54.5, and 72.6 mg ER tablets. The recommended starting dose for gepirone is 18.2 mg daily and can be titrated based on patient response to a maximum dose of 72.6 mg once daily over a period of approximately 2 weeks. ¹³ Patients should be instructed to take gepirone with food due to the increase in bioavailability following oral administration.^13,16,17 Due to its availability as an ER formulation, gepirone should not be split, crushed, or chewed. The dose of gepirone should be decreased by 50% in patients taking moderate CYP3A4 inhibitors and should be avoided with strong CYP3A4 inhibitors. Dose titration should occur more slowly with a maximum dose of 36.3 mg after day 7 in the following patient populations: geriatric patients, those with renal impairment (CrCl < 50 mL/min), and those with moderate hepatic impairment (Child-Pugh Class B). Gepirone should be avoided in patients with severe hepatic impairment (Child-Pugh Class C). ¹³

Place in Therapy

Current clinical guidelines for depression are not explicit about the role in therapy of drug classes like 5HT_1A partial agonists, which up until now have not had an FDA indication for MDD and are only recommended for augmentation or alternative treatment. The American Psychological Association (APA) clinical guidelines for depression recommend the use of a second-generation antidepressant and/or psychotherapy (eg, cognitive behavioral therapy) for the initial treatment of depression in adult patients. ²³ The APA guidelines state that second-generation antidepressants refer to SSRIs (eg, citalopram, escitalopram, sertraline) and SNRIs (eg, duloxetine, venlafaxine) while other serotonin modulating agents, such as azapirones, should not be considered as first-line therapy options. If a patient were to be a partial responder or non-responder to an antidepressant, then it is recommended to switch from that agent to another, with a conditional recommendation to augment the treatment regimen with another antidepressant. If a switch in antidepressant therapy is warranted, options would include using either a different antidepressant within the same pharmacological class or an antidepressant with a differing mechanism of action as there is insufficient evidence supporting one option over the other. ²³

The Department of Veterans Affairs/Department of Defense (VA/DoD) clinical practice guidelines strongly recommend initiating antidepressant pharmacotherapy and/or psychotherapy based on patient-specific factors (eg, high suicidality, intolerable adverse effects, etc). For initial pharmacotherapy, or in patients who have responded well to pharmacotherapy in the past, they recommend selecting one of the following agents as first-line therapy in no hierarchical order: SSRIs, SNRIs, bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine. ²⁴ Within these guidelines, buspirone is more so considered as an augmentation or alternative pharmacotherapy option to these first-line agents.

It is imperative to note that these practice guidelines were updated in 2019 (APA) and 2022 (VA/DoD), meaning they would not mention gepirone, which was approved in the United States in 2023. Buspirone lacks an FDA indication for MDD and does not appear as a favorable option in either guideline with limited use as an off-label recommendation. The VA/DoD 2022 guidelines mention buspirone for depression treatment only in the context of treatment regimen augmentation or as an alternative therapy. ²⁴ It may be reasonable to consider azapirones similarly in the context of the hierarchical treatment for MDD, as augmentative or alternative therapy; however, treatment recommendations would favor the use of gepirone over buspirone due to its FDA approved indication and efficacy for MDD. Nevertheless, there are currently no clinical guidelines supporting the use of gepirone for the treatment of MDD. Additional clinical studies on the use of gepirone in MDD are warranted to determine its place amongst antidepressant therapy.

Conclusion

Gepirone is a 5HT_1A serotonin receptor agonist approved for the treatment of adult patients with MDD. Multiple phase 3 clinical trials have proven the safety and efficacy of gepirone when used for this indication. Gepirone is an additional azapirone medication approved in the United States for the treatment of MDD and would be expected to receive greater clinical relevance within practice guidelines, compared with buspirone, as either an alternative to failed first-line therapy or for those wanting to avoid adverse side effects of other therapies. Gepirone has been proven effective for the treatment of adult patients with MDD; however, additional studies are needed to definitively determine its place in therapy amongst other antidepressants.